Lipid based nanoemulsifying resveratrol for improved physicochemical characteristics, in vitro cytotoxicity and in vivo antiangiogenic efficacy.

PubMed

Pund, Swati; Thakur, Rohit; More, Umesh; Joshi, Amita

2014-08-01

Resveratrol, a dietary non-flavonoid polyphenolic phytoalexin, has gained attention in cancer chemoprevention. However, poor aqueous solubility and cellular bioavailability has limited its therapeutic application. We formulated a lipid based delivery system of resveratrol with self nanoemulsifying ability. Several edible and safe lipids, surfactants and cosolvents were screened for solubilization of resevratrol. Developed formulation comprised of Acrysol K 150 as a lipid and mixture of Labrasol and Transcutol HP as the surfactant system, as these components showed higher solubility. Pseudoternary phase diagram was constructed to identify the region of nanoemulsification. The formulations showed rapid emulsification with an average globule diameter; 85nm to 120nm and slight negative zeta potential. The nanocompositions exhibited cloud point above 55°C and were stable toward the gastrointestinal pH and thermodynamic stress testing. As compared to pristine resveratrol, the developed delivery system showed significant increase in vitro cytotoxicity in MCF-7 breast cancer cells. In vivo chick chorioallantoic membrane assay revealed enhanced antiangiogenic activity of composition with high lipid level. Briefly, lipid based nanoemulsifying resveratrol dramatically enhanced the anticancer and antiangiogenic activities, thus increasing its potential application in cancer chemotherapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Assessment of different formulations of oral Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine in rodent models for immunogenicity and protection against aerosol challenge with M. bovis.

PubMed

Clark, Simon; Cross, Martin L; Smith, Alan; Court, Pinar; Vipond, Julia; Nadian, Allan; Hewinson, R Glyn; Batchelor, Hannah K; Perrie, Yvonne; Williams, Ann; Aldwell, Frank E; Chambers, Mark A

2008-10-29

Bovine tuberculosis (bTB) caused by infection with Mycobacterium bovis is causing considerable economic loss to farmers and Government in the United Kingdom as its incidence is increasing. Efforts to control bTB in the UK are hampered by the infection in Eurasian badgers (Meles meles) that represent a wildlife reservoir and source of recurrent M. bovis exposure to cattle. Vaccination of badgers with the human TB vaccine, M. bovis Bacille Calmette-Guérin (BCG), in oral bait represents a possible disease control tool and holds the best prospect for reaching badger populations over a wide geographical area. Using mouse and guinea pig models, we evaluated the immunogenicity and protective efficacy, respectively, of candidate badger oral vaccines based on formulation of BCG in lipid matrix, alginate beads, or a novel microcapsular hybrid of both lipid and alginate. Two different oral doses of BCG were evaluated in each formulation for their protective efficacy in guinea pigs, while a single dose was evaluated in mice. In mice, significant immune responses (based on lymphocyte proliferation and expression of IFN-gamma) were only seen with the lipid matrix and the lipid in alginate microcapsular formulation, corresponding to the isolation of viable BCG from alimentary tract lymph nodes. In guinea pigs, only BCG formulated in lipid matrix conferred protection to the spleen and lungs following aerosol route challenge with M. bovis. Protection was seen with delivery doses in the range 10(6)-10(7) CFU, although this was more consistent in the spleen at the higher dose. No protection in terms of organ CFU was seen with BCG administered in alginate beads or in lipid in alginate microcapsules, although 10(7) in the latter formulation conferred protection in terms of increasing body weight after challenge and a smaller lung to body weight ratio at necropsy. These results highlight the potential for lipid, rather than alginate, -based vaccine formulations as suitable delivery vehicles for an oral BCG vaccine in badgers.

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations.

PubMed

Williams, Hywel D; Sassene, Philip; Kleberg, Karen; Calderone, Marilyn; Igonin, Annabel; Jule, Eduardo; Vertommen, Jan; Blundell, Ross; Benameur, Hassan; Müllertz, Anette; Pouton, Colin W; Porter, Christopher J H

2013-12-01

Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs. Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases. Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol. The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.

Formulation and characterization of lipid-based drug delivery system of raloxifene-microemulsion and self-microemulsifying drug delivery system

PubMed Central

Thakkar, Hetal; Nangesh, Jitesh; Parmar, Mayur; Patel, Divyakant

2011-01-01

Background: Raloxifene, a second-generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women is administered orally in the form of a tablet. The absolute bioavailability of the drug is only 2% because of extensive hepatic first-pass metabolism. Lipid-based formulations are reported to reduce the first-pass metabolism by promoting its lymphatic uptake. Materials and Methods: In the present investigation, microemulsion and Self-Microemulsifying Drug Delivery System (SMEDDS) formulations of Raloxifene were prepared. The prepared formulations were characterized for drug loading, size, transparency, zeta potential, Transmission Electron Microscopy (TEM) and in vitro intestinal permeability. Results: The results indicated that high drug loading, optimum size and desired zeta potential and transparency could be achieved with both SMEDDS and microemulsion. The TEM studies indicated the absence of aggregation with both the systems. The in vitro intestinal permeability results showed that the permeation of the drug from the microemulsion and SMEDDs was significantly higher than that obtained from the drug dispersion and marketed formulation. Conclusion: Lipid based formulations such as microemulsion and Self Microemulsifying drug delivery systems are expected to increase the oral bioavailability as evidenced by the increased intestinal permeation. PMID:21966167

Design, characterization, and clinical evaluation of argan oil nanostructured lipid carriers to improve skin hydration

PubMed Central

Tichota, Deise Michele; Silva, Ana Catarina; Sousa Lobo, José Manuel; Amaral, Maria Helena

2014-01-01

Given its advantages in skin application (eg, hydration, antiaging, and protection), argan oil could be used in both dermatological and cosmetic formulations. Therefore, the preparation of nanostructured lipid carriers (NLCs) using argan oil as a liquid lipid is a promising technique, since the former constitute well-established systems for dermal delivery. The aim of this work was to develop a topical formulation of argan oil NLCs to improve skin hydration. Firstly an NLC dispersion was developed and characterized, and afterward an NLC-based hydrogel was prepared. The in vivo evaluation of the suitability of the prepared formulation for the proposed application was assessed in volunteers, by measuring different skin-surface parameters for 1 month. An argan oil NLC-based hydrogel formulation was successfully prepared and characterized. Moreover, the entrapment of the NLCs in the hydrogel net did not affect their colloidal sizes. Additionally, it was observed that this formulation precipitated an increase in skin hydration of healthy volunteers. Therefore, we concluded that the preparation of NLC systems using argan oil as the liquid lipid is a promising strategy, since a synergistic effect on the skin hydration was obtained (ie, NLC occlusion plus argan oil hydration). PMID:25143733

Design, characterization, and clinical evaluation of argan oil nanostructured lipid carriers to improve skin hydration.

PubMed

Tichota, Deise Michele; Silva, Ana Catarina; Sousa Lobo, José Manuel; Amaral, Maria Helena

2014-01-01

Given its advantages in skin application (eg, hydration, antiaging, and protection), argan oil could be used in both dermatological and cosmetic formulations. Therefore, the preparation of nanostructured lipid carriers (NLCs) using argan oil as a liquid lipid is a promising technique, since the former constitute well-established systems for dermal delivery. The aim of this work was to develop a topical formulation of argan oil NLCs to improve skin hydration. Firstly an NLC dispersion was developed and characterized, and afterward an NLC-based hydrogel was prepared. The in vivo evaluation of the suitability of the prepared formulation for the proposed application was assessed in volunteers, by measuring different skin-surface parameters for 1 month. An argan oil NLC-based hydrogel formulation was successfully prepared and characterized. Moreover, the entrapment of the NLCs in the hydrogel net did not affect their colloidal sizes. Additionally, it was observed that this formulation precipitated an increase in skin hydration of healthy volunteers. Therefore, we concluded that the preparation of NLC systems using argan oil as the liquid lipid is a promising strategy, since a synergistic effect on the skin hydration was obtained (ie, NLC occlusion plus argan oil hydration).

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 4: proposing a new lipid formulation performance classification system.

PubMed

Williams, Hywel D; Sassene, Philip; Kleberg, Karen; Calderone, Marilyn; Igonin, Annabel; Jule, Eduardo; Vertommen, Jan; Blundell, Ross; Benameur, Hassan; Müllertz, Anette; Porter, Christopher J H; Pouton, Colin W

2014-08-01

The Lipid Formulation Classification System Consortium looks to develop standardized in vitro tests and to generate much-needed performance criteria for lipid-based formulations (LBFs). This article highlights the value of performing a second, more stressful digestion test to identify LBFs near a performance threshold and to facilitate lead formulation selection in instances where several LBF prototypes perform adequately under standard digestion conditions (but where further discrimination is necessary). Stressed digestion tests can be designed based on an understanding of the factors that affect LBF performance, including the degree of supersaturation generated on dispersion/digestion. Stresses evaluated included decreasing LBF concentration (↓LBF), increasing bile salt, and decreasing pH. Their capacity to stress LBFs was dependent on LBF composition and drug type: ↓LBF was a stressor to medium-chain glyceride-rich LBFs, but not more hydrophilic surfactant-rich LBFs, whereas decreasing pH stressed tolfenamic acid LBFs, but not fenofibrate LBFs. Lastly, a new Performance Classification System, that is, LBF composition independent, is proposed to promote standardized LBF comparisons, encourage robust LBF development, and facilitate dialogue with the regulatory authorities. This classification system is based on the concept that performance evaluations across three in vitro tests, designed to subject a LBF to progressively more challenging conditions, will enable effective LBF discrimination and performance grading. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Effects of a sphingolipid-enriched dairy formulation on postprandial lipid concentrations.

PubMed

Ohlsson, L; Burling, H; Duan, R-D; Nilsson, A

2010-11-01

The digestion of sphingolipids (SL) is slow and is catalyzed by mucosal enzymes. Dietary SL was shown to inhibit cholesterol absorption and to lower plasma cholesterol, triglycerides (TG) and hepatic fat accumulation in animal models. A dairy formulation based on fractionation of buttermilk, which is enriched in milk polar lipids of which SL account for a large part is now available. In this study, we examined whether this formulation, when ingested with a standard breakfast, exerted a different influence on postprandial lipids than an equivalent control formulation lacking the polar milk lipids. A total of 18 healthy male volunteers aged 22-65 years ingested a high-fat (40 g) standard breakfast together with a milk-like formulation containing 975 mg of milk SL (A) or the control formulation (B). Postprandial levels of TG, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, apolipoprotein AI (ApoAI), ApoB, glucose and insulin were measured 1 to 7 h after the meal. No difference was seen between experimental and control groups in postprandial levels of TG, insulin, ApoA1 or ApoB. After 1 hour there was a trend of lower cholesterol concentrations in large TG-rich lipoproteins after formulation A. The SL-rich buttermilk drink may affect cholesterol concentrations in TG-rich lipoproteins, but has no effect on postprandial TG after a breakfast with butter fat as the major lipid.

A Critical Review of Lipid-based Nanoparticles for Taxane Delivery

PubMed Central

Feng, Lan; Mumper, Russell J.

2012-01-01

Nano-based delivery systems have attracted a great deal of attention in the past two decades as a strategy to overcome the low therapeutic index of conventional anticancer drugs and delivery barriers in solid tumors. Myriads of preclinical studies have been focused on developing nano-based formulations to effectively deliver taxanes, one of the most important and most prescribed anticancer drug types in the clinic. Given the hydrophobic property of taxanes, lipid-based NPs, serve as a viable alternative delivery system. This critical review will provide an overview and perspective of the advancement of lipid-based nanoparticles for taxane delivery. Currently available formulations of taxanes and their drawbacks as well as criteria for idea taxane delivery system will be discussed. PMID:22796606

Nanoscale coordination polymers for anticancer drug delivery

NASA Astrophysics Data System (ADS)

Phillips, Rachel Huxford

This dissertation reports the synthesis and characterization of nanoscale coordination polymers (NCPs) for anticancer drug delivery. Nanoparticles have been explored in order to address the limitations of small molecule chemotherapeutics. NCPs have been investigated as drug delivery vehicles as they can exhibit the same beneficial properties as the bulk metal-organic frameworks as well as interesting characteristics that are unique to nanomaterials. Gd-MTX (MTX = methotrexate) NCPs with a MTX loading of 71.6 wt% were synthesized and stabilized by encapsulation within a lipid bilayer containing anisamide (AA), a small molecule that targets sigma receptors which are overexpressed in many cancer tissues. Functionalization with AA allows for targeted delivery and controlled release to cancer cells, as shown by enhanced efficacy against leukemia cells. The NCPs were doped with Ru(bpy)32+ (bpy = 2,2'-bipyridine), and this formulation was utilized as an optical imaging agent by confocal microscopy. NCPs containing the chemotherapeutic pemetrexed (PMX) were synthesized using different binding metals. Zr-based materials could not be stabilized by encapsulation with a lipid bilayer, and Gd-based materials showed that PMX had degraded during synthesis. However, Hf-based NCPs containing 19.7 wt% PMX were stabilized by a lipid coating and showed in vitro efficacy against non-small cell lung cancer (NSCLC) cell lines. Enhanced efficacy was observed for formulations containing AA. Additionally, NCP formulations containing the cisplatin prodrug disuccinatocisplatin were prepared; one of these formulations could be stabilized by encapsulation within a lipid layer. Coating with a lipid layer doped with AA rendered this formulation an active targeting agent. The resulting formulation proved more potent than free cisplatin in NSCLC cell lines. Improved NCP uptake was demonstrated by confocal microscopy and competitive binding assays. Finally, a Pt(IV) oxaliplatin prodrug was synthesized and incorporated in different NCPs using various binding metals. A moderate drug loading of 44.9 wt% was determined for Zr-based NCPs. This drug loading, along with a diameter less than 200 nm, make these particles promising candidates for further stabilization via lipid encapsulation.

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 1: method parameterization and comparison of in vitro digestion profiles across a range of representative formulations.

PubMed

Williams, Hywel D; Sassene, Philip; Kleberg, Karen; Bakala-N'Goma, Jean-Claude; Calderone, Marilyn; Jannin, Vincent; Igonin, Annabel; Partheil, Anette; Marchaud, Delphine; Jule, Eduardo; Vertommen, Jan; Maio, Mario; Blundell, Ross; Benameur, Hassan; Carrière, Frédéric; Müllertz, Anette; Porter, Christopher J H; Pouton, Colin W

2012-09-01

The Lipid Formulation Classification System Consortium is an industry-academia collaboration, established to develop standardized in vitro methods for the assessment of lipid-based formulations (LBFs). In this first publication, baseline conditions for the conduct of digestion tests are suggested and a series of eight model LBFs are described to probe test performance across different formulation types. Digestion experiments were performed in vitro using a pH-stat apparatus and danazol employed as a model poorly water-soluble drug. LBF digestion (rate and extent) and drug solubilization patterns on digestion were examined. To evaluate cross-site reproducibility, experiments were conducted at two sites and highly consistent results were obtained. In a further refinement, bench-top centrifugation was explored as a higher throughput approach to separation of the products of digestion (and compared with ultracentrifugation), and conditions under which this method was acceptable were defined. Drug solubilization was highly dependent on LBF composition, but poorly correlated with simple performance indicators such as dispersion efficiency, confirming the utility of the digestion model as a means of formulation differentiation. Copyright © 2012 Wiley Periodicals, Inc.

Drug solubility in lipid nanocarriers: Influence of lipid matrix and available interfacial area.

PubMed

Göke, Katrin; Bunjes, Heike

2017-08-30

Amongst other strategies for the formulation of poorly water-soluble drugs, solubilization of these drugs in lipid-based formulations is a promising option. Most screening methods for the identification of a suitable lipid-based formulation fail to elucidate the role interfacial effects play for drug solubility in disperse systems. In a novel screening approach called passive drug loading, different preformed lipid nanocarrier dispersions are incubated with drug powder. Afterwards, undissolved drug is filtered off and the amount of solubilized drug is determined. The aim of this study was to identify parameters for drug solubility in pure lipids as well as for drug loading to the lipid-water interface of lipid nanoparticles. Using passive loading, the solubility of eight poorly water-soluble drugs in seven lipid nanocarriers varying in particle size or lipid matrix was investigated. Drug solubility in the nanocarriers did not follow any apparent trend and different drugs dissolved best in different carriers. Drugs with a melting point below approximately 150°C displayed distinctly better solubility than higher melting drugs. Additionally, relating the specific lipid nanocarrier surface area to the drug solubility allowed drawing conclusions on the drug localization. Fenofibrate, dibucaine and, less distinctly also clotrimazole, which all melt below 150°C, were predominantly located in the lipid droplet core of the nanoparticles. In contrast, the five remaining drugs (betamethasone valerate, flufenamic acid, itraconazole, ketoconazole, mefenamic acid) were also located at the lipid-water interface to different, but substantial degrees. The ability to account for drug loading to the lipid-water interface is thus a major advantage of passive loading. Copyright © 2017 Elsevier B.V. All rights reserved.

Formulants of glyphosate-based herbicides have more deleterious impact than glyphosate on TM4 Sertoli cells.

PubMed

Vanlaeys, Alison; Dubuisson, Florine; Seralini, Gilles-Eric; Travert, Carine

2018-06-04

Roundup and Glyphogan are glyphosate-based herbicides containing the same concentration of glyphosate and confidential formulants. Formulants are declared as inert diluents but some are more toxic than glyphosate, such as the family of polyethoxylated alkylamines (POEA). We tested glyphosate alone, glyphosate-based herbicide formulations and POEA on the immature mouse Sertoli cell line (TM4), at concentrations ranging from environmental to agricultural-use levels. Our results show that formulations of glyphosate-based herbicides induce TM4 mitochondrial dysfunction (like glyphosate, but to a lesser extent), disruption of cell detoxification systems, lipid droplet accumulation and mortality at sub-agricultural doses. Formulants, especially those present in Glyphogan, are more deleterious than glyphosate and thus should be considered as active principles of these pesticides. Lipid droplet accumulation after acute exposure to POEA suggests the rapid penetration and accumulation of formulants, leading to mortality after 24 h. As Sertoli cells are essential for testicular development and normal onset of spermatogenesis, disturbance of their function by glyphosate-based herbicides could contribute to disruption of reproductive function demonstrated in mammals exposed to these pesticides at a prepubertal stage of development. Copyright © 2018 Elsevier Ltd. All rights reserved.

Disposition of lipid-based formulation in the intestinal tract affects the absorption of poorly water-soluble drugs.

PubMed

Iwanaga, Kazunori; Kushibiki, Toshihiro; Miyazaki, Makoto; Kakemi, Masawo

2006-03-01

Solvent Green 3 (SG), a model poorly water-soluble compound, was orally administered to rats with soybean oil emulsion or the Self-microemulsifying drug delivery system (SMEDDS) composed of Gelucire44/14. The bioavailability of SG after oral administration with SMEDDS was 1.7-fold higher than that with soybean oil emulsion. The intestinal absorption of lipid-based formulations themselves was evaluated by the in situ closed loop method. The effect of lipase and bile salt on their absorption was also evaluated. SMEDDS itself was rapidly absorbed in the intestine even in the absence of lipase and bile salt, and the absorption was increased by the addition of lipase and bile salt. On the other hand, no soybean oil emulsion was absorbed in the absence of lipase and bile salt. However, mixed micelle prepared from emulsion by incubating soybean oil emulsion with lipase and bile salt was rapidly absorbed through the intestine. Without lipase and bile salt, SG was not absorbed after administration with soybean oil emulsion. Therefore, we concluded that the degradation of soybean oil emulsion was needed for SG to be absorbed through the intestine. Furthermore, we investigated the intestinal absorption of SG after oral administration to rats whose chylomicron synthesis were inhibited by pretreatment with colchicine. Colchicine completely inhibited the intestinal absorption of SG after administration with each lipid-based formulation, suggesting that SG was absorbed from the intestine via a lymphatic route. Absorption of the dosage formulation should be paid attention when poorly water-soluble drugs are orally administered with lipid-based formulation.

Oral bioavailability assessment and intestinal lymphatic transport of Org 45697 and Org 46035, two highly lipophilic novel immunomodulator analogues.

PubMed

Caliph, Suzanne M; Faassen, W A Fried; Vogel, Gerard M; Porter, Christopher J H

2009-08-01

Org 45697 (MW 600.7, clogP 7.92, soybean oil solubility 50 mg/g) and Org 46035 (MW 601.6, clog P 8.46, soybean oil solubility 40 mg/g) are two poorly water soluble (<0.1 microg/ml), highly lipophilic drug candidates with immunomodulator activity and highly analogous chemical structures. After oral administration to conscious ambulatory rats in an aqueous-based methylcellulose/Tween 80 suspension, the bioavailability of both compounds was low (< 2% of administered dose). However, bioavailability was significantly increased (> 5 fold) after oral administration in a long chain triglyceride lipid (olive oil) formulation. Subsequent studies have explored the potential for solubilising formulations, including lipid-based formulations, to enhance the oral bioavailability of Org 45697 and Org 46035 and secondly to explore the potential contribution of intestinal lymphatic transport to intestinal absorption. The experimental data show that solubilising formulations may provide for significant increases in oral bioavailability for Org 45697 and Org 46035 and that after co-administration with lipid, 35-50% of the absorbed dose may be transported to the systemic circulation via the intestinal lymph. Interestingly, the lymphatic transport of the less lipid soluble analogue, Org 46035 was approximately 40% lower than that of Org 45697 suggesting that relatively subtle differences in lipid solubility can have significant impact on the extent of lymphatic transport.

A Healthy Balance of Plasma Cholesterol by a Novel Annurca Apple-Based Nutraceutical Formulation: Results of a Randomized Trial.

PubMed

Tenore, Gian Carlo; Caruso, Domenico; Buonomo, Giuseppe; D'Avino, Maria; Campiglia, Pietro; Marinelli, Luciana; Novellino, Ettore

2017-03-01

Cardiovascular diseases are nowadays preferential targets of preventive medicine through a straightforward therapy on lipid profile. However, statins, the first-line lipid-lowering drug therapy, specifically act on low-density lipoprotein cholesterol (LDL-C), having a modest effect on plasma high-density lipoprotein cholesterol (HDL-C) concentrations. Today, a number of novel HDL-targeted therapies are emerging, along with unexpected side effects. Thus, novel and possibly safe substances, able to correct impaired lipid profile in humans, are still in great demand. Herein, based on encouraging clinical data, we formulated a nutraceutical product (AppleMetS ® , AMS), based on a polyphenolic extract from Annurca apple, and demonstrated that two capsules a day of AMS, after one month, have a LDL-C lowering outcome equivalent to 40 mg of simvastatin or 10 mg of atorvastatin. Nevertheless, different from statin-based therapy, AMS exerted a notable effect on HDL (+49.2%). Based on the trial results, we can assert that AMS formulation could effectively integrate the current therapeutic arsenal to correct impaired lipid profile in humans. Specifically, AMS may be considered a complementary and/or alternative safe substance suitable for the treatment of mildly hypercholesterolemic subjects who do not present occurrence of atheromatous plaques yet.

A Healthy Balance of Plasma Cholesterol by a Novel Annurca Apple-Based Nutraceutical Formulation: Results of a Randomized Trial

PubMed Central

Tenore, Gian Carlo; Caruso, Domenico; Buonomo, Giuseppe; D'Avino, Maria; Campiglia, Pietro; Marinelli, Luciana

2017-01-01

Abstract Cardiovascular diseases are nowadays preferential targets of preventive medicine through a straightforward therapy on lipid profile. However, statins, the first-line lipid-lowering drug therapy, specifically act on low-density lipoprotein cholesterol (LDL-C), having a modest effect on plasma high-density lipoprotein cholesterol (HDL-C) concentrations. Today, a number of novel HDL-targeted therapies are emerging, along with unexpected side effects. Thus, novel and possibly safe substances, able to correct impaired lipid profile in humans, are still in great demand. Herein, based on encouraging clinical data, we formulated a nutraceutical product (AppleMetS®, AMS), based on a polyphenolic extract from Annurca apple, and demonstrated that two capsules a day of AMS, after one month, have a LDL-C lowering outcome equivalent to 40 mg of simvastatin or 10 mg of atorvastatin. Nevertheless, different from statin-based therapy, AMS exerted a notable effect on HDL (+49.2%). Based on the trial results, we can assert that AMS formulation could effectively integrate the current therapeutic arsenal to correct impaired lipid profile in humans. Specifically, AMS may be considered a complementary and/or alternative safe substance suitable for the treatment of mildly hypercholesterolemic subjects who do not present occurrence of atheromatous plaques yet. PMID:28296588

Rapid microwave-assisted synthesis of sub-30nm lipid nanoparticles.

PubMed

Dunn, Stuart S; Beckford Vera, Denis R; Benhabbour, S Rahima; Parrott, Matthew C

2017-02-15

Accessing the phase inversion temperature by microwave heating may enable the rapid synthesis of small lipid nanoparticles. Nanoparticle formulations consisted of surfactants Brij 78 and Vitamin E TPGS, and trilaurin, trimyristin, or miglyol 812 as nanoparticle lipid cores. Each formulation was placed in water and heated by microwave irradiation at temperatures ranging from 65°C to 245°C. We observed a phase inversion temperature (PIT) for these formulations based on a dramatic decrease in particle Z-average diameters. Subsequently, nanoparticles were manufactured above and below the PIT and studied for (a) stability toward dilution, (b) stability over time, (c) fabrication as a function of reaction time, and (d) transmittance of lipid nanoparticle dispersions. Lipid-based nanoparticles with distinct sizes down to 20-30nm and low polydispersity could be attained by a simple, one-pot microwave synthesis. This was carried out by accessing the phase inversion temperature using microwave heating. Nanoparticles could be synthesized in just one minute and select compositions demonstrated high stability. The notable stability of these particles may be explained by the combination of van der Waals interactions and steric repulsion. 20-30nm nanoparticles were found to be optically transparent. Published by Elsevier Inc.

Selection of a discriminant and biorelevant in vitro dissolution test for the development of fenofibrate self-emulsifying lipid-based formulations.

PubMed

Pestieau, Aude; Krier, Fabrice; Brouwers, Adeline; Streel, Bruno; Evrard, Brigitte

2016-09-20

Fenofibrate, a BCS class II compound, has a low bioavailability especially when taken orally on an empty stomach. The challenge to find a new formulation for providing bioavailability, independent of food, is still ongoing. If the development of a suitable oral delivery formulation of BCS class II compounds is a frequent and great challenge to formulation scientists, the in vitro evaluation of these new formulations is also a great challenge. The purpose of this study was therefore to select an in vitro dissolution test that would be useful and as biorelevant as possible for the development of fenofibrate self-emulsifying lipid-based formulations. In this context, three different fenofibrate formulations, for which in vivo data are available in the literature, were tested using different dissolution tests until we found the one that was the most suitable. As part of this approach, we started with the simplest in vitro dissolution tests and progressed to tests that were increasingly more complex. The first tests were different single phase dissolution tests: a test under sink conditions based on the USP monograph, and different tests under non-sink conditions in non-biorelevant and biorelevant media. Given the inconclusive results obtained with these tests, biphasic dissolution systems were then tested: one with USP apparatus type II alone and another which combined USP apparatus types II and IV. This last combined test seemed the most suitable in vitro dissolution test for the development of the future fenofibrate lipid-based formulations we intend to develop in our own laboratory. Copyright © 2016 Elsevier B.V. All rights reserved.

Cationic niosomes an effective gene carrier composed of novel spermine-derivative cationic lipids: effect of central core structures.

PubMed

Opanasopit, Praneet; Leksantikul, Lalita; Niyomtham, Nattisa; Rojanarata, Theerasak; Ngawhirunpat, Tanasait; Yingyongnarongkul, Boon-Ek

2017-05-01

Cationic niosomes formulated from Span 20, cholesterol (Chol) and novel spermine-based cationic lipids of multiple central core structures (di(oxyethyl)amino, di(oxyethyl)amino carboxy, 3-amino-1,2-dioxypropyl and 2-amino-1,3-dioxypropyl) were successfully prepared for improving transfection efficiency in vitro. The niosomes composed of spermine cationic lipid with central core structure of di(oxyethyl)amino revealed the highest gene transfection efficiency. To investigate the factors affecting gene transfection and cell viability including differences in the central core structures of cationic lipids, the composition of vesicles, molar ratio of cationic lipids in formulations and the weight ratio of niosomes to DNA. Cationic niosomes composed of nonionic surfactants (Span20), cholesterol and spermine-based cationic lipids of multiple central core structures were formulated. Gene transfection and cell viability were evaluated on a human cervical carcinoma cell line (HeLa cells) using pDNA encoding green fluorescent protein (pEGFP-C2). The morphology, size and charge were also characterized. High transfection efficiency was obtained from cationic niosomes composed of Span20:Chol:cationic lipid at the molar ratio of 2.5:2.5:0.5 mM. Cationic lipids with di(oxyethyl)amino as a central core structure exhibited highest transfection efficiency. In addition, there was also no serum effect on transfection efficiency. These novel cationic niosomes may constitute a good alternative carrier for gene transfection.

Optimization of β-carotene loaded solid lipid nanoparticles preparation using a high shear homogenization technique

NASA Astrophysics Data System (ADS)

Triplett, Michael D.; Rathman, James F.

2009-04-01

Using statistical experimental design methodologies, the solid lipid nanoparticle design space was found to be more robust than previously shown in literature. Formulation and high shear homogenization process effects on solid lipid nanoparticle size distribution, stability, drug loading, and drug release have been investigated. Experimentation indicated stearic acid as the optimal lipid, sodium taurocholate as the optimal cosurfactant, an optimum lecithin to sodium taurocholate ratio of 3:1, and an inverse relationship between mixing time and speed and nanoparticle size and polydispersity. Having defined the base solid lipid nanoparticle system, β-carotene was incorporated into stearic acid nanoparticles to investigate the effects of introducing a drug into the base solid lipid nanoparticle system. The presence of β-carotene produced a significant effect on the optimal formulation and process conditions, but the design space was found to be robust enough to accommodate the drug. β-Carotene entrapment efficiency averaged 40%. β-Carotene was retained in the nanoparticles for 1 month. As demonstrated herein, solid lipid nanoparticle technology can be sufficiently robust from a design standpoint to become commercially viable.

Recent Advances in Lipid-Based Vesicles and Particulate Carriers for Topical and Transdermal Application.

PubMed

Jain, Shashank; Patel, Niketkumar; Shah, Mansi K; Khatri, Pinak; Vora, Namrata

2017-02-01

In the recent decade, skin delivery (topical and transdermal) has gained an unprecedented popularity, especially due to increased incidences of chronic skin diseases, demand for targeted and patient compliant delivery, and interest in life cycle management strategies among pharmaceutical companies. Literature review of recent publications indicates that among various skin delivery systems, lipid-based delivery systems (vesicular carriers and lipid particulate systems) have been the most successful. Vesicular carriers consist of liposomes, ultradeformable liposomes, and ethosomes, while lipid particulate systems consist of lipospheres, solid lipid nanoparticles, and nanostructured lipid carriers. These systems can increase the skin drug transport by improving drug solubilization in the formulation, drug partitioning into the skin, and fluidizing skin lipids. Considering that lipid-based delivery systems are regarded as safe and efficient, they are proving to be an attractive delivery strategy for the pharmaceutical as well as cosmeceutical drug substances. However, development of these delivery systems requires comprehensive understanding of physicochemical characteristics of drug and delivery carriers, formulation and process variables, mechanism of skin delivery, recent technological advancements, specific limitations, and regulatory considerations. Therefore, this review article encompasses recent research advances addressing the aforementioned issues. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Design of lipid-based formulations for oral administration of poorly water-soluble drug fenofibrate: effects of digestion.

PubMed

Mohsin, Kazi

2012-06-01

Lipid-based drug carriers are likely to have influence on bioavailability through enhanced solubilization of the drug in the gastrointestinal tract. The study was designed to investigate the lipid formulation digestibility in the simulated gastro intestinal media. Fenofibrate was formulated in representative Type II, IIIA, IIIB and IV self-emulsifying/microemulsifying lipid delivery systems (SEDDS and SMEDDS designed for oral administration) using various medium-chain glyceride components, non-ionic surfactants and cosolvents as excipients. Soybean oil was used only as an example of long-chain triglycerides to compare the effects of formulation with their counterparts. The formulations were subjected to in vitro digestion specifically to predict the fate of the drug in the gastro intestinal tract after exposure of the formulation to pancreatic enzymes and bile. In vitro digestion experiments were carried out using a pH-stat maintained at pH 7.5 for 30 min using intestinal fluids simulating the fed and fasted states. The digestion rate was faster and almost completed in Type II and IIIA systems. Most of the surfactants used in the studies are digestible. However, the high concentration of surfactant and/or cosolvent used in Type IIIB or IV systems lowered the rate of digestion. The digestion of medium-chain triglycerides was faster than long-chain triglycerides, but kept comparatively less drug in the post digestion products. Medium-chain mixed glycerides are good solvents for fenofibrate as rapidly digested but to improve fenofibrate concentration in post digestion products the use of long-chain mixed glycerides are suggested for further investigations.

Effects of heterocyclic-based head group modifications on the structure-activity relationship of tocopherol-based lipids for non-viral gene delivery.

PubMed

Gosangi, Mallikarjun; Mujahid, Thasneem Yoosuf; Gopal, Vijaya; Patri, Srilakshmi V

2016-07-12

Gene therapy, a promising strategy for the delivery of therapeutic nucleic acids, is greatly dependent on the development of efficient vectors. In this study, we designed and synthesized several tocopherol-based lipids varying in the head group region. Here, we present the structure-activity relationship of stable aqueous suspensions of lipids that were synthetically prepared and formulated with 1,2-dioleoyl phosphatidyl ethanolamine (DOPE) as the co-lipid. The physicochemical properties such as the hydrodynamic size, zeta potential, stability and morphology of these formulations were investigated. Interaction with plasmid DNA was clearly demonstrated through gel binding and EtBr displacement assays. Further, the transfection potential was examined in mouse neuroblastoma Neuro-2a, hepatocarcinoma HepG2, human embryonic kidney and Chinese hamster ovarian cell lines, all of different origins. Cell-uptake assays with N-methylpiperidinium, N-methylmorpholinium, N-methylimidazolium and N,N-dimethylaminopyridinium head group containing formulations evidently depicted efficient cell uptake as observed by particulate cytoplasmic fluorescence. Trafficking of lipoplexes using an endocytic marker and rhodamine-labeled phospholipid DHPE indicated that the lipoplexes were not sequestered in the lysosomes. Importantly, lipoplexes were non-toxic and mediated good transfection efficiency as analyzed by β-Gal and GFP reporter gene expression assays which established the superior activity of lipids whose structures correlate strongly with the transfection efficiency.

The role of helper lipids in the intracellular disposition and transfection efficiency of niosome formulations for gene delivery to retinal pigment epithelial cells.

PubMed

Ojeda, Edilberto; Puras, Gustavo; Agirre, Mireia; Zarate, Jon; Grijalvo, Santiago; Eritja, Ramon; DiGiacomo, Luca; Caracciolo, Giulio; Pedraz, Jose-Luis

2016-04-30

In this work, we carried out a comparative study of four different niosome formulations based on the same cationic lipid and non-ionic tensoactive. The niosomes prepared by oil-in-water emulsion technique (o/w) only differed in the helper lipid composition: squalene, cholesterol, squalane or no helper lipid. Niosomes and nioplexes elaborated upon the addition of pCMS-EGFP reporter plasmid were characterized in terms of size, zeta potential and polydispersity index. The capacity of the niosomes to condense, release and protect the DNA against enzymatic degradation was evaluated by agarose gel electrophoresis. In vitro experiments were carried out to evaluate transfection efficiency and cell viability in retinal pigment epithelial cells. Moreover, uptake and intracellular trafficking studies were performed to further understand the role of the helper lipids in the transfection process. Interestingly, among all tested formulations, niosomes elaborated with squalene as helper lipid were the most efficient transfecting cells. Such transfection efficiency could be attributed to their higher cellular uptake and the particular entry pathways used, where macropinocytosis pathway and lysosomal release played an important role. Therefore, these results suggest that helper lipid composition is a crucial step to be considered in the design of niosome formulation for retinal gene delivery applications since clearly modulates the cellular uptake, internalization mechanism and consequently, the final transfection efficiency. Copyright © 2016 Elsevier B.V. All rights reserved.

In vitro anticancer evaluation of 5-fluorouracil lipid nanoparticles using B16F10 melanoma cell lines

NASA Astrophysics Data System (ADS)

Shenoy, Vikram S.; Gude, Rajiv P.; Murthy, Rayasa S. Ramachandra

2013-05-01

The present study is aimed to investigate the formulation and in vitro anticancer activities of solid lipid nanoparticles (SLNs) of 5-fluorouracil (5-FU) prepared using glyceryl monostearate (GMS) and cetyl palmitate (CP) by hot homogenization method. The lipids were selected based on the partition coefficient of 5-FU in lipids. The lipid nanoparticles were optimized for process and formulation parameters. The optimized nanoparticles were characterized for their zeta potential, morphology, release kinetics, and anticancer activity. Higher entrapments were achieved using a combination of emulsifiers. The zeta potential of the optimized CP and GMS SLN formulation were -8.26 and -9.35 mV, respectively. Both the optimized formulations were spherical. The in vitro release studies of SLNs of both the lipid carriers followed Peppas-Korsenmeyer equation when carried out at pH 3.5 and 7.4. The chemosensitivity assay carried out in B16F10 cell lines revealed that CP SLNs had better cytotoxicity than 5-FU solution and GMS SLNs at 48 h of incubation. Subtoxic concentration of 5-FU-loaded CP SLNs (0.12 μg/mL) possessed comparable antimigrational activity, colony inhibition activity, and cytopathic as that of 5-FU solution effects. The results indicated that encapsulating 5-FU in CP would be a promising delivery system for delivering 5-FU.

2’-Behenoyl-Paclitaxel Conjugate Containing Lipid Nanoparticles for the Treatment of Metastatic Breast Cancer

PubMed Central

Ma, Ping; Benhabbour, S. Rahima; Feng, Lan; Mumper, Russell J

2012-01-01

The aim of these studies was to develop a novel 2’-behenoyl-paclitaxel (C22-PX) conjugate nanoparticle (NP) formulation for the treatment of metastatic breast cancer. A lipophilic paclitaxel derivative C22-PX was synthesized and incorporated into lipid-based NPs. Free C22-PX and its NP formulation were evaluated in a series of in-vitro and in-vivo studies. The results demonstrated that C22-PX NPs were much better tolerated and had significantly higher plasma and tumor AUCs compared to Taxol at the maximum tolerated dose (MTD) in a subcutaneous 4T1 mouse mammary carcinoma model. These benefits resulted in significantly improved antitumor efficacy with the NP-based formulation. PMID:22902506

Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design.

PubMed

Emami, J; Mohiti, H; Hamishehkar, H; Varshosaz, J

2015-01-01

Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7(®) software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 μm, and 2.98 μm; respectively. Our results provide fundamental data for the application of SLNs in pulmonary delivery system of budesonide.

Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design

PubMed Central

Emami, J.; Mohiti, H.; Hamishehkar, H.; Varshosaz, J.

2015-01-01

Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7® software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 μm, and 2.98 μm; respectively. Our results provide fundamental data for the application of SLNs in pulmonary delivery system of budesonide. PMID:26430454

Dry powder inhaler formulation of lipid-polymer hybrid nanoparticles via electrostatically-driven nanoparticle assembly onto microscale carrier particles.

PubMed

Yang, Yue; Cheow, Wean Sin; Hadinoto, Kunn

2012-09-15

Lipid-polymer hybrid nanoparticles have emerged as promising nanoscale carriers of therapeutics as they combine the attractive characteristics of liposomes and polymers. Herein we develop dry powder inhaler (DPI) formulation of hybrid nanoparticles composed of poly(lactic-co-glycolic acid) and soybean lecithin as the polymer and lipid constituents, respectively. The hybrid nanoparticles are transformed into inhalable microscale nanocomposite structures by a novel technique based on electrostatically-driven adsorption of nanoparticles onto polysaccharide carrier particles, which eliminates the drawbacks of conventional techniques based on controlled drying (e.g. nanoparticle-specific formulation, low yield). First, we engineer polysaccharide carrier particles made up of chitosan cross-linked with tripolyphosphate and dextran sulphate to exhibit the desired aerosolization characteristics and physical robustness. Second, we investigate the effects of nanoparticle to carrier mass ratio and salt inclusion on the adsorption efficiency, in terms of the nanoparticle loading and yield, from which the optimal formulation is determined. Desorption of the nanoparticles from the carrier particles in phosphate buffer saline is also examined. Lastly, we characterize aerosolization efficiency of the nanocomposite product in vitro, where the emitted dose and respirable fraction are found to be comparable to the values of conventional DPI formulations. Copyright © 2012 Elsevier B.V. All rights reserved.

Cationic solid lipid nanoparticles enhance ocular hypotensive effect of melatonin in rabbit.

PubMed

Leonardi, Antonio; Bucolo, Claudio; Drago, Filippo; Salomone, Salvatore; Pignatello, Rosario

2015-01-15

The study was aimed at evaluating whether the ocular hypotensive effect of melatonin (MEL) was enhanced by its encapsulation in cationic solid lipid nanoparticles (cSLN), as well as at determining the tolerability of these formulations on the ocular surface. MEL was loaded in cSLN that had already been shown to be suitable for ophthalmic use. The formulations were prepared using Softisan(®) 100 as the main lipid matrix, with the presence of either stearic (SA) or palmitic acid (PA) as lipid modifiers. A fixed positive charge was provided by the addition of a cationic lipid (didecyldimethylammonium bromide). The ocular hypotensive effect was evaluated by measuring the intraocular pressure (IOP) during 24h in albino rabbits. MEL elicited a significant (p<0.01) IOP reduction in rabbit eye. All the formulations tested in vivo demonstrated a good tolerability. The nanocarrier containing SA was the most effective in terms of IOP reduction (maximum IOP reduction: -7 mmHg), and its effect lasted approximately 24h. The experimental data indicate that the new formulations based on cSLN loaded with MEL represent a potent anti-glaucoma treatment with a safe profile, warranting further clinical evaluation of the proposed nanotechnological strategy. Copyright © 2014. Published by Elsevier B.V.

Montmorillonite-lipid hybrid carriers for ionizable and neutral poorly water-soluble drugs: Formulation, characterization and in vitro lipolysis studies.

PubMed

Dening, Tahnee J; Rao, Shasha; Thomas, Nicky; Prestidge, Clive A

2017-06-30

Lipid-based formulations (LBFs) are a popular strategy for enhancing the gastrointestinal solubilization and absorption of poorly water-soluble drugs. In light of this, montmorillonite-lipid hybrid (MLH) particles, composed of medium-chain triglycerides, lecithin and montmorillonite clay platelets, have been developed as a novel solid-state LBF. Owing to the unique charge properties of montmorillonite, whereby the clay platelet surfaces carry a permanent negative charge and the platelet edges carry a pH-dependent charge, three model poorly water-soluble drugs with different charge properties; blonanserin (weak base, pKa 7.7), ibuprofen (weak acid, pKa 4.5) and fenofibrate (neutral), were formulated as MLH particles and their performance during biorelevant in vitro lipolysis at pH 7.5 was investigated. For blonanserin, drug solubilization during in vitro lipolysis was significantly reduced 3.4-fold and 3.2-fold for MLH particles in comparison to a control lipid solution and silica-lipid hybrid (SLH) particles, respectively. It was hypothesized that strong electrostatic interactions between the anionic montmorillonite platelet surfaces and cationic blonanserin molecules were responsible for the inferior performance of MLH particles. In contrast, no significant influence on drug solubilization was observed for ibuprofen- and fenofibrate-loaded MLH particles. The results of the current study indicate that whilst MLH particles are a promising novel formulation strategy for poorly water-soluble drugs, drug ionization tendency and the potential for drug-clay interactions must be taken into consideration to ensure an appropriate performance. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug Solubility in Fatty Acids as a Formulation Design Approach for Lipid-Based Formulations: A Technical Note.

PubMed

Lee, Yung-Chi; Dalton, Chad; Regler, Brian; Harris, David

2018-06-06

Lipid-based drug delivery systems have been intensively investigated as a means of delivering poorly water-soluble drugs. Upon ingestion, the lipases in the gastrointestinal tract digest lipid ingredients, mainly triglycerides, within the formulation into monoglycerides and fatty acids. While numerous studies have addressed the solubility of drugs in triglycerides, comparatively few publications have addressed the solubility of drugs in fatty acids, which are the end product of digestion and responsible for the solubility of drug within mixed micelles. The objective of this investigation was to explore the solubility of a poorly water-soluble drug in fatty acids and raise the awareness of the importance of drug solubility in fatty acids. The model API (active pharmaceutical ingredient), a weak acid, is considered a BCS II compound with an aqueous solubility of 0.02 μg/mL and predicted partition coefficient >7. The solubility of API ranged from 120 mg/mL to over 1 g/mL in fatty acids with chain lengths across the range C18 to C6. Hydrogen bonding was found to be the main driver of the solubilization of API in fatty acids. The solubility of API was significantly reduced by water uptake in caprylic acid but not in oleic acid. This report demonstrates that solubility data generated in fatty acids can provide an indication of the solubility of the drug after lipid digestion. This report also highlights the importance of measuring the solubility of drugs in fatty acids in the course of lipid formulation development.

Vitamin D3-Loaded Nanostructured Lipid Carriers as a Potential Approach for Fortifying Food Beverages; in Vitro and in Vivo Evaluation.

PubMed

Mohammadi, Maryam; Pezeshki, Akram; Mesgari Abbasi, Mehran; Ghanbarzadeh, Babak; Hamishehkar, Hamed

2017-04-01

Purpose: Nanostructured lipid carriers (NLCs) composed of solid lipid and oil are a new generation of lipid nanoparticles which have exhibited some merits over traditional used lipid nanoparticles in fortifying food and beverages and nutraceuticals delivery systems such as liposomes and solid lipid nanoparticles. Methods: In this study, Precirol and Compritol as solid lipids, Miglyol and Octyloctanoat as liquid lipids, Tween80, Tween20 and Poloxamer407 as surfactants were used to prepare vitamin D 3 -loaded NLC dispersion using hot homogenization method. The particle size and size distribution for all formulations were evaluated by immediately after production and during a storage period of 60 days. Results: The Precirol-based NLC showed superiority over Compritol-based NLC in the point of physical stability. Results clearly suggested that an optimum concentration of 3% of Poloxamer407 or 2% of Tween20 was sufficient to cover the surface of nanoparticles effectively and prevent agglomeration during the homogenization process. Octyloctanoat was introduced for the first time as a good substituent for Miglyol in the preparation of NLC formulations. The vitamin D 3 Intestinal absorption enhanced by the incorporating in NLCs. Conclusion: It was concluded that NLC showed a promising approach for fortifying beverages by lipophilic nutraceuticals such as vitamin D.

Vitamin D3-Loaded Nanostructured Lipid Carriers as a Potential Approach for Fortifying Food Beverages; in Vitro and in Vivo Evaluation

PubMed Central

Mohammadi, Maryam; Pezeshki, Akram; Mesgari Abbasi, Mehran; Ghanbarzadeh, Babak; Hamishehkar, Hamed

2017-01-01

Purpose: Nanostructured lipid carriers (NLCs) composed of solid lipid and oil are a new generation of lipid nanoparticles which have exhibited some merits over traditional used lipid nanoparticles in fortifying food and beverages and nutraceuticals delivery systems such as liposomes and solid lipid nanoparticles. Methods: In this study, Precirol and Compritol as solid lipids, Miglyol and Octyloctanoat as liquid lipids, Tween80, Tween20 and Poloxamer407 as surfactants were used to prepare vitamin D3-loaded NLC dispersion using hot homogenization method. The particle size and size distribution for all formulations were evaluated by immediately after production and during a storage period of 60 days. Results: The Precirol-based NLC showed superiority over Compritol-based NLC in the point of physical stability. Results clearly suggested that an optimum concentration of 3% of Poloxamer407 or 2% of Tween20 was sufficient to cover the surface of nanoparticles effectively and prevent agglomeration during the homogenization process. Octyloctanoat was introduced for the first time as a good substituent for Miglyol in the preparation of NLC formulations. The vitamin D3 Intestinal absorption enhanced by the incorporating in NLCs. Conclusion: It was concluded that NLC showed a promising approach for fortifying beverages by lipophilic nutraceuticals such as vitamin D. PMID:28507938

Optimization and design of ibuprofen-loaded nanostructured lipid carriers using a hybrid-design approach for ocular drug delivery

NASA Astrophysics Data System (ADS)

Rathod, Vishal

The objective of the present project was to develop the Ibuprofen-loaded Nanostructured Lipid Carrier (IBU-NLCs) for topical ocular delivery based on substantial pre-formulation screening of the components and understanding the interplay between the formulation and process variables. The BCS Class II drug: Ibuprofen was selected as the model drug for the current study. IBU-NLCs were prepared by melt emulsification and ultrasonication technique. Extensive pre-formulation studies were performed to screen the lipid components (solid and liquid) based on drug's solubility and affinity as well as components compatibility. The results from DSC & XRD assisted in selecting the most suitable ratio to be utilized for future studies. DynasanRTM 114 was selected as the solid lipid & MiglyolRTM 840 was selected as the liquid lipid based on preliminary lipid screening. The ratio of 6:4 was predicted to be the best based on its crystallinity index and the thermal events. As there are many variables involved for further optimization of the formulation, a single design approach is not always adequate. A hybrid-design approach was applied by employing the Plackett Burman design (PBD) for preliminary screening of 7 critical variables, followed by Box-Behnken design (BBD), a sub-type of response surface methodology (RSM) design using 2 relatively significant variables from the former design and incorporating Surfactant/Co-surfactant ratio as the third variable. Comparatively, KolliphorRTM HS15 demonstrated lower Mean Particle Size (PS) & Polydispersity Index (PDI) and KolliphorRTM P188 resulted in Zeta Potential (ZP) < -20 mV during the surfactant screening & stability studies. Hence, Surfactant/Cosurfactant ratio was employed as the third variable to understand its synergistic effect on the response variables. We selected PS, PDI, and ZP as critical response variables in the PBD since they significantly influence the stability & performance of NLCs. Formulations prepared using BBD were further characterized and evaluated concerning PS, PDI, ZP and Entrapment Efficiency (EE) to identify the multi-factor interactions between selected formulation variables. In vitro release studies were performed using Spectra/por dialysis membrane on Franz diffusion cell and Phosphate Saline buffer (7.4 pH) as the medium. Samples for assay, EE, Loading Capacity (LC), Solubility studies & in-vitro release were filtered using Amicon 50K and analyzed via UPLC system (Waters) at a detection wavelength of 220 nm. Significant variables were selected through PBD, and the third variable was incorporated based on surfactant screening & stability studies for the next design. Assay of the BBD based formulations was found to be within 95-104% of the theoretically calculated values. Further studies were investigated for PS, PDI, ZP & EE. PS was found to be in the range of 103-194 nm with PDI ranging from 0.118 to 0.265. The ZP and EE were observed to be in the range of -22.2 to -11 mV & 90 to 98.7 % respectively. Drug release of 30% was observed from the optimized formulation in the first 6 hr of in-vitro studies, and the drug release showed a sustained release of ibuprofen thereafter over several hours. These values also confirm that the production method, and all other selected variables, effectively promoted the incorporation of ibuprofen in NLC. Quality by Design (QbD) approach was successfully implemented in developing a robust ophthalmic formulation with superior physicochemical and morphometric properties. NLCs as the nanocarrier demonstrated promising perspective for topical delivery of poorly water-soluble drugs.

Nanostructured Lipid Carriers (NLC) as Vehicles for Topical Administration of Sesamol: In Vitro Percutaneous Absorption Study and Evaluation of Antioxidant Activity.

PubMed

Puglia, Carmelo; Lauro, Maria Rosaria; Offerta, Alessia; Crascì, Lucia; Micicchè, Lucia; Panico, Anna Maria; Bonina, Francesco; Puglisi, Giovanni

2017-03-01

Sesamol is a natural phenolic compound extracted from Sesamum indicum seed oil. Sesamol is endowed with several beneficial effects, but its use as a topical agent is strongly compromised by unfavorable chemical-physical properties. Therefore, to improve its characteristics, the aim of the present work was the formulation of nanostructured lipid carriers as drug delivery systems for topical administration of sesamol.Two different nanostructured lipid carrier systems have been produced based on the same solid lipid (Compritol® 888 ATO) but in a mixture with two different kinds of oil phase such as Miglyol® 812 (nanostructured lipid carrier-M) and sesame oil (nanostructured lipid carrier-PLUS). Morphology and dimensional distribution of nanostructured lipid carriers have been characterized by differential scanning calorimetry and photon correlation spectroscopy, respectively. The release pattern of sesamol from nanostructured lipid carriers was evaluated in vitro determining drug percutaneous absorption through excised human skin. Furthermore, an oxygen radical absorbance capacity assay was used to determine their antioxidant activity.From the results obtained, the method used to formulate nanostructured lipid carriers led to a homogeneous dispersion of particles in a nanometric range. Sesamol has been encapsulated efficiently in both nanostructured lipid carriers, with higher encapsulation efficiency values (> 90 %) when sesame oil was used as the oil phase (nanostructured lipid carrier-PLUS). In vitro evidences show that nanostructured lipid carrier dispersions were able to control the rate of sesamol diffusion through the skin, with respect to the reference formulations.Furthermore, the oxygen radical absorbance capacity assay pointed out an interesting and prolonged antioxidant activity of sesamol, especially when vehiculated by nanostructured lipid carrier-PLUS. Georg Thieme Verlag KG Stuttgart · New York.

Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation.

PubMed

Sambaraj, Swapna; Ammula, Divya; Nagabandi, Vijaykumar

2015-09-01

The main objective of the current research work was to formulate and evaluate furosemide loaded silica lipid hybrid microparticles for improved oral delivery. A novel silica-lipid hybrid microparticulate system is used for enhancing the oral absorption of low solubility and low permeability of (BCS Class IV) drugs. Silica-lipid hybrid microparticles include the drug solubilising effect of dispersed lipids and stabilizing effect of hydrophilic silica particles to increase drug solubilisation, which leads to enhanced oral bioavailability. The slica lipid hybrid (SLH) microparticles were composed of poorly soluble drug (furosemide), dispersion of oil phase (Soya bean oil and miglyol) in lecithin (Phospholipoid 90H), non-ionic surfactant (Polysorbate 80) and adsorbent (Aerosol 380). Saturation solubility studies were performed in different oils and surfactants with increased concentration of drug revealed increased solubility of furosemide. In vitro dissolution studies conducted under simulated gastric medium revealed 2-4 fold increase in dissolution efficiencies for SLH microparticles compared to that of pure drug (furosemide) and marketed formulation Lasix®. Ex vivo studies showed enhanced lipid digestibility, which improved drug permeability. Solid-state characterization of SLH microparticles by X-ray powder diffraction and Fourier transform infrared spectroscopic analysis confirmed non-crystalline nature and more compatibility of furosemide in silica-lipid hybrid microparticles. It can be concluded that the role of lipids and hydrophilic silica based carrier highlighted in enhancing solubility and permeability, and hence the oral bioavailability of poorly soluble drugs.

Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation

PubMed Central

Sambaraj, Swapna; Ammula, Divya; Nagabandi, Vijaykumar

2015-01-01

Purpose: The main objective of the current research work was to formulate and evaluate furosemide loaded silica lipid hybrid microparticles for improved oral delivery. A novel silica-lipid hybrid microparticulate system is used for enhancing the oral absorption of low solubility and low permeability of (BCS Class IV) drugs. Silica-lipid hybrid microparticles include the drug solubilising effect of dispersed lipids and stabilizing effect of hydrophilic silica particles to increase drug solubilisation, which leads to enhanced oral bioavailability. Methods: The slica lipid hybrid (SLH) microparticles were composed of poorly soluble drug (furosemide), dispersion of oil phase (Soya bean oil and miglyol) in lecithin (Phospholipoid 90H), non-ionic surfactant (Polysorbate 80) and adsorbent (Aerosol 380). Saturation solubility studies were performed in different oils and surfactants with increased concentration of drug revealed increased solubility of furosemide. Results: In vitro dissolution studies conducted under simulated gastric medium revealed 2-4 fold increase in dissolution efficiencies for SLH microparticles compared to that of pure drug (furosemide) and marketed formulation Lasix®. Ex vivo studies showed enhanced lipid digestibility, which improved drug permeability. Solid-state characterization of SLH microparticles by X-ray powder diffraction and Fourier transform infrared spectroscopic analysis confirmed non-crystalline nature and more compatibility of furosemide in silica-lipid hybrid microparticles. Conclusion: It can be concluded that the role of lipids and hydrophilic silica based carrier highlighted in enhancing solubility and permeability, and hence the oral bioavailability of poorly soluble drugs. PMID:26504763

A simple quantitative approach for the determination of long and medium chain lipids in bio-relevant matrices by high performance liquid chromatography with refractive index detection.

PubMed

Lee, Kathy Wai Yu; Porter, Christopher J H; Boyd, Ben J

2013-09-01

There is increasing attention in the literature towards understanding the behaviour of lipid-based drug formulations under digestion conditions using in vitro and in vivo methods. This necessitates a convenient method for quantitation of lipids and lipid digestion products. In this study, a simple and accessible method for the separation and quantitative determination of typical formulation and digested lipids using high performance liquid chromatography coupled to refractive index detection (HPLC-RI) is described. Long and medium chain lipids were separated and quantified in a biological matrix (gastrointestinal content) without derivatisation using HPLC-RI on C18 and C8 columns, respectively. The intra- and inter-assay accuracy was between 92% and 106%, and the assays were precise to within a coefficient of variation of less than 10% over the range of 0.1-2 mg/mL for both long and medium chain lipids. This method is also shown to be suitable for quantifying the lipolysis products collected from the gastrointestinal tract in the course of in vivo lipid digestion studies.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals.

PubMed

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals

PubMed Central

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations. PMID:28243062

Evaluation of hypericin-loaded solid lipid nanoparticles: physicochemical properties, photostability and phototoxicity.

PubMed

Youssef, Tareq; Fadel, Maha; Fahmy, Rania; Kassab, Kawser

2012-01-01

Hypericin (HYP), a natural photosensitizer, has powerful photo-oxidizing ability, tumor-seeking characteristics, and minimal dark toxicity; nevertheless, it has proven high lipid solubility compared to its sparingly water soluble nature. Therefore, its formulation into solid lipid nanoparticles (SLNs) has attracted increasing attention as a potential drug-delivery carrier. Two HYP-loaded SLNs formulations were prepared utilizing microemulsion-based technique. Thereafter, the physicochemical properties of the formulations were investigated and evaluated. HYP-loaded SLNs showed spherical shape with mean particle size ranging from 200-300 nm for both formulations (FA and FB). The encapsulation efficiencies reached above 80% and FA showed significant higher encapsulation than FB (P<0.05), also, the thermal analysis using differential scanning calorimetry (DSC) indicated good compatibility between hypericin and lipids forming the cores in both formulations. Spectroscopic measurements of the photostability study showed that hypericin encapsulation into SLNs improved its photostability, compared to free HYP in 0.1% ethanolic solution. However, photocytotoxicity studies on HepG2 cells revealed an evident inhibition of the photodynamic efficacy of HYP-loaded SLNs, compared to free HYP. In conclusion, although the elevated entrapment efficiency of HYP into SLNs increased its photostability, it decreased its phototoxicity which might be due to the quenching deactivation of HYP molecules resulting from SLN compactness and thickness structure. © 2012 Informa Healthcare USA, Inc.

Enhanced Oral Bioavailability of Efavirenz by Solid Lipid Nanoparticles: In Vitro Drug Release and Pharmacokinetics Studies

PubMed Central

Gaur, Praveen Kumar; Mishra, Shikha; Bajpai, Meenakshi; Mishra, Anushika

2014-01-01

Solid lipid nanoparticle is an efficient lipid based drug delivery system which can enhance the bioavailability of poorly water soluble drugs. Efavirenz is a highly lipophilic drug from nonnucleoside inhibitor category for treatment of HIV. Present work illustrates development of an SLN formulation for Efavirenz with increased bioavailability. At first, suitable lipid component and surfactant were chosen. SLNs were prepared and analyzed for physical parameters, stability, and pharmacokinetic profile. Efavirenz loaded SLNs were formulated using Glyceryl monostearate as main lipid and Tween 80 as surfactant. ESLN-3 has shown mean particle size of 124.5 ± 3.2 nm with a PDI value of 0.234, negative zeta potential, and 86% drug entrapment. In vitro drug release study has shown 60.6–98.22% drug release in 24 h by various SLN formulations. Optimized SLNs have shown good stability at 40°C ± 2°C and 75 ± 5% relative humidity (RH) for 180 days. ESLN-3 exhibited 5.32-fold increase in peak plasma concentration (C max⁡) and 10.98-fold increase in AUC in comparison to Efavirenz suspension (ES). PMID:24967360

Controlled penetration of ceramides into and across the stratum corneum using various types of microemulsions and formulation associated toxicity studies.

PubMed

Sahle, Fitsum F; Wohlrab, Johannes; Neubert, Reinhard H H

2014-02-01

Several skin diseases such as psoriasis and atopic dermatitis are associated with the depletion or disturbance of stratum corneum (SC) lipids such as ceramides (CERs), free fatty acids and cholesterol. Studies suggested that replenishment of these lipids might help to treat diseased, affected or aged skin. With this premises in mind, there are some formulations in the market that contain SC lipids and currently, to facilitate permeation of the lipids deep into the SC, various CERs, and other SC lipid microemulsions (MEs) were developed and characterised using lecithin or TEGO® CARE PL 4 (TCPL4) as base surfactants. However, to date, there are no reports that involve the permeability of SC lipids into and across the SC, and therefore, the penetration of CER [NP] as a model ceramide from various formulations was investigated ex vivo using Franz diffusion cell. Besides, the toxicity of the MEs was assessed using hen's egg test chorioallantoic membrane (HET-CAM). The results of the study showed that CER [NP] could not permeate into deeper layers of the SC from a conventional hydrophilic cream. Unlike the cream, CER [NP] permeated into the deeper layers of the SC from both type of MEs, where permeation of the CER was more and into deeper layers from droplet type and lecithin-based MEs than bicontinuous (BC) type and TCPL4 based MEs, respectively. The CER also permeated into deeper layers from ME gels which was, however, shallow and to a lesser extent when compared with the MEs. The results of HET-CAM showed that both MEs are safe to be used topically, with lecithin-based MEs exhibiting better safety profiles than TCPL4 based MEs. Concluding, the study showed that the MEs are safe to be used on the skin for the controlled penetration of CER [NP] deep into the SC. Copyright © 2013 Elsevier B.V. All rights reserved.

Protective effect of a lipid-based preparation from Mycobacterium smegmatis in a murine model of progressive pulmonary tuberculosis.

PubMed

García, Maria de los Angeles; Borrero, Reinier; Lanio, Maria E; Tirado, Yanely; Alvarez, Nadine; Puig, Alina; Aguilar, Alicia; Canet, Liem; Mata Espinoza, Dulce; Barrios Payán, Jorge; Sarmiento, María Elena; Hernández-Pando, Rogelio; Norazmi, Mohd-Nor; Acosta, Armando

2014-01-01

A more effective vaccine against tuberculosis (TB) is urgently needed. Based on its high genetic homology with Mycobacterium tuberculosis (Mtb), the nonpathogenic mycobacteria, Mycobacterium smegmatis (Ms), could be an attractive source of potential antigens to be included in such a vaccine. We evaluated the capability of lipid-based preparations obtained from Ms to provide a protective response in Balb/c mice after challenge with Mtb H37Rv strain. The intratracheal model of progressive pulmonary TB was used to assess the level of protection in terms of bacterial load as well as the pathological changes in the lungs of immunized Balb/c mice following challenge with Mtb. Mice immunized with the lipid-based preparation from Ms either adjuvanted with Alum (LMs-AL) or nonadjuvanted (LMs) showed significant reductions in bacterial load (P < 0.01) compared to the negative control group (animals immunized with phosphate buffered saline (PBS)). Both lipid formulations showed the same level of protection as Bacille Calmette and Guerin (BCG). Regarding the pathologic changes in the lungs, mice immunized with both lipid formulations showed less pneumonic area when compared with the PBS group (P < 0.01) and showed similar results compared with the BCG group. These findings suggest the potential of LMs as a promising vaccine candidate against TB.

Understanding the lipid-digestion processes in the GI tract before designing lipid-based drug-delivery systems.

PubMed

Bakala N'Goma, Jean-Claude; Amara, Sawsan; Dridi, Kaouthar; Jannin, Vincent; Carrière, Frédéric

2012-01-01

Many of the compounds present in lipid-based drug-delivery systems are esters, such as acylglycerols, phospholipids, polyethyleneglycol mono- and di-esters and polysorbate, which can be hydrolyzed by the various lipolytic enzymes present in the GI tract. Lipolysis of these compounds, along with dietary fats, affects the solubility, dispersion and bioavailibity of poorly water-soluble drugs. Pharmaceutical scientists have been taking a new interest in fat digestion in this context, and several studies presenting in vitro gastrointestinal lipolysis models have been published. In most models, it is generally assumed that pancreatic lipase is the main enzyme involved in the gastrointestinal lipolysis of lipid formulations. It was established, however, that gastric lipase, pancreatic carboxyl ester hydrolaze and pancreatic lipase-related protein 2 are the major players involved in the lipolysis of lipid excipients containing acylglycerols and polyethyleneglycol esters. These findings have shown that the lipolysis of lipid excipients may actually start in the stomach and involve several lipolytic enzymes. These findings should therefore be taken into account when testing in vitro the dispersion and bioavailability of poorly water-soluble drugs formulated with lipids. In this review, we present the latest data available about the lipolytic enzymes involved in gastrointestinal lipolysis and suggest tracks for designing physiologically relevant in vitro digestion models.

Effect of compositions in nanostructured lipid carriers (NLC) on skin hydration and occlusion.

PubMed

Loo, Ch; Basri, M; Ismail, R; Lau, Hln; Tejo, Ba; Kanthimathi, Ms; Hassan, Ha; Choo, Ym

2013-01-01

To study the effects of varying lipid concentrations, lipid and oil ratio, and the addition of propylene glycol and lecithin on the long-term physical stability of nanostructured lipid nanocarriers (NLC), skin hydration, and transepidermal water loss. The various NLC formulations (A1-A5) were prepared and their particle size, zeta potential, viscosity, and stability were analyzed. The formulations were applied on the forearms of the 20 female volunteers (one forearm of each volunteer was left untreated as a control). The subjects stayed for 30 minutes in a conditioned room with their forearms uncovered to let the skin adapt to the temperature (22°C ± 2°C) and humidity (50% ± 2%) of the room. Skin hydration and skin occlusion were recorded at day one (before treatment) and day seven (after treatment). Three measurements for skin hydration and skin occlusion were performed in each testing area. NLC formulations with the highest lipid concentration, highest solid lipid concentration, and additional propylene glycol (formulations A1, A2, and A5) showed higher physical stability than other formulations. The addition of propylene glycol into an NLC system helped to reduce the particle size of the NLC and enhanced its long-term physical stability. All the NLC formulations were found to significantly increase skin hydration compared to the untreated controls within 7 days. All NLC formulations exhibited occlusive properties as they reduced the transepidermal water loss within 7 days. This effect was more pronounced with the addition of propylene glycol or lecithin into an NLC formulation, whereby at least 60% reduction in transepidermal water loss was observed. NLCs with high lipid content, solid lipid content, phospholipid, and lecithin are a highly effective cosmetic delivery system for cosmetic topical applications that are designed to boost skin hydration.

Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion.

PubMed

Williams, Hywel D; Anby, Mette U; Sassene, Philip; Kleberg, Karen; Bakala-N'Goma, Jean-Claude; Calderone, Marilyn; Jannin, Vincent; Igonin, Annabel; Partheil, Anette; Marchaud, Delphine; Jule, Eduardo; Vertommen, Jan; Maio, Mario; Blundell, Ross; Benameur, Hassan; Carrière, Frédéric; Müllertz, Anette; Pouton, Colin W; Porter, Christopher J H

2012-11-05

The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a threshold value for SR(M) was evident, regardless of formulation composition and drug solubilization reduced markedly above SR(M) > 2.5. The threshold SR(M) may prove to be an effective tool in discriminating between LBFs based on performance.

Development of nanostructured lipid carriers containing salicyclic acid for dermal use based on the Quality by Design method.

PubMed

Kovács, A; Berkó, Sz; Csányi, E; Csóka, I

2017-03-01

The aim of our present work was to evaluate the applicability of the Quality by Design (QbD) methodology in the development and optimalization of nanostructured lipid carriers containing salicyclic acid (NLC SA). Within the Quality by Design methology, special emphasis is layed on the adaptation of the initial risk assessment step in order to properly identify the critical material attributes and critical process parameters in formulation development. NLC SA products were formulated by the ultrasonication method using Compritol 888 ATO as solid lipid, Miglyol 812 as liquid lipid and Cremophor RH 60® as surfactant. LeanQbD Software and StatSoft. Inc. Statistica for Windows 11 were employed to indentify the risks. Three highly critical quality attributes (CQAs) for NLC SA were identified, namely particle size, particle size distribution and aggregation. Five attributes of medium influence were identified, including dissolution rate, dissolution efficiency, pH, lipid solubility of the active pharmaceutical ingredient (API) and entrapment efficiency. Three critical material attributes (CMA) and critical process parameters (CPP) were identified: surfactant concentration, solid lipid/liquid lipid ratio and ultrasonication time. The CMAs and CPPs are considered as independent variables and the CQAs are defined as dependent variables. The 2 3 factorial design was used to evaluate the role of the independent and dependent variables. Based on our experiments, an optimal formulation can be obtained when the surfactant concentration is set to 5%, the solid lipid/liquid lipid ratio is 7:3 and ultrasonication time is 20min. The optimal NLC SA showed narrow size distribution (0.857±0.014) with a mean particle size of 114±2.64nm. The NLC SA product showed a significantly higher in vitro drug release compared to the micro-particle reference preparation containing salicylic acid (MP SA). Copyright © 2016 Elsevier B.V. All rights reserved.

Dermal quercetin lipid nanocapsules: Influence of the formulation on antioxidant activity and cellular protection against hydrogen peroxide.

PubMed

Hatahet, T; Morille, M; Shamseddin, A; Aubert-Pouëssel, A; Devoisselle, J M; Bégu, S

2017-02-25

Quercetin is a plant flavonoid with strong antioxidant and antiinflammatory properties interesting for skin protection. However, its poor water solubility limits its penetration and so its efficiency on skin. For this purpose, quercetin lipid nanocapsules were formulated implementing phase inversion technique wherein several modifications were introduced to enhance quercetin loading. Quercetin lipid nanocapsules were formulated with two particle size range, (50nm and 20nm) allowing a drug loading of 18.6 and 32mM respectively. The successful encapsulation of quercetin within lipid nanocapsules increased its apparent water solubility by more than 5000 fold (from 0.5μg/ml to about 5mg/ml). The physicochemical properties of these formulations such as surface charge, stability and morphology were characterized. Lipid nanocapsules had spherical shape and were stable for 28days at 25°C. Quercetin release from lipid nanocapsules was studied and revealed a prolonged release kinetics during 24h. Using DPPH assay, we demonstrated that the formulation process of lipid nanocapsules did not modify the antioxidant activity of quercetin in vitro (92.3%). With the goal of a future dermal application, quercetin lipid nanocapsules were applied to THP-1 monocytes and proved the cellular safety of the formulation up to 2μg/ml of quercetin. Finally, formulated quercetin was as efficient as the crude form in the protection of THP-1 cells from oxidative stress by exogenous hydrogen peroxide. With its lipophilic nature and occlusive effect on skin, lipid nanocapsules present a promising strategy to deliver quercetin to skin tissue and can be of value for other poorly water soluble drug candidates. Copyright © 2016 Elsevier B.V. All rights reserved.

Molecularly designed lipid microdomains for solid dispersions using a polymer/inorganic carrier matrix produced by hot-melt extrusion.

PubMed

Adler, Camille; Schönenberger, Monica; Teleki, Alexandra; Kuentz, Martin

2016-02-29

Amorphous solid dispersions have for many years been a focus in oral formulations, especially in combination with a hot-melt extrusion process. The present work targets a novel approach with a system based on a fatty acid, a polymer and an inorganic carrier. It was intended to adsorb the acidic lipid by specific molecular interactions onto the solid carrier to design disorder in the alkyl chains of the lipid. Such designed lipid microdomains (DLM) were created as a new microstructure to accommodate a compound in a solid dispersion. Vibrational spectroscopy, X-ray powder diffraction, atomic force microscopy as well as electron microscopic imaging were employed to study a system of stearic acid, hydroxypropylcellulose and aluminum magnesium silicate. β-carotene was used as a poorly water-soluble model substance that is difficult to formulate with conventional solid dispersion formulations. The results indicated that the targeted molecular excipient interactions indeed led to DLMs for specific compositions. The different methods provided complementary aspects and important insights into the created microstructure. The novel delivery system appeared to be especially promising for the formulation of oral compounds that exhibit both high crystal energy and lipophilicity. Copyright © 2015 Elsevier B.V. All rights reserved.

Structure relationship of cationic lipids on gene transfection mediated by cationic liposomes.

PubMed

Paecharoenchai, Orapan; Niyomtham, Nattisa; Apirakaramwong, Auayporn; Ngawhirunpat, Tanasait; Rojanarata, Theerasak; Yingyongnarongkul, Boon-ek; Opanasopit, Praneet

2012-12-01

The aim of this study was to investigate the transfection efficiency of cationic liposomes formulated with phosphatidylcholine (PC) and novel synthesized diethanolamine-based cationic lipids at a molar ratio of 5:1 in comparison with Lipofectamine™ 2000. Factors affecting transfection efficiency and cell viability, including the chemical structure of the cationic lipids, such as different amine head group (diamine and polyamine; and non-spermine and spermine) and acyl chain lengths (C14, C16, and C18) and the weight ratio of liposomes to DNA were evaluated on a human cervical carcinoma cell line (HeLa cells) using the pDNA encoding green fluorescent protein (pEGFP-C2). Characterizations of these lipoplexes in terms of size and charge measurement and agarose gel electrophoresis were performed. The results from this study revealed that almost no transfection was observed in the liposome formulations composed of cationic lipids with a non-spermine head group. In addition, the transfection efficiency of these cationic liposomes was in the following order: spermine-C14 > spermine-C16 > spermine-C18. The highest transfection efficiency was observed in the formulation of spermine-C14 liposomes at a weight ratio of 25; furthermore, this formulation was safe for use in vitro. In conclusion, cationic liposomes containing spermine head groups demonstrated promising potential as gene carriers.

Biological and Clinical Aspects of an Olive Oil-Based Lipid Emulsion-A Review.

PubMed

Cai, Wei; Calder, Phillip C; Cury-Boaventura, Maria F; De Waele, Elisabeth; Jakubowski, Julie; Zaloga, Gary

2018-06-15

Intravenous lipid emulsions (ILEs) have been an integral component of parenteral nutrition for more than 50 years. Numerous formulations are available and are based on vegetable (soybean, olive, coconut) and animal (fish) oils. Therefore, each of these formulations has a unique fatty acid composition that offers both benefits and limitations. As clinical experience and our understanding of the effects of fatty acids on various physiological processes has grown, there is evidence to suggest that some ILEs may have benefits compared with others. Current evidence suggests that olive oil-based ILE may preserve immune, hepatobiliary, and endothelial cell function, and may reduce lipid peroxidation and plasma lipid levels. There is good evidence from a large randomized controlled study to support a benefit of olive oil-based ILE over soybean oil-based ILE on reducing infections in critically ill patients. At present there is limited evidence to demonstrate a benefit of olive oil-based ILE over other ILEs on glucose metabolism, and few data exist to demonstrate a benefit on clinical outcomes such as hospital or intensive care unit stay, duration of mechanical ventilation, or mortality. We review the current research and clinical evidence supporting the potential positive biological and clinical aspects of olive oil-based ILE and conclude that olive oil-based ILE is well tolerated and provides effective nutritional support to various PN-requiring patient populations. Olive oil-based ILE appears to support the innate immune system, is associated with fewer infections, induces less lipid peroxidation, and is not associated with increased hepatobiliary or lipid disturbances. These data would suggest that olive oil-based ILE is a valuable option in various PN-requiring patient populations.

Formulation and acoustic studies of a new phase-shift agent for diagnostic and therapeutic ultrasound.

PubMed

Sheeran, Paul S; Luois, Samantha; Dayton, Paul A; Matsunaga, Terry O

2011-09-06

Recent efforts in the area of acoustic droplet vaporization with the objective of designing extravascular ultrasound contrast agents has led to the development of stabilized, lipid-encapsulated nanodroplets of the highly volatile compound decafluorobutane (DFB). We developed two methods of generating DFB droplets, the first of which involves condensing DFB gas (boiling point from -1.1 to -2 °C) followed by extrusion with a lipid formulation in HEPES buffer. Acoustic droplet vaporization of micrometer-sized lipid-coated droplets at diagnostic ultrasound frequencies and mechanical indices were confirmed optically. In our second formulation methodology, we demonstrate the formulation of submicrometer-sized lipid-coated nanodroplets based upon condensation of preformed microbubbles containing DFB. The droplets are routinely in the 200-300 nm range and yield microbubbles on the order of 1-5 μm once vaporized, consistent with ideal gas law expansion predictions. The simple and effective nature of this methodology allows for the development of a variety of different formulations that can be used for imaging, drug and gene delivery, and therapy. This study is the first to our knowledge to demonstrate both a method of generating ADV agents by microbubble condensation and formulation of primarily submicrometer droplets of decafluorobutane that remain stable at physiological temperatures. Finally, activation of DFB nanodroplets is demonstrated using pressures within the FDA guidelines for diagnostic imaging, which may minimize the potential for bioeffects in humans. This methodology offers a new means of developing extravascular contrast agents for diagnostic and therapeutic applications. © 2011 American Chemical Society

Lyophilization of a triply unsaturated phospholipid: Effects of trace metal contaminants

PubMed Central

Payton, N.M.; Wempe, M.F.; Betker, Jamie L.; Randolph, T.W.; Anchordoquy, T.J.

2013-01-01

As liquid liposomal formulations are prone to chemical degradation and aggregation, these formulations often require freeze drying (e.g. lyophilization) to achieve sufficient shelf-life. However, liposomal formulations may undergo oxidation during lyophilization and/or during prolonged storage. The goal of the current study was to characterize the degradation of 1, 2-dilinolenoyl-sn-glycero-3-phosphocholine (DLPC) during lyophilization, and to also probe the influence of metal contaminants in promoting the observed degradation. Aqueous sugar formulations containing DLPC (0.01 mg/ml) were lyophilized, and DLPC degradation was monitored using HPLC/UV and GC/MS methods. The effect of ferrous ion and sucrose concentration, as well as lyophilization stage promoting lipid degradation, was investigated. DLPC degradation increased with higher levels of ferrous ion. After lyophilization, 103.1% ± 1.1%, 66.9% ± 0.8%, and 28.7% ± 0.7% DLPC remained in the sucrose samples spiked with 0.0 ppm, 0.2 ppm and 1.0 ppm ferrous ion, respectively. Lipid degradation predominantly occurs during the freezing stage of lyophilization. Sugar concentration and buffer ionic strength also influence the extent of lipid degradation, and DLPC loss correlated with degradation product formation. We conclude that DLPC oxidation during the freezing stage of lyophilization dramatically compromises the stability of lipid-based formulations. In addition, we demonstrate that metal contaminants in sugars can become highly active when lyophilized in the presence of a reducing agent. PMID:23567484

Nanostructured Lipid Carrier for Topical Application of N-Acetyl Glucosamine.

PubMed

Aliasgharlou, Lavin; Ghanbarzadeh, Saeed; Azimi, Hamideh; Zarrintan, Mohammad Hossein; Hamishehkar, Hamed

2016-12-01

Purpose: Hyperpigmentation occurs when melanin is overproduced in certain spots on the skin and is one of the most challenging skin conditions to treat. Although it is usually harmless, for cosmetic reasons, it is dreadfully bothersome to those who undergo it. It was reported that N-acetyl-glucosamine (NAGA) prevents melanin synthesis and alters the expression of numerous genes related to pigmentation. In spite of these advantages, NAGA cannot be employed in topical formulations due to its extremely polar characteristics. Nanoparticles, especially lipid-based ones, have been introduced as an efficient carrier for dermal drug delivery. Methods: The aim of the present study was to load adequate hydrophilic NAGA to the lipophilic nanostructured lipid carriers (NLCs) for potential dermal application. NAGA-loaded NLCs were formulated, using hot homogenization technique, and the characteristics of the optimized formulation were analyzed by laser light scattering, X-ray diffraction, and scanning electron microscopy methods. Loading capacity percentage and in vitro release study were carried out by applying a validated HPLC method. The optimum formulation was utilized for the in vivo skin lightening evaluations in healthy volunteers. Results: NAGA-loaded NLCs demonstrated promising results (the size of 190 nm, narrow size distribution, loading capacity of 9%, and appropriate NAGA release profile) suitable for dermal delivery. XRD results exhibited a dramatic reduction in the crystalline structure of encapsulated NAGA. Dermoscopy images indicated a considerable decline in melanin distribution pattern in the majority of the cases treated with NAGA-loaded NLCs. Conclusion: Thus, this study has opened new horizons for the potential use of lipid based nanoparticles in the managing of hyperpigmentation.

Optimization and evaluation of lipid emulsions for intravenous co-delivery of artemether and lumefantrine in severe malaria treatment.

PubMed

Yang, Yinxian; Gao, Hailing; Zhou, Shuang; Kuang, Xiao; Wang, Zhenjie; Liu, Hongzhuo; Sun, Jin

2018-05-10

Parenteral therapy for severe and complicated malaria is necessary, but currently available parenteral antimalarials have their own drawbacks. As for recommended artemisinin-based combination therapy, antimalarial artemether and lumefantrine are limited in parenteral delivery due to their poor water solubility. Herein, the aim of this study was to develop the lipid-based emulsions for intravenous co-delivery of artemether and lumefantrine. The lipid emulsion was prepared by high-speed shear and high-pressure homogenization, and the formulations were optimized mainly by monitoring particle size distribution under autoclaved conditions. The final optimal formulation was with uniform particle size distribution (~ 220 nm), high encapsulation efficiency (~ 99%), good physiochemical stability, and acceptable hemolysis potential. The pharmacokinetic study in rats showed that C max of artemether and lumefantrine for the optimized lipid emulsions were significantly increased than the injectable solution, which was critical for rapid antimalarial activity. Furthermore, the AUC 0-t of artemether and lumefantrine in the lipid emulsion group were 5.01- and 1.39-fold of those from the solution, respectively, suggesting enhanced bioavailability. With these findings, the developed lipid emulsion is a promising alternative parenteral therapy for the malaria treatment, especially for severe or complicated malaria.

Formulation and Evaluation of Guggul Lipid Nanovesicles for Transdermal Delivery of Aceclofenac

PubMed Central

Gaur, Praveen Kumar; Mishra, Shikha; Aeri, Vidhu

2014-01-01

Context. Most new drugs have low water solubility and liposome is an important formulation to administer such drugs; however, it is quite unstable and has negligible systemic absorption. Objective. Aceclofenac nanovesicles were made using guggul lipid for formulating stable transdermal formulation. Materials and Methods. Guggul lipid was formulated into vesicles along with cholesterol and dicetyl phosphate using film hydration method. The formulations were analyzed for physicochemical properties and stability. Then its skin permeation and anti-inflammatory activity were determined. Results. Both categories of vesicles (PC and GL) showed optimum physicochemical properties; however, accelerated stability study showed considerable differences. GL-1 was appreciably stable for over 6 months at 4°C. Corresponding gels (PCG-1 and GLG-1) showed C max values at 4.98 and 7.32 μg/mL along with the T max values at 4 and 8 hours, respectively. GLG-1 inhibited edema production by 90.81% in 6 hours. Discussion. PC liposomes are unstable at higher temperature and upon longer storage. The formulation with higher lipid content (GL-1) showed good drug retention after 24 hours and appreciable stability both at higher temperature and for longer duration. Guggul lipid being a planar molecule might be stacked in vesicle wall with cholesterol. Conclusion. The composition of the nanovesicle played an important role in stability and drug permeation. Guggul lipid is suitable for producing stable vesicles. PMID:24672328

Physico-chemical separation process of nanoparticles in cosmetic formulations

NASA Astrophysics Data System (ADS)

Retamal Marín, R. R.; Babick, F.; Stintz, M.

2017-06-01

Understanding the world of nanoparticles, especially their interactions with the environment, begins with their correct detection and successive quantification. To achieve this purpose, one needs to perform correctly developed standard operating procedures (SOPs). Furthermore, the study of nanoparticles frequently requires their characterisation in complex media (e.g. in cosmetic formulations). In this study, a set of sample preparation procedures for the detection and extraction of NMs in emulsion-based formulations is proposed and their performance for model and real-life products is discussed. A separation or extraction of lipid phases is achieved by means of organic solvents. The polarity of the lipid phases is decisive for selecting an optimum solvent. The use of the Hansen Solubility Parameters (HSP) may clearly support this decision.

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation.

PubMed

Suys, Estelle J A; Chalmers, David K; Pouton, Colin W; Porter, Christopher J H

2018-06-04

The ability of lipid-based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastrointestinal (GI) fluids has generated significant interest in the past decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs) to the formulation. In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations. An in vitro model was first employed to assess drug (fenofibrate) solubilization and supersaturation on LBF dispersion and digestion. An in vitro-in situ model was subsequently employed to simultaneously evaluate the impact of PPI enhanced drug supersaturation on drug absorption in rats. The stabilizing effect of the polymers was polymer specific and most pronounced at higher drug loads. Polymers that were soluble in LBF allowed simple processing as single phase formulations, while formulations containing more hydrophilic polymers required polymer suspension in the formulation. The lipid-soluble polymers Eudragit (EU) RL100 and poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE) and the water-soluble polymer hydroxypropylmethyl cellulose (HPMC) E4M were identified as the most effective PPIs in delaying fenofibrate precipitation in vitro. An in vitro model of lipid digestion was subsequently coupled directly to an in situ single pass intestinal perfusion assay to evaluate the influence of PPIs on fenofibrate absorption from LBFs in vivo. This coupled model allowed for real-time evaluation of the impact of supersaturation stabilization on absorptive drug flux and provided better discrimination between the different PPIs and formulations. In the presence of the in situ absorption sink, increased fenofibrate supersaturation resulted in increased drug exposure, and a good correlation was found between the degree of in vitro supersaturation and in vivo drug exposure. An improved in vitro-in vivo correlation was apparent when comparing the same formulation under different supersaturation conditions. These observations directly exemplify the potential utility of PPIs in promoting drug absorption from LBF, via stabilization of supersaturation, and further confirm that relatively brief periods of supersaturation may be sufficient to promote drug absorption, at least for highly permeable drugs such as fenofibrate.

P5 HER2/neu-derived peptide conjugated to liposomes containing MPL adjuvant as an effective prophylactic vaccine formulation for breast cancer.

PubMed

Shariat, Sheida; Badiee, Ali; Jalali, Seyed Amir; Mansourian, Mercedeh; Yazdani, Mona; Mortazavi, Seyed Alireza; Jaafari, Mahmoud Reza

2014-12-01

Vaccines containing synthetic peptides derived from tumor-associated antigens (TAA) can elicit potent cytotoxic T lymphocyte (CTL) response if they are formulated in an optimal vaccine delivery system. The aim of this study was to develop a simple and effective lipid-based vaccine delivery system using P5 HER2/neu-derived peptide conjugated to Maleimide-PEG2000-DSPE. The conjugated lipid was then incorporated into liposomes composed of DMPC:DMPG:Chol:DOPE containing Monophosphoryl lipid A (MPL) (Lip-DOPE-P5-MPL). Different liposome formulations were prepared and characterized for their physicochemical properties. To evaluate anti-tumoral efficacy, BALB/c mice were immunized subcutaneously 3 times in two-week intervals and the generated immune response was studied. The results demonstrated that Lip-DOPE-P5-MPL induced a significantly higher IFN-γ production by CD8+ T cells intracellularly which represents higher CTL response in comparison with other control formulations. CTL response induced by this formulation caused the lowest tumor size and the longest survival time in a mice model of TUBO tumor. The encouraging results achieved by Lip-DOPE-P5-MPL formulation could make it a promising candidate in developing effective vaccines against Her2 positive breast cancers. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Effect of formulation and process variables on lipid based sustained release tablets via continuous twin screw granulation: A comparative study.

PubMed

Kallakunta, Venkata Raman; Tiwari, Roshan; Sarabu, Sandeep; Bandari, Suresh; Repka, Michael A

2018-05-14

The current study's aim is to prepare lipid based sustained release tablets via a twin-screw granulation technique and compare those dosage forms with conventional techniques, namely wet granulation and direct compression. The granules were successfully manufactured in a single-step, continuous twin-screw granulation process with a low proportion of binder (Klucel™ EF, HPC SSL) using Compritol® 888 ATO, Precirol® ATO 5 and Geleol™ as sustained release agents. The granules prepared showed good flow characteristics and compaction properties. DSC and XRD studies were conducted to characterize the granules prepared via a twin-screw granulation method and the results demonstrated the crystalline nature of lipids within the granules. FTIR data indicated that there were no interactions with the formulation components investigated. The formulations developed by all three methods were compressed into tablets with a mechanical strength of 14-16 KP. The tablets formulated were characterized for physicochemical properties, in vitro drug release studies, water uptake and erosion studies. These results showed that the drug was not completely released after 24 h for tablets developed by the wet granulation process using all three lipids. The tablets prepared by the direct compression method demonstrated a burst release within 8 to 10 h from Precirol ATO 5® and Geleol™ formulations compared to Compritol® 888 ATO. However, tablets prepared using twin-screw granulation exhibited sustained release of the drug over 24 h and the water uptake and erosion results were in accordance with dissolution data. Stability data for 45 days at accelerated conditions (40 °C/75% RH) showed similar release profiles with ƒ2 values above 50 for all of the twin screw granulation formulations, indicating the suitability of the process for formulating sustained release tablets. These findings of a single-step, continuous twin-screw granulation process are novel and demonstrate new opportunities for development of sustained release tablets. Copyright © 2017. Published by Elsevier B.V.

Solid lipid nanoparticles bearing oxybenzone: in-vitro and in-vivo evaluation.

PubMed

Gulbake, Arvind; Jain, Aviral; Khare, Piush; Jain, Sanjay K

2010-05-01

In the present project, Solid Lipid Nanoparticles (SLNs) bearing oxybenzone were prepared by ethanol injection method to improve its effectiveness as sunscreen. SLNs were characterized for particle size,polydispersity index, zeta potential and surface morphology. The optimized SLNs bearing oxybenzone were incorporated into water-removable cream base and compared with SLNs unloaded water-removable cream base for in vitro and in vivo parameters. Cream base formulation containing SLNs (Csd) with 5% oxybenzone showed slow drug release and better sun protecting factor (more than 25) compared to cream base containing 5% oxybenzone. Confocal Laser Scanning Microscopy was used to visualize the distribution of developed formulations in skin. CLSM indicated prolonged retention of SLNs in the stratum corneum as compared to plain cream base. These studies revealed that the cream base bearing SLNs exhibited good skin retention as well as enhanced sun protection effect compared to cream base.

Effect of compositions in nanostructured lipid carriers (NLC) on skin hydration and occlusion

PubMed Central

Loo, CH; Basri, M; Ismail, R; Lau, HLN; Tejo, BA; Kanthimathi, MS; Hassan, HA; Choo, YM

2013-01-01

Purpose To study the effects of varying lipid concentrations, lipid and oil ratio, and the addition of propylene glycol and lecithin on the long-term physical stability of nanostructured lipid nanocarriers (NLC), skin hydration, and transepidermal water loss. Methods The various NLC formulations (A1–A5) were prepared and their particle size, zeta potential, viscosity, and stability were analyzed. The formulations were applied on the forearms of the 20 female volunteers (one forearm of each volunteer was left untreated as a control). The subjects stayed for 30 minutes in a conditioned room with their forearms uncovered to let the skin adapt to the temperature (22°C ± 2°C) and humidity (50% ± 2%) of the room. Skin hydration and skin occlusion were recorded at day one (before treatment) and day seven (after treatment). Three measurements for skin hydration and skin occlusion were performed in each testing area. Results NLC formulations with the highest lipid concentration, highest solid lipid concentration, and additional propylene glycol (formulations A1, A2, and A5) showed higher physical stability than other formulations. The addition of propylene glycol into an NLC system helped to reduce the particle size of the NLC and enhanced its long-term physical stability. All the NLC formulations were found to significantly increase skin hydration compared to the untreated controls within 7 days. All NLC formulations exhibited occlusive properties as they reduced the transepidermal water loss within 7 days. This effect was more pronounced with the addition of propylene glycol or lecithin into an NLC formulation, whereby at least 60% reduction in transepidermal water loss was observed. Conclusion NLCs with high lipid content, solid lipid content, phospholipid, and lecithin are a highly effective cosmetic delivery system for cosmetic topical applications that are designed to boost skin hydration. PMID:23293516

Current Challenges and Future of Lipid nanoparticles formulations for topical drug application to oral mucosa, skin, and eye.

PubMed

Guilherme, Viviane A; Ribeiro, Ligia N M; Tofoli, Giovana Radomille; Franz-Montan, Michelle; de Paula, Eneida; de Jesus, Marcelo Bispo

2017-11-21

Topical drug administration offers an attractive route with minimal invasiveness. It also avoids limitations of intravenous administration such as the first pass metabolism and presystemic elimination within the gastrointestinal tract. Furthermore, topical drug administration is safe, have few side effects, is easy to apply, and offers a fast onset of action. However, the development of effective topical formulations still represents a challenge for the desired effect to be reached, locally or systemically. Solid lipid nanoparticles and nanostructured lipid carriers are particular candidates to overcome the problem of topical drug administration. The nanometric particle size of lipid nanoparticles favors the physical adhesion to the skin or mucosal, what can also be attained with the formation of hybrid (nanoparticles/polymer) systems. In this review, we discuss the major challenges for lipid nanoparticles formulations for topical application to oral mucosa, skin, and eye, highlighting the strategies to improve the performance of lipid nanoparticles for topical applications. Next, we critically analyzed the in vitro and in vivo approaches used to evaluate lipid nanoparticles performance and toxicity. We addressed some major drawbacks related to lipid nanoparticle topical formulations and concluded the key points that have to be overcome to help them to reach the market in topical formulations to oral mucosa, skin and eye. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Technology of stable, prolonged-release eye-drops containing Cyclosporine A, distributed between lipid matrix and surface of the solid lipid microspheres (SLM).

PubMed

Wolska, Eliza; Sznitowska, Małgorzata

2013-01-30

The aim of this study was to prepare solid lipid microspheres (SLM) with incorporated Cyclosporine A (Cs), suitable for ocular application. For this purpose, SLM were formulated by using different lipids and three different nonionic surfactants. The SLM were produced using a hot emulsification method. The SLM dispersions contained 10, 20 or 30% of lipid (w/w) and up to 2% (w/w) of Cs. The size of the microspheres with Cs ranged from 1 to 15 μm. Physically stable SLM with Cs were prepared using Compritol, as a lipid matrix, and Tween 80, as a surfactant. In contrast, dispersion with Precirol alone, formed semi-solid gels during storage, while in formulations with Precirol and Miglyol, crystals of Cs were observed. In vitro release profile of Compritol formulations showed that 40% of Cs is released within 1h, while the release of the following 40% takes more time, depending on lipid content in the formulations. The large part of Cs, added to SLM formulations (from 45 to 80%), was found on the surface of microparticles, but no drug crystallization occurred during a long-term storage. Copyright © 2012 Elsevier B.V. All rights reserved.

Optimization and characterization of stable lipid-based, oxygen-filled microbubbles by mixture design.

PubMed

Polizzotti, Brian D; Thomson, Lindsay M; O'Connell, Daniel W; McGowan, Francis X; Kheir, John N

2014-08-01

Tissue hypoxia is a final common pathway that leads to cellular injury and death in a number of critical illnesses. Intravenous injections of self-assembling, lipid-based oxygen microbubbles (LOMs) can be used to deliver oxygen gas, preventing organ injury and death from systemic hypoxemia. However, current formulations exhibit high polydispersity indices (which may lead to microvascular obstruction) and poor shelf-lives, limiting the translational capacity of LOMs. In this study, we report our efforts to optimize LOM formulations using a mixture response surface methodology (mRSM). We study the effect of changing excipient proportions (the independent variables) on microbubble diameter and product loss (the dependent variables). By using mRSM analysis, the experimental data were fit using a reduced Scheffé linear mixture model. We demonstrate that formulations manufactured from 1,2-distearoyl-sn-glycero-3-phosphocholine, corn syrup, and water produce micron-sized microbubbles with low polydispersity indices, and decreased product loss (relative to previously described formulations) when stored at room temperature over a 30-day period. Optimized LOMs were subsequently tested for their oxygen-releasing ability and found to have similar release kinetics as prior formulations. © 2014 Wiley Periodicals, Inc.

Oral vaccination of guinea pigs with a Mycobacterium bovis bacillus Calmette-Guerin vaccine in a lipid matrix protects against aerosol infection with virulent M. bovis.

PubMed

Clark, Simon; Cross, Martin L; Nadian, Allan; Vipond, Julia; Court, Pinar; Williams, Ann; Hewinson, R Glyn; Aldwell, Frank E; Chambers, Mark A

2008-08-01

Increased incidence of bovine tuberculosis (TB) in the United Kingdom caused by infection with Mycobacterium bovis is a cause of considerable economic loss to farmers and the government. The Eurasian badger (Meles meles) represents a wildlife source of recurrent M. bovis infections of cattle in the United Kingdom, and its vaccination against TB with M. bovis bacillus Calmette-Guérin (BCG) is an attractive disease control option. Delivery of BCG in oral bait holds the best prospect for vaccinating badgers over a wide geographical area. Using a guinea pig pulmonary challenge model, we evaluated the protective efficacy of candidate badger oral vaccines, based on broth-grown or ball-milled BCG, delivered either as aqueous suspensions or formulated in two lipids with differing fatty acid profiles (one being animal derived and the other being vegetable derived). Protection was determined in terms of increasing body weight after aerosol challenge with virulent M. bovis, reduced dissemination of M. bovis to the spleen, and, in the case of one oral formulation, restricted growth of M. bovis in the lungs. Only oral BCG formulated in lipid gave significant protection. These data point to the potential of the BCG-lipid formulation for further development as a tool for controlling tuberculosis in badgers.

Recommendations of the Oligonucleotide Safety Working Group's Formulated Oligonucleotide Subcommittee for the Safety Assessment of Formulated Oligonucleotide-Based Therapeutics.

PubMed

Marlowe, Jennifer L; Akopian, Violetta; Karmali, Priya; Kornbrust, Douglas; Lockridge, Jennifer; Semple, Sean

2017-08-01

The use of lipid formulations has greatly improved the ability to effectively deliver oligonucleotides and has been instrumental in the rapid expansion of therapeutic development programs using oligonucleotide drugs. However, the development of such complex multicomponent therapeutics requires the implementation of unique, scientifically sound approaches to the nonclinical development of these drugs, based upon a hybrid of knowledge and experiences drawn from small molecule, protein, and oligonucleotide therapeutic drug development. The relative paucity of directly applicable regulatory guidance documents for oligonucleotide therapeutics in general has resulted in the generation of multiple white papers from oligonucleotide drug development experts and members of the Oligonucleotide Safety Working Group (OSWG). The members of the Formulated Oligonucleotide Subcommittee of the OSWG have utilized their collective experience working with a variety of formulations and their associated oligonucleotide payloads, as well as their insights into regulatory considerations and expectations, to generate a series of consensus recommendations for the pharmacokinetic characterization and nonclinical safety assessment of this unique class of therapeutics. It should be noted that the focus of Subcommittee discussions was on lipid nanoparticle and other types of particulate formulations of therapeutic oligonucleotides and not on conjugates or other types of modifications of oligonucleotide structure intended to facilitate delivery.

Important role of phosphoramido linkage in imidazole-based dioleyl helper lipids for liposome stability and primary cell transfection.

PubMed

Mével, Mathieu; Haudebourg, Thomas; Colombani, Thibault; Peuziat, Pauline; Dallet, Laurence; Chatin, Benoît; Lambert, Olivier; Berchel, Mathieu; Montier, Tristan; Jaffrès, Paul-Alain; Lehn, Pierre; Pitard, Bruno

2016-01-01

To optimize synthetic gene delivery systems, there is a need to develop more efficient lipid formulations. Most cationic lipid formulations contain 'helper' neutral lipids because of their ability to increase DNA delivery, in particular by improving endosomal escape of DNA molecules via the pH-buffering effect of protonatable groups and/or fusion with the lipid bilayer of endosomes. We evaluated the influence of the linker structure between the two oleyl chains in the helper lipid on transfection efficiency in cell lines, as well as in primary cells (hepatocytes/cardiomyocytes). We reported the synthesis of two new pH-buffering imidazole helper lipids characterized by a polar headgroup containing one (compound 6) or two (compound 5) imidazole groups and two oleyl chains linked by an amide group. We studied their association with the aminoglycoside lipidic derivative dioleylsuccinylparomomycin (DOSP), which contains two oleyl chains linked to the aminoglycoside polar headgroup via an amide function. We compared the morphology and transfection properties of such binary liposomes of DOSP/5 and DOSP/6 with those of liposomes combining DOSP with another imidazole-based dioleyl helper lipid (MM27) in which a phosphoramido group acts as a linker between the two oleyl chains and imidazole function. The phosphoramido linker in the helper lipid induces a major difference in terms of morphology and resistance to decomplexation at physical pH for DOSP/helper lipid complexes. This hybrid dioleyl linker composition of DOSP/MM27 led to higher transfection efficiency in cell lines and in primary cells compared to complexes with homogeneous dioleyl linker. Copyright © 2015 John Wiley & Sons, Ltd.

Lipid nanocarriers: influence of lipids on product development and pharmacokinetics.

PubMed

Pathak, Kamla; Keshri, Lav; Shah, Mayank

2011-01-01

Lipid nanocarriers are on the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery. Owing to their size-dependent properties, lipid nanoparticles offer the possibility for development of new therapeutics and an alternative system to other colloidal counterparts for drug administration. An important point to be considered in the selection of a lipid for the carrier system is its effect on the properties of the nanocarrier and also its intended use, as different types of lipids differ in their nature. Researchers around the globe have tapped the potential of solid lipid nanoparticles (SLNs) in developing formulation(s) that can be administered by various routes such as oral, ocular, parenteral, topical, and pulmonary. Since the start of this millennium, a new generation of lipid nanoparticles, namely nanostructured lipid carriers (NLCs), lipid drug conjugates (LDCs), and pharmacosomes, has evolved that have the potential to overcome the limitations of SLNs. The current review article presents broad considerations on the influence of various types of lipids on the diverse characteristics of nanocarriers, encompassing their physicochemical, formulation, pharmacokinetic, and cytotoxic aspects.

“Click” Synthesis of Dextran Macrostructures for Combinatorial-Designed Self-Assembled Nanoparticles Encapsulating Diverse Anticancer Therapeutics

PubMed Central

Abeylath, Sampath C.; Amiji, Mansoor

2011-01-01

With the non-specific toxicity of anticancer drugs to healthy tissues upon systemic administration, formulations capable of enhanced selectivity in delivery to the tumor mass and cells are highly desirable. Based on the diversity of the drug payloads, we have investigated a combinatorial-designed strategy where the nano-sized formulations are tailored based on the physicochemical properties of the drug and the delivery needs. Individually functionalized C2 to C12 lipid-, thiol-, and poly(ethylene glycol) (PEG)-modified dextran derivatives were synthesized via “click” chemistry from O-pentynyl dextran and relevant azides. These functionalized dextrans in combination with anticancer drugs form nanoparticles by self-assembling in aqueous medium having PEG surface functionalization and intermolecular disulfide bonds. Using anticancer drugs with logP values ranging from −0.5 to 3.0, the optimized nanoparticles formulations were evaluated for preliminary cellular delivery and cytotoxic effects in SKOV3 human ovarian adenocarcinoma cells. The results show that with the appropriate selection of lipid-modified dextran, one can effectively tailor the self-assembled nano-formulation for intended therapeutic payload. PMID:21978947

Evaluating the predictability of the in vitro transfer model and in vivo rat studies as a surrogate to investigate the supersaturation and precipitation behaviour of different Albendazole formulations for humans.

PubMed

Ruff, Aaron; Holm, René; Kostewicz, Edmund S

2017-07-15

The present study investigated the ability of the in vitro transfer model and an in vivo pharmacokinetic study in rats to investigate the supersaturation and precipitation behaviour of albendazole (ABZ) relative to data from a human intestinal aspiration study reported in the literature. Two lipid based formulation systems, a hydroxypropyl-β-cyclodextrin (HPβCD) solution and the addition of a crystallization inhibitor (HPMC-E5) on the behaviour of ABZ was investigated. These formulations were investigated to represent differences in their ability to facilitate supersaturation within the small intestine. Overall, both the in vitro transfer model and the in vivo rat study were able to rank order the formulations (as aqueous suspension±HPMC

Lipid-formulated bcg as an oral-bait vaccine for tuberculosis: vaccine stability, efficacy, and palatability to brushtail possums (Trichosurus vulpecula) in New Zealand.

PubMed

Cross, Martin L; Henderson, Ray J; Lambeth, Matthew R; Buddle, Bryce M; Aldwell, Frank E

2009-07-01

Bovine tuberculosis (Tb), due to infection with virulent Mycobacterium bovis, represents a threat to New Zealand agriculture due to vectorial transmission from wildlife reservoir species, principally the introduced Australian brushtail possum (Trichosurus vulpecula). An oral-delivery wildlife vaccine has been developed to immunize possums against Tb, based on formulation of the human Tb vaccine (M. bovis BCG) in edible lipid matrices. Here BCG bacilli were shown to be stable in lipid matrix formulation for over 8 mo in freezer storage, for 7 wk under room temperature conditions, and for 3-5 wk under field conditions in a forest/pasture margin habitat (when maintained in weatherproof bait-delivery sachets). Samples of the lipid matrix were flavored and offered to captive possums in a bait-preference study: a combination of 10% chocolate powder with anise oil was identified as the most effective attractant/palatability combination. In a replicated field study, 85-100% of wild possums were shown to access chocolate-flavored lipid pellets, when baits were applied to areas holding approximately 600-800 possums/km(2). Finally, in a controlled vaccination/challenge study, chocolate-flavored lipid vaccine samples containing 10(8) BCG bacilli were fed to captive possums, which were subsequently challenged via aerosol exposure to virulent M. bovis: vaccine immunogenicity was confirmed, and protection was identified by significantly reduced postchallenge weight loss in vaccinated animals compared to nonvaccinated controls. These studies indicate that, appropriately flavored, lipid delivery matrices may form effective bait vaccines for the control of Tb in wildlife.

A targeted liposome delivery system for combretastatin A4: formulation optimization through drug loading and in vitro release studies.

PubMed

Nallamothu, Ramakrishna; Wood, George C; Kiani, Mohammad F; Moore, Bob M; Horton, Frank P; Thoma, Laura A

2006-01-01

Efficient liposomal therapeutics require high drug loading and low leakage. The objective of this study is to develop a targeted liposome delivery system for combretastatin A4 (CA4), a novel antivascular agent, with high loading and stable drug encapsulation. Liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, and distearoyl phosphoethanolamine-PEG-2000 conjugate (DSPE-PEG) were prepared by the lipid film hydration and extrusion process. Cyclic arginine-glycine-aspartic acid (RGD) peptides with affinity for alphav beta3-integrins overexpressed on tumor vascular endothelial cells were coupled to the distal end of polyethylene glycol (PEG) on the liposomes sterically stabilized with PEG (non-targeted liposomes; LCLs). Effect of lipid concentration, drug-to-lipid ratio, cholesterol, and DSPE-PEG content in the formulation on CA4 loading and its release from the liposomes was studied. Total liposomal CA4 levels obtained increased with increasing lipid concentration in the formulation. As the drug-to-lipid ratio increased from 10:100 to 20:100, total drug in the liposome formulation increased from 1.05+/-0.11 mg/mL to 1.55+/-0.13 mg/mL, respectively. When the drug-to-lipid ratio was further raised to 40:100, the total drug in liposome formulation did not increase, but the amount of free drug increased significantly, thereby decreasing the percent of entrapped drug. Increasing cholesterol content in the formulation decreased drug loading. In vitro drug leakage from the liposomes increased with increase in drug-to-lipid ratio or DSPE-PEG content in the formulation; whereas increasing cholesterol content of the formulation up to 30 mol-percent, decreased CA4 leakage from the liposomes. Ligand coupling to the liposome surface increased drug leakage as a function of ligand density. Optimized liposome formulation with 100 mM lipid concentration, 20:100 drug-to-lipid ratio, 30 mol-percent cholesterol, 4 mol-percent DSPE-PEG, and 1 mol-percent DSPE-PEG-maleimide content yielded 1.77+/-0.14 mg/mL liposomal CA4 with 85.70+/-1.71% of this being entrapped in the liposomes. These liposomes, with measured size of 123.84+/-41.23 nm, released no significant amount of the encapsulated drug over 48 h at 37 degrees C.

Protein-lipid nanohybrids as emerging platforms for drug and gene delivery: Challenges and outcomes.

PubMed

Gaber, Mohamed; Medhat, Waseem; Hany, Mark; Saher, Nourhan; Fang, Jia-You; Elzoghby, Ahmed

2017-05-28

Nanoparticulate drug delivery systems have been long used to deliver a vast range of drugs and bioactives owing to their ability to demonstrate novel physical, chemical, and/or biological properties. An exponential growth has spurred in research and development of these nanocarriers which led to the evolution of a great number of diverse nanosystems including liposomes, nanoemulsions, solid lipid nanoparticles (SLNs), micelles, dendrimers, polymeric nanoparticles (NPs), metallic NPs, and carbon nanotubes. Among them, lipid-based nanocarriers have made the largest progress whether commercially or under development. Despite this progress, these lipid-based nanocarriers suffer from several limitations that led to the development of many protein-coated lipid nanocarriers. To less extent, protein-based nanocarriers suffer from limitations that led to the fabrication of some lipid bilayer enveloping protein nanocarriers. This review discusses in-depth some limitations associated with the lipid-based or protein-based nanocarriers and the fruitful outcomes brought by protein-lipid hybridization. Also discussed are the various hybridization techniques utilized to formulate these protein-lipid nanohybrids and the mechanisms involved in the drug loading process. Copyright © 2017 Elsevier B.V. All rights reserved.

Cyclosporine a loaded solid lipid nanoparticles: optimization of formulation, process variable and characterization.

PubMed

Varia, Jigisha K; Dodiya, Shamsunder S; Sawant, Krutika K

2008-01-01

Solid lipid nanoparticles (SLNs) loaded with Cyclosporine A using glyceryl monostearate (GMS) and glyceryl palmitostearate (GPS) as lipid matrices were prepared by melt-homogenization using high-pressure homogenizer. Various process parameters such as homogenization pressure, homogenization cycles and formulation parameters such as ratio of drug: lipid, emulsifier: lipid and emulsifier: co-emulsifier were optimized using particle size and entrapment efficiencies as the dependent variables. The mean particle size of optimized batches of the GMS SLN and GPS SLN were found to be 131 nm and 158 nm and their entrapment efficiencies were 83 +/- 3.08% and 97 +/- 2.59% respectively. To improve the handling processing and stability of the prepared SLNs, the SLN dispersions were spray dried and its effect on size and reconstitution parameters were evaluated. The spray drying of SLNs did not significantly alter the size of SLNs and they exhibited good redispersibility. Solid state studies such as Infra Red Spectroscopy and Differential Scanning Calorimetry indicated absence of any chemical interaction between Cyclosporine A and the lipids. Scanning Electron Microscopy of optimized formulations showed spherical shape with smooth and non porous surface. In vitro release studies revealed that GMS based SLNs released the drug faster (41.12% in 20 hours) than GPS SLNs (7.958% in 20 hours). Release of Cyclosporine A from GMS SLN followed Higuchi equation better than first order while release from GPS SLN followed first order better than Higuchi model.

Nanostructured lipid carriers (NLCs) versus solid lipid nanoparticles (SLNs) for topical delivery of meloxicam.

PubMed

Khalil, Rawia M; Abd-Elbary, A; Kassem, Mahfoz A; Ghorab, Mamdouh M; Basha, Mona

2014-05-01

The aim of this study was to develop nanostructured lipid carriers (NLCs) as well as solid lipid nanoparticles (SLNs) and evaluate their potential in the topical delivery of meloxicam (MLX). The effect of various compositional variations on their physicochemical properties was investigated. Furthermore, MLX-loaded lipid nanoparticles-based hydrogels were formulated and the gels were evaluated as vehicles for topical application. The results showed that NLC and SLN dispersions had spherical shapes with an average size between 215 and 430 nm. High entrapment efficiency was obtained ranging from 61.94 to 90.38% with negatively charged zeta potential in the range of -19.1 to -25.7 mV. The release profiles of all formulations exhibited sustained release characteristics over 48 h and the release rates increased as the amount of liquid lipid in lipid core increased. Finally, Precirol NLC with 50% Miglyol® 812 and its corresponding SLN were incorporated in hydrogels. The gels showed adequate pH, non-Newtonian flow with shear-thinning behavior and controlled release profiles. The biological evaluation revealed that MLX-loaded NLC gel showed more pronounced effect compared to MLX-loaded SLN gel. It can be concluded that lipid nanoparticles represent promising particulate carriers for topical application.

Optimizing efficacy of Amphotericin B through nanomodification

PubMed Central

Barratt, Gillian; Bretagne, Stéphane

2007-01-01

The polyene antibiotic Amphotericin B (AMB) is one of the first therapeutic agents to be marketed commercially as nanosized formulations in which the drug is associated with lipids as liposomes or complexes. In this way, its renal toxicity is reduced and its therapeutic index improved. This review summarizes the particular properties of AMB which justify this type of formulation and the early work leading up to their development. The clinical results obtained in the treatment of fungal infections are reviewed and their activity against leishmaniasis is also evoked. Some newer formulations of AMB, based on both lipids and polymers are described. In particular, their potential by the oral and pulmonary routes are discussed. Finally, the development of targeted systems to deliver the drug to specific cells and tissues is considered. PMID:18019830

Solid Lipid Nanoparticle-Based Calix[n]arenes and Calix-Resorcinarenes as Building Blocks: Synthesis, Formulation and Characterization

PubMed Central

Montasser, Imed; Shahgaldian, Patrick; Perret, Florent; Coleman, Anthony W.

2013-01-01

Solid lipid nanoparticles (SLNs) have attracted increasing attention during recent years. This paper presents an overview about the use of calix[n]arenes and calix-resorcinarenes in the formulation of SLNs. Because of their specific inclusion capability both in the intraparticle spaces and in the host cavities as well as their capacity for functionalization, these colloidal nanostructures represent excellent tools for the encapsulation of different active pharmaceutical ingredients (APIs) in the area of drug targeting, cosmetic additives, contrast agents, etc. Various synthetic routes to the supramolecular structures will be given. These various routes lead to the formulation of the corresponding SLNs. Characterization, properties, toxicological considerations as well as numerous corresponding experimental studies and analytical methods will be also exposed and discussed. PMID:24196356

Assessing the heterogeneity level in lipid nanoparticles for siRNA delivery: size-based separation, compositional heterogeneity, and impact on bioperformance.

PubMed

Zhang, Jingtao; Pei, Yi; Zhang, Hangchun; Wang, Lei; Arrington, Leticia; Zhang, Ye; Glass, Angela; Leone, Anthony M

2013-01-07

A primary consideration when developing lipid nanoparticle (LNP) based small interfering RNA (siRNA) therapeutics is formulation polydispersity or heterogeneity. The level of heterogeneity of physicochemical properties within a pharmaceutical batch could greatly affect the bioperformance, quality, and ability of a manufacturer to consistently control and reproduce the formulations. This article studied the heterogeneity in the size, composition, and in vitro performance of siRNA containing LNPs, by conducting preparative scale fractionation using a sephacryl S-1000 based size-exclusion chromatography (SEC) method. Eight LNPs with size in the range of 60-190 nm were first evaluated by the SEC method for size polydispersity characterization, and it was found that LNPs in the range of 60-150 nm could be well-resolved. Two LNPs (LNP A and LNP B) with similar bulk properties were fractionated, and fractions were studied in-depth for potential presence of polydispersity in size, composition, and in vitro silencing, as well as cytotoxicity. LNP A was deemed to be monodisperse following results of a semipreparative SEC fractionation that showed similar size, chemical composition, in vitro silencing activity, and cytotoxicity across the fractions. Therefore, LNP A represents a relatively homogeneous formulation and offers less of a challenge in its pharmaceutical development. In contrast, LNP B fractions were shown to be significantly more polydisperse in size distribution. Interestingly, LNP B SEC fractions also exhibited profound compositional variations (e.g., 5 fold difference in N/P ratio and 3 fold difference in lipid composition) along with up to 40 fold differences in the in vitro silencing activity. The impact of LNP size and formulation composition on in vitro performance is also discussed. The present results demonstrate the complexity and potential for presence of heterogeneity in LNP-based siRNA drug products. This underscores the need for tools that yield a detailed characterization of LNP formulations. This capability in tandem with the pursuit of improved formulation and process design can lead to more facile development of LNP-based siRNA pharmaceuticals of higher quality.

Silica encapsulated lipid-based drug delivery systems for reducing the fed/fasted variations of ziprasidone in vitro.

PubMed

Dening, Tahnee J; Rao, Shasha; Thomas, Nicky; Prestidge, Clive A

2016-04-01

Ziprasidone is a poorly water-soluble antipsychotic drug that demonstrates low fasted state oral bioavailability and a clinically significant two-fold increase in absorption when dosed postprandially. Owing to significant compliance challenges faced by schizophrenic patients, a novel oral formulation of ziprasidone that demonstrates improved fasted state absorption and a reduced food effect is of major interest, and is therefore the aim of this research. Three lipid-based drug delivery systems (LBDDS) were developed and investigated: (a) a self-nanoemulsifying drug delivery system (SNEDDS), (b) a solid SNEDDS formulation, and (c) silica-lipid hybrid (SLH) microparticles. SNEDDS was developed using Capmul MCM® and Tween 80®, and solid SNEDDS was fabricated by spray-drying SNEDDS with Aerosil 380® silica nanoparticles as the solid carrier. SLH microparticles were prepared in a similar manner to solid SNEDDS using a precursor lipid emulsion composed of Capmul MCM® and soybean lecithin. The performance of the developed formulations was evaluated under simulated digesting conditions using an in vitro lipolysis model, and pure (unformulated) ziprasidone was used as a control. While pure ziprasidone exhibited the lowest rate and extent of drug solubilization under fasting conditions and a significant 2.4-fold increase in drug solubilization under fed conditions, all three LBDDS significantly enhanced the extent of drug solubilization under fasting conditions between 18- and 43-folds in comparison to pure drug. No significant difference in drug solubilization for the fed and fasted states was observed for the three LBDDS systems. To highlight the potential of LBDDS, mechanism(s) of action and various performance characteristics are discussed. Importantly, LBDDS are identified as an appropriate formulation strategy to explore further for the improved oral delivery of ziprasidone. Copyright © 2016 Elsevier B.V. All rights reserved.

Repaglinide-loaded solid lipid nanoparticles: effect of using different surfactants/stabilizers on physicochemical properties of nanoparticles.

PubMed

Ebrahimi, Hossein Ali; Javadzadeh, Yousef; Hamidi, Mehrdad; Jalali, Mohammad Barzegar

2015-09-21

Repaglinide is an efficient anti-diabetic drug which is prescribed widely as multi-dosage oral daily regimens. Due to the low compliance inherent to each multi-dosage regimen, development of prolonged-release formulations could enhance the overall drug efficacy in patient populations. Repaglinide-loaded solid lipid nanoparticles (SLNs) were developed and characterized in vitro. Various surfactants were used in this study during the nanocarrier preparation procedure and their corresponding effects on some physicochemical properties of SLNs such as size, zeta potential; drug loading parameters and drug release profiles was investigated. Stearic acid and glyceryl mono stearate (GMS) were used as lipid phase and phosphatidylcholin, Tween80, Pluronic F127, poly vinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) were used as surfactant/stabilizer. The results showed some variations between formulations; where the Tween80-based SLNs showed smallest size, the phosphatidylcholin-based SLNs indicated most prolonged drug release time and the highest loading capacity. SEM images of these formulations showed morphological variations and also confirmed the nanoscale size of these particles. The FTIR and DSC results demonstrated no interaction between drug and excipients. The invitro release profiles of different formulations were studied and observed slow release of drug from all formulations. However significant differences were found among them in terms of their initial burst release as well as the whole drug release profile. From fitting these data to various statistical models, the Peppas model was proposed as the best model to describe the statistical indices and, therefore, mechanism of drug release. The results of this study confirmed the effect of surfactant type on SLNs physicochemical properties such as morphological features, loading parameters, particle sizes and drug release kinetic. With respect to the outcome data, the mixture of phosphatidylcholin/Pluronic F127 was selected as the best surfactant/stabilizer to coat the lipid core comprising stearic acid and GMS.

Apparent lack of cross-reactivity for infusion-related reactions between two forms of lipid-based amphotericin B.

PubMed

Buckley, Mitchell S; Anderson, Clint S; Patel, Shardool A; Yerondopoulos, Melanie J; Wicks, Laura M; Martin, Mary T

2013-06-15

The case of a patient who experienced probable infusion-related reactions to amphotericin B lipid complex (ABLC) but tolerated continued amphotericin B therapy after a switch to an alternative lipid-based formulation is reported. A 28-year-old immunocompromised man with pneumonia, respiratory failure, and neutropenic fever was initiated on ABLC and other antibiotics for suspected invasive aspergillosis. Due to the patient's deteriorating renal function, the use of amphotericin B was deemed preferable to the standard therapy for invasive aspergillosis (voriconazole) even though he had experienced likely infusion-related reactions to ABLC on two prior occasions. During the infusion of ABLC, significant increases in the man's temperature, respiratory rate, systolic blood pressure, and heart rate were observed. Although those symptoms were suspected to be infusion related, it was decided that continuing amphotericin B therapy with an alternative lipid-based form of the drug was the best course of action. After the patient was switched to liposomal amphotericin B one day later, no further infusion-related adverse reactions were noted for the duration of therapy. While this case suggests that adverse reactions to one type of amphotericin B might not occur with the use of an alternative formulation, further research is needed to better define the potential for cross-reactivity among various forms of amphotericin B and related safe-infusion practices. A patient with invasive aspergillosis who experienced likely infusion- related reactions to ABLC was able to tolerate continued amphotericin B therapy after a switch to the liposomal formulation.

Identifying the Interaction of Vancomycin With Novel pH-Responsive Lipids as Antibacterial Biomaterials Via Accelerated Molecular Dynamics and Binding Free Energy Calculations.

PubMed

Ahmed, Shaimaa; Vepuri, Suresh B; Jadhav, Mahantesh; Kalhapure, Rahul S; Govender, Thirumala

2018-06-01

Nano-drug delivery systems have proven to be an efficient formulation tool to overcome the challenges with current antibiotics therapy and resistance. A series of pH-responsive lipid molecules were designed and synthesized for future liposomal formulation as a nano-drug delivery system for vancomycin at the infection site. The structures of these lipids differ from each other in respect of hydrocarbon tails: Lipid1, 2, 3 and 4 have stearic, oleic, linoleic, and linolenic acid hydrocarbon chains, respectively. The impact of variation in the hydrocarbon chain in the lipid structure on drug encapsulation and release profile, as well as mode of drug interaction, was investigated using molecular modeling analyses. A wide range of computational tools, including accelerated molecular dynamics, normal molecular dynamics, binding free energy calculations and principle component analysis, were applied to provide comprehensive insight into the interaction landscape between vancomycin and the designed lipid molecules. Interestingly, both MM-GBSA and MM-PBSA binding affinity calculations using normal molecular dynamics and accelerated molecular dynamics trajectories showed a very consistent trend, where the order of binding affinity towards vancomycin was lipid4 > lipid1 > lipid2 > lipid3. From both normal molecular dynamics and accelerated molecular dynamics, the interaction of lipid3 with vancomycin is demonstrated to be the weakest (∆G binding  = -2.17 and -11.57, for normal molecular dynamics and accelerated molecular dynamics, respectively) when compared to other complexes. We believe that the degree of unsaturation of the hydrocarbon chain in the lipid molecules may impact on the overall conformational behavior, interaction mode and encapsulation (wrapping) of the lipid molecules around the vancomycin molecule. This thorough computational analysis prior to the experimental investigation is a valuable approach to guide for predicting the encapsulation ability, drug release and further development of novel liposome-based pH-responsive nano-drug delivery system with refined structural and chemical features of potential lipid molecule for formulation development.

Efficient encapsulation of antisense oligonucleotides in lipid vesicles using ionizable aminolipids: formation of novel small multilamellar vesicle structures.

PubMed

Semple, S C; Klimuk, S K; Harasym, T O; Dos Santos, N; Ansell, S M; Wong, K F; Maurer, N; Stark, H; Cullis, P R; Hope, M J; Scherrer, P

2001-02-09

Typical methods used for encapsulating antisense oligodeoxynucleotides (ODN) and plasmid DNA in lipid vesicles result in very low encapsulation efficiencies or employ cationic lipids that exhibit unfavorable pharmacokinetic and toxicity characteristics when administered intravenously. In this study, we describe and characterize a novel formulation process that utilizes an ionizable aminolipid (1,2-dioleoyl-3-dimethylammonium propane, DODAP) and an ethanol-containing buffer system for encapsulating large quantities (0.15--0.25 g ODN/g lipid) of polyanionic ODN in lipid vesicles. This process requires the presence of up to 40% ethanol (v/v) and initial formulation at acidic pH values where the DODAP is positively charged. In addition, the presence of a poly(ethylene glycol)-lipid was required during the formulation process to prevent aggregation. The 'stabilized antisense-lipid particles' (SALP) formed are stable on adjustment of the external pH to neutral pH values and the formulation process allows encapsulation efficiencies of up to 70%. ODN encapsulation was confirmed by nuclease protection assays and (31)P NMR measurements. Cryo-electron microscopy indicated that the final particles consisted of a mixed population of unilamellar and small multilamellar vesicles (80--140 nm diameter), the relative proportion of which was dependent on the initial ODN to lipid ratio. Finally, SALP exhibited significantly enhanced circulation lifetimes in mice relative to free antisense ODN, cationic lipid/ODN complexes and SALP prepared with quaternary aminolipids. Given the small particle sizes and improved encapsulation efficiency, ODN to lipid ratios, and circulation times of this formulation compared to others, we believe SALP represent a viable candidate for systemic applications involving nucleic acid therapeutics.

Stability of total nutrient admixtures with lipid injectable emulsions in glass versus plastic packaging.

PubMed

Driscoll, David F; Silvestri, Anthony P; Bistrian, Bruce R; Mikrut, Bernard A

2007-02-15

The physical stability of two emulsions compounded as part of a total nutrient admixture (TNA) was studied in lipids packaged in either glass or plastic containers. Five weight-based adult TNA formulations that were designed to meet the full nutritional needs of adults with body weights between 40 and 80 kg were studied. Triplicate preparations of each TNA were assessed over 30 hours at room temperature by applying currently proposed United States Pharmacopeia (USP) criteria for mean droplet diameter, large-diameter tail, and globule-size distribution (GSD) for lipid injectable emulsions. In accordance with conditions set forth in USP chapter 729, the higher levels of volume-weighted percent of fat exceeding 5 microm (PFAT(5)) should not exceed 0.05% of the total lipid concentration. Significant differences were noted among TNA admixtures based on whether the lipid emulsion product was manufactured in glass or plastic. The plastic-contained TNAs failed the proposed USP methods for large-diameter fat globules in all formulations from the outset, and 60% had significant growth in large-diameter fat globules over time. In contrast, glass-contained TNAs were stable throughout and in all cases would have passed proposed USP limits. Certain lipid injectable emulsions packaged in plastic containers have baseline abnormal GSD profiles compared with those packaged in glass containers. When used to compound TNAs, the abnormal profile worsens and produces less stable TNAs than those compounded with lipid injectable emulsions packaged in glass containers.

Design, synthesis, and in vitro transfection biology of novel tocopherol based monocationic lipids: a structure-activity investigation.

PubMed

Kedika, Bhavani; Patri, Srilakshmi V

2011-01-27

Herein, we report on the design, synthesis, and in vitro gene delivery efficacies of five novel tocopherol based cationic lipids (1-5) in transfecting CHO, B16F10, A-549, and HepG2 cells. The in vitro gene transfer efficiencies of lipids (1-5) were evaluated by both β-galactosidase reporter gene expression and inverted fluorescent microscopic experiments. The results of the present structure-activity investigation convincingly demonstrate that the tocopherol based lipid with three hydroxyl groups in its headgroup region showed 4-fold better transfection efficiency than the commercial formulation. The results also demonstrate that these tocopherol based lipids may be targeted to liver. Transfection efficiency of all the relevant lipids was maintained even when the serum was present during the transfection conditions. The results indicated that the designed systems are quite capable of transferring the DNA into all four types of cells studied with low or no toxicity.

Effect of lipid types on physicochemical characteristics, stability and antioxidant activity of gamma-oryzanol-loaded lipid nanoparticles.

PubMed

Ruktanonchai, Uracha; Sakulkhu, Usawadee; Bejrapha, Piyawan; Opanasopit, Praneet; Bunyapraphatsara, Nuntavan; Junyaprasert, Varaporn; Puttipipatkhachorn, Satit

2009-11-01

In the present study gamma-oryzanol, an antioxidant, was incorporated into three different types of solid lipid: wax, triglycerides, a mixture of glycerides as solid lipid nanoparticles (SLN) and liquid lipid (Miglyol 812) as nanoemulsion (NE). Instability was found only from NE due to its significant increase in particle size and decreased entrapment efficiency (%EE) at a storage temperature of 45 degrees C. Solid lipid type in SLN plays an important role only on %EE, but not chemical stability. A decrease in crystallinity of SLN was observed with the incorporation of gamma-oryzanol and low recrystallization index were found with two glycerides-based SLN. The in vitro release studies demonstrated that a biphasic release pattern fitted well with the Higuchi model of SLN formulations. In comparison, nearly constant release was observed in NE comprised of similar composition. Wax-based SLN demonstrated the lowest cytotoxicity. NE, wax-based SLN and a mixture of glycerides-based SLN were considered to enhance the antioxidant activity of gamma-oryzanol.

Preparation of ultra-fine powders from polysaccharide-coated solid lipid nanoparticles and nanostructured lipid carriers by innovative nano spray drying technology.

PubMed

Wang, Taoran; Hu, Qiaobin; Zhou, Mingyong; Xue, Jingyi; Luo, Yangchao

2016-09-10

In this study, five polysaccharides were applied as natural polymeric coating materials to prepare solid lipid nanoparticles (SLN) and nanostructure lipid carriers (NLC), and then the obtained lipid colloidal particles were transformed to solid powders by the innovative nano spray drying technology. The feasibility and suitability of this new technology to generate ultra-fine lipid powder particles were evaluated and the formulation was optimized. The spray dried SLN powder exhibited the aggregated and irregular shape and dimension, but small, uniform, well-separated spherical powder particles of was obtained from NLC. The optimal formulation of NLC was prepared by a 20-30% oleic acid content with carrageenan or pectin as coating material. Therefore, nano spray drying technology has a potential application to produce uniform, spherical, and sub-microscale lipid powder particles when the formulation of lipid delivery system is appropriately designed. Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization, sensorial evaluation and moisturizing efficacy of nanolipidgel formulations.

PubMed

Estanqueiro, M; Conceição, J; Amaral, M H; Sousa Lobo, J M

2014-04-01

Nanostructured lipid carriers (NLC) have been widely studied for cosmetic and dermatological applications due to their favourable properties that include the formation of an occlusive film on the skin surface that reduces the transepidermal water loss (TEWL) and increase in water content in the skin which improves the appearance on healthy human skin and reduces symptoms of some skin disorders like eczema. The main objective of this study was the development of semisolid formulations based NLC with argan oil or jojoba oil as liquid lipids, by addition of Carbopol®934 or Carbopol®980 as gelling agents, followed by comparison between instrumental analysis and sensorial evaluation and in vivo efficacy evaluation. Nanostructured lipid carriers dispersions were produced by the ultrasound technique, and to obtain a semisolid formulation, gelling agents were dispersed in the aqueous dispersion. Particle size, polydispersity index and zeta potential were determined. Instrumental characterization was performed by rheological and textural analysis; the sensorial evaluation was also performed. Finally, skin hydration and TEWL were studied by capacitance and evaporimetry evaluation, respectively. Particles showed a nanometric size in all the analysed formulations. All the gels present pseudoplastic behaviour. There is a correspondence between the properties firmness and adhesiveness as determined by textural analysis and the sensory evaluation. The formulations that showed a greater increase in skin hydration also presented appropriate technological and sensorial attributes for skin application. Nanolipidgel formulations with the addition of humectants are promising systems for cosmetic application with good sensory and instrumental attributes and moisturizing efficacy.

Review: Lipid Formulations for the Adult and Pediatric Patient: Understanding the Differences

PubMed Central

Anez-Bustillos, Lorenzo; Dao, Duy T.; Baker, Meredith A.; Fell, Gillian L.; Puder, Mark; Gura, Kathleen M.

2017-01-01

Intravenous lipid emulsions (IVLE) provide essential fatty acids (FA) and are a dense source of energy in parenteral nutrition (PN). Parenterally administered lipid was introduced in the 17th century but plagued with side effects. The formulation of lipid emulsions later on made it a relatively safe component for administration to patients. Many ingredients are common to all IVLE, yet the oil source(s) and its (their) percentage(s) makes them different from each other. The oil used dictates how IVLE are metabolized and cleared from the body. The FA present in each type of oil provide unique beneficial and detrimental properties. This review provides an overview of IVLE and discuss factors that would help clinicians choose the optimal product for their patients. Elucidating the characteristics of each oil source over time has resulted in an evolution of the different formulations currently available. Emulsions have gone from being solely made with soybean oil, to being combined with medium-chain triglycerides (i.e., coconut oil), olive oil, and more recently, fish oil. Unfortunately, the lipid, among other constituents in PN formulations, has been associated with the development of liver disease. Lipid-sparing or lipid-reduction strategies have therefore been proposed to avoid these complications. The ideal IVLE would reverse or prevent essential FA deficiency without leading to complications, while simultaneously providing energy to facilitate normal growth and development. Modifications in their ingredients, formulation, and dosing have made IVLE a relatively safe component alone or when added to PN formulations. The ideal emulsion, however, has yet to be developed. PMID:27533942

Hansen solubility parameters (HSP) for prescreening formulation of solid lipid nanoparticles (SLN): in vitro testing of curcumin-loaded SLN in MCF-7 and BT-474 cell lines.

PubMed

Doktorovova, Slavomira; Souto, Eliana B; Silva, Amélia M

2018-01-01

Curcumin, a phenolic compound from turmeric rhizome (Curcuma longa), has many interesting pharmacological effects, but shows very low aqueous solubility. Consequently, several drug delivery systems based on polymeric and lipid raw materials have been proposed to increase its bioavailability. Solid lipid nanoparticles (SLN), consisting of solid lipid matrix and a surfactant layer can load poorly water-soluble drugs, such as curcumin, deliver them at defined rates and enhance their intracellular uptake. In the present work, we demonstrate that, despite the drug's affinity to lipids frequently used in SLN production, the curcumin amount loaded in most SLN formulations may be too low to exhibit anticancer properties. The predictive curcumin solubility in solid lipids has been thoroughly analyzed by Hansen solubility parameters, in parallel with the lipid-screening solubility tests for a range of selected lipids. We identified the most suitable lipid materials for curcumin-loaded SLN, producing physicochemically stable particles with high encapsulation efficiency (>90%). Loading capacity of curcumin in SLN allowed preventing the cellular damage caused by cationic SLN on MCF-7 and BT-474 cells but was not sufficient to exhibit drug's anticancer properties. But curcumin-loaded SLN exhibited antioxidant properties, substantiating the conclusions that curcumin's effect in cancer cells is highly dose dependent.

Low-fat frankfurters formulated with a healthier lipid combination as functional ingredient: microstructure, lipid oxidation, nitrite content, microbiological changes and biogenic amine formation.

PubMed

Delgado-Pando, Gonzalo; Cofrades, Susana; Ruiz-Capillas, Claudia; Solas, Maria Teresa; Triki, Mehdi; Jiménez-Colmenero, Francisco

2011-09-01

Oil (healthier lipid combination of olive, linseed and fish oils)-in-water emulsions stabilized with different protein systems (prepared with sodium caseinate (SC), soy protein isolate (SPI), and microbial transglutaminase (MTG)) were used as pork backfat replacers in low-fat frankfurters. Microstructure, lipid oxidation, nitrite content, microbiological changes and biogenic amine formation of frankfurters were analyzed and found to be affected by the type of oil-in-water emulsion and by chilling storage (2° C, 41 days). Although the lipid oxidation levels attained were low, replacement of animal fat by healthier oil combinations in frankfurter formulation did promote a slight increase in lipid oxidation. Residual nitrite was affected (P < 0.05) by formulation and storage. Only 51-61% of the added nitrite was detectable in the product after processing and 17-46% at the end of storage. The microbial population was low in all formulations during chilling storage. Spermine was the most abundant amine (19-20 mg/kg), but similar in level to all samples. Copyright © 2011 Elsevier Ltd. All rights reserved.

Co-localization of fluorescent labeled lipid nanoparticles with specifically tagged subcellular compartments by single particle tracking at low nanoparticle to cell ratios.

PubMed

Tiffany, Matthew; Szoka, Francis C

2016-11-01

We utilized quantitative high-resolution single particle tracking to study the internalization and endosomal sorting of lipid nanoparticles (LNPs) by HeLa cells in vitro to gain a better understanding of how cells process LNPs that are used for siRNA delivery. We compared the trafficking of three formulations that have been demonstrated to deliver siRNA into cells. They were composed of either a tritratable anionic lipid, formulation of cholesterol hemisuccinate (CHEMS), or a titratatable cationic lipid formulation of 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA) or a non-titratable cationic formulation lipid formulation of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). They also contained either a substantial percentage of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol and 5 mole percent 1,2-dimyristoyl-sn-glycerol-[methoxy(polyethylene glycol)-2000 (PEG-DMG). We optically measured the endosomal pH experienced by individual LNPs, observed the internalization pathways used and tracked the particles as they co-localized with fluorescent protein tags on compartment-specific proteins, during endosomal sorting to the lysosome. The data revealed significant differences in the accumulation in subcellular compartments among the three formulations, which help to explain the observed effects LNP composition exerts on in vitro delivery efficiency.

Liposome production by microfluidics: potential and limiting factors

PubMed Central

Carugo, Dario; Bottaro, Elisabetta; Owen, Joshua; Stride, Eleanor; Nastruzzi, Claudio

2016-01-01

This paper provides an analysis of microfluidic techniques for the production of nanoscale lipid-based vesicular systems. In particular we focus on the key issues associated with the microfluidic production of liposomes. These include, but are not limited to, the role of lipid formulation, lipid concentration, residual amount of solvent, production method (including microchannel architecture), and drug loading in determining liposome characteristics. Furthermore, we propose microfluidic architectures for the mass production of liposomes with a view to potential industrial translation of this technology. PMID:27194474

Liposome production by microfluidics: potential and limiting factors.

PubMed

Carugo, Dario; Bottaro, Elisabetta; Owen, Joshua; Stride, Eleanor; Nastruzzi, Claudio

2016-05-19

This paper provides an analysis of microfluidic techniques for the production of nanoscale lipid-based vesicular systems. In particular we focus on the key issues associated with the microfluidic production of liposomes. These include, but are not limited to, the role of lipid formulation, lipid concentration, residual amount of solvent, production method (including microchannel architecture), and drug loading in determining liposome characteristics. Furthermore, we propose microfluidic architectures for the mass production of liposomes with a view to potential industrial translation of this technology.

Optimization of controlled release nanoparticle formulation of verapamil hydrochloride using artificial neural networks with genetic algorithm and response surface methodology.

PubMed

Li, Yongqiang; Abbaspour, Mohammadreza R; Grootendorst, Paul V; Rauth, Andrew M; Wu, Xiao Yu

2015-08-01

This study was performed to optimize the formulation of polymer-lipid hybrid nanoparticles (PLN) for the delivery of an ionic water-soluble drug, verapamil hydrochloride (VRP) and to investigate the roles of formulation factors. Modeling and optimization were conducted based on a spherical central composite design. Three formulation factors, i.e., weight ratio of drug to lipid (X1), and concentrations of Tween 80 (X2) and Pluronic F68 (X3), were chosen as independent variables. Drug loading efficiency (Y1) and mean particle size (Y2) of PLN were selected as dependent variables. The predictive performance of artificial neural networks (ANN) and the response surface methodology (RSM) were compared. As ANN was found to exhibit better recognition and generalization capability over RSM, multi-objective optimization of PLN was then conducted based upon the validated ANN models and continuous genetic algorithms (GA). The optimal PLN possess a high drug loading efficiency (92.4%, w/w) and a small mean particle size (∼100nm). The predicted response variables matched well with the observed results. The three formulation factors exhibited different effects on the properties of PLN. ANN in coordination with continuous GA represent an effective and efficient approach to optimize the PLN formulation of VRP with desired properties. Copyright © 2015 Elsevier B.V. All rights reserved.

Preformulation and formulation development of a bioactive nitroaromatic compound

NASA Astrophysics Data System (ADS)

Sena, Camila F. A.; Apolinário, Lívia S.; Duarte, Jaqueline A.; dos Santos, Giovanna C.; Monteiro, Liziane O. F.; de Oliveira, Mônica C.; Leite, Elaine A.; de Oliveira, Renata B.

2017-11-01

The N-(butanoyloxyethyl)-4-(chloromethyl)-3-nitrobenzamide (BNB) is a nitroaromatic derivative with significant antitumor activity. Preformulation, forced degradation (distilled water, acid and base hydrolysis, oxidation, and light), and formulation studies were performed to investigate the chemical behavior of the molecule, the physicochemical properties, and the impact of formulation variables. Pharmacokinetic properties for BNB were estimated in silico. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) containing BNB were developed by a hot melt homogenization method for parenteral administration. Degradation studies demonstrated that this compound is sensitive to hydrolysis. BNB was predicted to have a favorable absorption, distribution, metabolism, and excretion profile. The nanocarriers developed were characterized for particle size (PS = 61 to 85 nm), polydispersity index (PI < 0.3), zeta potential (ZP = - 22 to - 34 mV), and encapsulation efficiency (EE = 66 to 90%) and remained stable for 30 days of storage. These studies indicated that BNB (inhibitory concentration (IC50) 21.8 μM) and BNB-loaded NLC (IC50 33.7 μM) showed moderate cytotoxicity against breast cancer cell line. Blank formulations did not induce cytotoxicity and BNB-loaded SLN was able to potentiate the action of BNB (lC50 12.4 μM). BNB is a promising antitumor agent and it is possible to modulate its activity based on the particle size of the formulation.

Novel siRNA formulation to effectively knockdown mutant p53 in osteosarcoma.

PubMed

Kundu, Anup K; Iyer, Swathi V; Chandra, Sruti; Adhikari, Amit S; Iwakuma, Tomoo; Mandal, Tarun K

2017-01-01

The tumor suppressor p53 plays a crucial role in the development of osteosarcoma. The primary objective of this study is to develop and optimize lipid based nanoparticle formulations that can carry siRNA and effectively silence mutant p53 in 318-1, a murine osteosarcoma cell line. The nanoparticles were composed of a mixture of two lipids (cholesterol and DOTAP) and either PLGA or PLGA-PEG and prepared by using an EmulsiFlex-B3 high pressure homogenizer. A series of studies that include using different nanoparticles, different amount of siRNAs, cell numbers, incubation time, transfection media volume, and storage temperature was performed to optimize the gene silencing efficiency. Replacement of lipids by PLGA or PLGA-PEG decreased the particle size and overall cytotoxicity. Among all lipid-polymer nanoformulations, nanoparticles with 10% PLGA showed highest mutant p53 knockdown efficiency while maintaining higher cell viability when a nanoparticle to siRNA ratio equal to 6.8:0.66 and 75 nM siRNA was used. With long term storage the mutant p53 knockdown efficiency decreased to a greater extent. This study warrants a future evaluation of this formulation for gene silencing efficiency of mutant p53 in tissue culture and animal models for the treatment of osteosarcoma.

Improving ex vivo skin permeation of non-steroidal anti-inflammatory drugs: enhancing extemporaneous transformation of liposomes into planar lipid bilayers.

PubMed

Vázquez-González, Martha L; Bernad, Rafael; Calpena, Ana C; Domènech, Oscar; Montero, M T; Hernández-Borrell, Jordi

2014-01-30

Transdermal delivery of active principles is a versatile method widely used in medicine. The main drawback for the transdermal route, however, is the low efficiency achieved in the absorption of many drugs, mostly due to the complexity of the skin barrier. To improve drug delivery through the skin, we prepared and characterized liposomes loaded with ibuprofen and designed pharmaceutical formulations based on the extemporaneous addition of penetration enhancer (PE) surfactants. Afterwards, permeation and release studies were carried out. According to the permeation studies, the ibuprofen liposomal formulation supplemented with PEs exhibited similar therapeutic effects, but at lower doses (20%) comparing with a commercial formulation used as a reference. Atomic force microscopy (AFM) was used to investigate the effect caused by PEs on the adsorption mechanism of liposomal formulations onto the skin. Non-fused liposomes, bilayers and multilayered lipid structures were observed. The transformation of vesicles into planar structures is proposed as a possible rationale for explaining the lower doses required when a liposome formulation is supplemented with surfactant PEs. Copyright © 2013 Elsevier B.V. All rights reserved.

New lipid formulation of octenidine dihydrochloride.

PubMed

Szostak, Kamila; Czogalla, Aleksander; Przybyło, Magdalena; Langner, Marek

2018-06-01

Octenidine dihydrochloride is an effective antiseptic compound which mode of action is based on destabilization plasma membrane of microorganisms. This ensures that microorganisms cannot develop the drug resistance in a straightforward way, as the entire cellular structure, rather than specific molecular target is affected. Since the octenidine is a hydrophobic compound, it requires organic solvent such as phenoxyethanol in order to be effectively administered. However, the presence of phenoxyethanol has strong irritating effect, particularly when applied on open wounds and mucous membranes. Phospholipids are known as neutral excipients free of side effects and in their aggregated form may serve as solvent for octenidine. In this article, we propose a new antiseptic formulation composed of equimolar ratio of lipids and octenidine. The resulting particles are ∼4 nm in diameter showing that their topology is different from that known for liposomes. The new formulation has proven to be equally effective as octenidine dihydrochloride formulation marketed under the name of Octenisept®. The main advantage of the new formulation is that it does not contain phenoxyethanol, which opens new possibilities for broader application spectrum of octenidine, including treatments of mucous membranes and open wounds.

A novel surfactant-free lipid-based formulation for improving oral bioavailability of loratadine using colloidal silicon dioxide as emulsifier and solid carrier.

PubMed

Huang, Ri; Tan, Yonggang; Shen, Lao; Wang, Tao; Quan, Dongqin

2018-05-08

The purpose of this study was to develop an innovative surfactant-free lipid-based formulation (LF) for improving oral bioavailability of loratadine based on using solid particles colloidal silicon dioxide (CSD) as emulsifier and solid carrier. Loratadine was dissolved in oil solution with the aid of co-solvent and LF were prepared by a simple adsorption and milling technique. The LF Powder was evaluated in terms of angle of repose and X-ray powder diffraction. After dispersing and emulsifying in water, the particle size and morphology were also characterized. In vitro dissolution and pharmacokinetic behavior in vivo were also studied. Orthogonal design indicated that the amount of CSD in formulations had a major and significant influence on emulsification. The optimal formulation showed LF with good flowability and without crystallization or deposition of loratadine in it. After dispersing in water, an emulsion with mean droplet size of 1.2μm was obtained. Although the dissolution of drug from LF was slower in vitro in acidic aqueous solution, pharmacokinetic studies in vivo showed that the bioavailability of loratadine increased 2.49-fold by CF compared to commercial tablet. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies

PubMed Central

Bhaskar, Kesavan; Anbu, Jayaraman; Ravichandiran, Velayutham; Venkateswarlu, Vobalaboina; Rao, Yamsani Madhusudan

2009-01-01

The aim of the study is to prepare aqueous dispersions of lipid nanoparticles – flurbiprofen solid lipid nanoparticles (FLUSLN) and flurbiprofen nanostructured lipid carriers (FLUNLC) by hot homogenization followed by sonication technique and then incorporated into the freshly prepared hydrogels for transdermal delivery. They are characterized for particle size, for all the formulations, more than 50% of the particles were below 300 nm after 90 days of storage at RT. DSC analyses were performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by TEM which revealed fairly spherical shape of the formulations. Further they were evaluated for in vitro drug release characteristics, rheological behaviour, pharmacokinetic and pharmacodynamic studies. The pharmacokinetics of flurbiprofen in rats following application of SLN gel (A1) and NLC gel (B1) for 24 h were evaluated. The Cmax of the B1 formulation was 38.67 ± 2.77 μg/ml, which was significantly higher than the A1 formulation (Cmax = 21.79 ± 2.96 μg/ml). The Cmax and AUC of the B1 formulation were 1.8 and 2.5 times higher than the A1 gel formulation respectively. The bioavailability of flurbiprofen with reference to oral administration was found to increase by 4.4 times when gel formulations were applied. Anti-inflammatory effect in the Carrageenan-induced paw edema in rat was significantly higher for B1 and A1 formulation than the orally administered flurbiprofen. Both the SLN and NLC dispersions and gels enriched with SLN and NLC possessed a sustained drug release over period of 24 h but the sustained effect was more pronounced with the SLN and NLC gel PMID:19243632

Minoxidil-loaded nanostructured lipid carriers (NLC): characterization and rheological behaviour of topical formulations.

PubMed

Silva, A C; Santos, D; Ferreira, D C; Souto, E B

2009-03-01

Lipid nanoparticles are used as biocompatible carriers for several types of drugs intended for pharmaceutical, cosmetic, and biochemical purposes. The wide range of lipids and surfactants available for the production of such particles turns these carriers highly suitable for distinct applications (topical, dermal and transdermal, parenteral, pulmonary, and oral administration). This work describes the development of a special type of lipid particles, namely nanostructured lipid carriers (NLC), for minoxidil as an alternative to conventional topical alcoholic solutions. NLC were composed of stearic acid and oleic acid, being the matrix stabilized with poloxamer 188 in aqueous dispersion. To develop a suitable topical formulation, lipid dispersions were further mixed with freshly prepared Carbopol or perfluorocarbon based hydrogels. Minoxidil-loaded NLC were approximately 250 nm in size before the entrapment within the gel network and remained below 500 nm after mixing with both types of hydrogels. The occurrence of minoxidil crystallization in the aqueous phase of lipid dispersions was discarded under analysis by light microscopy and by scanning electron microscopy. Differential scanning calorimetry was used to assess the recrystallization index (i.e. measure of the percentage of lipid matrix that is crystallized) of the particles, which was shown to be 62% for minoxidil-free dispersions and 68% for minoxidil-loaded NLC dispersions. Rheological analysis of hydrogels containing NLC dispersions showed typical pseudoplastic behaviour which makes them suitable for topical purposes.

Lipid based delivery and immuno-stimulatory systems: Master tools to combat leishmaniasis.

PubMed

Sabur, Abdus; Asad, Mohammad; Ali, Nahid

2016-11-01

Disease management of leishmaniasis is appalling due to lack of a human vaccine and the toxicity and resistance concerns with limited therapeutic drugs. The challenges in development of a safe vaccine for generation and maintenance of robust antileishmanial protective immunity through a human administrable route of immunization can be addressed through immunomodulation and targeted delivery. The versatility of lipid based particulate system for deliberate delivery of diverse range of molecules including immunomodulators, antigens and drugs have essentially found pivotal role in design of proficient vaccination and therapeutic strategies against leishmaniasis. The prospects of lipid based preventive and curative formulations for leishmaniasis have been highlighted in this review. Copyright © 2016. Published by Elsevier Inc.

Solid lipid nanoparticles as an efficient drug delivery system of olmesartan medoxomil for the treatment of hypertension.

PubMed

Pandya, Nilima T; Jani, Parva; Vanza, Jigar; Tandel, Hemal

2018-05-01

The aim of the current investigation was to develop solid lipid nanoparticles of olmesartan medoxomil using hot homogenization method to improve its oral bioavailability. Central composite design was applied to optimize the formulation variables; lipid X1 (Glyceryl monostearate) and surfactant X2 (Poloxamer: Tween 80). The particle sizes were in the nanometer range and spherical shaped for all prepared solid lipid nanoparticles formulations and the zeta potential absolute values were high, predicting good long-term stability. In vitro study of olmesartan loaded solid lipid nanoparticle exhibited controlled release profile for at least 24 h. The rate and extent of drug diffusion was studied using dialysis sac, rat's stomach and intestine tissues; study demonstrated that drug release from the solid lipid nanoparticles was significantly higher than drug suspension. In vivo pharmacokinetic study of olmesartan loaded solid lipid nanoparticles revealed higher Cmax of 1610 ng/mL, higher AUC of 15492.50 ng/mL and increased relative bioavailability by almost 2.3 folds compared to marketed formulation. These results clearly indicate that olmesartan loaded solid lipid nanoparticles are shown to have enhanced bioavailability and effective therapeutic result and thus would be an excellent way to treat hypertension. Hence, these solid lipid nanoparticles could represent as a great potential for a possible alternative to conventional oral formulation in the treatment of hypertension. Copyright © 2018 Elsevier B.V. All rights reserved.

Nanosomal Docetaxel Lipid Suspension: A Guide to Its Use in Cancer.

PubMed

McKeage, Kate

2017-04-01

Nanosomal docetaxel lipid suspension (NDLS) [DoceAqualip] is a novel formulation of docetaxel approved in India for the treatment of breast cancer, hormone-refractory prostate cancer, locally advanced squamous cell carcinoma of the head and neck, non-small cell lung cancer and advanced gastric adenocarcinoma. The lipid-based delivery system of NDLS eliminates the need for polysorbate 80 and ethanol, which are contained in the conventional docetaxel formulation and are associated with hypersensitivity reactions and infusion-related toxicities. Because of the diminished potential for NDLS to cause hypersensitivity reactions compared with conventional docetaxel, corticosteroid premedication is not required with NDLS. In a randomized trial in patients with pretreated, locally advanced or metastatic breast cancer, the overall response rate was numerically higher with NDLS than with conventional docetaxel, and post-dose adverse events in the NDLS group were considered manageable and most resolved without sequelae, despite the lack of corticosteroid premedication.

Lipid-core nanocapsules as a nanomedicine for parenteral administration of tretinoin: development and in vitro antitumor activity on human myeloid leukaemia cells.

PubMed

Ourique, A F; Azoubel, S; Ferreira, C V; Silva, C B; Marchiori, M C L; Pohlmann, A R; Guterres, S S; Beck, R C R

2010-06-01

Tretinoin-loaded conventional nanocapsules have showed a significant protection of this drug against UVC radiation. However, this formulation presents a limited stability on storage. We hypothesized that the association of tretinoin to lipid-core nanocapsules could increase the physicochemical stability of such formulations, focusing on the development of a reliable nanomedicine for parenteral administration. However, this advantage should still be accompanied by the known photoprotective effect of conventional polymeric nanocapsules against the exposure of tretinoin to UV radiation. Results showed that tretinoin-loaded lipid-core nanocapsules improved the physicochemical stability of formulations under storage, without changing their ability to protect tretinoin either against UVA or UVC radiation. In addition, the effect of nanoencapsulation on the antiproliferative and differentiation properties of tretinoin was studied on human myeloid leukemia cells (HL60 cells) showing that tretinoin-loaded lipid-core nanocapsules presents a longer antitumor efficiency compared to the free tretinoin. These results allow us to propose the current formulation (tretinoin-loaded lipid-core nanocapsules) as a promising parenteral nanomedicine for the treatment of acute promyelocytic leukaemia.

Formulation and Evaluation of Solid Lipid Nanoparticles of Ramipril

PubMed Central

Ekambaram, P; Abdul, Hasan Sathali A

2011-01-01

Solid lipid nanoparticles are typically spherical with an average diameter between 1 and 1000 nm. It is an alternative carrier system to tradition colloidal carriers, such as, emulsions, liposomes, and polymeric micro and nanoparticles. Ramipril is an antihypertensive agent used in the treatment of hypertension. Its oral bioavailability is 28% and it is rapidly excreted through the renal route. This drug has many side effects such as, postural hypotension, hyperkalemia, and angioedema, when given as an immediate dosage form. To overcome the side effects and to increase the bioavailability of ramipril, solid lipid nanoparticles of ramipril are prepared by using lipids (glyceryl monostearate and glyceryl monooleate) with stabilizers (tween 80, poloxamer 188, and span 20). The prepared formulations have been evaluated for entrapment efficiency, drug content, in-vitro drug release, particle size analysis, scanning electron spectroscopy, Fourier transform-infrared studies, and stability. A formulation containing glyceryl monooleate, stabilized with span 20 as surfactant showed prolonged drug release, smaller particle size, and narrow particle size distribution, as compared to other formulations with different surfactants and lipids. PMID:21897661

Optimizing flurbiprofen-loaded NLC by central composite factorial design for ocular delivery.

PubMed

Gonzalez-Mira, E; Egea, M A; Souto, E B; Calpena, A C; García, M L

2011-01-28

The purpose of this study was to design and optimize a new topical delivery system for ocular administration of flurbiprofen (FB), based on lipid nanoparticles. These particles, called nanostructured lipid carriers (NLC), were composed of a fatty acid (stearic acid (SA)) as the solid lipid and a mixture of Miglyol(®) 812 and castor oil (CO) as the liquid lipids, prepared by the hot high pressure homogenization method. After selecting the critical variables influencing the physicochemical characteristics of the NLC (the liquid lipid (i.e. oil) concentration with respect to the total lipid (cOil/L (wt%)), the surfactant and the flurbiprofen concentration, on particle size, polydispersity index and encapsulation efficiency), a three-factor five-level central rotatable composite design was employed to plan and perform the experiments. Morphological examination, crystallinity and stability studies were also performed to accomplish the optimization study. The results showed that increasing cOil/L (wt%) was followed by an enhanced tendency to produce smaller particles, but the liquid to solid lipid proportion should not exceed 30 wt% due to destabilization problems. Therefore, a 70:30 ratio of SA to oil (miglyol + CO) was selected to develop an optimal NLC formulation. The smaller particles obtained when increasing surfactant concentration led to the selection of 3.2 wt% of Tween(®) 80 (non-ionic surfactant). The positive effect of the increase in FB concentration on the encapsulation efficiency (EE) and its total solubilization in the lipid matrix led to the selection of 0.25 wt% of FB in the formulation. The optimal NLC showed an appropriate average size for ophthalmic administration (228.3 nm) with a narrow size distribution (0.156), negatively charged surface (-33.3 mV) and high EE (∼90%). The in vitro experiments proved that sustained release FB was achieved using NLC as drug carriers. Optimal NLC formulation did not show toxicity on ocular tissues.

Optimizing flurbiprofen-loaded NLC by central composite factorial design for ocular delivery

NASA Astrophysics Data System (ADS)

Gonzalez-Mira, E.; Egea, M. A.; Souto, E. B.; Calpena, A. C.; García, M. L.

2011-01-01

The purpose of this study was to design and optimize a new topical delivery system for ocular administration of flurbiprofen (FB), based on lipid nanoparticles. These particles, called nanostructured lipid carriers (NLC), were composed of a fatty acid (stearic acid (SA)) as the solid lipid and a mixture of Miglyol® 812 and castor oil (CO) as the liquid lipids, prepared by the hot high pressure homogenization method. After selecting the critical variables influencing the physicochemical characteristics of the NLC (the liquid lipid (i.e. oil) concentration with respect to the total lipid (cOil/L (wt%)), the surfactant and the flurbiprofen concentration, on particle size, polydispersity index and encapsulation efficiency), a three-factor five-level central rotatable composite design was employed to plan and perform the experiments. Morphological examination, crystallinity and stability studies were also performed to accomplish the optimization study. The results showed that increasing cOil/L (wt%) was followed by an enhanced tendency to produce smaller particles, but the liquid to solid lipid proportion should not exceed 30 wt% due to destabilization problems. Therefore, a 70:30 ratio of SA to oil (miglyol + CO) was selected to develop an optimal NLC formulation. The smaller particles obtained when increasing surfactant concentration led to the selection of 3.2 wt% of Tween® 80 (non-ionic surfactant). The positive effect of the increase in FB concentration on the encapsulation efficiency (EE) and its total solubilization in the lipid matrix led to the selection of 0.25 wt% of FB in the formulation. The optimal NLC showed an appropriate average size for ophthalmic administration (228.3 nm) with a narrow size distribution (0.156), negatively charged surface (-33.3 mV) and high EE (~90%). The in vitro experiments proved that sustained release FB was achieved using NLC as drug carriers. Optimal NLC formulation did not show toxicity on ocular tissues.

Process optimization and photostability of silymarin nanostructured lipid carriers: effect on UV-irradiated rat skin and SK-MEL 2 cell line.

PubMed

Singh, Pooja; Singh, Mahendra; Kanoujia, Jovita; Arya, Malti; Saraf, Shailendra K; Saraf, Shubhini A

2016-10-01

The objective of the present work was to formulate a novel stable delivery system which would not only overcome the solubility issue of silymarin, but also help to increase the therapeutic value by better permeation, anticancer action and reduced toxicity. This was envisaged through the recent developments in nanotechnology, combined with the activity of the phytoconstituent silymarin. A 2(3) full factorial design based on three independent variables was used for process optimization of nanostructured lipid carriers (NLC). Developed formulations were evaluated on the basis of particle size, morphology, in vitro drug release, photostability and cell line studies. Optimized silymarin-NLC was incorporated into carbopol gel and further assessed for rheological parameters. Stable behaviour in presence of light was proven by photostability testing of formulation. Permeability parameters were significantly higher in NLC as compared to marketed phytosome formulation. The NLC based gel described in this study showed faster onset, and prolonged activity up to 24 h and better action against edema as compared to marketed formulation. In case of anticancer activity of silymarin-NLC against SK-MEL 2 cell lines, silymarin-NLC proved to possess anticancer activity in a dose-dependent manner (10-80 μM) and induced apoptosis at 80 μM in SK-MEL 2 cancer cells. This work documents for the first time that silymarin can be formulated into nanostructured lipoidal carrier system for enhanced permeation, greater stability as well as anticancer activity for skin.

Production of solid lipid nanoparticles (SLN): scaling up feasibilities.

PubMed

Dingler, A; Gohla, S

2002-01-01

Solid lipid nanoparticles (SLN/Lipopearls) are widely discussed as a new colloidal drug carrier system. In contrast to polymeric systems, such as Polylactic copolyol microcapsules, these systems show with a good biocompatibility, if applied parenterally. The solid lipid matrices can be comprised of fats or waxes, and allow protection of incorporated active ingredients against chemical and physical degradation. The SLN can either be produced by 'hot homogenization' of melted lipids at elevated temperatures or by a 'cold homogenization' process. This paper deals with production technologies for SLN formulations, based on non-ethoxylated fat components for topical application and high pressure homogenization. Based on the chosen fat components, a novel and easy manufacturing and scaling-up method was developed to maintain chemical and physical integrity of the encapsulated active ingredients in the carrier.

Solid Lipid Nanoparticle Formulations of Docetaxel Prepared with High Melting Point Triglycerides: In Vitro and in Vivo Evaluation

PubMed Central

2015-01-01

Docetaxel (DCX) is a second generation taxane. It is approved by the U.S. Food and Drug Administration for the treatment of various types of cancer, including breast, non-small cell lung, and head and neck cancers. However, side effects, including those related to Tween 80, an excipient in current DCX formulations, can be severe. In the present study, we developed a novel solid lipid nanoparticle (SLN) composition of DCX. Trimyristin was selected from a list of high melting point triglycerides as the core lipid component of the SLNs, based on the rate at which the DCX was released from the SLNs and the stability of the SLNs. The trimyristin-based, PEGylated DCX-incorporated SLNs (DCX-SLNs) showed significantly higher cytotoxicity against various human and murine cancer cells in culture, as compared to DCX solubilized in a Tween 80/ethanol solution. Moreover, in a mouse model with pre-established tumors, the new DCX-SLNs were significantly more effective than DCX solubilized in a Tween 80/ethanol solution in inhibiting tumor growth without toxicity, likely because the DCX-SLNs increased the concentration of DCX in tumor tissues, but decreased the levels of DCX in major organs such as liver, spleen, heart, lung, and kidney. DCX-incorporated SLNs prepared with one or more high-melting point triglycerides may represent an improved DCX formulation. PMID:24621456

Role of medium-chain fatty acids in the emulsification mechanistics of self-micro-emulsifying lipid formulations.

PubMed

Hasan, Naser M Y

2014-12-01

The objective of the present study was to design and develop stable o/w microemulsions comprising Miglyol 812, Imwitor 988 and Tagat TO as a non ionic surfactant. This was based on particle size measurements and phase behavior studies. The empirical role of incorporating medium-chain mono/di-glycerides in the lipid matrix in the mechanistic processes of emulsification was also established in various simulating physiological conditions. The efficiency of self-emulsification was evaluated under conditions of varying key compositions in the lipid mixtures; oil, cosurfactant and surfactant. Droplet diameter was measured using laser diffraction and light scattering techniques. Equilibrium phase studies were performed and phase boundaries were determined for the lipid-water systems. Microemulsion systems were produced from blends of Miglyol 812, Imwitor 988 and Tagat TO. An optimized formulation consisted of {Miglyol 812/Imwitor 988} and Tagat TO spontaneously self-emulsified in water producing dispersions with droplet diameters of ∼50 nm. Phase equilibrium diagrams have revealed significant enhancement in the water-solubilized region (L2) without any presence of liquid crystalline materials. Potential SMEDDS formulations for the bioavailability enhancement of poorly water-soluble compounds were developed by mixing blends of {Miglyol 812/Imwitor 988} and Tagat TO as a non-ionic surfactant. 'Diffusion and stranding' appears to be the dominant mechanism of emulsification.

Natural lipids-based NLC containing lidocaine: from pre-formulation to in vivo studies.

PubMed

Ribeiro, Lígia N M; Breitkreitz, Márcia C; Guilherme, Viviane A; da Silva, Gustavo H R; Couto, Verônica M; Castro, Simone R; de Paula, Bárbara O; Machado, Daisy; de Paula, Eneida

2017-08-30

In a nanotechnological approach we have investigated the use of natural lipids in the preparation of nanostructured lipid carriers (NLC). Three different NLC composed of copaiba oil and beeswax, sweet almond oil and shea butter, and sesame oil and cocoa butter as structural matrices were optimized using factorial analysis; Pluronic® 68 and lidocaine (LDC) were used as the colloidal stabilizer and model encapsulated drug, respectively. The optimal formulations were characterized by different techniques (IR-ATR, DSC, and TEM), and their safety and efficacy were also tested. These nanocarriers were able to upload high amounts of the anesthetic with a sustained in vitro release profile for 24h. The physicochemical stability in terms of size (nm), PDI, zeta potential (mV), pH, nanoparticle concentration (particles/mL), and visual inspection was followed during 12months of storage at 25°C. The formulations exhibited excellent structural properties and stability. They proved to be nontoxic in vitro (cell viability tests with Balb/c 3T3 fibroblasts) and significantly improved the in vivo effects of LDC, over the heart rate of zebra fish larvae and in the blockage of sciatic nerve in mice. The results from this study support that the proper combination of natural excipients is promising in DDS, taking advantage of the biocompatibility, low cost, and diversity of lipids. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel analytical methods to assess the chemical and physical properties of liposomes.

PubMed

Kothalawala, Nuwan; Mudalige, Thilak K; Sisco, Patrick; Linder, Sean W

2018-08-01

Liposomes are used in commercial pharmaceutical formulations (PFs) and dietary supplements (DSs) as a carrier vehicle to protect the active ingredient from degradation and to increase the half-life of the injectable. Even as the commercialization of liposomal products has rapidly increased, characterization methodologies to evaluate physical and chemical properties of the liposomal products have not been well-established. Herein we develop rapid methodologies to evaluate chemical and selected physical properties of liposomal formulations. Chemical properties of liposomes are determined by their lipid composition. The lipid composition is evaluated by first screening of the lipids present in the sample using HPLC-ELSD followed by HPLC-MSMS analysis with high mass accuracy (<5 ppm), fragmentation pattern and lipid structure databases searching. Physical properties such as particle size and size distribution were investigated using Tunable Resistive Pulse Sensing (TRPS). The developed methods were used to analyze commercially available PFs and DSs. As results, PFs contain distinct number of lipids as indicated by the manufacture, but DSs were more complicated containing a large number of lipids belonging to different sub-classes. Commercially available liposomes have particles with wide size distribution based on size measurements performed by TRPS. The high mass accuracy as well as identification lipids using multiple fragment ions aided to accurately identify the lipids and differentiate them from other lipophilic molecules. The developed analytical methodologies were successfully adapted to measure the physiochemical properties of commercial liposomes. Copyright © 2018. Published by Elsevier B.V.

Skin penetration and photoprotection of topical formulations containing benzophenone-3 solid lipid microparticles prepared by the solvent-free spray-congealing technique.

PubMed

Martins, Rodrigo Molina; Siqueira, Silvia; Fonseca, Maria José Vieira; Freitas, Luis Alexandre Pedro

2014-01-01

Solid-lipid microparticles loaded with high amounts of the sunscreen UV filter benzophenone-3 were prepared by spray congealing with the objective of decreasing its skin penetration and evaluate whether the sunscreen's photoprotection were impaired by the microencapsulation process. The microparticles were produced using the natural lipids carnauba wax or bees wax and three different concentrations of benzophenone-3 (30, 50 and 70%) using spray congealing technique. The microparticles presented properties suitable for topical application, such as spherical morphology, high encapsulation efficiency (95.53-102.2%), average particle sizes between 28.5 and 60.0 µm with polydispersivities from 1.2 to 2.5. In studies of in vitro skin penetration and preliminary stability, formulations of gel cream containing carnauba wax solid lipid microparticles and 70% benzophenone-3 when compared to the formulation added of bees wax solid-lipid microparticles containing 70% benzophenone-3, was stable considering the several parameters evaluated and were able to decrease the penetration of the UV filter into pig skin. Moreover, the formulations containing solid lipid microparticles with 70% benzophenone-3 increased the photoprotective capacity of benzophenone-3 under UV irradiation. The results show that spray-congealed microparticles are interesting solid forms to decrease the penetration solar filters in the skin without compromising their photoprotection.

Improved pharmacokinetics and antihyperlipidemic efficacy of rosuvastatin-loaded nanostructured lipid carriers.

PubMed

Rizwanullah, Md; Amin, Saima; Ahmad, Javed

2017-01-01

In the present study, rosuvastatin calcium-loaded nanostructured lipid carriers were developed and optimized for improved efficacy. The ROS-Ca-loaded NLC was prepared using melt emulsification ultrasonication technique and optimized by Box-Behnken statistical design. The optimized NLC composed of glyceryl monostearate (solid lipid) and capmul MCM EP (liquid lipid) as lipid phase (3% w/v), poloxamer 188 (1%) and tween 80 (1%) as surfactant. The mean particle size, polydispersity index (PDI), zeta potential (ζ) and entrapment efficiency (%) of optimized NLC formulation was observed to be 150.3 ± 4.67 nm, 0.175 ± 0.022, -32.9 ± 1.36 mV and 84.95 ± 5.63%, respectively. NLC formulation showed better in vitro release in simulated intestinal fluid (pH 6.8) than API suspension. Confocal laser scanning showed deeper permeation of formulation across rat intestine compared to rhodamine B dye solution. Pharmacokinetic study on female albino Wistar rats showed 5.4-fold increase in relative bioavailability with NLC compared to API suspension. Optimized NLC formulation also showed significant (p < 0.01) lipid lowering effect in hyperlipidemic rats. Therefore, NLC represents a great potential for improved efficacy of ROS-Ca after oral administration.

Optimization of drug loading to improve physical stability of paclitaxel-loaded long-circulating liposomes.

PubMed

Kannan, Vinayagam; Balabathula, Pavan; Divi, Murali K; Thoma, Laura A; Wood, George C

2015-01-01

The effect of formulation and process parameters on drug loading and physical stability of paclitaxel-loaded long-circulating liposomes was evaluated. The liposomes were prepared by hydration-extrusion method. The formulation parameters such as total lipid content, cholesterol content, saturated-unsaturated lipid ratio, drug-lipid ratio and process parameters such as extrusion pressure and number of extrusion cycles were studied and their impact on drug loading and physical stability was evaluated. A proportionate increase in drug loading was observed with increase in the total phospholipid content. Cholesterol content and saturated lipid content in the bilayer showed a negative influence on drug loading. The short-term stability evaluation of liposomes prepared with different drug-lipid ratios demonstrated that 1:60 as the optimum drug-lipid ratio to achieve a loading of 1-1.3 mg/mL without the risk of physical instability. The vesicle size decreased with an increase in the extrusion pressure and number of extrusion cycles, but no significant trends were observed for drug loading with changes in process pressure or number of cycles. The optimization of formulation and process parameters led to a physically stable formulation of paclitaxel-loaded long-circulating liposomes that maintain size, charge and integrity during storage.

Nanosized soy phytosome-based thermogel as topical anti-obesity formulation: an approach for acceptable level of evidence of an effective novel herbal weight loss product.

PubMed

El-Menshawe, Shahira F; Ali, Adel A; Rabeh, Mohamed A; Khalil, Nermeen M

2018-01-01

Herbal supplements are currently available as a safer alternative to manage obesity, which has become a rising problem over the recent years. Many chemical drugs on the market are designed to prevent or manage obesity but high cost, low efficacy, and multiple side effects limit its use. Nano lipo-vesicles phytosomal thermogel of Soybean, Glycine max ( L .) Merrill, was formulated and evaluated in an attempt to investigate its anti-obesity action on body weight gain, adipose tissue size, and lipid profile data. Three different techniques were used to prepare phytosome formulations including solvent evaporation, cosolvency, and salting out. The optimized phytosome formulation was then selected using Design Expert ® (version 7.0.0) depending on the highest entrapment efficiency, minimum particle size (PS), and maximum drug release within 2 hours as responses for further evaluation. The successful phytosome complex formation was investigated by means of Fourier-transform infrared spec troscopy and determination of PS and zeta potential. Phytosome vesicles' shape was evaluated using transmission electron microscope to ensure its spherical shape. After characterization of the optimized phytosome formulation, it was incorporated into a thermogel formulation. The obtained phytosomal thermogel formulation was evaluated for its clarity, homogeneity, pH, and gel transformation temperature besides rheology behavior and permeation study. An in vivo study was done to investigate the anti-weight-gain effect of soy phytosomal ther mogel. EE was found to be >99% for all formulations, PS ranging from 51.66-650.67 while drug release was found to be (77.61-99.78) in range. FTIR and TEM results confirmed the formation of phytosome complex. In vivo study showed a marked reduction in body weight, adipose tissue weight and lipid profile. Concisely, soy phytosomal thermogel was found to have a local anti-obesity effect on the abdomen of experimental male albino rats with a slight systemic effect on the lipid profile data.

Pluronic-Functionalized Silica-Lipid Hybrid Microparticles: Improving the Oral Delivery of Poorly Water-Soluble Weak Bases.

PubMed

Rao, Shasha; Richter, Katharina; Nguyen, Tri-Hung; Boyd, Ben J; Porter, Christopher J H; Tan, Angel; Prestidge, Clive A

2015-12-07

A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.

Lipid-based colloidal carriers for peptide and protein delivery – liposomes versus lipid nanoparticles

PubMed Central

Martins, Susana; Sarmento, Bruno; Ferreira, Domingos C; Souto, Eliana B

2007-01-01

This paper highlights the importance of lipid-based colloidal carriers and their pharmaceutical implications in the delivery of peptides and proteins for oral and parenteral administration. There are several examples of biomacromolecules used nowadays in the therapeutics, which are promising candidates to be delivered by means of liposomes and lipid nanoparticles, such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). Several production procedures can be applied to achieve a high association efficiency between the bioactives and the carrier, depending on the physicochemical properties of both, as well as on the production procedure applied. Generally, this can lead to improved bioavailability, or in case of oral administration a more consistent temporal profile of absorption from the gastrointestinal tract. Advantages and drawbacks of such colloidal carriers are also pointed out. This article describes strategies used for formulation of peptides and proteins, methods used for assessment of association efficiency and practical considerations regarding the toxicological concerns. PMID:18203427

Controlling Release of Integral Lipid Nanoparticles Based on Osmotic Pump Technology.

PubMed

Tian, Zhiqiang; Yu, Qin; Xie, Yunchang; Li, Fengqian; Lu, Yi; Dong, Xiaochun; Zhao, Weili; Qi, Jianping; Wu, Wei

2016-08-01

To achieve controlled release of integral nanoparticles by the osmotic pump strategy using nanostructured lipid carriers (NLCs) as model nanoparticles. NLCs was prepared by a hot-homogenization method, transformed into powder by lyophilization, and formulated into osmotic pump tablets (OPTs). Release of integral NLCs was visualized by live imaging after labeling with a water-quenching fluorescent probe. Effects of formulation variables on in vitro release characteristics were evaluated by measuring the model drug fenofibrate. Pharmacokinetics were studied in beagle dogs using the core tablet and a micronized fenofibrate formulation as references. NLCs are released through the release orifices of the OPTs as integral nanoparticles. Near zero-order kinetics can be achieved by optimizing the influencing variables. After oral administration, decreased C max and steady drug levels for as long as over 24 h are observed. NLC-OPTs show an oral bioavailability of the model drug fenofibrate similar to that of the core tablets, which is about 1.75 folds that of a fast-release formulation. Controlled release of integral NLCs is achieved by the osmotic pump strategy.

Fat emulsions based on structured lipids (1,3-specific triglycerides): an investigation of the in vivo fate.

PubMed

Hedeman, H; Brøndsted, H; Müllertz, A; Frokjaer, S

1996-05-01

Structured lipids (1,3-specific triglycerides) are new chemical entities made by enzymatic transesterification of the fatty acids in the 1,3 positions of the triglyceride. The purpose of this study is to characterize structured lipids with either short chain fatty acids or medium chain fatty acids in the 1,3 positions with regard to their hydrophobicity, and investigate the in vivo fate in order to evaluate the potential of structured lipids as core material in fat emulsions used as parenteral drug delivery system. The lipids were characterized by employing reversed phase high performance liquid chromatography. The biodistribution of radioactively labeled emulsions was studied in rats. By employing high performance liquid chromatography a rank order of the hydrophobicities of the lipids could be given, with the triglycerides containing long chain fatty acids being the most hydrophobic and the structured lipid with short chain fatty acids in the 1,3 positions the least. When formulated as fat emulsions, the emulsion based on structured lipids with short fatty acids in the 1,3 positions was removed slower from the general blood circulation compared to emulsions based on lipids with long chain fatty acids in the 1,3 positions. The type of core material influences the in vivo circulation time of fat emulsions.

Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and future directions

PubMed Central

Jensen, Gordon L.; Koletzko, Berthold V.; Singer, Pierre; Wanten, Geert J. A.

2010-01-01

Background Energy deficit is a common and serious problem in intensive care units and is associated with increased rates of complications, length of stay, and mortality. Parenteral nutrition (PN), either alone or in combination with enteral nutrition, can improve nutrient delivery to critically ill patients. Lipids provide a key source of calories within PN formulations, preventing or correcting energy deficits and improving outcomes. Discussion In this article, we review the role of parenteral lipid emulsions (LEs) in the management of critically ill patients and highlight important biologic activities associated with lipids. Soybean-oil-based LEs with high contents of polyunsaturated fatty acids (PUFA) were the first widely used formulations in the intensive care setting. However, they may be associated with increased rates of infection and lipid peroxidation, which can exacerbate oxidative stress. More recently developed parenteral LEs employ partial substitution of soybean oil with oils providing medium-chain triglycerides, ω-9 monounsaturated fatty acids or ω-3 PUFA. Many of these LEs have demonstrated reduced effects on oxidative stress, immune responses, and inflammation. However, the effects of these LEs on clinical outcomes have not been extensively evaluated. Conclusions Ongoing research using adequately designed and well-controlled studies that characterize the biologic properties of LEs should assist clinicians in selecting LEs within the critical care setting. Prescription of PN containing LEs should be based on available clinical data, while considering the individual patient’s physiologic profile and therapeutic requirements. PMID:20072779

Self-micelle formation and the incorporation of lipid in the formulation affect the intestinal absorption of Panax notoginseng.

PubMed

Xiong, Jing; Guo, Jianxin; Huang, Luosheng; Meng, Boyu; Ping, Qineng

2008-08-06

The purpose of this research is to evaluate the effect of self-micelle formation and incorporation of lipid in the formulation on absorption of ginsenosides Rg1 and Rb1 from intestinal tract in rats. Ginsenosides Rg1 and Rb1 were extracted from Panax notoginseng saponins (PNS). The critical micellar concentration (CMC) of PNS in deionzied water was determined to be 0.339 mg/ml. At normal physiological ionic strengths, PNS was salted out from the solution above the CMC. The particle size of the micelle grows as PNS concentration increases. By in situ injection to a closed loop of the rat jejunum, AUC0-6h obtained after administration of low concentration solution (12 mg/ml) was 3.61 times for ginsenoside Rg1 and 3.84-folds for ginsenoside Rb1 compared with high concentration solution (120 mg/ml). The release rate of ginsenosides in aqueous medium was too slow to complete in 24h, especially for Rb1. The data suggested that the self-micelle formation tendency in ginsenosides might prevent them from permeation or absorption through the cell membrane of gastrointestinal (GI) tract. To inhibit the formation of micelles, lipid was incorporated in the PNS formulation. The intraduodenal bioavailability in rats showed that the bioavailability was enhanced remarkably relative to the aqueous solution. AUC 0-infinity of ginsenoside Rg1 and Rb1 in the lipid-based formulation were 207.52+/-53.95 and 1961.72+/-686.60 microg ml(-1) h, compared with 7.87+/-2.85 and 148.58+/-36.73 microg ml(-1) h, respectively from its aqueous solution. These findings suggested a new strategy to increase the absorption of amphiphilic saponins.

Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study.

PubMed

Shah, Nirmal V; Seth, Avinash K; Balaraman, R; Aundhia, Chintan J; Maheshwari, Rajesh A; Parmar, Ghanshyam R

2016-05-01

The objective of present work was to utilize potential of nanostructured lipid carriers (NLCs) for improvement in oral bioavailability of raloxifene hydrochloride (RLX). RLX loaded NLCs were prepared by solvent diffusion method using glyceryl monostearate and Capmul MCM C8 as solid lipid and liquid lipid, respectively. A full 3(2) factorial design was utilized to study the effect of two independent parameters namely solid lipid to liquid lipid ratio and concentration of stabilizer on the entrapment efficiency of prepared NLCs. The statistical evaluation confirmed pronounced improvement in entrapment efficiency when liquid lipid content in the formulation increased from 5% w/w to 15% w/w. Solid-state characterization studies (DSC and XRD) in optimized formulation NLC-8 revealed transformation of RLX from crystalline to amorphous form. Optimized formulation showed 32.50 ± 5.12 nm average particle size and -12.8 ± 3.2 mV zeta potential that impart good stability of NLCs dispersion. In vitro release study showed burst release for initial 8 h followed by sustained release up to 36 h. TEM study confirmed smooth surface discrete spherical nano sized particles. To draw final conclusion, in vivo pharmacokinetic study was carried out that showed 3.75-fold enhancements in bioavailability with optimized NLCs formulation than plain drug suspension. These results showed potential of NLCs for significant improvement in oral bioavailability of poorly soluble RLX.

Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study

PubMed Central

Shah, Nirmal V.; Seth, Avinash K.; Balaraman, R.; Aundhia, Chintan J.; Maheshwari, Rajesh A.; Parmar, Ghanshyam R.

2016-01-01

The objective of present work was to utilize potential of nanostructured lipid carriers (NLCs) for improvement in oral bioavailability of raloxifene hydrochloride (RLX). RLX loaded NLCs were prepared by solvent diffusion method using glyceryl monostearate and Capmul MCM C8 as solid lipid and liquid lipid, respectively. A full 32 factorial design was utilized to study the effect of two independent parameters namely solid lipid to liquid lipid ratio and concentration of stabilizer on the entrapment efficiency of prepared NLCs. The statistical evaluation confirmed pronounced improvement in entrapment efficiency when liquid lipid content in the formulation increased from 5% w/w to 15% w/w. Solid-state characterization studies (DSC and XRD) in optimized formulation NLC-8 revealed transformation of RLX from crystalline to amorphous form. Optimized formulation showed 32.50 ± 5.12 nm average particle size and −12.8 ± 3.2 mV zeta potential that impart good stability of NLCs dispersion. In vitro release study showed burst release for initial 8 h followed by sustained release up to 36 h. TEM study confirmed smooth surface discrete spherical nano sized particles. To draw final conclusion, in vivo pharmacokinetic study was carried out that showed 3.75-fold enhancements in bioavailability with optimized NLCs formulation than plain drug suspension. These results showed potential of NLCs for significant improvement in oral bioavailability of poorly soluble RLX. PMID:27222747

Utilization of smoked salmon trim in extruded smoked salmon jerky.

PubMed

Kong, J; Dougherty, M P; Perkins, L B; Camire, M E

2012-06-01

During smoked salmon processing, the dark meat along the lateral line is removed before packaging; this by-product currently has little economic value. In this study, the dark meat trim was incorporated into an extruded jerky. Three formulations were processed: 100% smoked trim, 75% : 25% smoked trim : fresh salmon fillet, and 50% : 50% smoked trim : fresh salmon blends (w/w basis). The base formulation contained salmon (approximately 83.5%), tapioca starch (8%), pregelatinized potato starch (3%), sucrose (4%), salt (1.5%), sodium nitrate (0.02%), and ascorbyl palmitate (0.02% of the lipid content). Blends were extruded in a laboratory-scale twin-screw extruder and then hot-smoked for 5 h. There were no significant differences among formulations in moisture, water activity, and pH. Protein was highest in the 50 : 50 blend jerky. Ash content was highest in the jerky made with 100% trim. Total lipids and salt were higher in the 100% trim jerky than in the 50 : 50 blend. Hot smoking did not adversely affect docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) content in lipids from 100% smoked trim jerky. Servings of salmon jerky made with 75% and 100% smoked trim provided at least 500 mg of EPA and DHA. The 50 : 50 formulation had the highest Intl. Commission on Illumination (CIE) L*, a*, and b* color values. Seventy consumers rated all sensory attributes as between "like slightly" and "like moderately." With some formulation and processing refinements, lateral line trim from smoked salmon processors has potential to be incorporated into acceptable, healthful snack products. Dark meat along the lateral line is typically discarded by smoked salmon processors. This omega-3 fatty acid rich by-product can be used to make a smoked salmon jerky that provides a convenient source of these healthful lipids for consumers. © 2012 Institute of Food Technologists®

Nanostructured lipid carriers for the topical delivery of tretinoin.

PubMed

Ghate, Vivek M; Lewis, Shaila A; Prabhu, Prabhakara; Dubey, Akhilesh; Patel, Nilkumar

2016-11-01

Cosmetic skin care products currently in the market demonstrate an increasing trend toward antiaging products. Selection of the right formulation approach is the key to successful consumer acceptance. Nanostructured lipid carriers (NLCs) for dermal application can render added benefits to the formulation. Tretinoin a derivative of vitamin A, is a retinoid with anti-aging and anti-acne potential. The present study was aimed at formulating NLCs of tretinoin for reducing the skin irritation potential, increasing the drug loading capacity and prolonging the duration of action. The NLCs were optimized using the response surface methodology based on the particle size. Preliminary study, suggested the use of stearic acid, oleic acid, Tween 80 and Span 60 as solid lipid, liquid lipid and surfactants respectively formed a stable dispersion. NLCs of tretinoin were prepared by hot melt microemulsion and hot melt probe sonication methods. The properties of the optimized NLCs such as morphology, size, Zeta potential, stability and in vitro drug release were investigated. Tretinoin loaded NLCs in carbopol gel showed a sustained release pattern with isopropyl alcohol as the receptor fluid compared to the marketed gel using Franz diffusion cells. Eight prepared gel formulations tested were found to follow the Higuchi model of drug release. Stability studies indicated that the formulations stored at refrigeration and room temperature showed no noticeable differences in the drug content and release profiles in vitro, after a period of 4 weeks. In vivo skin irritation test on male Wister rats indicated no irritation or erythema after application of the NLCs loaded gel repeated for a period of 7 days compared to the application of marketed tretinoin gel which showed irritation and slight erythema within 3 days. The results showed that the irritation potential of tretinoin was reduced, the drug loading was increased and the drug release was prolonged by the incorporation into the NLCs. Copyright © 2016 Elsevier B.V. All rights reserved.

Lipid-Based Nanoparticles as Pharmaceutical Drug Carriers: From Concepts to Clinic

PubMed Central

Puri, Anu; Loomis, Kristin; Smith, Brandon; Lee, Jae-Ho; Yavlovich, Amichai; Heldman, Eli; Blumenthal, Robert

2010-01-01

In recent years, various nanotechnology platforms in the area of medical biology, including both diagnostics and therapy, have gained remarkable attention. Moreover, research and development of engineered multifunctional nanoparticles as pharmaceutical drug carriers have spurred exponential growth in applications to medicine in the last decade. Design principles of these nanoparticles, including nano-emulsions, dendrimers, nano-gold, liposomes, drug-carrier conjugates, antibody-drug complexes, and magnetic nanoparticles, are primarily based on unique assemblies of synthetic, natural, or biological components, including but not limited to synthetic polymers, metal ions, oils, and lipids as their building blocks. However, the potential success of these particles in the clinic relies on consideration of important parameters such as nanoparticle fabrication strategies, their physical properties, drug loading efficiencies, drug release potential, and, most importantly, minimum toxicity of the carrier itself. Among these, lipid-based nanoparticles bear the advantage of being the least toxic for in vivo applications, and significant progress has been made in the area of DNA/RNA and drug delivery using lipid-based nanoassemblies. In this review, we will primarily focus on the recent advances and updates on lipid-based nanoparticles for their projected applications in drug delivery. We begin with a review of current activities in the field of liposomes (the so-called honorary nanoparticles), and challenging issues of targeting and triggering will be discussed in detail. We will further describe nanoparticles derived from a novel class of amphipathic lipids called bolaamphiphiles with unique lipid assembly features that have been recently examined as drug/DNA delivery vehicles. Finally, an overview of an emerging novel class of particles (based on lipid components other than phospholipids), solid lipid nanoparticles and nanostructured lipid carriers will be presented. We conclude with a few examples of clinically successful formulations of currently available lipid-based nanoparticles. PMID:20402623

Relevance of Lipid-Based Products in the Management of Dry Eye Disease.

PubMed

Garrigue, Jean-Sébastien; Amrane, Mourad; Faure, Marie-Odile; Holopainen, Juha M; Tong, Louis

2017-11-01

Components of the ocular surface synergistically contribute to maintaining and protecting a smooth refractive layer to facilitate the optimal transmission of light. At the air-water interface, the tear film lipid layer (TFLL), a mixture of lipids and proteins, plays a key role in tear surface tension and is important for the physiological hydration of the ocular surface and for ocular homeostasis. Alterations in tear fluid rheology, differences in lipid composition, or downregulation of specific tear proteins are found in most types of ocular surface disease, including dry eye disease (DED). Artificial tears have long been a first line of treatment in DED and aim to replace or supplement tears. More recently, lipid-containing eye drops have been developed to more closely mimic the combination of aqueous and lipid layers of the TFLL. Over the last 2 decades, our understanding of the nature and importance of lipids in the tear film in health and disease has increased substantially. The aim of this article is to provide a brief overview of our current understanding of tear film properties and review the effectiveness of lipid-based products in the treatment of DED. Liposome lid sprays, emulsion eye drops, and other lipid-containing formulations are discussed.

Formulation and evaluation of voriconazole ophthalmic solid lipid nanoparticles in situ gel.

PubMed

Pandurangan, Dinesh Kumar; Bodagala, Prathima; Palanirajan, Vijayaraj Kumar; Govindaraj, Saravanan

2016-01-01

In the present investigation, solid lipid nanoparticles (SLNs)-loaded in situ gel with voriconazole drug was formulated. Further, the formulation was characterized for pH, gelling capacity, entrapment efficiency, in vitro drug release, drug content, and viscosity. Voriconazole is an antifungal drug used to treat various infections caused by yeast or other types of fungi. Film hydration technique was used to prepared SLNs from lecithin and cholesterol. Based on the entrapment efficiency 67.2-97.3% and drug release, the optimized formulation NF1 of SLNs was incorporated into in situ gels. The in situ gels were prepared using viscosity-enhancing polymers such as Carbopol and (hydroxypropyl)methyl cellulose (HPMC). Formulated SLN in situ gel formulations were characterized, which showed pH 4.9-7.1, drug content 65.69-96.3%, and viscosity (100 rpm) 120-620 cps. From the characterizations given above, F6 was optimized and evaluated for microbial assay and ocular irritation studies. Microbial assay was conducted by the cup-plate method using Candida albicans as the test organism. An ocular irritation study was conducted on albino rabbits. The results revealed that there was no ocular damage to the cornea, conjunctiva, or iris. Stability studies were carried out on the F6 formulation for 3 months, which showed that the formulation had good stability. These results indicate that the studied SLNs-loaded in situ gel is a promising vehicle for ocular delivery.

Scaling up feasibility of the production of solid lipid nanoparticles (SLN).

PubMed

Gohla, S H; Dingler, A

2001-01-01

Solid lipid nanoparticles (SLN/Lipopearls) are widely discussed as colloidal drug carrier system. In contrast to polymeric systems, such as polylactic copolyol capsules, these systems show up with a good biocompatibility, if applied parenterally. The solid lipid matrices can be comprised of fats or waxes and allow protection of incorporated active ingredients against chemical and physical degradation. The SLN can either be produced by "hot homogenisation" of melted lipids at elevated temperatures or a "cold homogenization" process. This paper deals with production technologies for SLN formulations, based on non-ethoxylated fat components for topical application and high pressure homogenization (APV Deutschland GmbH, D-Lübeck). Based on the chosen fat components, a novel and easy manufacturing and scaling up method was developed to maintain chemical and physical integrity of encapsulated active and carrier.

Lipid Nanoparticles: A novel approach for brain targeting.

PubMed

Shankar, Ravi; Joshi, Monika; Pathak, Kamla

2018-06-10

Brain is a delicate organ, separated from general circulation and is characterized by the presence of relatively impermeable Blood Brain Barrier (BBB). The BBB maintains homeostasis in the brain thus restricting the entrance of foreign bodies and several molecules from reaching the brain. As a result several promising molecules do not reach the target site and fail to produce in vivo response. Nevertheless, lipid nanoparticles are taken up readily by the brain because of their lipophilic nature. The bioacceptable and biodegradable nature of lipid nanoparticles makes them less toxic and suited for brain targeting. In the present review the BBB, mechanism of transport across the BBB, strategies to bypass the blood-brain barrier have been presented. The aptness of lipid nanoparticles for brain targeting has been highlighted. The proposed mechanism of uptake of the lipid nanoparticles, methods of prolonging the plasma retention and various methods of preparation for formulation of effective delivery systems for brain targeting have been included and dealt in this review. Lipid based formulations can be designated as the current and future generation of drug delivery systems as these possess tremendous potential to bypass BBB and reach the target site due to their small size and ability to dodge the reticular endothelial system. However, these nanostructures need to be investigated intensively to successfully reach the clinical trials stage. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Substitution of Standard Soybean Oil with Olive Oil-Based Lipid Emulsion in Parenteral Nutrition: Comparison of Vascular, Metabolic, and Inflammatory Effects

PubMed Central

Siqueira, Joselita; Smiley, Dawn; Newton, Christopher; Le, Ngoc-Anh; Gosmanov, Aidar R.; Spiegelman, Ronnie; Peng, Limin; Osteen, Samantha J.; Jones, Dean P.; Quyyumi, Arshed A.; Ziegler, Thomas R.

2011-01-01

Context: Soybean oil-based lipid emulsions are the only Food and Drug Administration-approved lipid formulation for clinical use in parenteral nutrition (PN). Recently concerns with its use have been raised due to the proinflammatory effects that may lead to increased complications because they are rich in ω-6 polyunsaturated fatty acids. Methods: This was a prospective, randomized, controlled, crossover study comparing the vascular, metabolic, immune, and inflammatory effects of 24-h infusion of PN containing soybean oil-based lipid emulsion (Intralipid), olive oil-based (ClinOleic), lipid free, and normal saline in 12 healthy subjects. Results: Soybean oil-PN increased systolic blood pressure compared with olive oil-PN (P < 0.05). Soybean oil PN reduced brachial artery flow-mediated dilatation from baseline (−23% at 4 h and −25% at 24 h, both P < 0.01); in contrast, olive oil PN, lipid free PN, and saline did not change either systolic blood pressure or flow-mediated dilatation. Compared with saline, soybean oil PN, olive oil PN, and lipid free PN similarly increased glucose and insulin concentrations during infusion (P < 0.05). There were no significant changes in plasma free fatty acids, lipid profile, inflammatory and oxidative stress markers, immune function parameters, or sympathetic activity between soybean oil- and olive oil-based lipid emulsions. Conclusion: The 24-h infusion of PN containing soybean oil-based lipid emulsion increased blood pressure and impaired endothelial function compared with PN containing olive oil-based lipid emulsion and lipid-free PN in healthy subjects. These vascular changes may have significant implications in worsening outcome in subjects receiving nutrition support. Randomized controlled trials with relevant clinical outcome measures are needed in patients receiving PN with olive oil-based and soybean oil-based lipid emulsions. PMID:21832112

Applications and limitations of lipid nanoparticles in dermal and transdermal drug delivery via the follicular route.

PubMed

Lauterbach, Andreas; Müller-Goymann, Christel C

2015-11-01

Lipid nanoparticles (LN) such as solid lipid nanoparticles (SLN) and nanolipid carriers (NLC) feature several claimed benefits for topical drug therapy including biocompatible ingredients, drug release modification, adhesion to the skin, and film formation with subsequent hydration of the superficial skin layers. However, penetration and permeation into and across deeper skin layers are restricted due to the barrier function of the stratum corneum (SC). As different kinds of nanoparticles provide the potential for penetration into hair follicles (HF) LN are applicable drug delivery systems (DDS) for this route in order to enhance the dermal and transdermal bioavailability of active pharmaceutical ingredients (API). Therefore, this review addresses the HF as application site, published formulations of LN which showed follicular penetration (FP), and characterization methods in order to identify and quantify the accumulation of API delivered by the LN in the HF. Since LN are based on lipids that appear in human sebum which is the predominant medium in HF an increased localization of the colloidal carriers as well as a promoted drug release may be assumed. Therefore, sebum-like lipid material and a size of less or equal 640 nm are appropriate specifications for FP of particulate formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

Quality by design case study 1: Design of 5-fluorouracil loaded lipid nanoparticles by the W/O/W double emulsion - Solvent evaporation method.

PubMed

Amasya, Gulin; Badilli, Ulya; Aksu, Buket; Tarimci, Nilufer

2016-03-10

With Quality by Design (QbD), a systematic approach involving design and development of all production processes to achieve the final product with a predetermined quality, you work within a design space that determines the critical formulation and process parameters. Verification of the quality of the final product is no longer necessary. In the current study, the QbD approach was used in the preparation of lipid nanoparticle formulations to improve skin penetration of 5-Fluorouracil, a widely-used compound for treating non-melanoma skin cancer. 5-Fluorouracil-loaded lipid nanoparticles were prepared by the W/O/W double emulsion - solvent evaporation method. Artificial neural network software was used to evaluate the data obtained from the lipid nanoparticle formulations, to establish the design space, and to optimize the formulations. Two different artificial neural network models were developed. The limit values of the design space of the inputs and outputs obtained by both models were found to be within the knowledge space. The optimal formulations recommended by the models were prepared and the critical quality attributes belonging to those formulations were assigned. The experimental results remained within the design space limit values. Consequently, optimal formulations with the critical quality attributes determined to achieve the Quality Target Product Profile were successfully obtained within the design space by following the QbD steps. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis, characterization, and evaluation of ionizable lysine-based lipids for siRNA delivery.

PubMed

Walsh, Colin L; Nguyen, Juliane; Tiffany, Matthew R; Szoka, Francis C

2013-01-16

We report the synthesis and characterization of a series of ionizable lysine-based lipids (ILL), novel lipids containing a lysine headgroup linked to a long-chain dialkylamine through an amide linkage at the lysine α-amine. These ILLs contain two ionizable amines and a carboxylate, and exhibit pH-dependent lipid ionization that varies with lipid structure. The synthetic scheme employed allows for the simple, orthogonal manipulation of lipids. This provides a method for the development of a compositionally diverse library with varying ionizable headgroups, tail structures, and linker regions. A focused library of four ILLs was synthesized to determine the impact of hydrophobic fluidity, lipid net charge, and lipid pK(a) on the biophysical and siRNA transfection characteristics of this new class of lipids. We found that manipulation of lipid structure impacts the protonation behavior, electrostatically driven membrane disruption, and ability to promote siRNA mediated knockdown in vitro. ILL-siRNA liposomal formulations were tested in a murine Factor VII model; however, no significant siRNA-mediated knockdown was observed. These results indicate that ILL may be useful in vitro transfection reagents, but further optimization of this new class of lipids is required to develop an effective in vivo siRNA delivery system.

Essential Oils Loaded in Nanosystems: A Developing Strategy for a Successful Therapeutic Approach

PubMed Central

Bilia, Anna Rita; Guccione, Clizia; Isacchi, Benedetta; Righeschi, Chiara; Firenzuoli, Fabio; Bergonzi, Maria Camilla

2014-01-01

Essential oils are complex blends of a variety of volatile molecules such as terpenoids, phenol-derived aromatic components, and aliphatic components having a strong interest in pharmaceutical, sanitary, cosmetic, agricultural, and food industries. Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, and other medicinal properties such as analgesic, sedative, anti-inflammatory, spasmolytic, and locally anaesthetic remedies. In this review their nanoencapsulation in drug delivery systems has been proposed for their capability of decreasing volatility, improving the stability, water solubility, and efficacy of essential oil-based formulations, by maintenance of therapeutic efficacy. Two categories of nanocarriers can be proposed: polymeric nanoparticulate formulations, extensively studied with significant improvement of the essential oil antimicrobial activity, and lipid carriers, including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano- and microemulsions. Furthermore, molecular complexes such as cyclodextrin inclusion complexes also represent a valid strategy to increase water solubility and stability and bioavailability and decrease volatility of essential oils. PMID:24971152

Computational prediction of formulation strategies for beyond-rule-of-5 compounds.

PubMed

Bergström, Christel A S; Charman, William N; Porter, Christopher J H

2016-06-01

The physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non-traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of 'formulate-ability' during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Diazepam-loaded solid lipid nanoparticles: design and characterization.

PubMed

Abdelbary, Ghada; Fahmy, Rania H

2009-01-01

The aim of the present study was to investigate the feasibility of the inclusion of a water-insoluble drug (diazepam, DZ) into solid lipid nanoparticles (SLNs), which offer combined advantages of rapid onset and prolonged release of the drug. This work also describes a new approach to prepare suppositories containing DZ-loaded SLN dispersions, as potential drug carrier for the rectal route. Modified high-shear homogenization and ultrasound techniques were employed to prepare SLNs. The effect of incorporation of different concentrations of Compritol ATO 888 or Imwitor 900K and Poloxamer 188 or Tween 80 was investigated. Results showed that varying the type or concentration of lipid matrix or surfactant had a noticeable influence on the entrapment efficiencies, particle size, and release profiles of prepared SLNs. Differential scanning calorimetry and X-ray diffraction measurements showed that the majority of SLNs possessed less ordered arrangements of crystals than the corresponding bulk lipids, which was favorable for increasing the drug loading capacity. Transmission electron microscopy and laser diffractometry studies revealed that the prepared nanoparticles were round and homogeneous and 60% of the formulations were less than 500 nm. Additionally, SLN formulations showed significant (P < 0.05) prolonged release than DZ solution. The subsequent step encompassed the preparation and evaluation of SLN-based suppositories utilizing SLN formulations that illustrated optimal release profiles. The in vitro release of DZ from the suppositories prepared using DZ-loaded SLN dispersions (equivalent to 2 mg DZ) was significantly (P < 0.05) extended compared to suppositories containing 2 mg DZ free drug.

Pharmaceutical analysis of synthetic lipid A-based vaccine adjuvants in poly (D,L-lactic-co-glycolic acid) nanoparticle formulations.

PubMed

Hamdy, Samar; Haddadi, Azita; Somayaji, Vishwa; Ruan, David; Samuel, John

2007-08-15

The present study had two main objectives. First, was to compare the immune stimulatory effect of two synthetic lipid A analogues (7-acyl lipid A and pentaerythritol-based lipid A (PET lipid A)) on maturation/stimulation of bone marrow derived dendritic cells (DCs). Our second objective was to develop a liquid chromatography/mass spectrometry (LC-MS) method for the quantitative analysis of lipid A-based vaccine adjuvants. Treatment of immature DCs with 7-acyl lipid A and PET lipid A up regulated the surface expression of CD86 and CD40 molecules, and also induced similar profile of pro-inflammatory cytokine secretion. LC-MS analyses were performed using a Waters Micromass ZQ 4000 spectrometer, coupled to a Waters 2795 separations module with an autosampler. Calibration curves with R(2)>0.999 were constructed over the concentration range of 1.25-20 microg/ml for the solution of 7-acyl lipid A and PET lipid A. The method was tested in a 3 day validation protocol. The accuracy of the assay at different concentrations tested ranged from 89 to 108% and from 92 to 107% for 7-acyl lipid A and PET lipid A, respectively. The limit of quantification for both 7-acyl lipid A and PET lipid A was 1.25 microg/ml (signal/noise (S/N)) ratio >15:1. The sensitivity of the method (the limit of detection) was 0.35 and 0.15 ng for 7-acyl lipid A and PET lipid A, respectively (S/N ratio between 4:1 or 3:1). As a preliminary application, this method has been successfully applied to the determination of 7-acyl lipid A and PET lipid A content in poly (D,L-lactic-co-glycolic acid) nanoparticles (PLGA-NP).

Preparation and Evaluation of Montelukast Sodium Loaded Solid Lipid Nanoparticles

PubMed Central

Priyanka, K; Sathali, A Abdul Hasan

2012-01-01

Solid lipid nanoparticles (SLNs) are an alternative carrier system used to load the drug for targeting, to improve the bioavailability by increasing its solubility, and protecting the drug from presystemic metabolism. The avoidance of presystemic metabolism is due to the nano-metric size range, so that the liver cannot uptake the drug from the delivery system and is not metabolized by the liver. Montelukast sodium is an anti-asthmatic drug, because of its poor oral bioavailability, presystemic metabolism, and decreased half-life; it was chosen to formulate as the solid lipid nanoparticle (SLN) system by hot homogenization followed by an ultrasonication method, to overcome the above. Compritol ATO 888, stearic acid, and glyceryl monostearate were used as a lipid matrix and polyvinyl alcohol as a surfactant. The prepared formulations have been evaluated for entrapment efficiency, drug content, in vitro drug release, particle size analysis, scanning electron microscopy, Fourier transform-infrared studies (FT-IR), differential scanning calorimetry (DSC), and stability. Particle size analysis revealed that the SLN prepared from the higher melting point lipid showed a larger particle size and with increased carbon chain length of the fatty acids. Entrapment efficiency (EE) was ranging from 42% to 92%. In vitro release studies showed maximum cumulative drug release was obtained for F 1 (59.1%) containing stearic acid, and the lowest was observed for F 18 (28.1%) containing compritol ATO 888 after 12 h and all the formulations followed first-order release kinetics. FT-IR and DSC studies revealed no interaction between drug and lipids. Studies showed that increase in lipid concentration, increased particle size, EE, and maintained the sustained release of drug. Among all, compritol ATO 888 was chosen as the best lipid for formulating SLN because it had high EE and sustained the drug release. PMID:23112531

Role of cholesterol on the transfection barriers of cationic lipid/DNA complexes

NASA Astrophysics Data System (ADS)

Pozzi, Daniela; Cardarelli, Francesco; Salomone, Fabrizio; Marchini, Cristina; Amenitsch, Heinz; Barbera, Giorgia La; Caracciolo, Giulio

2014-08-01

Most lipid formulations need cholesterol for efficient transfection, but the precise motivation remains unclear. Here, we have investigated the effect of cholesterol on the transfection efficiency (TE) of cationic liposomes made of 1,2-dioleoyl-3-trimethylammonium-propane and dioleoylphosphocholine in Chinese hamster ovary cells. The transfection mechanisms of cholesterol-containing lipoplexes have been investigated by TE, synchrotron small angle X-ray scattering, and laser scanning confocal microscopy experiments. We prove that cholesterol-containing lipoplexes enter the cells using different endocytosis pathways. Formulations with high cholesterol content efficiently escape from endosomes and exhibit a lamellar-nonlamellar phase transition in mixture with biomembrane mimicking lipid formulations. This might explain both the DNA release ability and the high transfection efficiency. These studies highlight the enrichment in cholesterol as a decisive factor for transfection and will contribute to the rational design of lipid nanocarriers with superior TE.

Formulation and evaluation of metoclopramide solid lipid nanoparticles for rectal suppository.

PubMed

Mohamed, Radwa A; Abass, Haidy A; Attia, Mohamed A; Heikal, Ola A

2013-11-01

The purpose of this study was to formulate and characterize metoclopramide solid lipid nanoparticles (MCP-SLNs) and incorporating it into suppository bases for treatment of nausea and vomiting, produced with chemotherapeutic agents, using one dose per day. MCP-SLNs was prepared using high shear homogenization (hot homogenization) technique using different surfactants (tween 80, poloxamer 407, poloxamer 188 and cremophore) in two different concentrations (2.5% and 5%) then solid lipid nanoparticle (SLN), whose release percentage above 50%, was incorporated into suppository for treatment of nausea and vomiting. The prepared SLN and suppositories were then evaluated and characterized. Formulation of poloxamer 407 with compritol and drug (F9) produced highest in-vitro % release (80%). Transmission electron microscopy showed that SLN had round and spherical shape in form of solid dispersion or drug-enriched core. Particle size analysis of SLN showed a size range of 24.99-396.8 nm. Negative zeta potential proves complete drug entrapment. In-vivo study of MCP-SLN suppositories produced the same %GE as the market metoclopramide (MCP) suppository (Primperan) with sustained release effect. MCP-SLN suppositories (formula F) can reverse decrease in %GE because of emesis with sustained release effect. So it succeeded to be an alternative to MCP suppositories with no multiple dosing. © 2013 Royal Pharmaceutical Society.

Delivery of kinesin spindle protein targeting siRNA in solid lipid nanoparticles to cellular models of tumor vasculature

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ying, Bo; Campbell, Robert B., E-mail: robert.campbell@mcphs.edu

2014-04-04

Highlights: • siRNA-lipid nanoparticles are solid particles not lipid bilayers with aqueous core. • High, but not low, PEG content can prevent nanoparticle encapsulation of siRNA. • PEG reduces cellular toxicity of cationic nanoparticles in vitro. • PEG reduces zeta potential while improving gene silencing of siRNA nanoparticles. • Kinesin spindle protein can be an effective target for tumor vascular targeting. - Abstract: The ideal siRNA delivery system should selectively deliver the construct to the target cell, avoid enzymatic degradation, and evade uptake by phagocytes. In the present study, we evaluated the importance of polyethylene glycol (PEG) on lipid-based carriermore » systems for encapsulating, and delivering, siRNA to tumor vessels using cellular models. Lipid nanoparticles containing different percentage of PEG were evaluated based on their physical chemical properties, density compared to water, siRNA encapsulation, toxicity, targeting efficiency and gene silencing in vitro. siRNA can be efficiently loaded into lipid nanoparticles (LNPs) when DOTAP is included in the formulation mixture. However, the total amount encapsulated decreased with increase in PEG content. In the presence of siRNA, the final formulations contained a mixed population of particles based on density. The major population which contains the majority of siRNA exhibited a density of 4% glucose, and the minor fraction associated with a decreased amount of siRNA had a density less than PBS. The inclusion of 10 mol% PEG resulted in a greater amount of siRNA associated with the minor fraction. Finally, when kinesin spindle protein (KSP) siRNA was encapsulated in lipid nanoparticles containing a modest amount of PEG, the proliferation of endothelial cells was inhibited due to the efficient knock down of KSP mRNA. The presence of siRNA resulted in the formation of solid lipid nanoparticles when prepared using the thin film and hydration method. LNPs with a relatively modest amount of PEG can sufficiently encapsulate siRNA, improve cellular uptake and the efficiency of gene silencing.« less

Synthesis and evaluation of mesoporous carbon/lipid bilayer nanocomposites for improved oral delivery of the poorly water-soluble drug, nimodipine.

PubMed

Zhang, Yanzhuo; Zhao, Qinfu; Zhu, Wufu; Zhang, Lihua; Han, Jin; Lin, Qisi; Ai, Fengwei

2015-07-01

A novel mesoporous carbon/lipid bilayer nanocomposite (MCLN) with a core-shell structure was synthesized and characterized as an oral drug delivery system for poorly water-soluble drugs. The objective of this study was to investigate the potential of MCLN-based formulation to modulate the in vitro release and in vivo absorption of a model drug, nimodipine (NIM). NIM-loaded MCLN was prepared by a procedure involving a combination of thin-film hydration and lyophilization. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), specific surface area analysis, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were employed to characterize the NIM-loaded MCLN formulation. The effect of MCLN on cell viability was assessed using the MTT assay. In addition, the oral bioavailability of NIM-loaded MCLN in beagle dogs was compared with that of the immediate-release formulation, Nimotop®. Our results demonstrate that the NIM-loaded MCLN formulation exhibited a typical sustained release pattern. The NIM-loaded MCLN formulation achieved a greater degree of absorption and longer lasting plasma drug levels compared with the commercial formulation. The relative bioavailability of NIM for NIM-loaded MCLN was 214%. MCLN exhibited negligible toxicity. The data reported herein suggest that the MCLN matrix is a promising carrier for controlling the drug release rate and improving the oral absorption of poorly water-soluble drugs.

Application of Box-Behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: Optimization, in vitro release, ocular tolerance, and antibacterial activity.

PubMed

Baig, Mirza Salman; Ahad, Abdul; Aslam, Mohammed; Imam, Syed Sarim; Aqil, Mohd; Ali, Asgar

2016-04-01

The aim of the present study was to develop and optimize levofloxacin loaded solid lipid nanoparticles for the treatment of conjunctivitis. Box-Behnken experimental design was applied for optimization of solid lipid nanoparticles. The independent variables were stearic acid as lipid (X1), Tween 80 as surfactant (X2) and sodium deoxycholate as co-surfactant (X3) while particle size (Y1) and entrapment efficiency (Y2) were the dependent variables. Further in vitro release and antibacterial activity in vitro were also performed. The optimized formulation of levofloxacin provides particle size of 237.82 nm and showed 78.71% entrapment efficiency and achieved flux 0.2,493 μg/cm(2)/h across excised goat cornea. In vitro release study showed prolonged drug release from the optimized formulation following Korsmeyer-Peppas model. Antimicrobial study revealed that the developed formulation possesses antibacterial activity against Staphylococcus aureus, and Escherichia coli equivalent to marketed eye drops. HET-CAM test demonstrated that optimized formulation was found to be non-irritant and safe for topical ophthalmic use. Our results concluded that solid lipid nanoparticles are an efficient carrier for ocular delivery of levofloxacin and other drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

The Effects of Lipoplex Formulation Variables on the Protein Corona and Comparisons with in vitro Transfection Efficiency

PubMed Central

Betker, Jamie L.; Gomez, Joe; Anchordoquy, Thomas J.

2013-01-01

The use of lipoplexes for the intracellular delivery of nucleic acids typically involves the optimization of several parameters that are known to affect delivery. Researchers commonly vary charge ratio, and often incorporate different amounts of helper lipids (e.g., cholesterol) to optimize formulations for transfection in cell culture and in vivo. The results of such experiments are often interpreted in the context of nuclease resistance and cell association, but effects on the protein corona are usually not considered. While many studies have demonstrated that lipoplex structure and function can be dramatically compromised in the presence of serum, little attention has been paid to the adsorption of specific proteins and how this might be affected by formulation parameters. In this study, we characterize changes in the protein corona that occur as DOTAP-based lipoplexes are formulated with different amounts of cholesterol and prepared at different charge ratios. Our results demonstrate a significant effect of lipid composition on both total protein adsorption as well as the individual proteins from fetal calf serum that are associated with lipoplexes. In addition, we show that PEGylation increases protein adsorption with our formulations; effects that depend on the type of PEG conjugate employed in the lipoplex. Attempts to identify a specific protein responsible for enhancing transfection were unsuccessful. PMID:23920037

Ex vivo Skin Permeation of Betulin from Water-in-Oil Foams.

PubMed

Färber, Anna; Daniels, Rolf

2016-01-01

Triterpenes of the outer bark of birch are known to improve wound healing. An oleogel with these triterpenes as active principle is approved by the European Medicines Agency. As foams can be applied without touching the skin, they might be an advantageous application form. A comparable wound-healing effect can be expected when the permeation flux of the triterpenes from different types of formulations, namely oleogels, water-in-oil emulsions and water-in-oil foams, is similar. The tested formulations were based on three lipids (medium-chain trigylcerides, sunflower oil and paraffin) which differ in their polarity and solvent power for the triterpenes. Infinite dose permeation experiments were performed using porcine skin which was injured by either tape stripping or skin grafting. The results showed that steady-state permeation flux and lag time depend clearly on the depth of the skin lesion. Moreover, it was substantially affected by the lipid used as basis for the different formulations. In contrast, the different formulation types showed a comparable permeation behaviour leading to the conclusion that all formulation types can be used alike for the treatment of wounds, and the results that have already been obtained with oleogels can be directly translated to the foam with its superior use properties. © 2016 S. Karger AG, Basel.

Formulation and Optimization of Candesartan Cilexetil Nano Lipid Carrier: In Vitro and In Vivo Evaluation.

PubMed

Paudel, Anjan; Ameeduzzafar; Imam, Syed Sarim; Fazil, Mohd; Khan, Shahroz; Hafeez, Abdul; Ahmad, Farhan Jalees; Ali, Asgar

2017-01-01

The objective of this study was to formulate and optimize Candesartan Cilexetil (CC) loaded nanostructured lipid carriers (NLCs) for enhanced oral bioavailability. Glycerol monostearate (GMS), Oleic acid, Tween 80 and Span 40 were selected as a solid lipid, liquid lipid, surfactant and co- surfactant, respectively. The CC-NLCs were prepared by hot emulsion probe sonication technique and optimized using experimental design approach. The formulated CC-NLCs were evaluated for various physicochemical parameters and further optimized formulation (CC-NLC-Opt) was assessed for in vivo pharmacokinetic and pharmacodynamic activity. The optimized formulation (CC-NLC-Opt) showed particle size (183.5±5.89nm), PDI (0.228±0.13), zeta potential (-28.2±0.99mV), and entrapment efficiency (88.9±3.69%). The comparative in vitro release study revealed that CC-NLC-Opt showed significantly better (p<0.05) release and enhanced permeation as compared to CC-suspension. The in vivo pharmacokinetic study gave many folds increase in oral bioavailability than CC suspension, which was further confirmed by antihypertensive activity in a murine model. Thus, the results of ex vivo permeation, pharmacokinetic study and pharmacodynamics study suggest the potential of CC-NLCs for improved oral delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation, optimization and in vivo evaluation.

PubMed

Nooli, Mounika; Chella, Naveen; Kulhari, Hitesh; Shastri, Nalini R; Sistla, Ramakrishna

2017-04-01

Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery. Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug-excipients interactions, powder X-ray diffraction analysis and drug release in vitro. The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100 nm, PDI 0.291, zeta potential of -23.4 mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration. In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.

Microphase separation in solid lipid dosage forms as the cause of drug release instability.

PubMed

Lopes, Diogo Gomes; Koutsamanis, Ioannis; Becker, Karin; Scheibelhofer, Otto; Laggner, Peter; Haack, Detlev; Stehr, Michael; Zimmer, Andreas; Salar-Behzadi, Sharareh

2017-01-30

Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40°C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage. Copyright © 2016 Elsevier B.V. All rights reserved.

Role of Components in the Formation of Self-microemulsifying Drug Delivery Systems.

PubMed

Gurram, A K; Deshpande, P B; Kar, S S; Nayak, Usha Y; Udupa, N; Reddy, M S

2015-01-01

Pharmaceutical research is focused in designing novel drug delivery systems to improve the bioavailability of poorly water soluble drugs. Self-microemulsifying drug delivery systems, one among the lipid-based dosage forms were proven to be promising in improving the oral bioavailability of such drugs by enhancing solubility, permeability and avoiding first-pass metabolism via enhanced lymphatic transport. Further, they have been successful in avoiding both inter and intra individual variations as well as the dose disproportionality. Aqueous insoluble drugs, in general, show greater solubility in lipid based excipients, and hence they are formulated as lipid based drug delivery systems. The extent of solubility of a hydrophobic drug in lipid excipients i.e. oil, surfactant and co-surfactant (components of self-microemulsifying drug delivery systems) greatly affects the drug loading and in producing stable self-microemulsifying drug delivery systems. The present review highlighted the influence of physicochemical factors and structural features of the hydrophobic drug on its solubility in lipid excipients and an attempt was made to explore the role of each component of self-microemulsifying drug delivery systems in the formation of stable microemulsion upon dilution.

Composite starch-based coatings applied to strawberries (Fragaria ananassa).

PubMed

García, M A; Martino, M N; Zaritzky, N E

2001-08-01

Starch-based coatings were used to the extend storage life of strawberries (Fragaria ananassa) stored at 0 degree C and 84.8% relative humidity. Effects of coating formulation (including starch type, plasticizer, lipid and antimicrobial agent) were analysed with respect to fruit quality. Plasticizer addition was necessary for film and coating integrity to avoid pores and cracks. Plasticizer presence reduced weight losses and maintained surface colour of fruits. Amylomaize coatings showed lower water vapour and gas permeabilities and decreased weight losses for longer periods than corn starch ones. Coatings with sorbitol showed lower permeabilities than glycerol ones. Coatings with antimicrobial agents decreased microbial counts, extending storage life of coated fruits by 10 to 14 days in comparison to the control. The addition of 2 g/l sunflower oil to the formulations decreased the water vapour permeability of starch-based films, maintained the surface colour of coated fruits and controlled effectively fruit weight losses during storage. Lipid addition minimized the effects of starch and plasticizer types. Composite starch-based coatings showed selective gas permeability (CO2 higher than O2) which helps to delay senescence of fruits.

Bioactive formulations prepared from fruiting bodies and submerged culture mycelia of the Brazilian edible mushroom Pleurotus ostreatoroseus Singer.

PubMed

Corrêa, Rúbia Carvalho Gomes; de Souza, Aloisio Henrique Pereira; Calhelha, Ricardo C; Barros, Lillian; Glamoclija, Jasmina; Sokovic, Marina; Peralta, Rosane Marina; Bracht, Adelar; Ferreira, Isabel C F R

2015-07-01

Pleurotus ostreatoroseus is a Brazilian edible mushroom whose chemical characterization and bioactivity still remain underexplored. In this study, the hydrophilic and lipophilic compounds as well as the antioxidant, anti-inflammatory and antimicrobial activities of formulations (ethanol extracts) prepared with its fruiting bodies and submerged culture mycelia were compared. The bioactive formulations contain at least five free sugars, four organic acids, four phenolic compounds and two tocopherols. The fruiting body-based formulation revealed higher reducing power, DPPH scavenging activity, β-carotene bleaching inhibition and lipid peroxidation inhibition in brain homogenates than the mycelium-based preparation, as well as higher anti-inflammatory and antimicrobial activities. The absence of hepatotoxicity was confirmed in porcine liver primary cells. These functional responses can be related to the levels of bioactive components including phenolic acids, organic acids and tocopherols.

Lipid nanocarriers and molecular targets for malaria chemotherapy.

PubMed

Jain, Kunal; Sood, Sumeet; Gowthamarajan, Kuppusamy

2014-03-01

Malaria is the most serious tropical disease of humankind and a cause of much debilitation and morbidity throughout the world especially in endemic areas like India and Africa. The development of drug resistance may be due to insufficient drug concentration in presence of high parasite load. In addition, the present pharmaceutical dosage forms are ineffective thereby necessitating the development of novel dosage forms which are effective, safe and affordable to underprivileged population of the developing world. The rapid advancement of nanotechnology has raised the possibility of using lipid nanocarriers that interact within biological environment for treatment of infectious diseases. Thus, lipid based nano-delivery systems offer a platform to formulate old and toxic antimalarial drugs thereby modifying their pharmacokinetic profile, biodistribution and targetability. Further, there is a need to develop new chemotherapy based approaches for inhibiting the parasite-specific metabolic pathways. The present review highlights the advances in lipid nanocarriers and putative molecular targets for antimalarial chemotherapy.

Optimization and physicochemical characterization of a cationic lipid-phosphatidylcholine mixed emulsion formulated as a highly efficient vehicle that facilitates adenoviral gene transfer.

PubMed

Kim, Soo-Yeon; Lee, Sang-Jin; Kim, Jin-Ki; Choi, Han-Gon; Lim, Soo-Jeong

2017-01-01

Cationic lipid-based nanoparticles enhance viral gene transfer by forming electrostatic complexes with adenoviral vectors. We recently demonstrated the superior complexation capabilities of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) emulsion compared with a liposomal counterpart but the cytotoxicity of DOTAP emulsions remained a challenge. The present study is aimed at formulating an emulsion capable of acting as a highly effective viral gene transfer vehicle with reduced cytotoxicity and to physicochemically characterize the structures of virus-emulsion complexes in comparison with virus-liposome complexes when the only difference between emulsions and liposomes was the presence or absence of inner oil core. The emulsion formulation was performed by 1) reducing the content of DOTAP while increasing the content of zwitterionic lipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 2) optimizing the oil content. The complexation capability of formulated DOTAP:DMPC mixed emulsions was similar to those of emulsions containing DOTAP alone while displaying significantly lower cytotoxicity. The complexation capabilities of the DOTAP:DMPC mixed emulsion were serum-compatible and were monitored in a variety of cell types, whereas its liposomal counterpart was totally ineffective. Characterization by scanning electron microscopy, transmission electron microscopy, atomic force microscopy, and dynamic light scattering studies indicated that the optimized emulsions spontaneously surrounded the virus particles to generate emulsions that encapsulated the viral particles, whereas viral particles merely attached to the surfaces of the counterpart liposomes to form multiviral aggregates. Overall, these studies demonstrated that optimized DOTAP:DMPC mixed emulsions are potentially useful for adenoviral gene delivery due to less cytotoxicity and the unique ability to encapsulate the viral particle, highlighting the importance of nanoparticle formulation.

Optimization and physicochemical characterization of a cationic lipid-phosphatidylcholine mixed emulsion formulated as a highly efficient vehicle that facilitates adenoviral gene transfer

PubMed Central

Kim, Soo-Yeon; Lee, Sang-Jin; Kim, Jin-Ki; Choi, Han-Gon; Lim, Soo-Jeong

2017-01-01

Cationic lipid-based nanoparticles enhance viral gene transfer by forming electrostatic complexes with adenoviral vectors. We recently demonstrated the superior complexation capabilities of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) emulsion compared with a liposomal counterpart but the cytotoxicity of DOTAP emulsions remained a challenge. The present study is aimed at formulating an emulsion capable of acting as a highly effective viral gene transfer vehicle with reduced cytotoxicity and to physicochemically characterize the structures of virus-emulsion complexes in comparison with virus–liposome complexes when the only difference between emulsions and liposomes was the presence or absence of inner oil core. The emulsion formulation was performed by 1) reducing the content of DOTAP while increasing the content of zwitterionic lipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 2) optimizing the oil content. The complexation capability of formulated DOTAP:DMPC mixed emulsions was similar to those of emulsions containing DOTAP alone while displaying significantly lower cytotoxicity. The complexation capabilities of the DOTAP:DMPC mixed emulsion were serum-compatible and were monitored in a variety of cell types, whereas its liposomal counterpart was totally ineffective. Characterization by scanning electron microscopy, transmission electron microscopy, atomic force microscopy, and dynamic light scattering studies indicated that the optimized emulsions spontaneously surrounded the virus particles to generate emulsions that encapsulated the viral particles, whereas viral particles merely attached to the surfaces of the counterpart liposomes to form multiviral aggregates. Overall, these studies demonstrated that optimized DOTAP:DMPC mixed emulsions are potentially useful for adenoviral gene delivery due to less cytotoxicity and the unique ability to encapsulate the viral particle, highlighting the importance of nanoparticle formulation. PMID:29070949

Studying the effectiveness of penetration enhancers to deliver retinol through the stratum cornum by in vivo confocal Raman spectroscopy.

PubMed

Mélot, Mickaël; Pudney, Paul D A; Williamson, Ann-Marie; Caspers, Peter J; Van Der Pol, Andre; Puppels, Gerwin J

2009-08-19

The purpose of this study is to monitor in vivo the effect of chemical penetration enhancers on the delivery of trans-retinol into human skin. Chemical penetration enhancers reversibly alter barrier properties of the SC by disruption of the membrane structures or maximising drug solubility with the skin. So far, most of permeation or penetration experiments are performed in vitro. Raman spectroscopy is uniquely placed to be able to measure biological processes in vivo and this paper shows for the first time that the effect of penetration enhancer on the delivery of trans-retinol can successfully be measured in vivo using this technique. Here, the volar forearm of volunteers was treated with four formulations. One formulation is a highly effective model delivery system identified from ex vivo experiments: trans-retinol in Propylene Glycol (PG)/ethanol, with PG being a well-known and efficient penetration enhancer. The other three formulations are based on 0.3% trans-retinol in Caprylic/Capric Acid Triglyceride (MYRITOL 318), an oil commonly used in skin creams but in two of them a specific penetration enhancer is added. One contains a lipid extractor, Triton X 100, whereas another formulation contains a lipid fluidiser, Oleic Acid. Solutions were applied once and measurements were performed up to 6 h after treatment. Remarkable differences in the delivery of trans-retinol between formulation with or without penetration enhancer can clearly be seen. Moreover, the type of penetration enhancer is also shown to influence the delivery. While using the Oleic Acid, which is a lipid fluidiser, a better delivery of trans-retinol in the skin can be detected. For the first time, the effect of penetration enhancer on the delivery of trans-retinol has been monitored, non invasively in vivo, with time.

Formulation of a novel oxybenzone-loaded nanostructured lipid carriers (NLCs).

PubMed

Sanad, Rania A; Abdelmalak, Nevine Shawky; Elbayoomy, Tahany S; Badawi, Alia A

2010-12-01

The objective of the current study was to formulate oxybenzone into nanostructured lipid carriers (NLCs) to enhance its sunscreening efficacy and safety. NLCs of oxybenzone were prepared by the solvent diffusion method. A complete 2(3) factorial design was used for the evaluation of the prepared oxybenzone NLCs. The study design involves the investigation of the effect of three independent variables namely liquid lipid type (Miglyol 812 and oleic acid), liquid lipid concentration (15% and 30%), and oxybenzone concentration (5% and 10% with respect to total lipids) on the particle size (p.s.) , the entrapment efficiency (EE%) and the in vitro drug release after 8 h. The prepared NLCs were spherical in overall shape and were below 0.8 microm. Miglyol 812 and 30% liquid lipid were found to significantly decrease the p.s. and increase the EE% when compared to oleic acid and 15% liquid lipid. Increasing oxybenzone concentration increased significantly the p.s. but did not affect the EE%. NLCs prepared using Miglyol 812, 15% liquid lipid, and 10% oxybenzone showed slower drug release when compared to those prepared using oleic acid, 30% liquid lipid, and 5% oxybenzone, respectively. The candidate oxybenzone-loaded NLC dispersion was then formulated into gel. The incorporation of oxybenzone into NLCs greatly increased the in vitro sun protection factor and erythemal UVA protection factor of oxybenzone more than six- and eightfold, respectively, while providing the advantage of overcoming side effects of free oxybenzone as evidenced by very low irritation potential.

Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach.

PubMed

Thanki, Kaushik; Zeng, Xianghui; Justesen, Sarah; Tejlmann, Sarah; Falkenberg, Emily; Van Driessche, Elize; Mørck Nielsen, Hanne; Franzyk, Henrik; Foged, Camilla

2017-11-01

Safety and efficacy of therapeutics based on RNA interference, e.g., small interfering RNA (siRNA), are dependent on the optimal engineering of the delivery technology, which is used for intracellular delivery of siRNA to the cytosol of target cells. We investigated the hypothesis that commonly used and poorly tolerated cationic lipids might be replaced with more efficacious and safe lipidoids as the lipid component of siRNA-loaded lipid-polymer hybrid nanoparticles (LPNs) for achieving more efficient gene silencing at lower and safer doses. However, formulation design of such a complex formulation is highly challenging due to a strong interplay between several contributing factors. Hence, critical formulation variables, i.e. the lipidoid content and siRNA:lipidoid ratio, were initially identified, followed by a systematic quality-by-design approach to define the optimal operating space (OOS), eventually resulting in the identification of a robust, highly efficacious and safe formulation. A 17-run design of experiment with an I-optimal approach was performed to systematically assess the effect of selected variables on critical quality attributes (CQAs), i.e. physicochemical properties (hydrodynamic size, zeta potential, siRNA encapsulation/loading) and the biological performance (in vitro gene silencing and cell viability). Model fitting of the obtained data to construct predictive models revealed non-linear relationships for all CQAs, which can be readily overlooked in one-factor-at-a-time optimization approaches. The response surface methodology further enabled the identification of an OOS that met the desired quality target product profile. The optimized lipidoid-modified LPNs revealed more than 50-fold higher in vitro gene silencing at well-tolerated doses and approx. a twofold increase in siRNA loading as compared to reference LPNs modified with the commonly used cationic lipid dioleyltrimethylammonium propane (DOTAP). Thus, lipidoid-modified LPNs show highly promising prospects for efficient and safe intracellular delivery of siRNA. Copyright © 2017 Elsevier B.V. All rights reserved.

Relevance of Lipid-Based Products in the Management of Dry Eye Disease

PubMed Central

Amrane, Mourad; Faure, Marie-Odile; Holopainen, Juha M.; Tong, Louis

2017-01-01

Abstract Components of the ocular surface synergistically contribute to maintaining and protecting a smooth refractive layer to facilitate the optimal transmission of light. At the air–water interface, the tear film lipid layer (TFLL), a mixture of lipids and proteins, plays a key role in tear surface tension and is important for the physiological hydration of the ocular surface and for ocular homeostasis. Alterations in tear fluid rheology, differences in lipid composition, or downregulation of specific tear proteins are found in most types of ocular surface disease, including dry eye disease (DED). Artificial tears have long been a first line of treatment in DED and aim to replace or supplement tears. More recently, lipid-containing eye drops have been developed to more closely mimic the combination of aqueous and lipid layers of the TFLL. Over the last 2 decades, our understanding of the nature and importance of lipids in the tear film in health and disease has increased substantially. The aim of this article is to provide a brief overview of our current understanding of tear film properties and review the effectiveness of lipid-based products in the treatment of DED. Liposome lid sprays, emulsion eye drops, and other lipid-containing formulations are discussed. PMID:28956698

Nanosized soy phytosome-based thermogel as topical anti-obesity formulation: an approach for acceptable level of evidence of an effective novel herbal weight loss product

PubMed Central

El-Menshawe, Shahira F; Ali, Adel A; Rabeh, Mohamed A; Khalil, Nermeen M

2018-01-01

Purpose Herbal supplements are currently available as a safer alternative to manage obesity, which has become a rising problem over the recent years. Many chemical drugs on the market are designed to prevent or manage obesity but high cost, low efficacy, and multiple side effects limit its use. Nano lipo-vesicles phytosomal thermogel of Soybean, Glycine max (L.) Merrill, was formulated and evaluated in an attempt to investigate its anti-obesity action on body weight gain, adipose tissue size, and lipid profile data. Methods Three different techniques were used to prepare phytosome formulations including solvent evaporation, cosolvency, and salting out. The optimized phytosome formulation was then selected using Design Expert® (version 7.0.0) depending on the highest entrapment efficiency, minimum particle size (PS), and maximum drug release within 2 hours as responses for further evaluation. The successful phytosome complex formation was investigated by means of Fourier-transform infrared spec troscopy and determination of PS and zeta potential. Phytosome vesicles’ shape was evaluated using transmission electron microscope to ensure its spherical shape. After characterization of the optimized phytosome formulation, it was incorporated into a thermogel formulation. The obtained phytosomal thermogel formulation was evaluated for its clarity, homogeneity, pH, and gel transformation temperature besides rheology behavior and permeation study. An in vivo study was done to investigate the anti-weight-gain effect of soy phytosomal ther mogel. Results EE was found to be >99% for all formulations, PS ranging from 51.66–650.67 while drug release was found to be (77.61–99.78) in range. FTIR and TEM results confirmed the formation of phytosome complex. In vivo study showed a marked reduction in body weight, adipose tissue weight and lipid profile. Conclusion Concisely, soy phytosomal thermogel was found to have a local anti-obesity effect on the abdomen of experimental male albino rats with a slight systemic effect on the lipid profile data. PMID:29391791

The impact of particle preparation methods and polymorphic stability of lipid excipients on protein distribution in microparticles.

PubMed

Liu, Jingying; Christophersen, Philip C; Yang, Mingshi; Nielsen, Hanne M; Mu, Huiling

2017-12-01

The present study aimed at elucidating the influence of polymorphic stability of lipid excipients on the physicochemical characters of different solid lipid microparticles (SLM), with the focus on the alteration of protein distribution in SLM. Labeled lysozyme was incorporated into SLM prepared with different excipients, i.e. trimyristin (TG14), glyceryl distearate (GDS), and glyceryl monostearate (GMS), by water-oil-water (w/o/w) or solid-oil-water (s/o/w) method. The distribution of lysozyme in SLM and the release of the protein from SLM were evaluated by confocal laser scanning microscopy. The storage stability of SLM was characterized by HPLC, differential scanning calorimetry, X-ray powder diffraction, and scanning electron microscopy. Lysozyme was displayed as small scattered domains inside GDS and GMS SLM, whereas it was incorporated in the core of TG14 SLM formulated by the w/o/w method or evenly distributed in TG14 SLM prepared by the s/o/w method. Stability study at 37 °C revealed that only TG14 SLM made by the w/o/w method was able to maintain the lysozyme amount both on the particle surface and released from the SLM. Elevated storage temperature induced polymorphic transition of lipids in GDS and GMS SLM, which was, however, not remarkable for the TG14 SLM. Lipid excipients and particle preparation methods were found to differently affect the lysozyme distribution in SLM, owning to varied storage stabilities of the lipids. The present study provides updated knowledge for rational development of lipid-based formulations for oral delivery of peptide or protein drugs.

Development of edible films obtained from submicron emulsions based on whey protein concentrate, oil/beeswax and brea gum.

PubMed

Cecchini, Juan Pablo; Spotti, María J; Piagentini, Andrea M; Milt, Viviana G; Carrara, Carlos R

2017-06-01

Edible films with whey protein concentrate (WPC) with a lipid component, sunflower oil (O) or beeswax (W), to enhance barrier to water vapor were obtained. Brea gum was used as emulsifier and also as matrix component. In order to achieve emulsion with small and homogeneous droplet size, an ultrasonicator equipment was used after obtaining a pre-emulsion using a blender. The films were made by casting. Effects of lipid fraction on droplet size, zeta potential, mechanical properties, water vapor permeability (WVP), solubility, and optical properties were determined. The droplet size of emulsions with BG decreased when decreasing the lipid content in the formulation. The zeta potential was negative for all the formulations, since the pH was close to 6 for all of them and pI of BG is close to 2.5, and pI of ß-lactoglobulin and α-lactalbumin (main proteins in WPC) are 5.2 and 4.1, respectively. Increasing W or SO content in blended films reduced the tensile strength and puncture resistance significantly. BG and WPC films without lipid presented better mechanical properties. The presence of lipids decreased the WVP, as expected, and those films having BG improved this property. BG films were slightly amber as a result of the natural color of the gum. BG has shown to be a good polysaccharide for emulsifying the lipid fraction and improving the homogeneity and mechanical properties of the films with WPC and beeswax or oil.

Lipid nanoparticles (SLN & NLC) for delivery of vitamin E: a comprehensive review.

PubMed

Saez, V; Souza, I D L; Mansur, C R E

2018-04-01

The antioxidative and photoprotective properties of vitamin E have caused it to be included as an active agent in various pharmaceutical and cosmetic products. However, its lipophilicity, chemical instability and poor skin penetration have limited the effectiveness of these formulations. For that reason, many attempts to include it in different drug delivery systems have been made. In recent decades, lipid nanoparticles have received special attention due to their advantages of compatibility with the skin, ability to enhance penetration of drugs in the stratum corneum, protection of the encapsulated substance against degradation induced by the external medium and control of drug release. This work reviews the current status of the encapsulation of vitamin E in lipid nanoparticles. We describe the most important methods for obtaining and characterizing lipid nanoparticles containing vitamin E (LNP-VE), various techniques for the evaluation of vitamin E's properties after encapsulation, the main in vitro and in vivo studies of the potential effectiveness or toxicity of LNP-VE, the formulations and stability studies of this delivery system, the commercial products based on LNP-VE and the regulatory aspects related to lipid nanoparticles. Finally, we discuss the most relevant advantages of encapsulating vitamin E in such particles and critical aspects that still demand attention to enhance the potential of solid lipid nanoparticles to deliver vitamin E. © 2018 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Multifunctional pH-Sensitive Amino Lipids for siRNA Delivery.

PubMed

Gujrati, Maneesh; Vaidya, Amita; Lu, Zheng-Rong

2016-01-20

RNA interference (RNAi) represents a powerful modality for human disease therapy that can regulate gene expression signature using small interfering RNA (siRNA). Successful delivery of siRNA into the cytoplasm of target cells is imperative for efficient RNAi and also constitutes the primary stumbling block in the clinical applicability of RNAi. Significant progress has been made in the development of lipid-based siRNA delivery systems, which have practical advantages like simple chemistry and easy formulation of nanoparticles with siRNA. This review discusses the recent development of pH-sensitive amino lipids, with particular focus on multifunctional pH-sensitive amino lipids for siRNA delivery. The key components of these multifunctional lipids include a protonatable amino head group, distal lipid tails, and two cross-linkable thiol groups, which together facilitate the facile formation of stable siRNA-nanoparticles, easy surface modification for target-specific delivery, endosomal escape in response to the pH decrease during subcellular trafficking, and reductive dissociation of the siRNA-nanoparticles for cytoplasmic release of free siRNA. By virtue of these properties, multifunctional pH-sensitive lipids can mediate efficient cytosolic siRNA delivery and gene silencing. Targeted siRNA nanoparticles can be readily formulated with these lipids, without the need for other helper lipids, to promote systemic delivery of therapeutic siRNAs. Such targeted siRNA nanoparticles have been shown to effectively regulate the expression of cancer-related genes, resulting in significant efficacy in the treatment of aggressive tumors, including metastatic triple negative breast cancer. These multifunctional pH-sensitive lipids constitute a promising platform for the systemic and targeted delivery of therapeutic siRNA for the treatment of human diseases. This review summarizes the structure-property relationship of the multifunctional pH-sensitive lipids and their efficacy in in vitro and in vivo siRNA delivery and gene silencing.

pH-Cleavable Nucleoside Lipids: A New Paradigm for Controlling the Stability of Lipid-Based Delivery Systems.

PubMed

Oumzil, Khalid; Benizri, Sébastien; Tonelli, Giovanni; Staedel, Cathy; Appavoo, Ananda; Chaffanet, Max; Navailles, Laurence; Barthélémy, Philippe

2015-11-01

Lipid-based delivery systems are an established technology with considerable clinical acceptance and several applications in human. Herein, we report the design, synthesis and evaluation of novel orthoester nucleoside lipids (ONLs) for the modulation of liposome stability. The ONLs contain head groups with 3'-orthoester nucleoside derivatives featuring positive or negative charges. The insertion of the orthoester function in the NL structures allows the formation of pH-sensitive liposomes. ONL-based liposomes can be hydrolyzed to provide nontoxic products, including nucleoside derivatives and hexadecanol. To allow the release to be tunable at different hydrolysis rates, the charge of the polar head structure is modulated, and the head group can be released at a biologically relevant pH. Crucially, when ONLs are mixed with natural phosphocholine lipids (PC), the resultant liposome evolves toward the formation of a hexadecanol/PC lamellar system. Biological evaluation shows that stable nucleic acid lipid particles (SNALPs) formulated with ONLs and siRNAs can effectively enter into tumor cells and release their nucleic acid payload in response to an intracellular acidic environment. This results in a much higher antitumor activity than conventional SNALPs. The ability to use pH-cleavable nucleolipids to control the stability of lipid-based delivery systems represents a promising approach for the intracellular delivery of drug cargos. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Optimization and characterization of liposome formulation by mixture design.

PubMed

Maherani, Behnoush; Arab-tehrany, Elmira; Kheirolomoom, Azadeh; Reshetov, Vadzim; Stebe, Marie José; Linder, Michel

2012-02-07

This study presents the application of the mixture design technique to develop an optimal liposome formulation by using the different lipids in type and percentage (DOPC, POPC and DPPC) in liposome composition. Ten lipid mixtures were generated by the simplex-centroid design technique and liposomes were prepared by the extrusion method. Liposomes were characterized with respect to size, phase transition temperature, ζ-potential, lamellarity, fluidity and efficiency in loading calcein. The results were then applied to estimate the coefficients of mixture design model and to find the optimal lipid composition with improved entrapment efficiency, size, transition temperature, fluidity and ζ-potential of liposomes. The response optimization of experiments was the liposome formulation with DOPC: 46%, POPC: 12% and DPPC: 42%. The optimal liposome formulation had an average diameter of 127.5 nm, a phase-transition temperature of 11.43 °C, a ζ-potential of -7.24 mV, fluidity (1/P)(TMA-DPH)((¬)) value of 2.87 and an encapsulation efficiency of 20.24%. The experimental results of characterization of optimal liposome formulation were in good agreement with those predicted by the mixture design technique.

Formulation and characterization of hydrophilic drug diclofenac sodium-loaded solid lipid nanoparticles based on phospholipid complexes technology.

PubMed

Liu, Dongfei; Chen, Li; Jiang, Sunmin; Zhu, Shuning; Qian, Yong; Wang, Fengzhen; Li, Rui; Xu, Qunwei

2014-03-01

To successfully prepare the diclofenac sodium (DS)-loaded solid lipid nanoparticles (SLNs), phospholipid complexes (PCs) technology was applied here to improve the liposolubility of DS. Solid lipid nanoparticles (SLNs) loaded with phospholipid complexes (PCs) were prepared by the modified emulsion/solvent evaporation method. DS could be solubilized effectively in the organic solvents with the existence of phospholipid and apparent partition coefficient of DS in PCs increased significantly. X-ray diffraction analysis suggested that DS in PCs was either molecularly dispersed or in an amorphous form. However, no significant difference was observed between the Fourier transform infrared spectroscopy (FT-IR) spectra of physical mixture and that of PCs. Particles with small sizes, narrow polydispersity indexes and high entrapment efficiencies could be obtained with the addition of PCs. Furthermore, according to the transmission electron microscopy, a core-shell structure was likely to be formed. The presence of PCs caused the change of zeta potential and retarded the drug release of SLNs, which indicated that phospholipid formed multilayers around the solid lipid core of SLNs. Both FT-IR and differential scanning calorimetry analysis also illustrated that some weak interactions between DS and lipid materials might take place during the preparation of SLNs. In conclusion, the model hydrophilic drug-DS can be formulated into the SLNs with the help of PCs.

Production of solid lipid submicron particles for protein delivery using a novel supercritical gas-assisted melting atomization process.

PubMed

Salmaso, Stefano; Elvassore, Nicola; Bertucco, Alberto; Caliceti, Paolo

2009-02-01

A supercritical carbon dioxide micronization technique based on gas-assisted melting atomization has been designed to prepare protein-loaded solid lipid submicron particles. The supercritical process was applied to homogeneous dispersions of insulin in lipid mixtures: (1) tristearin, Tween-80, phosphatidylcholine and 5 kDa PEG (1:0.1:0.9:1 and 1:0.1:0.9:2 weight ratio); and (2) tristearin, dioctyl sulfosuccinate and phosphatidylcholine (1:1:0.5 weight ratio). Optimized process conditions yielded dry nonagglomerated powders with high product recovery (70%, w/w). Dynamic light scattering and transmission electron microscopy showed that two size fractions of particles, with 80-120 and 200-400 nm diameters, were produced. In all final products, dimethylsulfoxide used to prepare the insulin/lipid mixture was below 20 ppm. Protein encapsulation efficiency increased up to 80% as the DMSO content in the insulin/lipid mixture increased. Compared to the particles without PEG, the polymer-containing particles dispersed rapidly in water, and the dispersions were more stable under centrifugation as less than 20% of suspended particles precipitated after extensive centrifugation. In vitro, the protein was slowly released from the formulation without PEG, while a burst and faster release were obtained from the formulations containing PEG. Subcutaneous injection to diabetic mice of insulin extracted from the particles showed that the supercritical process did not impair the protein hypoglycemic activity.

Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides.

PubMed

Holm, René; Porter, Christopher J H; Edwards, Glenn A; Müllertz, Anette; Kristensen, Henning G; Charman, William N

2003-09-01

The potential for lipidic self-microemulsifying drug delivery systems (SMEDDS) containing triglycerides with a defined structure, where the different fatty acids on the glycerol backbone exhibit different metabolic fate, to improve the lymphatic transport and the portal absorption of a poorly water-soluble drug, halofantrine, were investigated in fasted lymph cannulated canines. Two different structured triglycerides were incorporated into the SMEDDS; 1,3-dioctanoyl-2-linoleyl-sn-glycerol (C8:0-C18:2-C8:0) (MLM) and 1,3-dilinoyl-2-octanoyl-sn-glycerol (C18:2-C8:0-C18:2) (LML). A previously optimised SMEDDS formulation for halofantrine, comprising of triglyceride, Cremophor EL, Maisine 35-1 and ethanol was selected for bioavailability assessment. The extent of lymphatic transport via the thoracic duct was 17.9% of the dose for the animals dosed with the MLM SMEDDS and 27.4% for LML. Also the plasma availability was affected by the triglyceride incorporated into the multi-component delivery system and availabilities of 56.9% (MLM) and 37.2% (LML) were found. These data indicate that the pharmaceutical scientist can use the structure of the lipid to affect the relative contribution of the two absorption pathways. The MLM formulation produced a total bioavailability of 74.9%, which is higher than the total absorption previously observed after post-prandial administration. This could indicate the utility of disperse lipid-base formulations based on structured triglycerides for the oral delivery of halofantrine, and potentially other lipophilic drugs.

Design and ocular tolerance of flurbiprofen loaded ultrasound-engineered NLC.

PubMed

Gonzalez-Mira, E; Egea, M A; Garcia, M L; Souto, E B

2010-12-01

Packaging small drug molecules, such as non-steroidal anti-inflammatory drugs (NSAIDs) into nanoparticulate systems has been reported as a promising approach to improve the drug's bioavailability, biocompatibility and safety profiles. In the last 20 years, lipid nanoparticles (lipid dispersions) entered the nanoparticulate library as novel carrier systems due to their great potential as an alternative to other systems such as polymeric nanoparticles and liposomes for several administration routes. For ocular instillation nanoparticulate carriers are required to have a low mean particle size, with the lowest polydispersity as possible. The purpose of this work was to study the combined influence of 2-level, 4-factor variables on the formulation of flurbiprofen (FB), a lipophilic NSAID, in lipid carriers currently named as nanostructured lipid carriers (NLC). NLC were produced with stearic acid (SA) and castor oil (CO) stabilized by Tween® 80 (non-ionic surfactant) in aqueous dispersion. A 2(4) full factorial design based on 4 independent variables was used to plan the experiments, namely, the percentage of SA with regard to the total lipid, the FB concentration, the stabilizer concentration, and the storage conditions (i.e., storage temperature). The effects of these parameters on the mean particle size, polydispersity index (PI) and zeta potential (ZP) were investigated as dependent variables. The optimization process was achieved and the best formulation corresponded to the NLC formulation composed of 0.05 (wt%) FB, 1.6 (wt%) Tween® 80 and a 50:50 ratio of SA to CO, with an average diameter of 288 nm, PI 0.245 of and ZP of -29 mV. This factorial design study has proven to be a useful tool in optimizing FB-loaded NLC formulations. Stability of the optimized NLC was predicted using a TurbiScanLab® and the ocular tolerance was assessed in vitro and in vivo by the Eytex® and Draize test, respectively. The developed systems were shown physico-chemically stable with high tolerance for eye instillation. Copyright © 2010 Elsevier B.V. All rights reserved.

Crystals and crystallization in oil-in-water emulsions: implications for emulsion-based delivery systems.

PubMed

McClements, David Julian

2012-06-15

Many bioactive components intended for oral ingestion (pharmaceuticals and nutraceuticals) are hydrophobic molecules with low water-solubilities and high melting points, which poses considerable challenges to the formulation of oral delivery systems. Oil-in-water emulsions are often suitable vehicles for the encapsulation and delivery of this type of bioactive component. The bioactive component is usually dissolved in a carrier lipid phase by either dilution and/or heating prior to homogenization, and then the carrier lipid and water phases are homogenized to form an emulsion consisting of small oil droplets dispersed in water. The successful development of this kind of emulsion-based delivery system depends on a good understanding of the influence of crystals on the formation, stability, and properties of emulsions. This review article addresses the physicochemical phenomena associated with the encapsulation, retention, crystallization, release, and absorption of hydrophobic bioactive components within emulsions. This knowledge will be useful for the rational formulation of effective emulsion-based delivery systems for oral delivery of crystalline hydrophobic bioactive components in the food, health care, and pharmaceutical industries. Copyright © 2012 Elsevier B.V. All rights reserved.

Influence of cyclodextrin complexation on the in vivo photoprotective effects of oxybenzone.

PubMed

Felton, Linda A; Wiley, Cody J; Godwin, Donald A

2004-01-01

The objective of the current study was to investigate the influence of cyclodextrin complexation on the in vivo photoprotective effects of a model ultraviolet (UV) absorber, oxybenzone, and to compare these novel sunscreens to a commercial SPF 30 sunscreen product. Aqueous-based solutions and suspensions containing 2.7 mg/mL oxybenzone and up to 20% (w/w) hydroxypropyl-beta-cyclodextrin (HPCD) were prepared. The sunscreens were applied to the dorsal skin of SKH-1 hairless mice and the animals were exposed to up to two minimal erythemal doses (MEDs) of UV radiation. Control animals received no sunscreen treatment. Lipid damage, as quantified by decreases in the lipid melting temperature of the epidermis, was determined using differential scanning calorimetry immediately after UV exposure. The number of sunburn cells (SBCs) and the extent of edema were measured 24 hours postexposure. Results showed that all oxybenzone-containing formulations decreased the number of SBCs formed, diminished swelling, and reduced the physical damage to the skin structure, in comparison to control. Thus, complexation did not prevent oxybenzone from reacting with light. The 20% HPCD formulation exhibited more substantial photoprotection at UV exposures of one or two MEDs, as evidenced by the formation of fewer SBCs. The 5% HPCD formulation also provided substantial protection against epidermal lipid damage. These studies demonstrate that inclusion of HPCD in sunscreen formulations may enhance the in vivo photoprotective effects of the UV absorbers. No single HPCD-containing sunscreen, however, was found to be equivalent to a commercially available sunscreen product for all biomarkers investigated.

Preparation and characterization of oxybenzone-loaded solid lipid nanoparticles (SLNs) with enhanced safety and sunscreening efficacy: SPF and UVA-PF.

PubMed

Sanad, R A; Abdel Malak, N S; El-Bayoomy, T S; Badawi, A A

2010-12-01

The objective of the current study was to formulate solid lipid nanoparticles of oxybenzone to enhance its sunscreening efficacy while reducing its side effects. Solid lipid nanoparticles (SLNs) of oxybenzone were prepared by the solvent diffusion method. A complete 2(4) factorial design was used to optimize preparations. The study design involves the investigation of four independent variables, namely lipid type (Glyceryl monostearate, GMS; and Witepsol E85, WE85), lipid concentration (5 and 10%), polyvinyl alcohol (PVA) concentration (1 and 2%), and ethanol/acetone ratios (1:1 and 3:1, v/v), in terms of their effect on the particle size and entrapment efficiency. GMS was found to significantly increase the p.s. and EE%. SLNs prepared using 10% lipid had slower drug release compared to those prepared using 5%. The candidate oxybenzone-loaded SLN formula (SLN2) consisting of 0.5% oxybenzone, 10% GMS, 1% PVA, and ethanol/acetone (1:1, v/v) was then formulated into a gel and compared to the corresponding free oxybenzone nanosuspension and placebo SLN. The formulations were evaluated for skin irritation, in vitro sun protection factor, and ultraviolet A protection factors. The incorporation of oxybenzone into solid lipid nanoparticles greatly increased the SPF and UVA protection factor of oxybenzone more than five-fold while providing the advantage of overcoming skin irritancy problems.

Predicting the influence of liposomal lipid composition on liposome size, zeta potential and liposome-induced dendritic cell maturation using a design of experiments approach.

PubMed

Soema, Peter C; Willems, Geert-Jan; Jiskoot, Wim; Amorij, Jean-Pierre; Kersten, Gideon F

2015-08-01

In this study, the effect of liposomal lipid composition on the physicochemical characteristics and adjuvanticity of liposomes was investigated. Using a design of experiments (DoE) approach, peptide-containing liposomes containing various lipids (EPC, DOPE, DOTAP and DC-Chol) and peptide concentrations were formulated. Liposome size and zeta potential were determined for each formulation. Moreover, the adjuvanticity of the liposomes was assessed in an in vitro dendritic cell (DC) model, by quantifying the expression of DC maturation markers CD40, CD80, CD83 and CD86. The acquired data of these liposome characteristics were successfully fitted with regression models, and response contour plots were generated for each response factor. These models were applied to predict a lipid composition that resulted in a liposome with a target zeta potential. Subsequently, the expression of the DC maturation factors for this lipid composition was predicted and tested in vitro; the acquired maturation responses corresponded well with the predicted ones. These results show that a DoE approach can be used to screen various lipids and lipid compositions, and to predict their impact on liposome size, charge and adjuvanticity. Using such an approach may accelerate the formulation development of liposomal vaccine adjuvants. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Improving In Vivo Efficacy of Bioactive Molecules: An Overview of Potentially Antitumor Phytochemicals and Currently Available Lipid-Based Delivery Systems

PubMed Central

Torres, Carlos; Vázquez, Luis; Reglero, Guillermo; Fornari, Tiziana

2017-01-01

Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association. PMID:28555156

In Vivo Formation of Cubic Phase in Situ after Oral Administration of Cubic Phase Precursor Formulation Provides Long Duration Gastric Retention and Absorption for Poorly Water-Soluble Drugs.

PubMed

Pham, Anna C; Hong, Linda; Montagnat, Oliver; Nowell, Cameron J; Nguyen, Tri-Hung; Boyd, Ben J

2016-01-04

Lipid-based liquid crystalline systems based on the combination of digestible and nondigestible lipids have been proposed as potential sustained release delivery systems for oral delivery of poorly water-soluble drugs. The potential for cubic phase liquid crystal formation to induce dramatically extended gastric retention in vivo has been shown previously to strongly influence the resulting pharmacokinetics of incorporated drug. In vitro studies showing the in situ formation of cubic phase from a disordered precursor comprising a mixture of digestible and nondigestible lipids under enzymatic digestion have also recently been reported. Combining both concepts, here we show the potential for such systems to form in vivo, increasing gastric retention, and providing a sustained release effect for a model poorly water-soluble drug cinnarizine. A mixture of phytantriol and tributyrin at an 85:15 mass ratio, shown previously to form cubic phase under the influence of digestion, induced a similar pharmacokinetic profile to that in the absence of tributyrin, but completely different from tributyrin alone. The gastric retention of the formulation, assessed using micro-X-ray CT imaging, was also consistent with the pharmacokinetic behavior, where phytantriol alone and with 15% tributyrin was greater than that of tributyrin in the absence of phytantriol. Thus, the concept of precursor lipid systems that form cubic phase in situ during digestion in vivo has been demonstrated and opens new opportunities for sustained release of poorly water-soluble drugs.

Nano vesicular lipid carriers of angiotensin II receptor blocker: Anti-hypertensive and skin toxicity study in focus.

PubMed

Ahad, Abdul; Aqil, Mohd; Kohli, Kanchan; Sultana, Yasmin; Mujeeb, Mohd

2016-05-01

Nanoethosomal carriers of valsartan have been previously prepared, characterized and optimized. A gel formulation of valsartan vesicular lipid carriers was composed of Carbopol(®) (1% w/w), polyethylene glycol-400 (15% w/w) and triethanolamine (0.5% w/w). The influence of the valsartan nanoethosomal formulation developed on the blood pressure of experimental hypertensive rats, and its potential for skin irritation, are presented in this report. The experimental rats were divided into three groups; the control group received no treatment (Group A). Group B was administered methyl prednisolone acetate (20 mg/kg/week) for two weeks (hypertensive control). Group C received methyl prednisolone acetate, followed by administration of the valsartan ethosomal formulation. The blood pressure of the rats was measured using a non-invasive rat blood pressure instrument based on the tail-cuff technique. The statistical analysis was performed using GraphPad InStat 3 software. The treatment group showed a significant (P < 0.05) and constant fall in blood pressure, for up to 48 h. The valsartan ethosomal formulation was found to be effective, with a 34.11% reduction in blood pressure. The formulation's potential for skin irritation was assessed by the Draize irritation score test, which ruled out the possibility of any skin irritation caused by application of the formulation in rats. Our results suggest that nanoethosomes are efficient carriers for transdermal delivery of valsartan, for the management of hypertension.

Tools for Early Prediction of Drug Loading in Lipid-Based Formulations

PubMed Central

2015-01-01

Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R2 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R2 0.85; Polysorbate 80, R2 0.90; Cremophor EL, R2 0.93). A melting point below 150 °C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R2 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R2 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug. PMID:26568134

Tools for Early Prediction of Drug Loading in Lipid-Based Formulations.

PubMed

Alskär, Linda C; Porter, Christopher J H; Bergström, Christel A S

2016-01-04

Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R(2) 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R(2) 0.85; Polysorbate 80, R(2) 0.90; Cremophor EL, R(2) 0.93). A melting point below 150 °C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R(2) 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R(2) 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug.

Influence of poloxamers on the dissolution performance and stability of controlled-release formulations containing Precirol ATO 5.

PubMed

Jannin, V; Pochard, E; Chambin, O

2006-02-17

Lipid excipients are usually used for the development of sustained-release formulations. When used in relatively high quantities, Precirol ATO 5 imparts sustained-release properties to solid oral dosage forms, by forming a lipid matrix. To control or adjust the drug release kinetics from such lipid matrix however, one must often resort to complementary ingredients or techniques. This study investigates the influence of poloxamers (Lutrol) included in lipid matrices composed of glyceryl palmitostearate (Precirol ATO 5) on their dissolution performance and their stability. The addition of these hydrophilic polymers in the lipid matrix increased the amount of theophylline released thanks to the swelling of the hydrophilic polymer and the creation of a porous network into the inert lipid matrix. The grade and the quantity of Lutrol could modulate the extent of drug release. Theophylline was released mainly by the matrix erosion but also by diffusion through the pores as suggested by the Peppas' model. Moreover, the addition of Lutrol enhanced the stability during storage. The theophylline release was quite steady after 6 months in different conditions (temperature and humidity). Thus, the mixture of glyceryl palmitostearate and poloxamers is an approach with many advantages for the development of controlled-release formulations by capsule molding.

Preparation and characterization of solid lipid nanoparticles-a review.

PubMed

Parhi, Rabinarayan; Suresh, Padilama

2012-03-01

In the present scenario, most of the developed and new discovered drugs are posing real challenge to the formulation scientists due to their poor aqueous solubility which in turn is responsible for poor bioavailability. One of the approach to overcome above problem is the packaging of the drug in to particulate carrier system. Among various carriers, lipid emerged as very attractive candidate because of its unique property of enhancing the bioavailability of poorly water soluble drugs. Solid lipid, one of the physical forms of lipid, is used to formulate nanoparticles, popularly known as Solid lipid nanoparticles (SLNs), as an alternative carrier system to emulsions, liposomes and polymeric micro- and nano-particles. SLNs combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews numerous production techniques for SLNs along with their advantages and disadvantages. Special attention is paid to the characterization of the SLNs by using various analytical tools. It also emphasizes on physical state of lipid (supercooled melts, different lipid modifications).

In vitro and in vivo characterisation of PEG-lipid-based micellar complexes of salmon calcitonin for pulmonary delivery.

PubMed

Baginski, Leonie; Gobbo, Oliviero L; Tewes, Frederic; Salomon, Johanna J; Healy, Anne Marie; Bakowsky, Udo; Ehrhardt, Carsten

2012-06-01

To investigate DSPE-PEG(2000)-based micellar formulations of salmon calcitonin (sCT) for their ability to improve pulmonary delivery. Micelles were characterised by DLS and (31)P-NMR spectroscopy. Stability against sCT degrading peptidases, trypsin, α-chymotrypsin and neutrophil elastase as well as their influence on transepithelial absorption was investigated in vitro. In vivo performance of sCT micelles was studied in an experimental model of intratracheal aerosolisation into rats. Micelles with a mean hydrodynamic diameter of 12 nm spontaneously assembled, when a total concentration of 0.02 mM of PEG-lipid and sCT (at 1:1 molar ratio) was exceeded. Nuclear magnetic resonance confirmed the presence of small micellar structures. The micellar formulation showed increased stability against enzymatic digestion. In vitro studies also showed that sCT micelles were able to enhance transepithelial absorption. Data obtained from in vivo experiments provided evidence of significantly (P < 0.05) higher mean plasma concentrations of sCT, after inhalation of micelles compared to sCT solution, at 60 and 90 min, a significantly higher AUC (inf) and a relative bioavailability of 160 ± 55% when compared to plain sCT solution. The herein described PEG-lipid micelles are promising carriers for enhanced pulmonary delivery of sCT.

Rational design on controlled release ion-exchange polymeric microspheres and polymer-lipid hybrid nanoparticles for the delivery of water-soluble drugs through a multidisciplinary approach

NASA Astrophysics Data System (ADS)

Li, Yongqiang

Sulfopropyl dextran sulfate (SP-DS) microspheres and polymer-lipid hybrid nanoparticles (PLN) for the delivery of water-soluble anticancer drugs and P-glycoprotein inhibitors were developed by our group recently and demonstrated effectiveness in local chemotherapy. To optimize the delivery performance of these particulate systems, particularly PLN, an integrated multidisciplinary approach was developed, based on an in-depth understanding of drug-excipient interactions, internal structure, drug loading and release mechanisms, and application of advanced modeling/optimization techniques. An artificial neural networks (ANN) simulator capable of formulation optimization and drug release prediction was developed. In vitro drug release kinetics of SP-DS microspheres, with various drug loading and in different release media, were predicted by ANN. The effects of independent variables on drug release were evaluated. Good modeling performance suggested that ANN is a useful tool to predict drug release from ion-exchange microspheres. To further improve the performance of PLN, drug-polymer-lipid interactions were characterized theoretically and experimentally using verapamil hydrochloride (VRP) as a model drug and dextran sulfate sodium (DS) as a counter-ion polymer. VRP-DS complexation followed a stoichiometric rule and solid-state transformation of VRP were observed. Dodecanoic acid (DA) was identified as the lead lipid carrier material. Based upon the optimized drug-polymer-lipid interactions, PLN with high drug loading capacity (36%, w/w) and sustained release without initial burst release were achieved. VRP remained amorphous and was molecularly dispersed within PLN. H-bonding contributed to the miscibility between the VRP-DS complex and DA. Drug release from PLN was mainly controlled by diffusion and ion-exchange processes. Drug loading capacity and particle size of PLN depend on the formulation factors of the weight ratio of drug to lipid and concentrations of surfactants applied. A three-factor spherical composite experimental design was used to map the cause-and-effect relationship. PLN with high drug loading efficiency (92%) and small particle size (100 nm) were predicted by ANN and confirmed by experiment. The roles of various factors on the properties of PLN were also investigated. In summary, this thesis demonstrates that an integrated multidisciplinary strategy ranging from preformulation to formulation to optimization is suitable for the rational design of SP-DS microspheres and PLN with desired properties.

DOTAP cationic liposomes prefer relaxed over supercoiled plasmids.

PubMed

Even-Chen, S; Barenholz, Y

2000-12-20

Cationic liposomes and DNA interact electrostatically to form complexes called lipoplexes. The amounts of unbound (free) DNA in a mixture of cationic liposomes and DNA at different cationic lipid:DNA molar ratios can be used to describe DNA binding isotherms; these provide a measure of the binding efficiency of DNA to different cationic lipid formulations at various medium conditions. In order to quantify the ratio between the various forms of naked DNA and supercoiled, relaxed and single-stranded DNA, and the ratio between cationic lipid bound and unbound DNA of various forms we developed a simple, sensitive quantitative assay using agarose gel electrophoresis, followed by staining with the fluorescent cyanine DNA dyes SYBR Green I or SYBR Gold. This assay was compared with that based on the use of ethidium bromide (the most commonly used nucleic acid stain). Unlike ethidium bromide, SYBR Green I DNA sensitivity and concentration-dependent fluorescence intensity were identical for supercoiled and nicked-relaxed forms. DNA detection by SYBR Green I in solution is approximately 40-fold more sensitive than by ethidium bromide for double-stranded DNA and approximately 10-fold for single-stranded DNA, and in agarose gel it is 16-fold more sensitive for double-stranded DNA compared with ethidium bromide. SYBR Gold performs similarly to SYBR Green I. This study shows that: (a) there is no significant difference in DNA binding isotherms to the monocationic DOTAP (DOTAP/DOPE) liposomes and to the polycationic DOSPA (DOSPA/DOPE) liposomes, even when four DOSPA positive charges are involved in the electrostatic interaction with DNA; (b) the helper lipids affect DNA binding, as DOTAP/DOPE liposomes bind more DNA than DOTAP/cholesterol; (c) in the process of lipoplex formation, when the DNA is a mixture of two forms, supercoiled and nicked-relaxed (open circular), there is a preference for the binding to the cationic liposomes of plasmid DNA in the nicked-relaxed over the supercoiled form. This preference is much more pronounced when the cationic liposome formulation is based on the monocationic lipid DOTAP than on the polycationic lipid DOSPA. The preference of DOTAP formulations to bind to the relaxed DNA plasmid suggests that the binding of supercoiled DNA is weaker and easier to dissociate from the complex.

Role of medium-chain fatty acids in the emulsification mechanistics of self-micro-emulsifying lipid formulations

PubMed Central

Hasan, Naser M.Y.

2014-01-01

Purpose The objective of the present study was to design and develop stable o/w microemulsions comprising Miglyol 812, Imwitor 988 and Tagat TO as a non ionic surfactant. This was based on particle size measurements and phase behavior studies. The empirical role of incorporating medium-chain mono/di-glycerides in the lipid matrix in the mechanistic processes of emulsification was also established in various simulating physiological conditions. Methods The efficiency of self-emulsification was evaluated under conditions of varying key compositions in the lipid mixtures; oil, cosurfactant and surfactant. Droplet diameter was measured using laser diffraction and light scattering techniques. Equilibrium phase studies were performed and phase boundaries were determined for the lipid–water systems. Results Microemulsion systems were produced from blends of Miglyol 812, Imwitor 988 and Tagat TO. An optimized formulation consisted of {Miglyol 812/Imwitor 988} and Tagat TO spontaneously self-emulsified in water producing dispersions with droplet diameters of ∼50 nm. Phase equilibrium diagrams have revealed significant enhancement in the water-solubilized region (L2) without any presence of liquid crystalline materials. Conclusions Potential SMEDDS formulations for the bioavailability enhancement of poorly water-soluble compounds were developed by mixing blends of {Miglyol 812/Imwitor 988} and Tagat TO as a non-ionic surfactant. ‘Diffusion and stranding’ appears to be the dominant mechanism of emulsification. PMID:25561872

Glyceryl monooleyl ether-based liquid crystalline nanoparticles as a transdermal delivery system of flurbiprofen: characterization and in vitro transport.

PubMed

Uchino, Tomonobu; Murata, Akiko; Miyazaki, Yasunori; Oka, Toshihiko; Kagawa, Yoshiyuki

2015-01-01

Liquid crystalline nanoparticles (LCNs) were prepared using glyceryl monooleyl ether (GME) by the modified film rehydration method. Hydrogenated lecithin (HL), 1,3-butylene glycol (1,3-BG), and Poloxamer 407 were used as additives. The prepared LCN formulations were evaluated based on particle size, small-angle X-ray diffraction (SAXS) analysis, (1)H- and (19)F-NMR spectra, and in vitro skin permeation across Yucatan micropig skin. The composition (weight percent) of the LCN formulations were GME-HL-1,3-BG (4 : 1 : 15), 4% GME-based LCN and GME-HL-1,3-BG (8 : 1 : 15), 8% GME-based LCN and their mean particle sizes were 130-175 nm. Flurbiprofen 5 and 10 mg was loaded into 4% GME-based LCN and 8% GME-based LCN systems, respectively. The results of SAXS and NMR suggested that both flurbiprofen-loaded formulations consist of particles with reverse type hexagonal phase (formation of hexosome) and flurbiprofen molecules were localized in the lipid domain through interaction of flurbiprofen with the lipid components. Flurbiprofen transport from the LCN systems across the Yucatan micropig skin was increased compared to flurbiprofen in citric buffer (pH=3.0). The 8% GME-based LCN systems was superior to the 4% GME-based LCN for flurbiprofen transport. Since the internal hexagonal phase in the 8% GME-based LCN systems had a higher degree of order compared to the 4% GME-based LCN in SAXS patterns, the 8% GME-based LCN system had a larger surface area, which might influence flurbiprofen permeation. These results indicated that the GME-based LCN system is effective in improving the skin permeation of flurbiprofen across the skin.

Chlorogenic acid stabilized nanostructured lipid carriers (NLC) of atorvastatin: formulation, design and in vivo evaluation.

PubMed

Khan, Saba; Baboota, Sanjula; Ali, Javed; Narang, R S; Narang, Jasjeet K

2016-01-01

The present work was aimed at developing an optimized oral nanostructured lipid carrier (NLC) formulation of poorly soluble atorvastatin Ca (AT Ca) and assessing its in vitro release, oral bioavailability and pharmacodynamic activity. In this study, chlorogenic acid, a novel excipient having synergistic cholesterol lowering activity was utilized and explored in NLC formulation development. The drug-loaded NLC formulations were prepared using a high pressure homogenization technique and optimized by the Box-Behnken statistical design using the Design-Expert software. The optimized NLC formulation was composed of oleic acid and stearic acid as lipid phase (0.9% w/v), poloxamer 188 as surfactant (1% w/v) and chlorogenic acid (0.05% w/v). The mean particle size, polydispersity index (PDI) and % drug entrapment efficiency of optimized NLC were 203.56 ± 8.57 nm, 0.27 ± 0.028 and 83.66 ± 5.69, respectively. In vitro release studies showed that the release of drug from optimized NLC formulations were markedly enhanced as compared to solid lipid nanoparticles (SLN) and drug suspension. The plasma concentration time profile of AT Ca in rats showed 3.08- and 4.89-fold increase in relative bioavailability of developed NLC with respect to marketed preparation (ATORVA® tablet) and drug suspension, respectively. Pharmacodynamic study suggested highly significant (**p < 0.01) reduction in the cholesterol and triglyceride values by NLC in comparison with ATORVA® tablet. Therefore, the results of in vivo studies demonstrated promising prospects for successful oral delivery of AT Ca by means of its chlorogenic acid integrated NLC.

Long-Circulating Curcumin-Loaded Liposome Formulations with High Incorporation Efficiency, Stability and Anticancer Activity towards Pancreatic Adenocarcinoma Cell Lines In Vitro.

PubMed

Mahmud, Mohamed; Piwoni, Adriana; Filipczak, Nina; Janicka, Martyna; Gubernator, Jerzy

2016-01-01

The incorporation of hydrophobic drugs into liposomes improve their bioavailability and leads to increased stability and anticancer activity, along with decreased drug toxicity. Curcumin (Cur) is a natural polyphenol compound with a potent anticancer activity in pancreatic adenocarcinoma (PA). In the present study, different types of Cur-loaded liposomal formulations were prepared and characterized in terms of size, shape, zeta potential, optimal drug-to-lipid ratio and stability at 4°C, 37°C; and in human plasma in vitro. The best formulation in terms of these parameters was PEGylated, cholesterol-free formulation based upon hydrogenated soya PC (HSPC:DSPE-PEG2000:Cur, termed H5), which had a 0.05/10 molar ratio of drug-to-lipid, was found to be stable and had a 96% Cur incorporation efficiency. All Cur-loaded liposomal formulations had potent anticancer activity on the PA cancer cell lines AsPC-1 and BxPC-3, and were less toxic to a normal cell line (NHDF). Furthermore, apoptosis-induction induced by Cur in PA cells was associated with morphological changes including cell shrinkage, cytoplasmic blebbing, irregularity in shape and the externalization of cell membrane phosphatidylserine, which was preceded by an increase in intracellular reactive oxygen species (ROS) generation and caspase 3/7 activation. Because the liposomal formulations tested here, especially the H5 variant which exhibited slow release of the Cur in the human plasma test, the formulation may be stable enough to facilitate the accumulation of pharmacologically active amounts of Cur in target cancer tissue by EPR. Therefore, our formulations could serve as a promising therapeutic approach for pancreatic cancer and other cancers.

Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines

PubMed Central

Zgair, Atheer; Wong, Jonathan CM; Lee, Jong Bong; Mistry, Jatin; Sivak, Olena; Wasan, Kishor M; Hennig, Ivo M; Barrett, David A; Constantinescu, Cris S; Fischer, Peter M; Gershkovich, Pavel

2016-01-01

There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines. PMID:27648135

Remote-loading labeling of liposomes with (99m)Tc-BMEDA and its stability evaluation: effects of lipid formulation and pH/chemical gradient.

PubMed

Li, Shihong; Goins, Beth; Phillips, William T; Bao, Ande

2011-03-01

Efficient, convenient, and stable radiolabeling plays a critical role for the monitoring of liposome behavior via either blood sampling, organ distribution, or noninvasive nuclear imaging. The direct labeling of liposome-carrying drugs without any prior modification undoubtedly is convenient and optimal for liposomal drug testing. In this article, we investigated the effect of various lipid formulations and pH/chemical gradients on the radiolabeling efficiency and entrapment stability of technetium-99m ((99m)Tc) remotely loaded into liposomes, using (99m)Tc-N,N-bis(2-mercaptoethyl)-N',N'-diethyl-ethylenediamine ((99m)Tc-BMEDA) complex. The tested liposomes either contained unsaturated lipid or possessed various surface charges. (99m)Tc could be efficiently loaded into various premanufactured liposomes containing either an ammonium sulfate pH, citrate pH, or glutathione (GSH) chemical gradient. (99m)Tc-entrapment stabilities of these liposomes in phosphate-buffered saline (PBS; pH 7.4) buffer at 25°C were mainly dependent on the pH/chemical gradient, but not lipid formulation. Stability sequence was ammonium sulfate pH-gradient>citrate pH-gradient>GSH-gradient. Stabilities of (99m)Tc-liposomes in 50% fetal bovine serum (FBS)/PBS (pH 7.4) buffer at 37°C are dependent on both lipid formulation and pH/chemical gradient. Specifically, (99m)Tc labeling of the ammonium sulfate pH-gradient liposomes were less stable in 50% FBS/PBS than in PBS, whereas noncationic liposomes with citrate pH- or GSH-gradient displayed higher stability, except that anionic citrate pH-gradient liposomes showed no stability difference in these two media. Cationic liposomes aggregated in 50% FBS/PBS, forming a new discrete fraction with larger particle sizes. These in vitro characterization results have indicated the optimism of using (99m)Tc-BMEDA for labeling pH/GSH gradient liposomes without the requirement of modifying lipid formulation for liposomal therapeutic-agent development.

Effective Targeted Gene Delivery to Dendritic Cells via Synergetic Interaction of Mannosylated Lipid with DOPE and BCAT

PubMed Central

Kim, Hee-Kwon; Wei, Huiling; Kulkarni, Aditya; Pogranichniy, Roman M.; Thompson, David H.

2012-01-01

The efficient delivery of plasmids encoding antigenic determinants into dendritic cells (DCs) that control immune response is a promising strategy for rapid development of new vaccines. In this study, we prepared a series of targeted cationic lipoplex based on two synthetic lipid components, mannose-poly(ethylene glycol, MW3000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (Mannose-PEG3000-DSPE) and O-(2R-1,2-di-O-(1'Z,9'Z-octadecadienyl)-glycerol)-3-N-(bis-2-aminoethyl)-carbamate (BCAT), that were formulated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) for evaluation as non-viral vectors for transgene expression in DCs. First, we optimized the N:P ratio for maximum transfection and then screened the effects of mannose targeting for further enhancement of transfection levels. Our results indicate that efficient delivery of gWIZ GFP plasmid into DCs was observed for mannose compositions of ~10%, whereas low transfection efficiencies were observed with non-targeted formulations. Mannose-targeted lipofectamine complexes also showed high GFP expression levels in DCs relative to non-targeted lipofectamine controls. The best transfection performance was observed using 10 mol % Mannose-PEG3000-DSPE, 60 mol% BCAT, and 30 mol % DOPE, indicating that the most efficient delivery into DCs occurs via synergistic interaction between mannose targeting and acid-labile, fusogenic BCAT:DOPE formulations. Our data suggest that mannose-PEG3000-DSPE:BCAT:DOPE formulations may be effective gene delivery vehicles for the development of DC-based vaccines. PMID:22229467

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif.

PubMed

Molinos-Albert, Luis M; Bilbao, Eneritz; Agulló, Luis; Marfil, Silvia; García, Elisabet; Rodríguez de la Concepción, Maria Luisa; Izquierdo-Useros, Nuria; Vilaplana, Cristina; Nieto-Garai, Jon A; Contreras, F-Xabier; Floor, Martin; Cardona, Pere J; Martinez-Picado, Javier; Clotet, Bonaventura; Villà-Freixa, Jordi; Lorizate, Maier; Carrillo, Jorge; Blanco, Julià

2017-01-13

The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants.

Dual-modality NIRF-MRI cubosomes and hexosomes: High throughput formulation and in vivo biodistribution.

PubMed

Tran, Nhiem; Bye, Nicole; Moffat, Bradford A; Wright, David K; Cuddihy, Andrew; Hinton, Tracey M; Hawley, Adrian M; Reynolds, Nicholas P; Waddington, Lynne J; Mulet, Xavier; Turnley, Ann M; Morganti-Kossmann, M Cristina; Muir, Benjamin W

2017-02-01

Engineered nanoparticles with multiple complementary imaging modalities are of great benefit to the rapid treatment and diagnosis of disease in various organs. Herein, we report the formulation of cubosomes and hexosomes that carry multiple amphiphilic imaging contrast agents in their self-assembled lipid bilayers. This is the first report of the use of both near infrared fluorescent (NIRF) imaging and gadolinium lipid based magnetic resonance (MR) imaging modalities in cubosomes and hexosomes. High-throughput screening was used to rapidly optimize formulations with desirable nano-architectures and low in vitro cytotoxicity. The dual-modal imaging nanoparticles in vivo biodistribution and organ specific contrast enhancement were then studied. The NIRF in vivo imaging results indicated accumulation of both cubosomes and hexosomes in the liver and spleen of mice up to 20h post-injection. Remarkably, the biodistribution of the nanoparticle formulations was affected by the mesophase (i.e. cubic or hexagonal), a finding of significant importance for the future use of these compounds, with hexosomes showing higher accumulation in the spleen than the liver compared to cubosomes. Furthermore, in vivo MRI data of animals injected with either type of lyotropic liquid crystal nanoparticle displayed enhanced contrast in the liver and spleen. Copyright © 2016 Elsevier B.V. All rights reserved.

Voriconazole-Loaded Nanostructured Lipid Carriers for Ocular Drug Delivery.

PubMed

Andrade, Lígia M; Rocha, Kamilla A D; De Sá, Fernando A P; Marreto, Ricardo N; Lima, Eliana M; Gratieri, Tais; Taveira, Stephânia F

2016-06-01

To design and evaluate the potential of a topical delivery system for ocular administration of voriconazole, based on cationic nanostructured lipid carriers (NLCs). NLC dispersions composed of glyceryl behenate/capric caprylic triglyceride, polysorbate 80, sorbitan trioleate, and cetylpyridinium chloride were obtained and characterized. Ex vivo permeations experiments were performed to evaluate their drug delivery potential. NLCs presented a mean diameter of 250.2 ± 03.1 nm, narrow polydispersity index (0.288 ± 0.03), positive zeta potential (31.22 ± 3.8 mV), and over 75% encapsulation efficiency. Ex vivo ocular experiments proved that NLCs were able to deliver therapeutically relevant drug amounts to the cornea after only 30 minutes (13.88 ± 0.24 μg/cm). The formulation was nonexpensive, easy to prepare, and composed of well-tolerated and accepted excipients. Further in vivo experiments are necessary to confirm the improved performance and tolerability of the formulation.

Solvent-free melting techniques for the preparation of lipid-based solid oral formulations.

PubMed

Becker, Karin; Salar-Behzadi, Sharareh; Zimmer, Andreas

2015-05-01

Lipid excipients are applied for numerous purposes such as taste masking, controlled release, improvement of swallowability and moisture protection. Several melting techniques have evolved in the last decades. Common examples are melt coating, melt granulation and melt extrusion. The required equipment ranges from ordinary glass beakers for lab scale up to large machines such as fluid bed coaters, spray dryers or extruders. This allows for upscaling to pilot or production scale. Solvent free melt processing provides a cost-effective, time-saving and eco-friendly method for the food and pharmaceutical industries. This review intends to give a critical overview of the published literature on experiences, formulations and challenges and to show possibilities for future developments in this promising field. Moreover, it should serve as a guide for selecting the best excipients and manufacturing techniques for the development of a product with specific properties using solvent free melt processing.

Innovations in the development of healthier chicken sausages formulated with different lipid sources.

PubMed

Andrés, S C; Zaritzky, N E; Califano, A N

2009-08-01

Long-chain polyunsaturated n-3 fatty acids are critical nutrients for human health and the fortification of foods with these fatty acids is an important emerging area from the commercial and academic point of view. Development, characterization, and changes during refrigerated vacuum storage of low-fat chicken sausages formulated with preemulsified squid oil were examined and compared with those formulated with beef tallow. Physicochemical analysis and process yield after heat treatment were determined; the heat-treated sausages were evaluated by purge loss, color, texture, microstructure by SEM, microbial counts, fatty acid profile, lipid oxidation, and sensory analysis during refrigerated vacuum storage. Process yield of both formulations was higher than 97% and purge losses during storage were lower than 7%. Purge losses of oil-formulated sausages were lower than those with beef tallow. Sausages with squid oil resulted in higher lightness, lower redness and yellowness, and lower texture profile analysis parameters than the formulation prepared with beef tallow. Microstructure of both formulations was similar, except for the fat droplets that microscopic observations showed in the sausages made with beef tallow. Low lipid oxidation was detected in formulation with squid oil due to the the combination of ingredients and storage conditions. Microbial counts of both products were less than 5 log cfu/g at the end of 90 d of storage. The sausage formulated with squid oil presented more than 30 and 40 g/100 g of monounsaturated and polyunsaturated fatty acids, respectively. Docosahexaenoic acid was the predominant polyunsaturated fatty acid, followed by eicosapentaenoic acid and linoleic acid. Both products showed safe sanitary conditions, good sensory acceptability, and presented very good stability and quality attributes, but sausages formulated with squid oil showed a better fatty acid profile according to nutritional criteria.

Impact of gastrointestinal lipolysis on oral lipid-based formulations and bioavailability of lipophilic drugs.

PubMed

Carrière, Frédéric

2016-06-01

Oil-in-water emulsions are common vehicles for lipids as nutrients and for the delivery of poorly water-soluble drugs. Enhancing oral bioavailability of these drugs using lipid-based formulations (LBF) or self-emulsifying drug delivery systems is one of the current challenges in pharmaceutical industry. Many of the compounds found in LBF (acylglycerols, surfactants with esterified fatty acids, …) are however potential substrates for digestive enzymes. Their digestion (or lipolysis) in the gastrointestinal (GI) tract is critical for drug dissolution and absorption: it can be beneficial (drug solubilization/dispersion) or deleterous (drug precipitation) depending on the drug-LBF association. A better understanding of the fate of LBF in the GI tract is therefore required to engineer efficient lipid-based drug delivery systems. In vitro models for testing simultaneously LBF digestion and drug dispersion are in development to predict drug solubilization and bioavailability, select the best drug-LBF association and obtain better in vitro-in vivo correlations. So far, research in this area has focused on LBF lipolysis under intestinal conditions because the small intestine is the main target for drug delivery and absorption, as well as the main site of digestion by pancreatic enzymes. Lipolysis however starts within the stomach through the action of gastric lipase, the first enzyme involved in fat digestion in humans. In vitro digestion experiments show that most LBFs are submitted to gastric lipolysis, and therefore, both intragastric and intestinal digestions are critical for the fate of LBF and drug solubility. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Development, characterization, and evaluation of sunscreen cream containing solid lipid nanoparticles of silymarin.

PubMed

Netto MPharm, Gladyston; Jose, Jobin

2017-12-10

Most of the sunscreen formulations mainly contain chemicals or synthetic molecules. Nowadays, researchers are mainly focussing on herbal formulations due to toxicity of the synthetic molecules. Silymarin is a natural flavonoids having excellent antioxidant properties. Solid lipid nanoparticles are novel drug carriers which improve the drug stability and tolerance effect and also enhance the permeation effect. This study aimed at the preparation of solid lipid nanoparticles containing silymarin that will be incorporated into a sunscreen cream and determine its sun protection factor. The solid lipid nanoparticles were prepared by micro-emulsion method; here, the glyceryl monostearate was used as lipid, and Tween 80 was used as an emulsifier. The solid lipid nanoparticles were evaluated for drug entrapment, particle size and morphology, zeta potential, and polydispersity index. The dispersion was formulated into sunscreen cream and evaluated for various parameters, such as extrudability, viscosity, spreadability, drug content, in vitro drug release, ex vivo permeation of drug, in vitro and in vivo sun protection factor determination, in vivo skin irritation test, and accelerated stability studies. The results suggested that as the concentration of emulsifier increased, the entrapment efficiency of silymarin increased. In vitro and in vivo sun protection factor determination showed that SPF of 13.80 and 14.1, respectively. Stability studies were performed under accelerated conditions, and it did not show any appreciable change in parameters. These results indicated that the sunscreen containing silymarin solid lipid nanoparticles exhibited better photoprotective action. © 2017 Wiley Periodicals, Inc.

Lipid-based oral delivery systems for skin deposition of a potential chemopreventive DIM derivative: characterization and evaluation.

PubMed

Boakye, Cedar H A; Patel, Ketan; Patel, Apurva R; Faria, Henrique A M; Zucolotto, Valtencir; Safe, Stephen; Singh, Mandip

2016-10-01

The objective of this study was to explore the oral route as a viable potential for the skin deposition of a novel diindolylmethane derivative (DIM-D) for chemoprevention activity. Various lipid-based oral delivery systems were optimized and compared for enhancing DIM-D's oral bioavailability and skin deposition. Preformulation studies were performed to evaluate the log P and solubility of DIM-D. Microsomal metabolism, P-glycoprotein efflux, and caco-2 monolayer permeability of DIM-D were determined. Comparative evaluation of the oral absorption and skin deposition of DIM-D-loaded various lipid-based formulations was performed in rats. DIM-D showed pH-dependent solubility and a high log P value. It was not a strong substrate of microsomal degradation and P-glycoprotein. SMEDDs comprised of medium chain triglycerides, monoglycerides, and kolliphor-HS15 (36.70 ± 0.42 nm). SNEDDs comprised of long chain triglycerides, cremophor RH40, labrasol, and TPGS (84.00 ± 14.14 nm). Nanostructured lipid carriers (NLC) consisted of compritol, miglyol, and surfactants (116.50 ± 2.12 nm). The blank formulations all showed >70 % cell viability in caco-2 cells. Differential Scanning Calorimetry confirmed the amorphization of DIM-D within the lipid matrices while Atomic Force Microscopy showed particle size distribution similar to the dynamic light scattering data. DIM-D also showed reduced permeation across caco-2 monolayer that was enhanced (p < 0.05) by SNEDDs in comparison to SMEDDs and NLC. Fabsolute for DIM-D SNEDDs, SMEDDs, and NLC was 0.14, 0.04, and 0.007, respectively. SNEDDs caused 53.90, 11.32, and 15.08-fold more skin deposition of DIM-D than the free drug, SMEDDs, and NLC, respectively, at 2 h following oral administration and shows a viable potential for use in skin cancer chemoprevention. Graphical Abstract ᅟ.

Curcumin-loaded solid lipid nanoparticles have prolonged in vitro antitumour activity, cellular uptake and improved in vivo bioavailability.

PubMed

Sun, Jiabei; Bi, Chao; Chan, Hok Man; Sun, Shaoping; Zhang, Qingwen; Zheng, Ying

2013-11-01

The aim of the present study was to blend liquid lipids with solid lipids to encapsulate curcumin in solid lipid nanoparticles (SLNs), thereby improving the dispersibility and chemical stability of curcumin, prolonging its antitumour activity and cellular uptake and enhancing its bioavailability. Curcumin-loaded SLNs (C-SLNs) were prepared by high-pressure homogenisation with liquid lipid Sefsol-218(®). The morphology, stability and release of curcumin in the optimised formulation were investigated. The anti-cancer activity of the formulation was evaluated in MCF-7 cells. Fluorescence spectrophotometry was used to quantify cellular uptake of the drug. The pharmacokinetic profiles of curcumin in SLNs after intravenous administration were studied in rats. Blending Sefsol-218(®) into a lipid matrix reduced the particle size without improving drug loading. An optimised formulation consisting of Dynasan 114(®), Sefsol-218(®), and Pluronic F68(®) (630:70:300, w/w) loaded with 0.8% drug was prepared. This formulation could be dispersed in water with a mean particle size of 152.8 ± 4.7 nm and a 90% entrapment efficiency. Curcumin displayed a two-phase sustained release profile from C-SLNs with improved chemical stability. Compared to the solubilised solution, C-SLNs exhibited prolonged inhibitory activity in cancer cells, as well as time-dependent increases in intracellular uptake. After intravenous administration to rats, the bioavailability of curcumin was increased by 1.25-fold. C-SLNs with improved dispersibility and chemical stability in an aqueous system have been successfully developed. C-SLNs may represent a potentially useful cancer therapeutic curcumin delivery system. Copyright © 2013 Elsevier B.V. All rights reserved.

Formulation and Characterization of Echogenic Lipid–Pluronic Nanobubbles

PubMed Central

Krupka, Tianyi M.; Solorio, Luis; Wilson, Robin E.; Wu, Hanping; Azar, Nami; Exner, Agata A.

2012-01-01

The advent of microbubble contrast agents has enhanced the capabilities of ultrasound as a medical imaging modality and stimulated innovative strategies for ultrasound-mediated drug and gene delivery. While the utilization of microbubbles as carrier vehicles has shown encouraging results in cancer therapy, their applicability has been limited by a large size which typically confines them to the vasculature. To enhance their multifunctional contrast and delivery capacity, it is critical to reduce bubble size to the nanometer range without reducing echogenicity. In this work, we present a novel strategy for formulation of nanosized, echogenic lipid bubbles by incorporating the surfactant Pluronic, a triblock copolymer of ethylene oxide copropylene oxide coethylene oxide into the formulation. Five Pluronics (L31, L61, L81, L64 and P85) with a range of molecular weights (Mw: 1100 to 4600 Da) were incorporated into the lipid shell either before or after lipid film hydration and before addition of perfluorocarbon gas. Results demonstrate that Pluronic–lipid interactions lead to a significantly reduced bubble size. Among the tested formulations, bubbles made with Pluronic L61 were the smallest with a mean hydrodynamic diameter of 207.9 ± 74.7 nm compared to the 880.9 ± 127.6 nm control bubbles. Pluronic L81 also significantly reduced bubble size to 406.8 ± 21.0 nm. We conclude that Pluronic is effective in lipid bubble size control, and Pluronic Mw, hydrophilic–lipophilic balance (HLB), and Pluronic/ lipid ratio are critical determinants of the bubble size. Most importantly, our results have shown that although the bubbles are nanosized, their stability and in vitro and in vivo echogenicity are not compromised. The resulting nanobubbles may be better suited for contrast enhanced tumor imaging and subsequent therapeutic delivery. PMID:19957968

Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA

NASA Astrophysics Data System (ADS)

Li, Bin; Luo, Xiao; Deng, Binbin; Giancola, Jolynn B.; McComb, David W.; Schmittgen, Thomas D.; Dong, Yizhou

2016-02-01

Lipid-like nanoparticles (LLNs) have shown great potential for RNA delivery. Lipid-like compounds are key components in LLNs. In this study, we investigated the effects of local structural transformation of lipid-like compounds on delivery of messenger RNA. Our results showed that position change of functional groups on lipid-like compounds can dramatically improve delivery efficiency. We then optimized formulation ratios of TNT-b10 LLNs, a lead material, increasing delivery efficiency over 2-fold. More importantly, pegylated TNT-b10 LLNs is stable for over four weeks and is over 10-fold more efficient than that of its counterpart TNT-a10 LLNs. Additionally, the optimal formulation O-TNT-b10 LLNs is capable of delivering mRNA encoding luciferase in vivo. These results provide useful insights into the design of next generation LLNs for mRNA delivery.

Optimization of nanostructured lipid carriers for topical delivery of nimesulide using Box-Behnken design approach.

PubMed

Moghddam, Seyedeh Marziyeh Mahdavi; Ahad, Abdul; Aqil, Mohd; Imam, Syed Sarim; Sultana, Yasmin

2017-05-01

The aim of the present study was to develop and optimize topically applied nimesulide-loaded nanostructured lipid carriers. Box-Behnken experimental design was applied for optimization of nanostructured lipid carriers. The independent variables were ratio of stearic acid: oleic acid (X 1 ), poloxamer 188 concentration (X 2 ) and lecithin concentration (X 3 ) while particle size (Y 1 ) and entrapment efficiency (Y 2 ) were the chosen responses. Further, skin penetration study, in vitro release, confocal laser scanning microscopy and stability study were also performed. The optimized nanostructured lipid carriers of nimesulide provide reasonable particle size, flux, and entrapment efficiency. Optimized formulation (F9) with mean particle size of 214.4 ± 11 nm showed 89.4 ± 3.40% entrapment efficiency and achieved mean flux 2.66 ± 0.09 μg/cm 2 /h. In vitro release study showed prolonged drug release from the optimized formulation following Higuchi release kinetics with R 2 value of 0.984. Confocal laser scanning microscopy revealed an enhanced penetration of Rhodamine B-loaded nanostructured lipid carriers to the deeper layers of the skin. The stability study confirmed that the optimized formulation was considerably stable at refrigerator temperature as compared to room temperature. Our results concluded that nanostructured lipid carriers are an efficient carrier for topical delivery of nimesulide.

High throughput screening: an in silico solubility parameter approach for lipids and solvents in SLN preparations.

PubMed

Shah, Malay; Agrawal, Yadvendra

2013-01-01

The present paper describes an in silico solubility behavior of drug and lipids, an essential screening study in preparation of solid lipid nanoparticles (SLN). Ciprofloxacin HCl was selected as a model drug along with 11 lipids and 5 organic solvents. In silico miscibility study of drug/lipid/solvent was performed using Hansen solubility parameter approach calculated by group contribution method of Van Krevelen and Hoftyzer. Predicted solubility was validated by determining solubility of lipids in various solvent at different temperature range, while miscibility of drug in lipids was determined by apparent solubility study and partition experiment. The presence of oxygen and OH functionality increases the polarity and hydrogen bonding possibilities of the compound which has reflected the highest solubility parameter values for Geleol and Capmul MCM C8. Ethyl acetate, Geleol and Capmul MCM C8 was identified as suitable organic solvent, solid lipid and liquid lipid respectively based on a solubility parameter approach which was in agreement with the result of an apparent solubility study and partition coefficient. These works demonstrate the validity of solubility parameter approach and provide a feasible predictor to the rational selection of excipients in designing SLN formulation.

α-Tocopherol/chitosan-based nanoparticles: characterization and preliminary investigations for emulsion systems application

NASA Astrophysics Data System (ADS)

Aresta, Antonella; Calvano, Cosima Damiana; Trapani, Adriana; Zambonin, Carlo Giorgio; De Giglio, Elvira

2014-02-01

The processes of lipids oxidation represent a great concern for the consumer health because they are one of the major causes of quality deterioration in fat-containing products. One of the most effective methods of delaying lipid oxidation consists in incorporating antioxidants. The present investigation describes the formulation of chitosan and novel glycol chitosan nanoparticles (NPs) loaded with α-Tocopherol (αToc-NPs). The obtained NPs were characterized by various techniques, such as particle size (showing mean diameters in the range 335-503 nm) and zeta potential measurements, X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. The NPs were, then, added in the preparation of oil-in-water simple emulsion both to make the lipophilic αToc available in an aqueous medium and to prevent emulsion oxidation. For this purpose, a new highly sensitive, simple and solvent-free method based on a solid phase microextraction (SPME) coupled to gas chromatography mass spectrometry was developed for the determination of αToc in aqueous medium. All the parameters influencing SPME, including fiber coating, time and temperature extraction, pH, ionic strength and desorption conditions, have been carefully screened. The method was successfully applied to the determination of vitamin in the αToc-NPs and its release from NPs-enriched simple emulsion formulations. SPME provided high recovery yields and the limits of detection and of quantification in emulsion were 0.1 and 0.5 μg/mg, respectively. The precision of the method has been also estimated. The delay of the lipid oxidation by the proposed formulations has been evaluated exploiting the Kreis test on αToc-NPs-enriched emulsions.

Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

PubMed Central

Jang, Yura; Chung, Hye Jin; Hong, Jung Wan; Yun, Cheol-Won; Chung, Hesson

2017-01-01

Paclitaxel is a most widely used anticancer drug with low oral bioavailability, thus it is currently administered via intravenous infusion. DHP107 is a lipid-based paclitaxel formulation that can be administered as an oral solution. In this study, we investigated the mechanism of paclitaxel absorption after oral administration of DHP107 in mice and rats by changing the dosing interval, and evaluated the influence of bile excretion. DHP107 was orally administered to mice at various dosing intervals (2, 4, 8, 12, 24 h) to examine how residual DHP107 affected paclitaxel absorption during subsequent administration. Studies with small-angle X-ray diffraction (SAXS) and cryo-transmission electron microscopy (cryo-TEM) showed that DHP107 formed a lipidic sponge phase after hydration. The AUC values after the second dose were smaller than those after the first dose, which was correlated to the induction of expression of P-gp and CYP in the livers and small intestines from 2 h to 7 d after the first dose. The smaller AUC value observed after the second dose was also attributed to the intestinal adhesion of residual formulation. The adhered DHP107 may have been removed by ingested food, thus resulting in a higher AUC. In ex vivo and in vivo mucoadhesion studies, the formulation adhered to the villi for up to 24 h, and the amount of DHP107 that adhered was approximately half that of monoolein. The paclitaxel absorption after administration of DHP107 was not affected by bile in the cholecystectomy mice. The dosing interval and food intake affect the oral absorption of paclitaxel from DHP107, which forms a mucoadhesive sponge phase after hydration. Bile excretion does not affect the absorption of paclitaxel from DHP107 in vivo. PMID:27867185

Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase.

PubMed

Jang, Yura; Chung, Hye Jin; Hong, Jung Wan; Yun, Cheol-Won; Chung, Hesson

2017-01-01

Paclitaxel is a most widely used anticancer drug with low oral bioavailability, thus it is currently administered via intravenous infusion. DHP107 is a lipid-based paclitaxel formulation that can be administered as an oral solution. In this study, we investigated the mechanism of paclitaxel absorption after oral administration of DHP107 in mice and rats by changing the dosing interval, and evaluated the influence of bile excretion. DHP107 was orally administered to mice at various dosing intervals (2, 4, 8, 12, 24 h) to examine how residual DHP107 affected paclitaxel absorption during subsequent administration. Studies with small-angle X-ray diffraction (SAXS) and cryo-transmission electron microscopy (cryo-TEM) showed that DHP107 formed a lipidic sponge phase after hydration. The AUC values after the second dose were smaller than those after the first dose, which was correlated to the induction of expression of P-gp and CYP in the livers and small intestines from 2 h to 7 d after the first dose. The smaller AUC value observed after the second dose was also attributed to the intestinal adhesion of residual formulation. The adhered DHP107 may have been removed by ingested food, thus resulting in a higher AUC. In ex vivo and in vivo mucoadhesion studies, the formulation adhered to the villi for up to 24 h, and the amount of DHP107 that adhered was approximately half that of monoolein. The paclitaxel absorption after administration of DHP107 was not affected by bile in the cholecystectomy mice. The dosing interval and food intake affect the oral absorption of paclitaxel from DHP107, which forms a mucoadhesive sponge phase after hydration. Bile excretion does not affect the absorption of paclitaxel from DHP107 in vivo.

Preparation, Characterization and Evaluation of Quetiapine Fumarate Solid Lipid Nanoparticles to Improve the Oral Bioavailability

PubMed Central

Narala, Arjun; Veerabrahma, Kishan

2013-01-01

Quetiapine fumarate is an antipsychotic drug with poor oral bioavailability (9%) due to first-pass metabolism. Present work is an attempt to improve oral bioavailability of quetiapine fumarate by incorporating in solid lipid nanoparticles (SLN). Six quetiapine fumarate SLN formulations were developed using three different lipids by hot homogenisation followed by ultrasonication. The drug excipient compatibility was studied by differential scanning calorimetry (DSC). Stable quetiapine fumarate SLNs having a mean particle size of 200–250 nm with entrapment efficiency varying in between 80% and 92% were developed. The physical stability of optimized formulation F3 was checked at room temperature for 2 months. Comparative bioavailability studies were conducted in male Wistar rats after oral administration of quetiapine fumarate suspension and SLN formulation. The relative bioavailability of quetiapine fumarate from optimized SLN preparation was increased by 3.71 times when compared with the reference quetiapine fumarate suspension. The obtained results are indicative of SLNs as potential lipid carriers for improving the bioavailability of quetiapine fumarate by minimizing first-pass metabolism. PMID:26555970

A Glu-urea-Lys Ligand-conjugated Lipid Nanoparticle/siRNA System Inhibits Androgen Receptor Expression In Vivo

PubMed Central

Lee, Justin B; Zhang, Kaixin; Tam, Yuen Yi C; Quick, Joslyn; Tam, Ying K; Lin, Paulo JC; Chen, Sam; Liu, Yan; Nair, Jayaprakash K; Zlatev, Ivan; Rajeev, Kallanthottathil G; Manoharan, Muthiah; Rennie, Paul S; Cullis, Pieter R

2016-01-01

The androgen receptor plays a critical role in the progression of prostate cancer. Here, we describe targeting the prostate-specific membrane antigen using a lipid nanoparticle formulation containing small interfering RNA designed to silence expression of the messenger RNA encoding the androgen receptor. Specifically, a Glu-urea-Lys PSMA-targeting ligand was incorporated into the lipid nanoparticle system formulated with a long alkyl chain polyethylene glycol-lipid to enhance accumulation at tumor sites and facilitate intracellular uptake into tumor cells following systemic administration. Through these features, and by using a structurally refined cationic lipid and an optimized small interfering RNA payload, a lipid nanoparticle system with improved potency and significant therapeutic potential against prostate cancer and potentially other solid tumors was developed. Decreases in serum prostate-specific antigen, tumor cellular proliferation, and androgen receptor levels were observed in a mouse xenograft model following intravenous injection. These results support the potential clinical utility of a prostate-specific membrane antigen–targeted lipid nanoparticle system to silence the androgen receptor in advanced prostate cancer. PMID:28131285

Composition and consumer acceptability of a novel extrusion-cooked salmon snack.

PubMed

Kong, J; Dougherty, M P; Perkins, L B; Camire, M E

2008-04-01

The objectives of this study were to develop a value-added jerky-style snack from salmon flesh and to minimize loss of healthful lipids during processing. Three formulations were extruded in a laboratory-scale twin-screw extruder. The base formulation included Atlantic salmon (82%, w/w), sucrose (4%), pregelatinized starch (3%), modified tapioca starch (3%), salt (2%), and teriyaki flavoring (2%). Three oil binding agents (tapioca starch, high-amylose cornstarch, oat fiber) were each studied at the 4% level. Barrel temperature, from feed to die, was 65, 155, 155, and 80 degrees C. Screw speed was 250 rpm. Feed rate was 220 g/min. Extrudates were convection-dried at 93 degrees C for 40 min. A texture analyzer was used to evaluate textural properties. Sixty-three consumers evaluated the hedonic attributes of the snacks. Extrusion cooking did not adversely affect content of omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in Atlantic salmon. The oat fiber formulation had the highest lipid (17.49%) content. The other formulations had higher moisture content. A serving (28 g) of the oat formulation provides 0.6 g EPA + DHA. Snacks containing oat fiber had the highest CIE L* and b* values. Snacks containing oat fiber required greater force to bend, cut, and puncture. The oat fiber formulation had the lowest overall acceptability. This portable snack could appeal to consumers who are interested in the health benefits of fish and omega-3 fatty acids and provide salmon processors with a value-added solution for processing by-products.

Release of Liposomal Contents by Cell-Secreted Matrix Metalloproteinase-9

PubMed Central

Banerjee, Jayati; Hanson, Andrea J.; Gadam, Bhushan; Elegbede, Adekunle I.; Tobwala, Shakila; Ganguly, Bratati; Wagh, Anil; Muhonen, Wallace W.; Law, Benedict; Shabb, John B.; Srivastava, D. K.; Mallik, Sanku

2011-01-01

Liposomes have been widely used as a drug delivery vehicle and currently, more than 10 liposomal formulations are approved by the Food and Drug Administration for clinical use. However, upon targeting, the release of the liposome-encapsulated contents is usually slow. We have recently demonstrated that contents from appropriately-formulated liposomes can be rapidly released by the cancer-associated enzyme matrix metalloproteinase-9 (MMP-9). Herein, we report our detailed studies to optimize the liposomal formulations. By properly selecting the lipopeptide, the major lipid component and their relative amounts, we demonstrate that the contents are rapidly released in the presence of cancer-associated levels of recombinant human MMP-9. We observed that the degree of lipid mismatch between the lipopepides and the major lipid component profoundly affects the release profiles from the liposomes. By utilizing the optimized liposomal formulations, we also demonstrate that cancer cells (HT-29) which secrete low levels of MMP-9 failed to release significant amount of the liposomal contents. Metastatic cancer cells (MCF7) secreting high levels of the enzyme rapidly release the encapsulated contents from the liposomes. PMID:19601658

Development and characterization of controlled release polar lipid microparticles of candesartan cilexetil by solid dispersion

PubMed Central

Kamalakkannan, V; Puratchikody, A; Ramanathan, L

2013-01-01

Candesartan cilexetil (CC) is a newer class of angiotensin II receptor antagonist used for the treatment of hypertension. The solubility of the CC is very poor and its oral bioavailability is only 15%. The controlledrelease polar lipid microparticles of CC (formulations F1, F2, F3 and F4) were prepared using variable erodible lipophilic excipients like hydrogenated castor oil, stearic acid, cetostearyl alcohol and carnauba wax by fusion method. The particle sizes of polar lipid microparticles were less than 50 microns and they were irregular in shape. Drug content ranged between 98.96 ± 2.1 and 101.9 ± 1.6% were present in all the formulations. The formulation F3 showed better drug release throughout the study period in a controlled release manner. Moreover, the in vitro release showed that all the formulations were best fitted to Higuchi model. Accelerated stability studies indicated that there was no significant changes in the chemical and physical characteristics of the formulated drug product during initial and at the end of the study period. The FTIR and DSC studies showed that there was no interaction between the drug and lipophilic excipients and no polymorphic transitions in all formulations. The X-ray diffraction peak of solid dispersion indicated that the crystalline nature of CC disappeared and no new peaks could be observed, suggesting the absence of interaction between drug and excipients. PMID:24019822

Influence of grape seed extract and zinc containing multivitamin-mineral nutritional food supplement on lipid profile in normal and diet-induced hypercholesterolemic rats.

PubMed

Satyam, Shakta Mani; Bairy, Laxminarayana Kurady; Pirasanthan, Rajadurai

2014-12-01

Zincovit tablet is combination of grape seed extract and zinc containing multivitamin-mineral nutritional food supplement. To investigate the influence of single combined formulation of grape seed extract and zinc containing multivitamin-mineral nutritional food supplement tablets (Zincovit) on lipid profile in normal and diet-induced hypercholesterolemic rats. Anti-hyperlipidemic activity of combined formulation of grape seed extract and Zincovit tablets doses ranged from 40 to 160 mg/kg, p.o. was evaluated in normal and diet-induced hypercholesterolemic rats. Hypercholesterolemic animals treated with combined formulation of grape seed extract and Zincovit tablets (nutritional food supplement) at 40, 80 and 160 mg/kg exhibited drastic decrease in serum triglycerides, total cholesterol, LDL-C, VLDL-C and rise of HDL-C in comparison to hypercholesterolemic control group animals. The anti-hyperlipidemic effect of single combined formulation of grape seed extract and Zincovit tablet was comparable with the standard drug atorvastatin treated animals and the variations were statistically non-significant. There was no significant impact of combined formulation of grape seed extract and Zincovit tablets on lipid profile among normal animals in comparison with normal control group. The present study demonstrated that the single combined formulation of grape seed extract and Zincovit tablet is the potential functional nutritional food supplements that could offer a novel therapeutic opportunity against diet-induced hypercholesterolemia in Wistar rats.

Nano-Science-Engineering-Technology Applications to Food and Nutrition.

PubMed

Nakajima, Mitsutoshi; Wang, Zheng; Chaudhry, Qasim; Park, Hyun Jin; Juneja, Lekh R

2015-01-01

Nanoscale Science, Engineering and Technology are applied to Food and Nutrition. Various delivery systems include nanoemulsions, microemulsions, solid lipid nanoparticles, micelles, and liposomes. The nanoscale systems have advantages, such as higher bioavailabitity, and other physicochemical properties. The symposium will provide an overview of the formulation, characterization, and utilization of nanotechnology-based food and nutrition.

Multiscale structures of lipids in foods as parameters affecting fatty acid bioavailability and lipid metabolism.

PubMed

Michalski, M C; Genot, C; Gayet, C; Lopez, C; Fine, F; Joffre, F; Vendeuvre, J L; Bouvier, J; Chardigny, J M; Raynal-Ljutovac, K

2013-10-01

On a nutritional standpoint, lipids are now being studied beyond their energy content and fatty acid (FA) profiles. Dietary FA are building blocks of a huge diversity of more complex molecules such as triacylglycerols (TAG) and phospholipids (PL), themselves organised in supramolecular structures presenting different thermal behaviours. They are generally embedded in complex food matrixes. Recent reports have revealed that molecular and supramolecular structures of lipids and their liquid or solid state at the body temperature influence both the digestibility and metabolism of dietary FA. The aim of the present review is to highlight recent knowledge on the impact on FA digestion, absorption and metabolism of: (i) the intramolecular structure of TAG; (ii) the nature of the lipid molecules carrying FA; (iii) the supramolecular organization and physical state of lipids in native and formulated food products and (iv) the food matrix. Further work should be accomplished now to obtain a more reliable body of evidence and integrate these data in future dietary recommendations. Additionally, innovative lipid formulations in which the health beneficial effects of either native or recomposed structures of lipids will be taken into account can be foreseen. Copyright © 2013 Elsevier Ltd. All rights reserved.

Color profiles and stability of acylated and nonacylated anthocyanins as novel pigment sources in a lipstick model: A viable alternative to synthetic colorants.

PubMed

Westfall, Alexandra; Giusti, Mónica

Cosmetics, such as lipstick, can affect an individual's perception of attractiveness and morale. Consumer concern with the safety of synthetic colorants has made the need for alternative natural color sources increasingly urgent. Our goal was to evaluate the feasibility of anthocyanin (ACN) extracts as colorants in lipstick formulations. Lipstick formulations were colored with ACN-rich materials. Accelerated environmental testing typical of the cosmetic industry were used: incubation at 20°, 37°, and 45°C for 12 weeks and temperature abuse cycles between 20°/37°C or -20°/20°C. Color (CIELab) and total monomeric ACN (pH-differential) changes were monitored to determine shelf stability of the product. All formulations exhibited acceptable color for lipsticks. Shelf stability was determined to exceed 2 year based on the accelerated testing conditions. Formulations containing cyanidin as their main ACN were the most stable (elderberry, purple corn, and purple sweet potato). ACNs could be used as suitable alternatives to synthetic colorants in lipid-based topical formulations.

Characteristics of lipids and their feeding value in swine diets

USDA-ARS?s Scientific Manuscript database

In livestock diets, energy is one of the most expensive nutritional components of feed formulation. Because lipids are a concentrated energy source, inclusion of lipids are known to affect growth rate and feed efficiency, but are also known to affect diet palatability, feed dustiness, and pellet qua...

Development and evaluation of resveratrol, Vitamin E, and epigallocatechin gallate loaded lipid nanoparticles for skin care applications.

PubMed

Chen, Jin; Wei, Ning; Lopez-Garcia, Maria; Ambrose, Dianna; Lee, Jason; Annelin, Colin; Peterson, Teresa

2017-08-01

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been studied as potential carriers for both dermal and transdermal drug delivery. SLN contain lipid droplets that are fully crystallized and have a highly-ordered crystalline structure. NLC are modified SLN in which the lipid phase contains both solid and liquid lipids at room temperature. SLN and NLC are thought to combine the advantages of polymeric particles, liposomes and emulsions. Therefore they provide high encapsulation percentages, better protection for incorporated actives and allow for control of desired release profile. In this work, Resveratrol, Vitamin E (VE), and Epigallocatechin Gallate (EGCG) all potent antioxidants known to provide protection to the skin, were formulated into lipid nanoparticles. Several different formulations were successfully developed and demonstrated high uniformity and stability. Both resveratrol and VE lipid nanoparticles provided effective protection of actives against UV induced degradation. However, lipid nanoparticles did not show protection from UV degradation for EGCG in this work. An active release study exhibited a sustained release of resveratrol over 70% after 24h. Skin penetration studies showed that lipid nanoparticles directionally improved the penetration of resveratrol through the stratum corneum. Our findings suggest that lipid nanoparticles are promising viable carriers for the delivery of resveratrol and VE to provide longlasting antioxidant benefits to the skin. Copyright © 2017 Elsevier B.V. All rights reserved.

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

PubMed Central

Molinos-Albert, Luis M.; Bilbao, Eneritz; Agulló, Luis; Marfil, Silvia; García, Elisabet; Concepción, Maria Luisa Rodríguez de la; Izquierdo-Useros, Nuria; Vilaplana, Cristina; Nieto-Garai, Jon A.; Contreras, F.-Xabier; Floor, Martin; Cardona, Pere J.; Martinez-Picado, Javier; Clotet, Bonaventura; Villà-Freixa, Jordi; Lorizate, Maier; Carrillo, Jorge; Blanco, Julià

2017-01-01

The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants. PMID:28084464

Pharmaceutical Dispersion Techniques for Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs.

PubMed

Zhang, Xingwang; Xing, Huijie; Zhao, Yue; Ma, Zhiguo

2018-06-23

Over the past decades, a large number of drugs as well as drug candidates with poor dissolution characteristics have been witnessed, which invokes great interest in enabling formulation of these active ingredients. Poorly water-soluble drugs, especially biopharmaceutical classification system (BCS) II ones, are preferably designed as oral dosage forms if the dissolution limit can be broken through. Minimizing a drug’s size is an effective means to increase its dissolution and hence the bioavailability, which can be achieved by specialized dispersion techniques. This article reviews the most commonly used dispersion techniques for pharmaceutical processing that can practically enhance the dissolution and bioavailability of poorly water-soluble drugs. Major interests focus on solid dispersion, lipid-based dispersion (nanoencapsulation), and liquisolid dispersion (drug solubilized in a non-volatile solvent and dispersed in suitable solid excipients for tableting or capsulizing), covering the formulation development, preparative technique and potential applications for oral drug delivery. Otherwise, some other techniques that can increase the dispersibility of a drug such as co-precipitation, concomitant crystallization and inclusion complexation are also discussed. Various dispersion techniques provide a productive platform for addressing the formulation challenge of poorly water-soluble drugs. Solid dispersion and liquisolid dispersion are most likely to be successful in developing oral dosage forms. Lipid-based dispersion represents a promising approach to surmounting the bioavailability of low-permeable drugs, though the technique needs to traverse the obstacle from liquid to solid transformation. Novel dispersion techniques are highly encouraged to develop for formulation of poorly water-soluble drugs.

Influence of Surfactant and Lipid Type on the Physicochemical Properties and Biocompatibility of Solid Lipid Nanoparticles

PubMed Central

Pizzol, Carine Dal; Filippin-Monteiro, Fabíola Branco; Restrepo, Jelver Alexander Sierra; Pittella, Frederico; Silva, Adny Henrique; de Souza, Paula Alves; de Campos, Angela Machado; Creczynski-Pasa, Tânia Beatriz

2014-01-01

Nine types of solid lipid nanoparticle (SLN) formulations were produced using tripalmitin (TPM), glyceryl monostearate (GM) or stearic acid (SA), stabilized with lecithin S75 and polysorbate 80. Formulations were prepared presenting PI values within 0.25 to 0.30, and the physicochemical properties, stability upon storage and biocompatibility were evaluated. The average particle size ranged from 116 to 306 nm, with a negative surface charge around −11 mV. SLN presented good stability up to 60 days. The SLN manufactured using SA could not be measured by DLS due to the reflective feature of this formulation. However, TEM images revealed that SA nanoparticles presented square/rod shapes with an approximate size of 100 nm. Regarding biocompatibility aspects, SA nanoparticles showed toxicity in fibroblasts, causing cell death, and produced high hemolytic rates, indicating toxicity to red blood cells. This finding might be related to lipid type, as well as, the shape of the nanoparticles. No morphological alterations and hemolytic effects were observed in cells incubated with SLN containing TPM and GM. The SLN containing TPM and GM showed long-term stability, suggesting good shelf-life. The results indicate high toxicity of SLN prepared with SA, and strongly suggest that the components of the formulation should be analyzed in combination rather than separately to avoid misinterpretation of the results. PMID:25141003

A novel nanoscale-dispersed eye ointment for the treatment of dry eye disease

NASA Astrophysics Data System (ADS)

Zhang, Wenjian; Wang, Yan; Lee, Benjamin Tak Kwong; Liu, Chang; Wei, Gang; Lu, Weiyue

2014-03-01

A novel nanoscale-dispersed eye ointment (NDEO) for the treatment of severe evaporative dry eye has been successfully developed. The excipients used as semisolid lipids were petrolatum and lanolin, as used in conventional eye ointment, which were coupled with medium-chain triglycerides (MCT) as a liquid lipid; both phases were then dispersed in polyvinyl pyrrolidone solution to form a nanodispersion. Single-factor experiments were conducted to optimize the formulations. A transmission electron micrograph showed that the ointment matrix was entrapped in the nanoemulsion of MCT, with a mean particle size of about 100 nm. The optimized formulation of NDEO was stable when stored for six months at 4 °C, and demonstrated no cytotoxicity to human corneal epithelial cells when compared with commercial polymer-based artificial tears (Tears Natural® Forte). The therapeutic effects of NDEO were evaluated on a mouse model with ‘dry eye’. Both the tear break-up time and fluorescein staining demonstrated therapeutic improvement, displaying a trend of positive correlation with higher concentrations of ointment matrix in the NDEO formulations compared to a marketed product. Histological evaluation demonstrated that the NDEO restored the normal corneal and conjunctival morphology and is safe for ophthalmic application.

Assay to detect lipid peroxidation upon exposure to nanoparticles.

PubMed

Potter, Timothy M; Neun, Barry W; Stern, Stephan T

2011-01-01

This chapter describes a method for the analysis of human hepatocarcinoma cells (HEP G2) for lipid peroxidation products, such as malondialdehyde (MDA), following treatment with nanoparticle formulations. Oxidative stress has been identified as a likely mechanism of nanoparticle toxicity, and cell-based in vitro systems for evaluation of nanoparticle-induced oxidative stress are widely considered to be an important component of biocompatibility screens. The products of lipid peroxidation, lipid hydroperoxides, and aldehydes, such as MDA, can be measured via a thiobarbituric acid reactive substances (TBARS) assay. In this assay, which can be performed in cell culture or in cell lysate, MDA combines with thiobarbituric acid (TBA) to form a fluorescent adduct that can be detected at an excitation wavelength of 530 nm and an emission wavelength of 550 nm. The results are then expressed as MDA equivalents, normalized to total cellular protein (determined by Bradford assay).

Ciclopirox delivery into the human nail plate using novel lipid diffusion enhancers.

PubMed

Hafeez, Farhaan; Hui, Xiaoying; Selner, Marc; Rosenthal, Bert; Maibach, Howard

2014-06-01

Onychomycosis is a common fungal infection of the nail plate and bed that affects up to 14% of the population and can have a substantial impact on the quality of life of those affected. This study compared the onychopharmacokinetics, nail absorption, nail distribution, and nail penetration of [(14)C]-ciclopirox dissolved in novel lipid diffusion enhancers with that of a commercial ciclopirox nail lacquer using the in vitro finite dose model. The penetration rate of ciclopirox was determined by applying doses of topical formulation twice daily to human nail plates for 11 d. Drug absorption was then measured by monitoring its rate of appearance in each nail layer and in the cotton pad/nail supporting bed. After a multiple day treatment, cumulative concentrations of ciclopirox formulated with lipid enhancers in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of the commercial ciclopirox lacquer (p < 0.001) as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of the causative dermatophyte species. When formulated with lipid enhancers, the amount of ciclopirox in the ventral/intermediate layer and supporting bed dramatically exceed the inhibitory concentration of ciclopirox for the most common onychomycosis organisms. These results suggest that topical ciclopirox with lipid enhancers has the potential to be an effective topical treatment for onychomycosis, and the lipidic pathway of the nail can be utilized as a means of effective transungual delivery.

Lipid-based formulations for danazol containing a digestible surfactant, Labrafil M2125CS: in vivo bioavailability and dynamic in vitro lipolysis.

PubMed

Larsen, Anne; Holm, René; Pedersen, Mette Lund; Müllertz, Anette

2008-12-01

To evaluate the use of Labrafil M2125CS as a lipid vehicle for danazol. Further, the possibility of predicting the in vivo behavior with a dynamic in vitro lipolysis model was evaluated. Danazol (28 mg/kg) was administered orally to rats in four formulations: an aqueous suspension, two suspensions in Labrafil M2125CS (1 and 2 ml/kg) and a solution in Labrafil M2125CS (4 ml/kg). The obtained absolute bioavailabilities of danazol were 1.5 +/- 0.8%; 7.1 +/- 0.6%; 13.6 +/- 1.4% and 13.3 +/- 3.4% for the aqueous suspension, 1, 2 and 4 ml Labrafil M2125CS per kg respectively. Thus administration of danazol with Labrafil M2125CS resulted in up to a ninefold increase in the bioavailability, and the bioavailability was dependent on the Labrafil M2125CS dose. In vitro lipolysis of the formulations was able to predict the rank order of the bioavailability from the formulations, but not the absorption profile of the in vivo study. The bioavailability of danazol increased when Labrafil M2125CS was used as a vehicle, both when danazol was suspended and solubilized in the vehicle. The dynamic in vitro lipolysis model could be used to rank the bioavailabilities of the in vivo data.

Amphotericin B formulations: a comparative review of efficacy and toxicity.

PubMed

Hamill, Richard J

2013-06-01

Because of the increasing prevalence and changing microbiological spectrum of invasive fungal infections, some form of amphotericin B still provides the most reliable and broad spectrum therapeutic alternative. However, the use of amphotericin B deoxycholate is accompanied by dose-limited toxicities, most importantly, infusion-related reactions and nephrotoxicity. In an attempt to improve the therapeutic index of amphotericin B, three lipid-associated formulations were developed, including amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD). The lipid composition of all three of these preparations differs considerably and contributes to substantially different pharmacokinetic parameters. ABLC is the largest of the lipid preparations. Because of its size, it is taken up rapidly by macrophages and becomes sequestered in tissues of the mononuclear phagocyte system such as the liver and spleen. Consequently, compared with the conventional formulation, it has lower circulating amphotericin B serum concentrations, reflected in a marked increase in volume of distribution and clearance. Lung levels are considerably higher than those achieved with other lipid-associated preparations. The recommended therapeutic dose of ABLC is 5 mg/kg/day. Because of its small size and negative charge, L-AmB avoids substantial recognition and uptake by the mononuclear phagocyte system. Therefore, a single dose of L-AmB results in a much higher peak plasma level (Cmax) than conventional amphotericin B deoxycholate and a much larger area under the concentration-time curve. Tissue concentrations in patients receiving L-AmB tend to be highest in the liver and spleen and much lower in kidneys and lung. Recommended therapeutic dosages are 3-6 mg/kg/day. After intravenous infusion, ABCD complexes remain largely intact and are rapidly removed from the circulation by cells of the macrophage phagocyte system. On a milligram-to-milligram basis, the Cmax achieved is lower than that attained by conventional amphotericin B, although the larger doses of ABCD that are administered produce an absolute level that is similar to amphotericin B. ABCD exhibits dose-limiting, infusion-related toxicities; consequently, the administered dosages should not exceed 3-4 mg/kg/day. The few comparative clinical trials that have been completed with the lipid-associated formulations have not demonstrated important clinical differences among these agents and amphotericin B for efficacy, although there are significant safety benefits of the lipid products. Furthermore, only one published trial has ever compared one lipid product against another for any indication. The results of these trials are particularly difficult to interpret because of major heterogeneities in study design, disease definitions, drug dosages, differences in clinical and microbiological endpoints as well as specific outcomes examined. Nevertheless, it is possible to derive some general conclusions given the available data. The most commonly studied syndrome has been empiric therapy for febrile neutropenic patients, where the lipid-associated preparations did not appear to provide a survival benefit over conventional amphotericin B deoxycholate, but did offer a significant advantage for the prevention of various breakthrough invasive fungal infections. For treatment of documented invasive fungal infections that usually involved hematological malignancy patients, no individual randomized trial has demonstrated a mortality benefit due to therapy with one of the lipid formulations. Results from meta-analyses have been contradictory, with one demonstrating a mortality benefit from all-cause mortality and one that did not demonstrate a mortality benefit. In the only published study to examine HIV-infected patients with disseminated histoplasmosis, clinical success and mortality were significantly better with L-AmB compared with amphotericin B deoxycholate; there were no differences in microbiological outcomes between treatment groups. The lipid-associated preparations were not significantly better than amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis for either clinical or microbiological outcomes that were studied. In all of the trials that specifically examined renal toxicity, the lipid-associated formulations were significantly less nephrotoxic than amphotericin B deoxycholate. Infusion-related reactions occurred less frequently with L-AmB when compared with amphotericin B deoxycholate; however, ABCD had equivalent or more frequent infusion-related reactions than conventional amphotericin B, and this resulted in the cessation of at least one clinical trial. At the present time, this particular lipid formulation is no longer commercially available. For the treatment of most invasive fungal infections, an amphotericin B lipid formulation provides a safer alternative than conventional amphotericin B, with at least equivalent efficacy. As the cost of therapy with these agents continues to decline, these drugs will likely maintain their important role in the antifungal drug armamentarium because of their efficacy and improved safety profile.

Novel strategies for the formulation and processing of poorly water-soluble drugs.

PubMed

Göke, Katrin; Lorenz, Thomas; Repanas, Alexandros; Schneider, Frederic; Steiner, Denise; Baumann, Knut; Bunjes, Heike; Dietzel, Andreas; Finke, Jan H; Glasmacher, Birgit; Kwade, Arno

2018-05-01

Low aqueous solubility of active pharmaceutical ingredients presents a serious challenge in the development process of new drug products. This article provides an overview on some of the current approaches for the formulation of poorly water-soluble drugs with a special focus on strategies pursued at the Center of Pharmaceutical Engineering of the TU Braunschweig. These comprise formulation in lipid-based colloidal drug delivery systems and experimental as well as computational approaches towards the efficient identification of the most suitable carrier systems. For less lipophilic substances the preparation of drug nanoparticles by milling and precipitation is investigated for instance by means of microsystem-based manufacturing techniques and with special regard to the preparation of individualized dosage forms. Another option to overcome issues with poor drug solubility is the incorporation into nanospun fibers. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel diindolylmethane derivatives based NLC formulations to improve the oral bioavailability and anticancer effects in triple negative breast cancer

PubMed Central

Godugu, Chandraiah; Doddapaneni, Ravi; Safe, Stephen H.; Singh, Mandip

2017-01-01

The present study demonstrates the promising anticancer effects of novel C-substituted diindolylmethane (DIM) derivatives DIM-10 and DIM-14 in aggressive TNBC models. In vitro studies demonstrated that these compounds possess strong anticancer effects. Caco-2 permeability studies resulted in poor permeability and poor oral bioavailability was demonstrated by pharmacokinetic studies. Nano structured lipid carrier (NLC) formulations were prepared to increase the clinical acceptance of these compounds. Significant increase in oral bioavailability was observed with NLC formulations. Compared to DIM-10, DIM-10 NLC formulation showed increase in Cmax and AUC values by 4.73 and 11.19-folds, respectively. Similar pattern of increase was observed with DIM-14 NLC formulations. In dogs DIM-10 NLC formulations showed an increase of 2.65 and 2.94-fold in Cmax and AUC, respectively. The anticancer studies in MDA-MB-231 orthotopic TNBC models demonstrated significant reduction in tumor volumes in DIM-10 and DIM-14 NLC treated animals. Our studies suggest that NLC formulation of both DIM-10 and 14 is effective in TNBC models. PMID:27586082

Evaluation of plant based formulation on adolescent obesity and its associated bio-markers: a randomized, double blind, placebo controlled study.

PubMed

Shivakumar, S; Ilango, K; Dubey, G P; Subhasree, N; Agrawal, Aruna

2015-04-01

Obesity and overweight are the fifth most fatal diseases leading to an increased rate of morbidity and mortality in global population, with its incidence increasing drastically. Taking this into consideration we have conducted the present study in order to explore the efficacy of plant based formulation in the management of adolescent obesity and its associated biomarkers. Randomized, double blind, placebo controlled trial was conducted in 130 obese adolescent of both sexes, with BMI above 25kg/m(2). The subjects were randomly assigned into test formulation group (TFG) and placebo group (PG). TFG received two 500mg capsule containing test formulation whereas, the PG received two 500mg of cellulose powder containing capsule daily for 3 months. The parameters such as blood pressure, inflammatory cytokines, adipokines and lipid profile were assessed in all subjects pre and post treatment. There was a considerable improvement in the levels of lipid profile, inflammatory cytokines, adipokines and blood pressure after treatment in TFG compared to PG. The statistical difference obtained between the groups after three months of treatment for the various biomarkers are given as mean with 95% CI for BMI (-1.4±0.6 (-2.5 to -0.7)), total cholesterol mg/dl (-20.9±5.0 (-30.8 to -11.0)), triglyceride mg/dl (-12.9±5.7 (-23.9 to -1.2)), HDL-c mg/dl (7.2±0.8 (5.6-8.8)), IL-6 (-0.7±0.1 (-0.9 to -0.6)), hs C-reactive protein (CRP) mg/l(-1.0±0.01 (-1.2 to -0.8)), adiponectin µg/ml(4.9±0.4 (4.2-5.7)), leptin ng/ml (-8.0±1.4 (-10.7 to -5.3)), diastolic blood pressure (DBP) mmHg (-10.4±0.8 (-12.0 to -8.7)) and systolic blood pressure (SBP) mmHg (-6.7±0.7 (-8.1 to -5.3)). Also, there was a statistical significance within group TFG. The study concludes that the test formulation may prevent the future cardio vascular risk incidence in obese adolescents by reducing inflammation, overweight, lipid profile and by regulating adipokines. Thus it may help to improve the health pattern in obese patients with least side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Attenuated Total Reflection Fourier Transform Infrared (ATR FT-IR) Spectroscopy as an Analytical Method to Investigate the Secondary Structure of a Model Protein Embedded in Solid Lipid Matrices.

PubMed

Zeeshan, Farrukh; Tabbassum, Misbah; Jorgensen, Lene; Medlicott, Natalie J

2018-02-01

Protein drugs may encounter conformational perturbations during the formulation processing of lipid-based solid dosage forms. In aqueous protein solutions, attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy can investigate these conformational changes following the subtraction of spectral interference of solvent with protein amide I bands. However, in solid dosage forms, the possible spectral contribution of lipid carriers to protein amide I band may be an obstacle to determine conformational alterations. The objective of this study was to develop an ATR FT-IR spectroscopic method for the analysis of protein secondary structure embedded in solid lipid matrices. Bovine serum albumin (BSA) was chosen as a model protein, while Precirol AT05 (glycerol palmitostearate, melting point 58 ℃) was employed as the model lipid matrix. Bovine serum albumin was incorporated into lipid using physical mixing, melting and mixing, or wet granulation mixing methods. Attenuated total reflection FT-IR spectroscopy and size exclusion chromatography (SEC) were performed for the analysis of BSA secondary structure and its dissolution in aqueous media, respectively. The results showed significant interference of Precirol ATO5 with BSA amide I band which was subtracted up to 90% w/w lipid content to analyze BSA secondary structure. In addition, ATR FT-IR spectroscopy also detected thermally denatured BSA solid alone and in the presence of lipid matrix indicating its suitability for the detection of denatured protein solids in lipid matrices. Despite being in the solid state, conformational changes occurred to BSA upon incorporation into solid lipid matrices. However, the extent of these conformational alterations was found to be dependent on the mixing method employed as indicated by area overlap calculations. For instance, the melting and mixing method imparted negligible effect on BSA secondary structure, whereas the wet granulation mixing method promoted more changes. Size exclusion chromatography analysis depicted the complete dissolution of BSA in the aqueous media employed in the wet granulation method. In conclusion, an ATR FT-IR spectroscopic method was successfully developed to investigate BSA secondary structure in solid lipid matrices following the subtraction of lipid spectral interference. The ATR FT-IR spectroscopy could further be applied to investigate the secondary structure perturbations of therapeutic proteins during their formulation development.

Paclitaxel loaded folic acid targeted nanoparticles of mixed lipid-shell and polymer-core: in vitro and in vivo evaluation.

PubMed

Zhao, Peiqi; Wang, Hanjie; Yu, Man; Liao, Zhenyu; Wang, Xianhuo; Zhang, Fei; Ji, Wei; Wu, Bing; Han, Jinghua; Zhang, Haichang; Wang, Huaqing; Chang, Jin; Niu, Ruifang

2012-06-01

A functional drug carrier comprised of folic acid modified lipid-shell and polymer-core nanoparticles (FLPNPs) including poly(D,L-lactide-co-glycolide) (PLGA) core, PEGylated octadecyl-quaternized lysine modified chitosan (PEG-OQLCS) as lipid-shell, folic acid as targeting ligand and cholesterol was prepared and evaluated for targeted delivery of paclitaxel (PTX). Confocal microscopy analysis confirmed the coating of the lipid-shell on the polymer-core. Physicochemical characterizations of FLPNPs, such as particle size, zeta potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. The internalization efficiency and targeting ability of FLPNPs were demonstrated by flow cytometry and confocal microscopy. PTX loaded FLPNPs showed a significantly higher cytotoxicity than the commercial PTX formulation (Taxol®). The intravenous administration of PTX encapsulated FLPNPs led to tumor regression and improvement of animal survival in a murine model, compared with that observed with Taxol® and biodistribution study showed that PTX concentration in tumor for PTX encapsulated FLPNPs was higher than other PTX formulations. Our data indicate that PTX loaded FLPNPs are a promising nano-sized drug formulation for cancer therapy. Copyright © 2012 Elsevier B.V. All rights reserved.

Skin photoprotection improvement: synergistic interaction between lipid nanoparticles and organic UV filters.

PubMed

Nikolić, S; Keck, C M; Anselmi, C; Müller, R H

2011-07-29

A photoprotective formulation was developed with an increased sunprotection factor (SPF), compared to a conventional nanoemulsion, but having the same concentration of three molecular sunscreens, namely ethylhexyl triazone, bis-ethylhexyloxyphenol methoxyphenyl triazine, and ethylhexyl methoxycinnamate. The sunscreen mixture was incorporated into nanostructured lipid carriers (NLCs). The ability of nine different solid lipids to yield stable aqueous NLC suspensions was assessed. After the production by hot high pressure homogenization, the NLC were analyzed in terms of particle size, physical state, particle shape, ultraviolet absorbance and stability. The particle size for all NLC was around 200 nm after production. The NLC suspension with carnauba wax had superior UV absorbance, NLC from bees wax showed similar efficiency as the reference emulsion. The NLC formulations were incorporated into hydrogel formulations and the in vitro SPF was measured. This study demonstrated that approximately 45% higher SPF values could be obtained when the organic UV filters were incorporated into carnauba wax NLC, in comparison to the reference nanoemulsion and bees wax NLC. The data showed that the synergistic effect of NLC and incorporated sunscreens depends not only on the solid state of the lipid but also on its type. Copyright © 2011 Elsevier B.V. All rights reserved.

Development of γ-Oryzanol Rich Extract from Leum Pua Glutinous Rice Bran Loaded Nanostructured Lipid Carriers for Topical Delivery.

PubMed

Pornputtapitak, Warangkana; Pantakitcharoenkul, Jaturavit; Panpakdee, Ratchada; Teeranachaideekul, Veerawat; Sinchaipanid, Nuttanan

2018-02-01

Leum Pua is native Thai glutinous rice that contains antioxidants higher than white rice and other colored rice. One of the major antioxidants in rice brans is γ-oryzanol (GO). In this study, Leum Pua glutinous rice bran was extracted by different solvents. Oleic acid (~40 g/100 g extract), linoleic acid (~30 g/100 g extract), and palmitic acid (~20 g/100 g extract) were found to be major lipid components in the extracts. Methanol extract showed less variety of lipid components compared to the others. However, hexane extract showed the highest percent of γ-oryzanol compared to other solvents. Therefore, the hexane extract was selected to prepare nanostructured lipid carriers (NLC). The prepared NLC had small particles in the size range of 142.9 ± 0.4 nm for extract-loaded NLC and 137.1 ± 0.5 nm for GO-loaded NLC with narrow size distribution (PI < 0.1) in both formulations. The release profile of extract-loaded NLC formulation was slightly higher than GO-loaded NLC formulation. However, they did not follow the Higuchi model because of small amounts of γ-oryzanol loaded in NLC particles.

Lipidology and lipidomics--quo vadis? A new era for the physical chemistry of lipids.

PubMed

Mouritsen, Ole G

2011-11-21

Our picture of lipid membranes has come a long way since Gorter and Grendel in 1925 formulated the lipid bilayer hypothesis. Most modern textbook models of membranes are based on the Singer-Nicolson model from 1972, although we have in recent years seen significant amendments to this model, not least fuelled by the finding of lipid membrane domains and the subsequent 'raft rush'. The science of lipids, lipidology, has now become an established discipline, acknowledging that lipids organize in space and time and display emergent physico-chemical properties that are beyond the chemical nature of the individual molecules and which collectively control membrane function. Recently, lipidomics has been followed as a new discipline in the omics-sequel, characterized by an explosion in detailed data for lipid profiles of tissues, cells, and subcellular components. The focus is now swinging toward enumerating individual lipid species, determining their identity, and quantitating their amount. Time is ripe to marry the two disciplines, both in order to take lipidomics beyond the stage of 'stamp collection' and in order to incorporate into the lipidology approach the new knowledge about the individual lipid species. As an important matchmaker for this marriage, the physical chemistry of lipids in lipid bilayers and membranes is entering a new era of renaissance. This journal is © the Owner Societies 2011

Solid lipid particles for oral delivery of peptide and protein drugs II--the digestion of trilaurin protects desmopressin from proteolytic degradation.

PubMed

Christophersen, Philip Carsten; Zhang, Long; Müllertz, Anette; Nielsen, Hanne Mørck; Yang, Mingshi; Mu, Huiling

2014-09-01

To investigate the in vitro release and degradation of desmopressin from saturated triglyceride microparticles under both lipolytic and proteolytic conditions. The release of desmopressin from different solid lipid microparticles in the absence and presence of a microbial lipase and protease was determined. Trilaurin (TG12), trimyristin (TG14), tripalmitin (TG16), and tristearin (TG18) were used as lipid excipients to produce solid lipid microparticles. In the presence of lipase, the rate of drug release from different lipid particles was in the order of TG14 > TG16 > TG18, which is the same rank order as the lipid degradation rate. A reverse rank order was found for the protection of desmopressin from enzymatic degradation due to spatial separation of desmopressin from the protease. TG12 accelerated the release of desmopressin from all lipid particles when added as either drug-free microparticles to the lipolysis medium or incorporated in TG16 particles. Additionally, TG12 particles protected desmopressin from degradation when present in the lipolysis medium with the other lipid microparticles. TG12 is a very interesting lipid for oral lipid formulations containing peptides and proteins as it alters release and degradation of the incorporated desmopressin. The present study demonstrates the possibility of bio-relevant in vitro evaluation of lipid-based solid particles.

Lipid-drug-conjugate (LDC) solid lipid nanoparticles (SLN) for the delivery of nicotine to the oral cavity - optimization of nicotine loading efficiency.

PubMed

Ding, Yuan; Nielsen, Kent A; Nielsen, Bruno P; Bøje, Niels W; Müller, Rainer H; Pyo, Sung Min

2018-03-12

Nicotine, obtained from tobacco leaves, has been used to promote the cessation of smoking and reduce the risk of COPD and lung cancer. Incorporating the active in lipid nanoparticles is an effective tool to minimize its irritation potential and to use the particles as intermediate to produce final products. However, as a hydrophilic active, it is a challenge to prepare nicotine loaded lipid nanoparticles with high drug loading. In this study, lipid-drug-conjugates (LDC) were formed by nicotine and different fatty acids to enable the production of sufficiently loaded nicotine lipid nanoparticles. The encapsulation efficiency of nicotine in LDC-containing SLN was about 50%, which increased at least fourfold compared to the non-LDC formulations (around 10%) due to the increased lipophilicity of nicotine by strong interactions between positively charged nicotine and negatively charged fatty acids (formation of LDCs). The z-average of all formulations (150 to 350 nm) proved to be in the required submicron size range with a narrow size distribution. In summary, nicotine loaded LDC lipid nanoparticles with high drug loading were successfully developed with Kolliwax® S and stearic acid as counter-ion forming the LDC and hydrogenated sunflower oil (HSO) as lipid particle matrix. Copyright © 2018. Published by Elsevier B.V.

Optimizing Cationic and Neutral Lipids for Efficient Gene Delivery at High Serum Content

PubMed Central

Majzoub, Ramsey N.; Hwu, Yeu-kuang; Liang, Keng S.; Leal, Cecília; Safinya, Cyrus R.

2014-01-01

Background Cationic liposome (CL)-DNA complexes are promising gene delivery vectors with potential applications in gene therapy. A key challenge in creating CL-DNA complexes for applications is that their transfection efficiency (TE) is adversely affected by serum. In particular, little is known about the effects of high serum contents on TE even though this may provide design guidelines for applications in vivo. Methods We prepared CL-DNA complexes in which we varied the neutral lipid (DOPC, glycerol-monooleate (GMO), cholesterol), the headgroup charge and chemical structure of the cationic lipid, and the ratio of neutral to cationic lipid; we then measured the TE of these complexes as a function of serum content and assessed their cytotoxicity. We tested selected formulations in two human cancer cell lines (M21/melanoma and PC-3/prostate cancer). Results In the absence of serum, all CL-DNA complexes of custom-synthesized multivalent lipids show high TE. Certain combinations of multivalent lipids and neutral lipids, such as MVL5(5+)/GMO-DNA complexes or complexes based on the dendritic-headgroup lipid TMVLG3(8+) exhibited high TE both in the absence and presence of serum. Although their TE still dropped to a small extent in the presence of serum, it reached or surpassed that of benchmark commercial transfection reagents, in particular at high serum content. Conclusions Two-component vectors (one multivalent cationic lipid and one neutral lipid) can rival or surpass benchmark reagents at low and high serum contents (up to 50%, v/v). We suggest guidelines for optimizing the serum resistance of CL-DNA complexes based on a given cationic lipid. PMID:24753287

The effect of a cinnamon-, chromium- and magnesium-formulated honey on glycaemic control, weight loss and lipid parameters in type 2 diabetes: an open-label cross-over randomised controlled trial.

PubMed

Whitfield, Patricia; Parry-Strong, Amber; Walsh, Emily; Weatherall, Mark; Krebs, Jeremy D

2016-04-01

This randomised controlled trial assessed the acute and long-term effects of daily supplementation of kanuka honey, formulated with cinnamon, chromium and magnesium on glucose metabolism, weight and lipid parameters in individuals with type 2 diabetes. Twelve individuals with type 2 diabetes received 53.5 g of a formulated honey and a control (non-formulated) kanuka honey in a random order for 40 days, using cross-over design. Fasting glucose, insulin, HbA1c, lipids and anthropometric measures were measured at baseline and end of treatment. A meal tolerance test was performed at baseline to assess acute metabolic response. There was no statistically significant difference in acute glucose metabolism between treatment groups, as measured by the Matsuda index and AUC for glucose and insulin. After the 40-day intervention with honey, fasting glucose did not differ significantly between the two treatments (95 % CI -2.6 to 0.07). There was no statistically significant change in HbA1c or fasting insulin. There was a statistically significant reduction in total cholesterol by -0.29 mmol/L (95 % CI -0.57 to -0.23), LDL cholesterol by -0.29 mmol/L (95 % CI -0.57 to -0.23) and weight by -2.2 kg (95 % CI -4.2 to -0.1). There was a trend towards increased HDL and reduced systolic blood pressure in the intervention treatment. The addition of cinnamon, chromium and magnesium supplementation to kanuka honey was not associated with a significant improvement in glucose metabolism or glycaemic control in individuals with type 2 diabetes. Use of the formulated honey was associated with a reduction in weight and improvements in lipid parameters, and should be investigated further.

Nanotechnology Formulations for Antibacterial Free Fatty Acids and Monoglycerides.

PubMed

Jackman, Joshua A; Yoon, Bo Kyeong; Li, Danlin; Cho, Nam-Joon

2016-03-03

Free fatty acids and monoglycerides have long been known to possess broad-spectrum antibacterial activity that is based on lytic behavior against bacterial cell membranes. Considering the growing challenges of drug-resistant bacteria and the need for new classes of antibiotics, the wide prevalence, affordable cost, and broad spectrum of fatty acids and monoglycerides make them attractive agents to develop for healthcare and biotechnology applications. The aim of this review is to provide a brief introduction to the history of antimicrobial lipids and their current status and challenges, and to present a detailed discussion of ongoing research efforts to develop nanotechnology formulations of fatty acids and monoglycerides that enable superior in vitro and in vivo performance. Examples of nano-emulsions, liposomes, solid lipid nanoparticles, and controlled release hydrogels are presented in order to highlight the potential that lies ahead for fatty acids and monoglycerides as next-generation antibacterial solutions. Possible application routes and future directions in research and development are also discussed.

Ivermectin lipid-based nanocarriers as novel formulations against head lice.

PubMed

Ullio-Gamboa, Gabriela; Palma, Santiago; Benoit, Jean Pierre; Allemandi, Daniel; Picollo, María Inés; Toloza, Ariel Ceferino

2017-08-01

The use of pyrethroids to control the human head louse, Pediculus humanus capitis De Geer (Anoplura: Pediculidae), has suffered considerable loss of efficacy due to the evolution of resistance. Thus, the development of efficiently insecticide delivery systems is imperative for the control of head lice. We studied the insecticidal activity of ivermectin-loaded lipid nanocapsules (IVM-LNC) against permethrin-resistant head lice from Argentina. The LNC, prepared by a phase inversion procedure, were characterized in terms of size, surface potential, and physical stability. These nanoparticles were nearly spherical with mean diameters of 55 nm and narrow size distribution (PI ≤ 0.2). The KT 50 mortality values of head lice after exposure to two IVM-LNC formulations (0.11 and 0.28%) were significantly smaller (5 and 3 h, respectively) compared to those exposed only to LNC control group (8 h). This investigation showed the effectiveness in the encapsulation of ivermectin (IVM) into stable LNC dispersion with a potential clinical activity against head lice.

Further optimization of culture method for rat keratinocytes: titration of glucose and sodium chloride.

PubMed

Oku, H; Yamashita, M; Iwasaki, H; Chinen, I

1999-02-01

The present study further improved the serum-free method of culturing rat keratinocytes. To obtain the best growth of rat keratinocytes, we modified our previous serum-free medium (MCDB153 based medium), particularly the amounts of glucose and sodium chloride (NaCl). Titration experiments showed the optimal concentration to be 0.8 mM for glucose and 100 mM for NaCl. This modification eliminated the requirement for albumin, which had been essential for colony formation when our previous medium was used. Titration of glucose and NaCl, followed by adjustment of essential amino acids and growth factors, produced a new formulation. More satisfactory and better growth was achieved with the new medium than with the previous medium. Accumulation of monoalkyldiacylglycerol (MADAG) was consistently noted in this study, representing the unusual lipid profile. A tendency toward normalization was, however, noted with the neutral lipid profile of keratinocytes cultivated in the new medium: lower production of MADAG was obtained with the new formulation, rather than the previous one.

Drug delivery to the ocular posterior segment using lipid emulsion via eye drop administration: effect of emulsion formulations and surface modification.

PubMed

Ying, Lin; Tahara, Kohei; Takeuchi, Hirofumi

2013-09-10

This work explored submicron-sized lipid emulsion as potential carriers for intraocular drug delivery to the posterior segment via eye drops. The effects of physicochemical properties of lipid emulsion on drug delivery were evaluated in vivo using mice. Different formulations of submicron-sized lipid emulsions were prepared using a high pressure homogenization system. Using coumairn-6 as a model drug and fluorescent marker, fluorescence could be observed in the retina after administration of the lipid emulsion. The fluorescence intensity observed after administration of medium chain triglycerides containing the same amount of coumarin-6 was much lower than that observed after administration of lipid emulsions. The inner oil property and phospholipid emulsifier did not affect the drug delivery efficiency to the retina. However, compared with unmodified emulsions, the fluorescence intensity in the retina increased by surface modification using a positive charge inducer and the functional polymers chitosan (CS) and poloxamer 407 (P407). CS-modified lipid emulsions could be electrostatically interacted with the eye surface. By its adhesive property, poloxamer 407, a surface modifier, possibly increased the lipid emulsion retention time on the eye surface. In conclusion, we suggested that surface-modified lipid emulsions could be promising vehicles of hydrophobic drug delivery to the ocular posterior segment. Copyright © 2013. Published by Elsevier B.V.

Ursolic acid rich Ocimum sanctum L leaf extract loaded nanostructured lipid carriers ameliorate adjuvant induced arthritis in rats by inhibition of COX-1, COX-2, TNF-α and IL-1: Pharmacological and docking studies

PubMed Central

Abuzinadah, Mohammed F.; Alkreathy, Huda M.; Banaganapalli, Babajan; Mujeeb, Mohd

2018-01-01

Background Ursolic acid (UA) is a promising molecule with anti-inflammatory, analgesic and potential anti-arthritic activity. Methods This study was undertaken to make formulation and evaluation of Ocimum sanctum L. leaf extract (OLE) loaded nano-structured lipid carriers (OLE-NLCs) for improved transdermal delivery of UA. Different surfactants, solid lipids and liquid lipids were used for the preparation of NLCs. The NLCs were developed using emulsion solvent diffusion and evaporation method. Different physicochemical properties, entrapment efficacy, in vitro release evaluation, and ex vivo permeation studies of the prepared NLCs were carried out. The in vivo anti-arthritic activity of OLE-loaded NLC gel and control gel formulation (OLE free NLC gel) against Complete Freund's Adjuvant (CFA) induced arthritis in wister albino rats was also carried out. Results OLE-NLCs were composed of spherical particles having a mean particle size of ~120 nm, polydispersity index of ~0.162 and zeta potential of ~ -27 mV. The high entrapment efficiency (EE) of UA ~89.56% was attained. The in vitro release study demonstrated a prolonged release of UA from the NLCs up to 12 h. The developed formulation was found to be significantly better with respect to the drug permeation amount with an enhancement ratio of 2.69 as compared with marketed formulation. The in vivo biological activity investigations, studies showed that the newly prepared NLCs formulation of OLE showed excellent anti-arthritic activity and the results were found at par with standard marketed diclofenac gel for its analgesic and anti-arthritic activities. These results were also supported by radiological analysis and molecular docking studies. Conclusion The overall results proved that the prepared OLE-NLCs were very effective for the treatment of arthritis and the results were found at par with standard marketed the standard formulation of diclofenac gel. PMID:29558494

Solid lipid nanoparticles as carrier for sunscreens: in vitro release and in vivo skin penetration.

PubMed

Wissing, S A; Müller, R H

2002-06-17

The aim of this study was the comparison of two different formulations (solid lipid nanoparticles (SLN) and conventional o/w emulsion) as carrier systems for the molecular sunscreen oxybenzone. The influence of the carrier on the rate of release was studied in vitro with a membrane-free model. The release rate could be decreased by up to 50% with the SLN formulation. Further in vitro measurements with static Franz diffusion cells were performed. In vivo, penetration of oxybenzone into stratum corneum on the forearm was investigated by the tape stripping method. It was shown that the rate of release is strongly dependent upon the formulation and could be decreased by 30-60% in SLN formulations. In all test models, oxybenzone was released and penetrated into human skin more quickly and to a greater extent from the emulsions. The rate of release also depends upon the total concentration of oxybenzone in the formulation. In vitro-in vivo correlations could be made qualitatively.

Safranal-loaded solid lipid nanoparticles: evaluation of sunscreen and moisturizing potential for topical applications

PubMed Central

Khameneh, Bahman; Halimi, Vahid; Jaafari, Mahmoud Reza; Golmohammadzadeh, Shiva

2015-01-01

Objective(s): In the current study, sunscreen and moisturizing properties of solid lipid nanoparticle (SLN)-safranal formulations were evaluated. Materials and Methods: Series of SLN were prepared using glyceryl monostearate, Tween 80 and different amounts of safranal by high shear homogenization, and ultrasound and high-pressure homogenization (HPH) methods. SLN formulations were characterized for size, zeta potential, morphology, thermal properties, and encapsulation efficacy. The Sun Protection Factor (SPF) of the products was determined in vitro using transpore tape. The moisturizing activity of the products was also evaluated by corneometer. Results: The SPF of SLN-safranal formulations was increased when the amount of safranal increased. Mean particle size for all formulas was approximately 106 nm by probe sonication and 233 nm using HPH method. The encapsulation efficiency of safranal was around 70% for all SLN-safranal formulations. Conclusion: The results conclude that SLN-safranal formulations were found to be effective for topical delivery of safranal and succeeded in providing appropriate sunscreen properties. PMID:25810877

Engineering of budesonide-loaded lipid-polymer hybrid nanoparticles using a quality-by-design approach.

PubMed

Leng, Donglei; Thanki, Kaushik; Fattal, Elias; Foged, Camilla; Yang, Mingshi

2017-08-25

Chronic obstructive pulmonary disease (COPD) is a complex disease, characterized by persistent airflow limitation and chronic inflammation. The purpose of this study was to design lipid-polymer hybrid nanoparticles (LPNs) loaded with the corticosteroid, budesonide, which could potentially be combined with small interfering RNA (siRNA) for COPD management. Here, we prepared LPNs based on the biodegradable polymer poly(dl-lactic-co-glycolic acid) (PLGA) and the cationic lipid dioleyltrimethylammonium propane (DOTAP) using a double emulsion solvent evaporation method. A quality-by-design (QbD) approach was adopted to define the optimal formulation parameters. The quality target product profile (QTPP) of the LPNs was identified based on risk assessment. Two critical formulation parameters (CFPs) were identified, including the theoretical budesonide loading and the theoretical DOTAP loading. The CFPs were linked to critical quality attributes (CQAs), which included the intensity-based hydrodynamic particle diameter (z-average), the polydispersity index (PDI), the zeta-potential, the budesonide encapsulation efficiency, the actual budesonide loading and the DOTAP encapsulation efficiency. A response surface methodology (RSM) was applied for the experimental design to evaluate the influence of the CFPs on the CQAs, and to identify the optimal operation space (OOS). All nanoparticle dispersions displayed monodisperse size distributions (PDI<0.2) with z-averages of approximately 150nm, suggesting that the size is not dependent on the investigated CFPs. In contrast, the zeta-potential was highly dependent on the theoretical DOTAP loading. Upon increased DOTAP loading, the zeta-potential reached a maximal point, after which it remained stable at the maximum value. This suggests that the LPN surface is covered by DOTAP, and that the DOTAP loading is saturable. The actual budesonide loading of the LPNs was mainly dependent on the initial amount of budesonide, and a clear positive effect was observed, which shows that the interaction between drug and PLGA increases when increasing the initial amount of budesonide. The OOS was modeled by applying the QTPP. The OOS had a budesonide encapsulation efficiency higher than 30%, a budesonide loading above 15μg budesonide/mg PLGA, a zeta-potential higher than 35mV and a DOTAP encapsulation efficiency above 50%. This study shows the importance of systematic formulation design for understanding the effect of formulation parameters on the characteristics of LPNs, eventually resulting in the identification of an OOS. Copyright © 2017 Elsevier B.V. All rights reserved.

Polar Quassinoids in Standardized Eurycoma longifolia Extract Formulated into a Lipid-Based Solid Dispersion to Improve Rat Sperm Count.

PubMed

Ma, Hai-Qiu; Ebrahimi, Forough; Low, Bin-Seng; Khan, Nurzalina Abdul Karim; Chan, Kit-Lam

2017-12-01

Eurycoma longifolia Jack is popularly sought in Southeast Asian countries for traditional remedies to improve sexual performance and fertility. 13α(21)-Epoxyeurycomanone and eurycomanone, two major quassinoids in a root extract (TAF2) were reported to improve rat spermatogenesis and fertility. Unfortunately, these quassinoids possess low bioavailability because of high aqueous solubility and low lipid membrane permeability. Often, other possible barriers may be P-glycoprotein (P-gp) efflux in the gut and presystemic hepatic metabolism. The present study attempted to solve these problems by formulating a lipid-based solid dispersion (TAF2-SD) of optimized mixture of TAF2 and emulsifiers, which was then orally administered to rats prior to sperm count analysis. The TAF2-SD-treated rats showed significantly twofold (p < 0.001) and fourfold (p < 0.001) higher sperm count than did TAF2-treated and vehicle-treated (control) rats, respectively. The study also demonstrated no significant in vitro ileal absorption changes of the quassinoids by P-gp efflux inhibitors and concentration change or secondary metabolite formation upon in vitro incubation with rat liver homogenates, suggesting that P-gp-mediated efflux and presystemic metabolism were not limiting their bioavailability. Further study on orally TAF2-treated rats confirmed that the area under the curve and bioavailability curve of each quassinoid in the absence and presence of ketoconazole were unchanged. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Diclofenac Loaded Lipid Nanovesicles Prepared by Double Solvent Displacement for Skin Drug Delivery.

PubMed

Sala, M; Locher, F; Bonvallet, M; Agusti, G; Elaissari, A; Fessi, H

2017-09-01

Herein, we detail a promising strategy of nanovesicle preparation based on control of phospholipid self-assembly: the Double Solvent Displacement. A systematic study was conducted and diclofenac as drug model encapsulated. In vitro skin studies were carried out to identify better formulation for dermal/transdermal delivery. This method consists in two solvent displacements. The first one, made in a free water environment, has allowed triggering a phospholipid pre-organization. The second one, based on the diffusion into an aqueous phase has led to liposome formation. Homogeneous liposomes were obtained with a size close to 100 nm and a negative zeta potential around -40 mV. After incorporation of acid diclofenac, we obtained nanoliposomes with a size between 101 ± 45 and 133 ± 66 nm, a zeta potential between 34 ± 2 and 49 ± 3 mV, and the encapsulation efficiency (EE%) was between 58 ± 3 and 87 ± 5%. In vitro permeation studies showed that formulation with higher EE% dispayed the higher transdermal passage (18,4% of the applied dose) especially targeting dermis and beyond. Our results suggest that our diclofenac loaded lipid vesicles have significant potential as transdermal skin drug delivery system. Here, we produced cost effective lipid nanovesicles in a merely manner according to a process easily transposable to industrial scale. Graphical Abstract ᅟ.

Porous Silica-Supported Solid Lipid Particles for Enhanced Solubilization of Poorly Soluble Drugs.

PubMed

Yasmin, Rokhsana; Rao, Shasha; Bremmell, Kristen E; Prestidge, Clive A

2016-07-01

Low dissolution of drugs in the intestinal fluid can limit their effectiveness in oral therapies. Here, a novel porous silica-supported solid lipid system was developed to optimize the oral delivery of drugs with limited aqueous solubility. Using lovastatin (LOV) as the model poorly water-soluble drug, two porous silica-supported solid lipid systems (SSL-A and SSL-S) were fabricated from solid lipid (glyceryl monostearate, GMS) and nanoporous silica particles Aerosil 380 (silica-A) and Syloid 244FP (silica-S) via immersion/solvent evaporation. SSL particles demonstrated significantly higher rate and extent of lipolysis in comparison with the pure solid lipid, depending on the lipid loading levels and the morphology. The highest lipid digestion was observed when silica-S was loaded with 34% (w/w) solid lipid, and differential scanning calorimeter (DSC) analysis confirmed the encapsulation of up to 2% (w/w) non-crystalline LOV in this optimal SSL-S formulation. Drug dissolution under non-digesting intestinal conditions revealed a three- to sixfold increase in dissolution efficiencies when compared to the unformulated drug and a LOV-lipid suspension. Furthermore, the SSL-S provided superior drug solubilization under simulated intestinal digesting condition in comparison with the drug-lipid suspension and drug-loaded silica. Therefore, solid lipid and nanoporous silica provides a synergistic effect on optimizing the solubilization of poorly water-soluble compound and the solid lipid-based porous carrier system provides a promising delivery approach to overcome the oral delivery challenges of poorly water-soluble drugs.

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

PubMed Central

Cho, Hyun-Jong; Park, Jin Woo; Yoon, In-Soo; Kim, Dae-Duk

2014-01-01

Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel. PMID:24531717

Investigation of surface-modified solid lipid nanocontainers formulated with a heterolipid-templated homolipid.

PubMed

Attama, A A; Müller-Goymann, C C

2007-04-04

There is increasing interest in the search for improved drug delivery systems with greater versatility. Consequently, many drug delivery systems have been studied. In this study, surface-modified lipid nanocontainers were formulated with a homolipid from Capra hircus (goat fat) templated with a heterolipid (Phospholipon 90G) which was also the surface modifier. The solid lipid nanocontainers (SLN) were formulated by hot high pressure homogenisation using increasing concentrations of polysorbate 80 as the mobile surfactant. Prior to SLN preparation, the templated homolipid was formulated by fusion to obtain a homogeneous lipid matrix, which was characterized using differential scanning calorimetry (DSC), polarized light microscopy (PLM) and wide angle X-ray diffraction (WAXD) to obtain its thermal and crystal characteristics. Isothermal heat conduction microcalorimetry (IMC) and freeze-fracture transmission electron microscopy (FFTEM) studies were carried out on the templated homolipid and SLN containing 1.0% (w/w) of polysorbate 80 to study their in situ crystallization kinetics and morphology, respectively. The formulated SLN were also subjected to time-resolved DSC, WAXD and particle size analyses for one month. The thermal and crystal characteristics were compared with those of the bulk lipid matrix (templated homolipid). Result of the particle size analysis indicated that the particles size remained roughly within the lower nanometer range after one month. FFTEM micrograph of the lipid matrices revealed lamellar sheets for Phospholipon 90G and layered triglyceride structures for the homolipid and Phospholipon 90G-templated homolipid. FFTEM micrograph of SLN revealed anisometric structures. PLM of the templated homolipid did not show, but goat fat (homolipid) alone showed slight growth in crystals with time. WAXD and DSC studies revealed minor increase in crystallinity of the new lipid matrix after one month and DSC also detected templation of homolipid by the heterolipid noted by the disappearance of the lower melting peak of the homolipid. However, for the SLN, WAXD results showed low crystalline particles while DSC only showed a very little endothermic process after one month of storage at 20 degrees C. The implication of this finding is that progression of the SLN to highly ordered particles over time would not occur. This will be favourable for any incorporated drug as drug expulsion, due to increase in crystallinity, will not occur. Result obtained from analysis of the isothermal crystallization exotherms indicated that the templated homolipid and SLN1 containing 1.0% polysorbate 80 possess similar nucleation mechanisms and growth dimensions different from the pure homolipid. The SLN containing 0.5 and 1.0% polysorbate 80 possessed good properties and could prove to be good delivery systems for drugs for parenteral or ocular administration. The result of this study also shows a method of improving natural lipids for use in particulate drug delivery systems.

Fabrication, characterisation and stability of oil-in-water emulsions stabilised by solid lipid particles: the role of particle characteristics and emulsion microstructure upon Pickering functionality.

PubMed

Zafeiri, I; Smith, P; Norton, I T; Spyropoulos, F

2017-07-19

The quest to identify and use bio-based particles with a Pickering stabilisation potential for food applications has lately been particularly substantial and includes, among other candidates, lipid-based particles. The present study investigates the ability of solid lipid particles to stabilise oil-in-water (o/w) emulsions against coalescence. Results obtained showed that emulsion stability could be achieved when low amounts (0.8 wt/wt%) of a surface active species (e.g. Tween 80 or NaCas) were used in particles' fabrication. Triple staining of the o/w emulsions enabled the visualisation of emulsion droplets' surface via confocal microscopy. This revealed an interfacial location of the lipid particles, hence confirming stabilisation via a Pickering mechanism. Emulsion droplet size was controlled by varying several formulation parameters, such as the type of the lipid and surface active component, the processing route and the polarity of the dispersed phase. Differential scanning calorimetry (DSC) was employed as the analytical tool to quantify the amount of crystalline material available to stabilise the emulsion droplets at different intervals during the experimental timeframe. Dissolution of lipid particles in the oil phase was observed and evolved distinctly between a wax and a triglyceride, and in the presence of a non-ionic surfactant and a protein. Yet, this behaviour did not result in emulsion destabilisation. Moreover, emulsion's thermal stability was found to be determined by the behaviour of lipid particles under temperature effects.

Oleic Acid enhances all-trans retinoic Acid loading in nano-lipid emulsions.

PubMed

Chinsriwongkul, Akhayachatra; Opanasopit, Praneet; Ngawhirunpat, Tanasait; Rojanarata, Theerasak; Sila-On, Warisada; Ruktanonchai, Uracha

2010-01-01

The aim of this study was to investigate the enhancement of all-trans retinoic acid (ATRA) loading in nano-lipid emulsions and stability by using oleic acid. The effect of formulation factors including initial ATRA concentration and the type of oil on the physicochemical properties, that is, percentage yield, percentage drug release, and photostability of formulations, was determined. The solubility of ATRA was increased in the order of oleic acid > MCT > soybean oil > water. The physicochemical properties of ATRA-loaded lipid emulsion, including mean particle diameter and zeta potential, were modulated by changing an initial ATRA concentration as well as the type and mixing ratio of oil and oleic acid as an oil phase. The particles of lipid emulsions had average sizes of less than 250 nm and negative zeta potential. The addition of oleic acid in lipid emulsions resulted in high loading capacity. The photodegradation rate was found to be dependent on the initial drug concentration but independent of the type of oily phase used in this study. The release rates were not affected by initial ATRA concentration but were affected by the type of oil, where oleic acid showed the highest release rate of ATRA from lipid emulsions.

Compartmentalized Low-Rank Recovery for High-Resolution Lipid Unsuppressed MRSI

PubMed Central

Bhattacharya, Ipshita; Jacob, Mathews

2017-01-01

Purpose To introduce a novel algorithm for the recovery of high-resolution magnetic resonance spectroscopic imaging (MRSI) data with minimal lipid leakage artifacts, from dual-density spiral acquisition. Methods The reconstruction of MRSI data from dual-density spiral data is formulated as a compartmental low-rank recovery problem. The MRSI dataset is modeled as the sum of metabolite and lipid signals, each of which is support limited to the brain and extracranial regions, respectively, in addition to being orthogonal to each other. The reconstruction problem is formulated as an optimization problem, which is solved using iterative reweighted nuclear norm minimization. Results The comparisons of the scheme against dual-resolution reconstruction algorithm on numerical phantom and in vivo datasets demonstrate the ability of the scheme to provide higher spatial resolution and lower lipid leakage artifacts. The experiments demonstrate the ability of the scheme to recover the metabolite maps, from lipid unsuppressed datasets with echo time (TE)=55 ms. Conclusion The proposed reconstruction method and data acquisition strategy provide an efficient way to achieve high-resolution metabolite maps without lipid suppression. This algorithm would be beneficial for fast metabolic mapping and extension to multislice acquisitions. PMID:27851875

Sustained release and permeation of timolol from surface-modified solid lipid nanoparticles through bioengineered human cornea.

PubMed

Attama, A A; Reichl, S; Müller-Goymann, C C

2009-08-01

The aim of the study was to formulate and evaluate surface-modified solid lipid nanoparticles sustained delivery system of timolol hydrogen maleate, a prototype ocular drug using a human cornea construct. Surface-modified solid lipid nanoparticles containing timolol with and without phospholipid were formulated by melt emulsification with high-pressure homogenization and characterized by particle size, wide-angle X-ray diffraction, encapsulation efficiency, and in vitro drug release. Drug transport studies through cornea bioengineered from human donor cornea cells were carried out using a modified Franz diffusion cell and drug concentration analyzed by high-performance liquid chromatography. Results show that surface-modified solid lipid nanoparticles possessed very small particles (42.9 +/- 0.3 nm, 47.2 +/- 0.3 nm, 42.7 +/- 0.7 nm, and 37.7 +/- 0.3 nm, respectively for SM-SLN 1, SM-SLN 2, SM-SLN 3, and SM-SLN 4) with low polydispersity indices, increased encapsulation efficiency (> 44%), and sustained in vitro release compared with unmodified lipid nanoparticles whose particles were greater than 160 nm. Permeation of timolol hydrogen maleate from the surface-modified lipid nanoparticles across the cornea construct was sustained compared with timolol hydrogen maleate solution in distilled water. Surface-modified solid lipid nanoparticles could provide an efficient way of improving ocular bioavailability of timolol hydrogen maleate.

Synergistic role of solid lipid and porous silica in improving the oral delivery of weakly basic poorly water soluble drugs.

PubMed

Yasmin, Rokhsana; Rao, Shasha; Bremmell, Kristen; Prestidge, Clive

2017-01-01

Oral absorption of weakly basic drugs (e.g. cinnarizine (CIN)) is limited by their pH dependent precipitation in intestinal conditions. To overcome this challenge, a novel drug delivery system composed of solid lipid and porous silica, namely silica encapsulated solid lipid (SESL) particles, was developed via hot homogenization of melted lipid dispersion, followed by ultra-sonication of the silica stabilized homogenized melted lipid dispersion. Scanning electron microscope (SEM) images of the SESL formulation revealed non-spherical and aggregated hybrid particles, with rough exterior and structured nanoparticles visible on the surface. A 1.5, 2.2 and 7-fold improvement in the dissolution of CIN was observed for the SESL particles, under simulated intestinal non-digesting conditions, in comparison to the drug loaded in solid lipid (CIN-SL) matrix, drug loaded in porous silica (CIN-PS) and pure drug powder. Under simulated intestinal digestive condition, significant improvement in the drug solubilization was reported for the SESL formulation in compared to the individual drug loaded systems i.e. CIN-PS and CIN-SL. Thereby, silica encapsulated solid lipid system provides a promising oral delivery approach for poorly water soluble weakly basic drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Stability of lipid encapsulated ferulic acid particles

USDA-ARS?s Scientific Manuscript database

Encapsulation of bioactive compounds by a solid lipid matrix provides stability and a mechanism for controlled release in formulated products. Phenolic compounds exhibit antioxidant and antimicrobial activities and have applications as functional food and feed additives. Ferulic acid, a common pheno...

Computer-Assisted Drug Formulation Design: Novel Approach in Drug Delivery.

PubMed

Metwally, Abdelkader A; Hathout, Rania M

2015-08-03

We hypothesize that, by using several chemo/bio informatics tools and statistical computational methods, we can study and then predict the behavior of several drugs in model nanoparticulate lipid and polymeric systems. Accordingly, two different matrices comprising tripalmitin, a core component of solid lipid nanoparticles (SLN), and PLGA were first modeled using molecular dynamics simulation, and then the interaction of drugs with these systems was studied by means of computing the free energy of binding using the molecular docking technique. These binding energies were hence correlated with the loadings of these drugs in the nanoparticles obtained experimentally from the available literature. The obtained relations were verified experimentally in our laboratory using curcumin as a model drug. Artificial neural networks were then used to establish the effect of the drugs' molecular descriptors on the binding energies and hence on the drug loading. The results showed that the used soft computing methods can provide an accurate method for in silico prediction of drug loading in tripalmitin-based and PLGA nanoparticulate systems. These results have the prospective of being applied to other nano drug-carrier systems, and this integrated statistical and chemo/bio informatics approach offers a new toolbox to the formulation science by proposing what we present as computer-assisted drug formulation design (CADFD).

Structure-activity relationship of carbamate-linked cationic lipids bearing hydroxyethyl headgroup for gene delivery.

PubMed

Zhi, Defu; Zhang, Shubiao; Qureshi, Farooq; Zhao, Yinan; Cui, Shaohui; Wang, Bing; Chen, Huiying; Yang, Baoling; Zhao, Defeng

2013-12-01

A novel series of carbamate-linked cationic lipids containing hydroxyl headgroup were synthesized and included in formulations for transfection assays. The DNA-lipid complexes were characterized for their ability to bind DNA, their size, ζ-potential and cytotoxicity. Compared with our previously reported cationic transfection lipid DDCDMA lacking the hydroxyl group and the commercially available, these cationic liposomes exhibited relatively higher transfection efficiency. Copyright © 2013 Elsevier B.V. All rights reserved.

Solid Lipid Nanoparticles of Guggul Lipid as Drug Carrier for Transdermal Drug Delivery

PubMed Central

Gaur, Praveen Kumar; Mishra, Shikha; Purohit, Suresh

2013-01-01

Diclofenac sodium loaded solid lipid nanoparticles (SLNs) were formulated using guggul lipid as major lipid component and analyzed for physical parameters, permeation profile, and anti-inflammatory activity. The SLNs were prepared using melt-emulsion sonication/low temperature-solidification method and characterized for physical parameters, in vitro drug release, and accelerated stability studies, and formulated into gel. Respective gels were compared with a commercial emulgel (CEG) and plain carbopol gel containing drug (CG) for ex vivo and in vivo drug permeation and anti-inflammatory activity. The SLNs were stable with optimum physical parameters. GMS nanoparticle 1 (GMN-1) and stearic acid nanoparticle 1 (SAN-1) gave the highest in vitro drug release. Guggul lipid nanoparticle gel 3 (GLNG-3) showed 104.68 times higher drug content than CEG in receptor fluid. The enhancement ratio of GLNG-3 was 39.43 with respect to CG. GLNG-3 showed almost 8.12 times higher C max than CEG at 4 hours. The AUC value of GLNG-3 was 15.28 times higher than the AUC of CEG. GLNG-3 showed edema inhibition up to 69.47% in the first hour. Physicochemical properties of major lipid component govern the properties of SLN. SLN made up of guggul lipid showed good physical properties with acceptable stability. Furthermore, it showed a controlled drug release profile along with a promising permeation profile. PMID:24058913

Systematic Approach for the Formulation and Optimization of Solid Lipid Nanoparticles of Efavirenz by High Pressure Homogenization Using Design of Experiments for Brain Targeting and Enhanced Bioavailability

PubMed Central

Gupta, Shweta; Kesarla, Rajesh; Chotai, Narendra; Misra, Ambikanandan

2017-01-01

The nonnucleoside reverse transcriptase inhibitors, used for the treatment of HIV infections, are reported to have low bioavailability pertaining to high first-pass metabolism, high protein binding, and enzymatic metabolism. They also show low permeability across blood brain barrier. The CNS is reported to be the most important HIV reservoir site. In the present study, solid lipid nanoparticles of efavirenz were prepared with the objective of providing increased permeability and protection of drug due to biocompatible lipidic content and nanoscale size and thus developing formulation having potential for enhanced bioavailability and brain targeting. Solid lipid nanoparticles were prepared by high pressure homogenization technique using a systematic approach of design of experiments (DoE) and evaluated for particle size, polydispersity index, zeta potential, and entrapment efficiency. Particles of average size 108.5 nm having PDI of 0.172 with 64.9% entrapment efficiency were produced. Zeta potential was found to be −21.2 mV and the formulation was found stable. The in-vivo pharmacokinetic studies revealed increased concentration of the drug in brain, as desired, when administered through intranasal route indicating its potential for an attempt towards complete eradication of HIV and cure of HIV-infected patients. PMID:28243600

Preparation and evaluation of miconazole nitrate-loaded solid lipid nanoparticles for topical delivery.

PubMed

Bhalekar, Mangesh R; Pokharkar, Varsha; Madgulkar, Ashwini; Patil, Nilam; Patil, Nilkanth

2009-01-01

The purpose of this study was to prepare miconazole nitrate (MN) loaded solid lipid nanoparticles (MN-SLN) effective for topical delivery of miconazole nitrate. Compritol 888 ATO as lipid, propylene glycol (PG) to increase drug solubility in lipid, tween 80, and glyceryl monostearate were used as the surfactants to stabilize SLN dispersion in the SLN preparation using hot homogenization method. SLN dispersions exhibited average size between 244 and 766 nm. All the dispersions had high entrapment efficiency ranging from 80% to 100%. The MN-SLN dispersion which showed good stability for a period of 1 month was selected. This MN-SLN was characterized for particle size, entrapment efficiency, and X-ray diffraction. The penetration of miconazole nitrate from the gel formulated using selected MN-SLN dispersion as into cadaver skins was evaluated ex-vivo using franz diffusion cell. The results of differential scanning calorimetry (DSC) showed that MN was dispersed in SLN in an amorphous state. The MN-SLN formulations could significantly increase the accumulative uptake of MN in skin over the marketed gel and showed a significantly enhanced skin targeting effect. These results indicate that the studied MN-SLN formulation with skin targeting may be a promising carrier for topical delivery of miconazole nitrate.

How relevant are assembled equilibrium samples in understanding structure formation during lipid digestion?

PubMed

Phan, Stephanie; Salentinig, Stefan; Hawley, Adrian; Boyd, Ben J

2015-10-01

Lipid-based formulations are gaining interest for use as drug delivery systems for poorly water-soluble drug compounds. During digestion, the lipolysis products self-assemble with endogenous surfactants in the gastrointestinal tract to form colloidal structures, enabling enhanced drug solubilisation. Although earlier studies in the literature focus on assembled equilibrium systems, little is known about structure formation under dynamic lipolysis conditions. The purpose of this study was to investigate the likely colloidal structure formation in the small intestine after the ingestion of lipids, under equilibrium and dynamic conditions. The structural aspects were studied using small angle X-ray scattering and dynamic light scattering, and were found to depend on lipid composition, lipid chain length, prandial state and emulsification. Incorporation of phospholipids and lipolysis products into bile salt micelles resulted in swelling of the structure. At insufficient bile salt concentrations, a co-existing lamellar phase was observed, due to a reduction in the solubilisation capacity for lipolysis products. Emulsification accelerated the rate of lipolysis and structure formation. Copyright © 2015 Elsevier B.V. All rights reserved.

In vitro evaluation of α-lipoic acid-loaded lipid nanocapsules for topical delivery.

PubMed

Xia, Nan; Liu, Tian; Wang, Qiang; Xia, Qiang; Bian, Xiaoli

2017-09-01

This study aimed at in vitro evaluation of α-lipoic acid-loaded lipid nanocapsules for topical delivery, which was prepared by hot high-pressure homogenisation. Stable particles could be formed and particle size was 148.54 ± 2.31 nm with polydispersity index below 0.15. Encapsulation efficiency and drug loading of α-lipoic acid were 95.23 ± 0.45% and 2.81 ± 0.37%. Antioxidant study showed α-lipoic acid could be protected by lipid nanocapsules without loss of antioxidant activity. Sustained release of α-lipoic acid from lipid nanocapsules was obtained and cumulative release was 62.18 ± 1.51%. In vitro percutaneous study showed the amount of α-lipoic acid distributed in skin was 1.7-fold than permeated. Cytotoxicity assay and antioxidant activity on L929 cells indicated this formulation had low cytotoxicity and ability of protecting cells from oxidative damage within specific concentration. These studies suggested α-lipoic acid-loaded lipid nanocapsules could be potential formulation for topical delivery.

Application of quality by design approach for intranasal delivery of rivastigmine loaded solid lipid nanoparticles: Effect on formulation and characterization parameters.

PubMed

Shah, Brijesh; Khunt, Dignesh; Bhatt, Himanshu; Misra, Manju; Padh, Harish

2015-10-12

In the present investigation, Quality by Design (QbD) approach was applied on the development and optimization of solid lipid nanoparticle (SLN) formulation of hydrophilic drug rivastigmine (RHT). RHT SLN were formulated by homogenization and ultrasonication method using Compritol 888 ATO, tween-80 and poloxamer-188 as lipid, surfactant and stabilizer respectively. The effect of independent variables (X1 - drug: lipid ratio, X2 - surfactant concentration and X3 - homogenization time) on quality attributes of SLN i.e. dependent variables (Y1 - size, Y2 - PDI and Y3 - %entrapment efficiency (%EE)) were investigated using 3(3) factorial design. Multiple linear regression analysis and ANOVA were employed to indentify and estimate the main effect, 2FI, quadratic and cubic effect. Optimized RHT SLN formula was derived from an overlay plot on which further effect of probe sonication was evaluated. Final RHT SLN showed narrow size distribution (PDI- 0.132±0.016) with particle size of 82.5±4.07 nm and %EE of 66.84±2.49. DSC and XRD study showed incorporation of RHT into imperfect crystal lattice of Compritol 888 ATO. In comparison to RHT solution, RHT SLN showed higher in-vitro and ex-vivo diffusion. The diffusion followed Higuchi model indicating drug diffusion from the lipid matrix due to erosion. Histopathology study showed intact nasal mucosa with RHT SLN indicating safety of RHT SLN for intranasal administration. Copyright © 2015 Elsevier B.V. All rights reserved.

Lamellar cationic lipid-DNA complexes from lipids with a strong preference for planar geometry: A Minimal Electrostatic Model.

PubMed

Perico, Angelo; Manning, Gerald S

2014-11-01

We formulate and analyze a minimal model, based on condensation theory, of the lamellar cationic lipid (CL)-DNA complex of alternately charged lipid bilayers and DNA monolayers in a salt solution. Each lipid bilayer, composed by a random mixture of cationic and neutral lipids, is assumed to be a rigid uniformly charged plane. Each DNA monolayer, located between two lipid bilayers, is formed by the same number of parallel DNAs with a uniform separation distance. For the electrostatic calculation, the model lipoplex is collapsed to a single plane with charge density equal to the net lipid and DNA charge. The free energy difference between the lamellar lipoplex and a reference state of the same number of free lipid bilayers and free DNAs, is calculated as a function of the fraction of CLs, of the ratio of the number of CL charges to the number of negative charges of the DNA phosphates, and of the total number of planes. At the isoelectric point the free energy difference is minimal. The complex formation, already favoured by the decrease of the electrostatic charging free energy, is driven further by the free energy gain due to the release of counterions from the DNAs and from the lipid bilayers, if strongly charged. This minimal model compares well with experiment for lipids having a strong preference for planar geometry and with major features of more detailed models of the lipoplex. © 2014 Wiley Periodicals, Inc.

Nanodiamond decorated liposomes as highly biocompatible delivery vehicles and a comparison with carbon nanotubes and graphene oxide.

PubMed

Wang, Feng; Liu, Juewen

2013-12-21

Studying interactions between nano-carbons and lipid membranes is important for multiplexed drug delivery, device fabrication and for understanding toxicity. Herein, we report that nanodiamond (ND, sp(3) carbon) forms a complex with highly biocompatible zwitterionic liposomes based on hydrogen bonding, which is confirmed by pH-dependent and urea-dependent assays. Despite such weak interaction, the complex is highly stable. Comparisons were made with two sp(2) carbons: nanoscale graphene oxide (NGO) and carbon nanotubes (CNTs), where CNT adsorption is the weakest. Adsorption of the nano-carbons does not induce liposome leakage or affect lipid phase transition temperature. Therefore, the potential toxicity of nano-carbons is unlikely to be related to direct membrane damage. ND facilitates cellular uptake of liposomes and co-delivery of negatively charged calcein and positively charged doxorubicin has been demonstrated. ND has the lowest toxicity, while CNTs and NGO are slightly more toxic. The effect of introducing fusogenic lipids and cholesterol was further studied to understand the effect of lipid formulation.

Lipid- and Polymer-Based Nanostructures for Cancer Theranostics

PubMed Central

Luk, Brian T.; Fang, Ronnie H.; Zhang, Liangfang

2012-01-01

The relatively new field of nanotheranostics combines the advantages of in vivo diagnosis with the ability to administer treatment through a single nano-sized carrier, offering new opportunities for cancer diagnosis and therapy. Nanotheranostics has facilitated the development of nanomedicine through direct visualization of drug blood circulation and biodistribution. From a clinical perspective, nanotheranostics allows therapies to be administered and monitored in real time, thus decreasing the potential of under- or over-dosing and allowing for more personalized treatment regimens. Herein, we review recent development of nanotheranostics using lipid- and polymer-based formulations, with a particular focus on their applications in cancer research. Recent advances in nanotechnology aimed to combine therapeutic molecules with imaging agents for magnetic resonance imaging, radionuclide imaging, or fluorescence imaging are discussed. PMID:23382770

Combination of Oxaliplatin and Vit.E-TPGS in Lipid Nanosystem for Enhanced Therapeutic Efficacy in Colon Cancers.

PubMed

Wang, Yanlei; Zhang, Xiang; Zhang, Wenqiang; Dong, Hao; Zhang, Wenjie; Mao, Jiajia; Dai, Yong

2018-01-08

The main aim of present study was to prepare the oxaliplatin (OXL)-loaded D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS)-based lipid nanoparticles to enhance the anticancer effect in colon cancer cells. The nanoparticles were nanosized and spherical shaped and exhibited controlled release kinetics. Flow cytometer and confocal laser scanning microscopy (CLSM) showed a remarkable uptake of nanoparticles in cancer cells in a time-dependent manner. The presence of TPGS remarkably increased the anticancer effect of OXL in HT-29 colon cancer cells. The IC50 value of free OXL was 4.25 μg/ml whereas IC50 value of OXL-loaded TPGS-based lipid nanoparticles (OXL/TLNP) was 1.12 μg/ml. The 3-fold lower IC50 value of OXL/TLNP indicates the superior anticancer effect of nanoparticle-based OXL. Consistently, OXL/TLNP induced a remarkable apoptosis of cancer cells. Approximately, ~52% of cells were in early apoptosis phase and ~13% of cells were in late apoptosis phase indicating the potent anticancer effect of the formulations. The findings from this study provide novel insights into the use of TPGS and lipid nanoparticle together for the better antitumor effect in colon cancers. Future studies will involve the detailed in vitro and in vivo studies on clinically relevant animals.

Impact of change of matrix crystallinity and polymorphism on ovalbumin release from lipid-based implants.

PubMed

Duque, Luisa; Körber, Martin; Bodmeier, Roland

2018-05-30

The objectives of this study were to prepare lipid-based implants by hot melt extrusion (HME) for the prolonged release of ovalbumin (OVA), and to relate protein release to crystallinity and polymorphic changes of the lipid matrix. Two lipids, glycerol tristearate and hydrogenated palm oil, with different composition and degree of crystallinity were studied. Solid OVA was dispersed within the lipid matrixes, which preserved its stability during extrusion. This was partially attributed to a protective effect of the lipidic matrix. The incorporation of OVA decreased the mechanical strength of the implants prepared with the more crystalline matrix, glycerol tristearate, whereas it remained comparable for the hydrogenated palm oil because of stronger physical and non-covalent interactions between the protein and this lipid. This was also the reason for the faster release of OVA from the glycerol tristearate matrix when compared to the hydrogenated palm oil (8 vs. 28 weeks). Curing induced and increased crystallinity, and changes in the release rate, especially for the more crystalline matrix. In this case, both an increase and a decrease in release, were observed depending on the tempering condition. Curing at higher temperatures induced a melt-mediated crystallization and solid state transformation of the glycerol tristearate matrix and led to rearrangements of the inner structure with the formation of larger pores, which accelerated the release. In contrast, changes in the hydrogenated palm oil under the same curing conditions were less noticeable leading to a more robust formulation, because of less polymorphic changes over time. This study helps to understand the effect of lipid matrix composition and crystallinity degree on the performance of protein-loaded implants, and to establish criteria for the selection of a lipid carrier depending on the release profile desired. Copyright © 2018. Published by Elsevier B.V.

A logical approach to optimize the nanostructured lipid carrier system of irinotecan: efficient hybrid design methodology

NASA Astrophysics Data System (ADS)

Mohan Negi, Lalit; Jaggi, Manu; Talegaonkar, Sushama

2013-01-01

Development of an effective formulation involves careful optimization of a number of excipient and process variables. Sometimes the number of variables is so large that even the most efficient optimization designs require a very large number of trials which put stress on costs as well as time. A creative combination of a number of design methods leads to a smaller number of trials. This study was aimed at the development of nanostructured lipid carriers (NLCs) by using a combination of different optimization methods. A total of 11 variables were first screened using the Plackett-Burman design for their effects on formulation characteristics like size and entrapment efficiency. Four out of 11 variables were found to have insignificant effects on the formulation parameters and hence were screened out. Out of the remaining seven variables, four (concentration of tween-80, lecithin, sodium taurocholate, and total lipid) were found to have significant effects on the size of the particles while the other three (phase ratio, drug to lipid ratio, and sonication time) had a higher influence on the entrapment efficiency. The first four variables were optimized for their effect on size using the Taguchi L9 orthogonal array. The optimized values of the surfactants and lipids were kept constant for the next stage, where the sonication time, phase ratio, and drug:lipid ratio were varied using the Box-Behnken design response surface method to optimize the entrapment efficiency. Finally, by performing only 38 trials, we have optimized 11 variables for the development of NLCs with a size of 143.52 ± 1.2 nm, zeta potential of -32.6 ± 0.54 mV, and 98.22 ± 2.06% entrapment efficiency.

Continuous production of fenofibrate solid lipid nanoparticles by hot-melt extrusion technology: a systematic study based on a quality by design approach.

PubMed

Patil, Hemlata; Feng, Xin; Ye, Xingyou; Majumdar, Soumyajit; Repka, Michael A

2015-01-01

This contribution describes a continuous process for the production of solid lipid nanoparticles (SLN) as drug-carrier systems via hot-melt extrusion (HME). Presently, HME technology has not been used for the manufacturing of SLN. Generally, SLN are prepared as a batch process, which is time consuming and may result in variability of end-product quality attributes. In this study, using Quality by Design (QbD) principles, we were able to achieve continuous production of SLN by combining two processes: HME technology for melt-emulsification and high-pressure homogenization (HPH) for size reduction. Fenofibrate (FBT), a poorly water-soluble model drug, was incorporated into SLN using HME-HPH methods. The developed novel platform demonstrated better process control and size reduction compared to the conventional process of hot homogenization (batch process). Varying the process parameters enabled the production of SLN below 200 nm. The dissolution profile of the FBT SLN prepared by the novel HME-HPH method was faster than that of the crude FBT and a micronized marketed FBT formulation. At the end of a 5-h in vitro dissolution study, a SLN formulation released 92-93% of drug, whereas drug release was approximately 65 and 45% for the marketed micronized formulation and crude drug, respectively. Also, pharmacokinetic study results demonstrated a statistical increase in Cmax, Tmax, and AUC0-24 h in the rate of drug absorption from SLN formulations as compared to the crude drug and marketed micronized formulation. In summary, the present study demonstrated the potential use of hot-melt extrusion technology for continuous and large-scale production of SLN.

Ionization behavior of amino lipids for siRNA delivery: determination of ionization constants, SAR, and the impact of lipid pKa on cationic lipid-biomembrane interactions.

PubMed

Zhang, Jingtao; Fan, Haihong; Levorse, Dorothy A; Crocker, Louis S

2011-03-01

Ionizable amino lipids are being pursued as an important class of materials for delivering small interfering RNA (siRNA) therapeutics, and research is being conducted to elucidate the structure-activity relationships (SAR) of these lipids. The pK(a) of cationic lipid headgroups is one of the critical physiochemical properties of interest due to the strong impact of lipid ionization on the assembly and performance of these lipids. This research focused on developing approaches that permit the rapid determination of the relevant pK(a) of the ionizable amino lipids. Two distinct approaches were investigated: (1) potentiometric titration of amino lipids dissolved in neutral surfactant micelles; and (2) pH-dependent partitioning of a fluorescent dye to cationic liposomes formulated from amino lipids. Using the approaches developed here, the pK(a) values of cationic lipids with distinct headgroups were measured and found to be significantly lower than calculated values. It was also found that lipid-lipid interaction has a strong impact on the pK(a) values of lipids. Lysis of model biomembranes by cationic lipids was used to evaluate the impact of lipid pK(a) on the interaction between cationic lipids and cell membranes. It was found that cationic lipid-biomembrane interaction depends strongly on lipid pK(a) and solution pH, and this interaction is much stronger when amino lipids are highly charged. The presence of an optimal pK(a) range of ionizable amino lipids for siRNA delivery was suggested based on these results. The pK(a) methods reported here can be used to support the SAR screen of cationic lipids for siRNA delivery, and the information revealed through studying the impact of pK(a) on the interaction between cationic lipids and cell membranes will contribute significantly to the design of more efficient siRNA delivery vehicles.

Genetic polymorphisms of LPL and HL and their association with the performance of Chinese sturgeons fed a formulated diet.

PubMed

He, Y; Shen, D; Liang, X F; Lu, R H; Xiao, H

2013-10-15

It is very important to investigate the reasons for the large individual differences in individual performance of food acceptance when using formulated diets for the successful culture of larvae and juveniles of the Chinese sturgeon Acipenser sinensis. Genetic differences of the mitochondrial control region were investigated by direct sequencing in two groups of Chinese sturgeon, which were apt to accept or refuse formulated diets. Among 968-bp sequences, 111 variable sites were identified. One variable site showed close association with the individual performance of specimens fed with formulated diets. The commercial diet for Chinese sturgeons usually contains high levels of lipids. Lipoprotein lipase (LPL) and hepatic lipase (HL) are two members of the lipase gene family, which are essential for the utilization of dietary lipid. Single nucleotide polymorphisms (SNPs) in intron 7 were detected in the two experimental groups of Chinese sturgeons. We were able to demonstrate that one SNP in the LPL gene and one SNP in the HL gene showed close association with the performance of sturgeons on the formulated diet.

Assessing the In Vitro Drug Release from Lipid-Core Nanocapsules: a New Strategy Combining Dialysis Sac and a Continuous-Flow System.

PubMed

de Andrade, Diego Fontana; Zuglianello, Carine; Pohlmann, Adriana Raffin; Guterres, Silvia Stanisçuaski; Beck, Ruy Carlos Ruver

2015-12-01

The in vitro assessment of drug release from polymeric nanocapsules suspensions is one of the most studied parameters in the development of drug-loaded nanoparticles. Nevertheless, official methods for the evaluation of drug release from submicrometric carriers are not available. In this work, a new approach to assess the in vitro drug release profile from drug-loaded lipid-core nanocapsules (LNC) was proposed. A continuous-flow system (open system) was designed to evaluate the in vitro drug release profiles from different LNC formulations containing prednisolone or clobetasol propionate (LNC-CP) as drug model (LNC-PD) using a homemade apparatus. The release medium was constantly renewed throughout the experiment. A dialysis bag containing 5 mL of formulation (0.5 mg mL(-1)) was maintained inside the apparatus, under magnetic stirring and controlled temperature (37°C). In parallel, studies based on the conventional dialysis sac technique (closed system) were performed. It was possible to discriminate the in vitro drug release profile of different formulations using the open system. The proposed strategy improved the sink condition, by constantly renewing the release medium, thus maintaining the drug concentration farther from the saturated concentration in the release medium. Moreover, problems due to sampling errors can be easily overcome using this semi-automated system, since the collection is done automatically without interference from the analyst. The system proposed in this paper brings important methodological and analytical advantages, becoming a promising prototype semi-automated apparatus for performing in vitro drug release studies from drug-loaded lipid-core nanocapsules and other related nanoparticle drug delivery systems.

Structure-activity correlation in transfection promoted by pyridinium cationic lipids.

PubMed

Parvizi-Bahktar, P; Mendez-Campos, J; Raju, L; Khalique, N A; Jubeli, E; Larsen, H; Nicholson, D; Pungente, M D; Fyles, T M

2016-03-21

The efficiency of the transfection of a plasmid DNA encoding a galactosidase promoted by a series of pyridinium lipids in mixtures with other cationic lipids and neutral lipids was assessed in CHO-K1 cells. We identify key molecular parameters of the lipids in the mixture - clog P, lipid length, partial molar volume - to predict the morphology of the lipid-DNA lipoplex and then correlate these same parameters with transfection efficiency in an in vitro assay. We define a Transfection Index that provides a linear correlation with normalized transfection efficiency over a series of 90 different lipoplex compositions. We also explore the influence of the same set of molecular parameters on the cytotoxicity of the formulations.

Diclofenac sodium delivery to the eye: in vitro evaluation of novel solid lipid nanoparticle formulation using human cornea construct.

PubMed

Attama, Anthony A; Reichl, Stephan; Müller-Goymann, Christel C

2008-05-01

Solid lipid nanoparticles (SLNs) were prepared with a combination of homolipid from goat (goat fat) and phospholipid, and evaluated for diclofenac sodium (DNa) delivery to the eye using bio-engineered human cornea, produced from immortalized human corneal endothelial cells (HENC), stromal fibroblasts and epithelial cells CEPI 17 CL 4. Encapsulation efficiency was high and sustained release of DNa and high permeation through the bio-engineered cornea were achieved. Results obtained in this work showed that permeation of DNa through the cornea construct was improved by formulation as SLN modified with phospholipid.

A new intranasal influenza vaccine based on a novel polycationic lipid-ceramide carbamoyl-spermine (CCS). II. Studies in mice and ferrets and mechanism of adjuvanticity.

PubMed

Even-Or, Orli; Joseph, Aviva; Itskovitz-Cooper, Noga; Samira, Sarit; Rochlin, Eli; Eliyahu, Hagit; Goldwaser, Itzik; Balasingam, Shobana; Mann, Alex J; Lambkin-Williams, Rob; Kedar, Eli; Barenholz, Yechezkel

2011-03-16

We recently showed that lipid assemblies comprised of a novel polycationic sphingolipid (ceramide carbamoyl-spermine, CCS) are an effective adjuvant/carrier when complexed with cholesterol (CCS/C) for influenza and other vaccines administered parenterally and intranasally (i.n.) in mice. Here we expand these studies to ferrets, an established model of influenza infection. We also address the question of why the CCS/C-based liposomal vaccine (also known as VaxiSome™) in mice is superior to vaccines based on liposomes of other lipid compositions (neutral, anionic or cationic). Ferrets immunized i.n. with CCS/C-influenza vaccine produced significantly higher hemagglutination inhibition (HI) antibody titers compared to ferrets immunized intramuscularly with the unadjuvanted influenza vaccine, indicating that the CCS/C-based vaccine is very immunogenic. Furthermore, the i.n. adjuvanted vaccine was shown to significantly reduce the severity of influenza virus infection in ferrets following homologous viral challenge as determined by weight loss, temperature rise and viral titer. No adverse reactions were observed. Pharmacokinetic and biodistribution studies following i.n. administration in mice of CCS/C-based vaccine showed that both the lipids and antigens are retained in the nose and lung for at least 24h, and it appears that this retention correlates with the superior immunogenicity elicited by the adjuvanted vaccine formulation. The CCS lipid also increases production of cytokines (mainly IFN gamma, IL-2 and IL-12) and co-stimulatory molecules' expression, which might further explain the robust adjuvantation of this liposome-based vaccine. Copyright © 2011 Elsevier Ltd. All rights reserved.

Formulation and pharmacokinetics of diclofenac lipid nanoemulsions for parenteral application.

PubMed

Ramreddy, Srividya; Kandadi, Prabhakar; Veerabrahma, Kishan

2012-01-01

The objective of the present study was to formulate and determine the pharmacokinetics of stable o/w parenteral lipid nanoemulsions (LNEs) of diclofenac acid used to treat arthritic conditions. The LNEs of diclofenac acid with a mean size ranging from 200 to 240 nm and a zeta potential of -29.4 ± 1.04 mV (negatively charged LNEs) and 62.1 ± 3.5 (positively charged LNEs) emulsions were prepared by hot homogenization and ultrasonication process. The influence of formulation variables, such as the change in proportion of cholesterol, was studied, and optimized formulations were developed. The optimized formulations were relatively stable during centrifugal stress, dilution stress, and storage. The drug content and entrapment efficiency were determined using high-performance liquid chromatography. The in vitro drug release was carried out in phosphate-buffered saline pH 7.4 and cumulative amount of drug released was estimated using a UV-visible spectro-photometer. During in vivo pharmacokinetic studies in male Wistar rats, diclofenac serum concentration from LNEs was higher than that of Voveran injection and was detectable up to 12 h. Diclofenac in LNEs showed improved pharmacokinetic profile with increase in area under the curve, elimination half-life and mean residence time in comparison to Voveran. Our aim was to prepare and determine the pharmacokinetics of injectable lipid nanoemulsions of diclofenac acid for treating arthritic conditions by reducing the frequency of dosing and pain at site of injection. The nanoemulsions of diclofenac acid were prepared by homogenization and ultrasonication process. The sizes and charges of oil globules were determined. The effect of cholesterol on stability of emulsion was studied, and an optimized preparation was developed. The optimized formulations were stable during centrifugation, dilution, and storage. The total amount of drug in emulsion and percentage amount of drug present in emulsion globules were determined using high-performance liquid chromatography. The drug release from preparation was carried out in phosphate-buffered saline pH 7.4. The cumulative amount of drug released was estimated using a spectrophotometer. The time course of the released drug in rat serum was determined. Diclofenac concentrations from lipid nanoemulsions were higher than that of Voveran injection (solution form) in serum.

Lyophilized silica lipid hybrid (SLH) carriers for poorly water-soluble drugs: physicochemical and in vitro pharmaceutical investigations.

PubMed

Yasmin, Rokhsana; Tan, Angel; Bremmell, Kristen E; Prestidge, Clive A

2014-09-01

Lyophilization was investigated to produce a powdery silica-lipid hybrid (SLH) carrier for oral delivery of poorly water-soluble drugs. The silica to lipid ratio, incorporation of cryoprotectant, and lipid loading level were investigated as performance indicators for lyophilized SLH carriers. Celecoxib, a nonsteroidal anti-inflammatory drug, was used as the model poorly soluble moiety to attain desirable physicochemical and in vitro drug solubilization properties. Scanning electron microscopy and confocal fluorescence imaging verified a nanoporous, homogenous internal matrix structures of the lyophilized SLH particles, prepared from submicron triglyceride emulsions and stabilized by porous silica nanoparticles (Aerosil 380), similar to spray-dried SLH. 20-50 wt % of silica in the formulation have shown to produce nonoily SLH agglomerates with complete lipid encapsulation. The incorporation of a cryoprotectant prevented irreversible aggregation of the silica-stabilized droplets during lyophilization, thereby readily redispersing in water to form micrometre-sized particles (<5 μm). The lyophilized SLH produced approximately 1.5-fold and fivefold increased drug solubilization than the pure drug under nondigesting and digesting conditions, respectively. The feasibility of lyophilization for producing nanostructured SLH formulations with desirable lipid loading and drug solubilization properties for enhanced oral delivery of poorly water-soluble therapeutics is confirmed. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Temozolomide-based dry powder formulations for lung tumor-related inhalation treatment.

PubMed

Wauthoz, Nathalie; Deleuze, Philippe; Saumet, Amandine; Duret, Christophe; Kiss, Robert; Amighi, Karim

2011-04-01

Temozolomide dry powder formulations for inhalation, performed with no excipient or with a lipid or lactose coating, have been evaluated. The particle size of raw temozolomide in suspension was reduced by a high-pressure homogenizing technique, and the solvent was evaporated by spray-drying to obtain a dry powder. The physicochemical properties of this powder were evaluated and included its crystalline state, thermal properties, morphology, particle size and moisture and drug content, and these properties were determined by X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, laser light scattering, thermogravimetric analysis and high-performance liquid chromatography, respectively. The aerodynamic properties and release profiles were also evaluated using a multistage liquid impinger and a modified USP type 2 dissolution apparatus adapted for inhaler products, respectively. The dry powder inhalation formulations had a high temozolomide content that ranged from 70% to 100% in the crystalline state and low moisture content. Aerodynamic evaluations showed high fine-particle fractions of up to 51% related to the metered dose. The dissolution profile revealed a similarly fast temozolomide release from the formulations. Dry temozolomide powder formulations, based on the use of acceptable excipients for inhalation and showing good dispersion properties, represent an attractive alternative for use in local lung cancer therapy.

Spectroscopic study of 3-Hydroxyflavone - protein interaction in lipidic bi-layers immobilized on silver nanoparticles

NASA Astrophysics Data System (ADS)

Voicescu, Mariana; Ionescu, Sorana; Nistor, Cristina L.

2017-01-01

The interaction of 3-Hydroxyflavone with serum proteins (BSA and HSA) in lecithin lipidic bi-layers (PC) immobilized on silver nanoparticles (SNPs), was studied by fluorescence and Raman spectroscopy. BSA secondary structure was quantified with a deconvolution algorithm, showing a decrease in α-helix structure when lipids were added to the solution. The effect of temperature on the rate of the excited-state intra-molecular proton transfer and on the dual fluorescence emission of 3-HF in the HSA/PC/SNPs systems was discussed. Evaluation of the antioxidant activity of 3-HF in HSA/PC/SNPs systems was also studied. The antioxidant activity of 3-HF decreased in the presence of SNPs. The results are discussed with relevance to the secondary structure of proteins and of the 3-HF based nano-systems to a topical formulation useful in the oxidative stress process.

Preclinical development of a non-toxic oral formulation of monoethanolamine, a lipid precursor, for prostate cancer treatment

PubMed Central

Saxena, Roopali; Yang, Chunhua; Rao, Mukkavilli; Turaga, Ravi Chakra; Garlapati, Chakravarthy; Gundala, Sushma Reddy; Myers, Kimberly; Ghareeb, Ahmed; Bhattarai, Shristi; Kamilinia, Golnaz; Bristi, Sangina; Su, Dan; Gadda, Giovanni; Rida, Padmashree C. G.; Cantuaria, Guilherme H.; Aneja, Ritu

2018-01-01

Purpose Most currently-available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly-dividing normal cells resulting in toxic side-effects. This non-specificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less-toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory. Herein, we report development of a novel non-toxic orally-deliverable anticancer formulation of monoethanolamine (Etn), for prostate cancer by targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis. Experimental Design We first evaluated GI-tract stability, drug-drug interaction liability, pharmacokinetic and toxicokinetic properties of Etn to evaluate its suitability as a non-toxic orally-deliverable agent. We next performed in vitro and in vivo experiments to investigate efficacy and mechanism of action. Results Our data demonstrate that Etn exhibits excellent bioavailability, GI-tract stability, and no drug-drug interaction liability. Remarkably, orally-fed Etn inhibited tumor growth in four weeks by ~67% in mice bearing human prostate cancer PC-3 xenografts without any apparent toxicity. Mechanistically, Etn exploits selective overexpression of choline kinase in cancer cells, resulting in accumulation of phosphoethanolamine (PhosE), accompanied by downregulation of HIF-1α that induces metabolic stress culminating into cell death. Conclusions Our study provides first evidence for the superior anticancer activity of Etn, a simple lipid precursor formulation, whose non-toxicity conforms to FDA-approved standards, compelling its clinical development for prostate cancer management. PMID:28167510

Reduction in blood pressure and serum lipids by lycosome formulation of dark chocolate and lycopene in prehypertension.

PubMed

Petyaev, Ivan M; Dovgalevsky, Pavel Y; Chalyk, Natalia E; Klochkov, Victor; Kyle, Nigel H

2014-11-01

Twenty-nine healthy volunteers aged 47-69 years old were randomly assigned to a 28-day oral intake of different dark chocolate (DC) formulations. The main group received daily 30 g of proprietary lycopene-containing (L-tug) lycosome formulation of DC with enhanced bioavailability of cocoa flavanols. Two control groups daily consumed either 30 g of regular DC alone or along with 7 mg of lycopene, which corresponds to the amount of lycopene ingested with L-tug formulation. It was found that L-tug was more efficient in reducing diastolic blood pressure (mean value of -6.22 mmHg, 95% CI: 5.00, 8.00) when compared with the regular DC group (-3.00 mmHg, P < 0.05) or the group which ingested the DC and lycopene as two separate formulations (mean reduction of -4 mmHg, 95% CI: 2.47, 6.00, P = 0.0262). Only marginal superiority for L-tug formulation in the reduction in systolic blood pressure was seen. However, the L-tug formulation was the only formulation of DC which affected serum lipids. There was a reduction in total cholesterol (from median 228.00 mg/dL [95% CI: 206.2, 242.5] to 187.00 mg/dL [95% CI: 166.2, 202.2, P < 0.05]) with corresponding decline of low-density lipoprotein (LDL) cholesterol (from a median of 166.00 mg/dL [95% CI: 130.8, 177.0] to 151.00 mg/dL [95% CI: 122.8, 167.4; P < 0.05]) at the end of the intervention period. Similar decline was seen in serum triglycerides (P < 0.05). Serum high-density lipoprotein (HDL) cholesterol, glucose levels, and C-reactive protein (CRP) values remained statistically unchanged in all study groups throughout the intervention period. A superior biological activity of the L-tug lycosome formulation of DC extending beyond its antihypertensive effect to lipid-lowering ability opens up new possibilities for the use of DC for health purposes helping to reduce daily caloric intake without compromising on the health benefits of DC consumption.

Solid lipid nanodispersions containing mixed lipid core and a polar heterolipid: characterization.

PubMed

Attama, A A; Schicke, B C; Paepenmüller, T; Müller-Goymann, C C

2007-08-01

This paper describes the characterization of solid lipid nanodispersions (SLN) prepared with a 1:1 mixture of theobroma oil and goat fat as the main lipid matrix and Phospholipon 90G (P90G) as a stabilizer heterolipid, using polysorbate 80 as the mobile surfactant, with a view to applying the SLN in drug delivery. The 1:1 lipid mixture and P90G constituting the lipid matrix was first homogeneously prepared by fusion. Thereafter, the SLN were formulated with a gradient of polysorbate 80 and constant lipid matrix concentration by melt-high pressure homogenisation. The SLN were characterized by time-resolved particle size analysis, zeta potential and osmotic pressure measurements, differential scanning calorimetry (DSC) and wide angle X-ray diffraction (WAXD). Transmission electron microscopy (TEM) and isothermal heat conduction microcalorimetry (IMC) which monitors the in situ crystallization were also carried out on the SLN containing P90G and 1.0 % w/w of polysorbate 80. The results obtained in these studies were compared with SLN prepared with theobroma oil with and without phospholipid. Particle size analysis of SLN indicated reduction in size with increase in concentration of mobile surfactant and was in the lower nanometer range after 3 months except SLN prepared without P90G or polysorbate 80. The lipid nanoparticles had negative potentials after 3 months. WAXD and DSC studies revealed low crystalline SLN after 3 months of storage except in WAXD of SLN formulated with 1.0 % w/w polysorbate 80. TEM micrograph of the SLN containing 1.0 % w/w polysorbate 80 revealed discrete particles whose sizes were in consonance with the static light scattering measurement. In situ crystallization studies in IMC revealed delayed crystallization of the SLN with 1.0 % w/w polysorbate 80. Results indicate lipid mixtures produced SLN with lower crystallinity and higher particle sizes compared with SLN prepared with theobroma oil alone with or without P90G, and would lead to higher drug incorporation efficiency when used in formulation of actives. Mixtures of theobroma oil and goat fat would be suitable for the preparation of nanostructured lipid carriers. SLN of theobroma oil containing phospholipid could prove to be a good ocular or parenteral drug delivery system considering the low particle size, particle size stability and in vivo tolerability of the component lipids. SLN prepared with lipid admixture, which had higher increase in d(90%) on storage are suitable for preparation of topical and transdermal products.

Self-Assembled Core-Shell-Type Lipid-Polymer Hybrid Nanoparticles: Intracellular Trafficking and Relevance for Oral Absorption.

PubMed

Li, Qiuxia; Xia, Dengning; Tao, Jinsong; Shen, Aijun; He, Yuan; Gan, Yong; Wang, Chi

2017-10-01

Lipid-polymer hybrid nanoparticles (NPs) are advantageous for drug delivery. However, their intracellular trafficking mechanism and relevance for oral drug absorption are poorly understood. In this study, self-assembled core-shell lipid-polymer hybrid NPs made of poly(lactic-co-glycolic acid) (PLGA) and various lipids were developed to study their differing intracellular trafficking in intestinal epithelial cells and their relevance for oral absorption of a model drug saquinavir (SQV). Our results demonstrated that the endocytosis and exocytosis of hybrid NPs could be changed by varying the kind of lipid. A glyceride mixture (hybrid NPs-1) decreased endocytosis but increased exocytosis in Caco-2 cells, whereas the phospholipid (E200) (hybrid NPs-2) decreased endocytosis but exocytosis was unaffected as compared with PLGA nanoparticles. The transport of hybrid NPs-1 in cells involved various pathways, including caveolae/lipid raft-dependent endocytosis, and clathrin-mediated endocytosis and macropinocytosis, which was different from the other groups of NPs that involved only caveolae/lipid raft-dependent endocytosis. Compared with that of the reference formulation (nanoemulsion), the oral absorption of SQV-loaded hybrid NPs in rats was poor, probably due to the limited drug release and transcytosis of NPs across the intestinal epithelium. In conclusion, the intracellular processing of hybrid NPs in intestinal epithelia can be altered by adding lipids to the NP. However, it appears unfavorable to use PLGA-based NPs to improve oral absorption of SQV compared with nanoemulsion. Our findings will be essential in the development of polymer-based NPs for the oral delivery of drugs with the purpose of improving their oral absorption. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Design, Synthesis, and Characterization of Novel Zwitterionic Lipids for Drug and siRNA Delivery Applications

NASA Astrophysics Data System (ADS)

Walsh, Colin L.

Lipid-based nanoparticles have long been used to deliver biologically active molecules such as drugs, proteins, peptides, DNA, and siRNA in vivo. Liposomes and lipoplexes alter the biodistribution, pharmacokinetics, and cellular uptake of their encapsulated or associated cargo. This can increase drug efficacy while reducing toxicity, resulting in an increased therapeutic index and better clinical outcomes. Unlike small molecule drugs, which passively diffuse through lipid membranes, nucleic acids and proteins require an active, carrier mediated escape mechanism to reach their site of action. As such, the therapeutic application and drug properties dictate the required biophysical characteristics of the lipid nanoparticle. These carrier properties depend on the structure and biophysical characteristics of the lipids and other components used to formulate them. This dissertation presents a series of studies related to the development of novel synthetic lipids for use in drug delivery systems. First, we developed a novel class of zwitterionic lipids with head groups containing a cationic amine and anionic carboxylate and ester-linked oleic acid tails. These lipids exhibit structure-dependent, pH-responsive biophysical properties, and may be useful components for next-generation drug delivery systems. Second, we extended the idea of amine/carboxylate containing zwitterionic head groups and synthesized a series of acetate terminated diacyl lipids containing a quaternary amine. These lipids have an inverted headgroup orientation compared to naturally occurring zwitterionic lipids, and show interesting salt-dependent biophysical properties. Third, we synthesized and characterized a focused library of ionizable lysine-based lipids, which contain a lysine head group linked to a long-chain dialkylamine. A focused library was synthesized to determine the impact of hydrophobic fluidity, lipid net charge, and lipid pKa on the biophysical and siRNA transfection characteristics of these lipids. Our results indicate that structural variations significantly impact the biophysical and transfection behavior of this class of lipids. In summary, we have synthesized several new classes of lipids with biophysical characteristics that may be useful for drug delivery applications. Our results show that slight modifications to lipid structure impacts their biophysical behavior, which in turn dictates their potential utility in drug delivery systems. Further understanding lipid structure-activity relationships will allow for the rational design and engineering of lipids with appropriate properties for specific delivery applications.

Liposome-encapsulated vincristine, vinblastine and vinorelbine: a comparative study of drug loading and retention.

PubMed

Zhigaltsev, Igor V; Maurer, Norbert; Akhong, Quet-Fah; Leone, Robert; Leng, Esther; Wang, Jinfang; Semple, Sean C; Cullis, Pieter R

2005-05-05

A comparative study of the loading and retention properties of three structurally very closely related vinca alkaloids (vincristine, vinorelbine and vinblastine) in liposomal formulations has been performed. All three vinca alkaloids showed high levels of encapsulation when accumulated into egg sphingomyelin/cholesterol vesicles in response to a transmembrane pH gradient generated by the use of the ionophore A23187 and encapsulated MgSO4. However, despite the close similarities of their structures the different vinca drugs exhibited very different release behavior, with vinblastine and vinorelbine being released faster than vincristine both in vitro and in vivo. The differences in loading and retention can be related to the lipophilicity of the drugs tested, where the more hydrophobic drugs are released more rapidly. It was also found that increasing the drug-to-lipid ratio significantly enhanced the retention of vinca alkaloids when the ionophore-based method was used for drug loading. In contrast, drug retention was not dependent on the initial drug-to-lipid ratio for vinca drugs loaded into liposomes containing an acidic citrate buffer. The differences in retention can be explained on the basis of differences in the physical state of the drug inside the liposomes. The drug-to-lipid ratio dependence of retention observed for liposomes loaded with the ionophore technique may provide a way to improve the retention characteristics of liposomal formulations of vinca drugs.

Development of gastroretentive metronidazole floating raft system for targeting Helicobacter pylori.

PubMed

Abou Youssef, Nancy Abdel Hamid; Kassem, Abeer Ahmed; El-Massik, Magda Abd Elsamea; Boraie, Nabila Ahmed

2015-01-01

The study demonstrates the feasibility of prolonging gastric residence time and release rate of metronidazole (Mz) by preparing floating raft system (FRS) using ion-sensitive in situ gel forming polymers. FRSs contained 3, 4, 5 and 0.5, 0.75, 1% w/v sodium alginate (Alg) and gellan gum (G), respectively, 0.25% w/v sodium citrate and calcium carbonate (C). Lipids: glyceryl mono stearate (GMS), Precirol(®) and Compritol(®) were incorporated into G-based formulations (G1%C1%). Mz:lipid ratio was 1:1, except for Mz:GMS, ratios of 1:1.5 and 1:2 were also investigated. Buoyancy, gelation capacity and viscosity parameters were evaluated. Drug release and kinetics for selected formulae were examined. The selected lipid containing formula was subjected to an accelerated stability testing. Alg4%C2% FRS exhibited short gelation lag time (3s), long duration (>24h), floating lag time 1m in and duration >24h, and a reliable sustained drug release (MDT 6h). Gellan gum FRSs achieved successful floating gastroretention, but failed to achieve the required gelation capacity. Incorporation of GMS (Mz:GMS 1:1) enhanced the gelation lag time and duration (6s and >24h, respectively), keeping sustained drug release and formulation stability. The improved characteristics of the selected FRS make them excellent candidates for gastric targeting to eradicate Helicobacter pylori. Copyright © 2015 Elsevier B.V. All rights reserved.

Analytical Characterization of an Oil-in-Water Adjuvant Emulsion.

PubMed

Sun, Jenny; Remmele, Richard L; Sanyal, Gautam

2017-07-01

Adjuvants are typically used in subunit vaccine formulations to enhance immune responses elicited by individual antigens. Physical chemical characterization of novel adjuvants is an important step in ensuring their effective use in vaccine formulations. This paper reports application of a panel of quantitative assays developed to analyze and characterize an oil-in-water adjuvant emulsion, which contains glucopyranosyl lipid A (GLA) and is a squalene-based emulsion. GLA is a fully synthetic analogue of monophosphoryl lipid A, which is a Toll-like receptor type 4 agonist and an FDA-approved adjuvant. The GLA-stable emulsion (GLA-SE) is currently being used for a respiratory syncytial virus vaccine in a phase 2 clinical trial. GLA was quantitated using reverse-phased high-performance liquid chromatography (RP-HPLC) coupled to a mass spectrometric detector, achieving higher assay sensitivity than the charged aerosol detection routinely used. Quantitation of the excipients of GLA-SE, including squalene, egg phosphatidyl choline, and Poloxamer 188, was achieved using a simple and rapid RP-HPLC method with evaporative light scattering detection, eliminating chemical derivatization typically required for these chromophore-lacking compounds. DL-α-tocopherol, the antioxidant of the GLA-SE, was quantitated using a RP-HPLC method with conventional UV detection. The experimental results compared well with values expected for these compounds based on targeted composition of the adjuvant. The assays were applied to identify degradation of individual components in a GLA-SE sample that degraded into distinct aqueous and oil phases. The methods developed and reported here are effective tools in monitoring physicochemical integrity of the adjuvant, as well as in formulation studies.

Advanced stable lipid-based formulations for a patient-centric product design.

PubMed

Becker, Karin; Saurugger, Eva-Maria; Kienberger, Diana; Lopes, Diogo; Haack, Detlev; Köberle, Martin; Stehr, Michael; Lochmann, Dirk; Zimmer, Andreas; Salar-Behzadi, Sharareh

2016-01-30

Multiparticulate dosage forms are a recent strategy to meet the special needs of children, elderly people and patients suffering from dysphagia. Our study presents a novel and cost-efficient approach for the manufacturing of a taste-masked multiparticulate system with a stable immediate release profile by applying lipid-based excipients in a solvent-free hot melt coating process. The thermosensitive N-acetylcysteine (N-ac) was used as model drug and hot-melt coated with a mixture of tripalmitin and polysorbate 65. A predictive in vitro method for the evaluation of the taste masking efficiency was developed based on the deprotonation of the carboxyl group of N-ac and the decline of pH, responsible for the unpleasant sour taste of the compound. The method was confirmed using in vivo studies. Differential scanning calorimetry and X-ray scattering experiments revealed polymorphic transformation and its dependency on transformation time, temperature and emulsifier concentration. During the process, the coating was transformed almost completely into the stable β-polymorph, leading to an unaltered dissolution profile during storage. A statistical design was conducted that revealed the critical process parameters affecting the taste masking efficiency and drug release. This study shows the successful application of solvent-free hot-melt coating in the development of a taste-masked and stable formulation. Copyright © 2015 Elsevier B.V. All rights reserved.

Surface chemistry and serum type both determine the nanoparticle-protein corona.

PubMed

Pozzi, Daniela; Caracciolo, Giulio; Capriotti, Anna Laura; Cavaliere, Chiara; La Barbera, Giorgia; Anchordoquy, Thomas J; Laganà, Aldo

2015-04-24

The protein corona that forms around nanoparticles in vivo is a critical factor that affects their physiological response. The potential to manipulate nanoparticle characteristics such that either proteins advantageous for delivery are recruited and/or detrimental proteins are avoided offers exciting possibilities for improving drug delivery. In this work, we used nanoliquid chromatography tandem mass spectrometry to characterize the corona of five lipid formulations after incubation in mouse and human plasma with the hope of providing data that may contribute to a better understanding of the role played by both the nanoparticle properties and the physiological environment in recruiting specific proteins to the corona. Notably, we showed that minor changes in the lipid composition might critically affect the protein corona composition demonstrating that the surface chemistry and arrangement of lipid functional groups are key players that regulate the liposome-protein interactions. Notably, we provided evidence that the protein corona that forms around liposomes is strongly affected by the physiological environment, i.e., the serum type. These results are likely to suggest that the translation of novel pharmaceutical formulations from animal models to the clinic must be evaluated on a case-by-case basis. In the present work nanoliquid chromatography tandem mass spectrometry was used to characterize the protein corona of five different liposome formulations after exposure to mouse and human plasma. The modern proteomic methods employed have clarified that the arrangement of lipid functional groups is a key player that regulates the liposome-protein interactions. We also clarified that the protein corona enrichment and complexity depend on the serum type. Our results suggest that the translational of novel pharmaceutical formulations from animal models to the clinic must be evaluated on a case-by-case basis. Copyright © 2015. Published by Elsevier B.V.

Optimised NLC: a nanotechnological approach to improve the anaesthetic effect of bupivacaine.

PubMed

Rodrigues da Silva, Gustavo H; Ribeiro, Lígia N M; Mitsutake, Hery; Guilherme, Viviane A; Castro, Simone R; Poppi, Ronei J; Breitkreitz, Márcia C; de Paula, Eneida

2017-08-30

The short time of action and systemic toxicity of local anaesthetics limit their clinical application. Bupivacaine is the most frequently used local anaesthetic in surgical procedures worldwide. The discovery that its S(-) enantiomeric form is less toxic than the R(+) form led to the introduction of products with enantiomeric excess (S75:R25 bupivacaine) in the market. Nevertheless, the time of action of bupivacaine is still short; to overcome that, bupivacaine S75:R25 (BVC S75 ) was encapsulated in nanostructured lipid carriers (NLC). In this work, we present the development of the formulation using chemometric tools of experimental design to study the formulation factors and Raman mapping associated with Classical Least Squares (CLS) to study the miscibility of the solid and the liquid lipids. The selected formulation of the nanostructured lipid carrier containing bupivacaine S75:R25 (NLC BVC ) was observed to be stable for 12 months under room conditions regarding particle size, polydispersion, Zeta potential and encapsulation efficiency. The characterisation by DSC, XDR and TEM confirmed the encapsulation of BVC S75 in the lipid matrix, with no changes in the structure of the nanoparticles. The in vivo analgesic effect elicited by NLC BVC was twice that of free BVC S75 . Besides improving the time of action , no statistical difference in the blockage of the sciatic nerve of rats was found between 0.125% NLC BVC and 0.5% free BVC S75 . Therefore, the formulation allows a reduction in the required anaesthesia dose, decreasing the systemic toxicity of bupivacaine, and opening up new possibilities for different clinical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Enhancement of oral bioavailability of atorvastatin calcium by self-emulsifying drug delivery systems (SEDDS).

PubMed

Kadu, Pawan J; Kushare, Sachin S; Thacker, Dhaval D; Gattani, Surendra G

2011-02-01

The aim of the present study was to formulate a self-emulsifying drug delivery system of atorvastatin calcium and its characterization including in vitro and in vivo potential. The solubility of atorvastatin calcium was determined in various vehicles such as Captex 355, Captex 355 EP/NF, Ethyl oleate, Capmul MCM, Capmul PG-8, Gelucire 44/14, Tween 80, Tween 20, and PEG 400. Pseudoternary phase diagrams were plotted on the basis of solubility data of drug in various components to evaluate the microemulsification region. Formulation development and screening was carried out based on results obtained from phase diagrams and characteristics of resultant microemulsion. Prepared formulations were tested for microemulsifying properties and evaluated for clarity, precipitation, viscosity determination, drug content and in vitro dissolution. The optimized formulation further evaluated for particle size distribution, zeta potential, stability studies and in vivo potential. In vivo performance of the optimized formulation was evaluated using a Triton-induced hypercholesterolemia model in male Albino Wistar rats. The formulation significantly reduced serum lipid levels as compared with atorvastatin calcium. Thus studies illustrated the potential use for the delivery of hydrophobic drug such as atorvastatin calcium by oral route.

Blueberries reduce lipid peroxidation and boost antioxidant enzymes in apoe knockout mice

USDA-ARS?s Scientific Manuscript database

ApoE knockout (ApoE-/-) mice fed AIN-93G diet (CD) formulated to contain 1 % freeze-dried whole wild blueberries (CD1 percent BB) were found to have significantly less atherosclerotic lesions in aorta. Biomarkers of lipid peroxidation, including F2-isoprostanes, hydroxyoctadecadienoic acids (HODEs) ...

Ultrasound active nanoscaled lipid formulations for thrombus lysis.

PubMed

Becker, Andreas; Marxer, Elena; Brüssler, Jana; Hoormann, Anne Sophia; Kuhnt, Daniela; Bakowsky, Udo; Nimsky, Christopher

2011-04-01

In the present study, we investigated the sonothrombolytic effect of new nanoscaled lipid formulations in human blood clots, using diagnostic ultrasound. Human blood clots of 1 ml were incubated with 1 μl of the different lipid dispersions DPPC/CH, DPPC/PEG40S, DSPC/PEG40S and the commercially available ultrasound contrast agent SonoVue®. Clots were stored for 3 days at 5 °C to obtain maximal clot retraction and lytic resistance. Each clot weight was determined before and after continuous insonation for 1h of insonation at 1.4 MHz. The pressure in the insonation chamber was 80 mm Hg to mimic middle arterial blood pressure. There were no significant differences in thrombus weight before insonation. All nanoscaled formulations and SonoVue® were able to reduce thrombus weight compared to the weight loss of clots that were not insonated but kept under pressure for one hour (p < 0.001). We found a highly significant weight reduction with DSPC/PEG40S compared to SonoVue® (p = 0.007). Nanoscaled DSPC/PEG40S dispersion could be a promising formulation in ultrasound enhanced thrombolysis even without thrombolytic drugs. Stable cavitation is a crucial parameter in fragmentation of thrombus architecture. Further studies of physicochemical properties of DSPC/PEG40S are necessary to corroborate our hypothesis. Copyright © 2010 Elsevier B.V. All rights reserved.

Engineering of a novel adjuvant based on lipid-polymer hybrid nanoparticles: A quality-by-design approach.

PubMed

Rose, Fabrice; Wern, Jeanette Erbo; Ingvarsson, Pall Thor; van de Weert, Marco; Andersen, Peter; Follmann, Frank; Foged, Camilla

2015-07-28

The purpose of this study was to design a novel and versatile adjuvant intended for mucosal vaccination based on biodegradable poly(DL-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with the cationic surfactant dimethyldioctadecylammonium (DDA) bromide and the immunopotentiator trehalose-6,6'-dibehenate (TDB) (CAF01) to tailor humoral and cellular immunity characterized by antibodies and Th1/Th17 responses. Such responses are important for the protection against diseases caused by intracellular bacteria such as Chlamydia trachomatis and Mycobacterium tuberculosis. The hybrid NPs were engineered using an oil-in-water single emulsion method and a quality-by-design approach was adopted to define the optimal operating space (OOS). Four critical process parameters (CPPs) were identified, including the acetone concentration in the water phase, the stabilizer [polyvinylalcohol (PVA)] concentration, the lipid-to-total solid ratio, and the total concentration. The CPPs were linked to critical quality attributes consisting of the particle size, polydispersity index (PDI), zeta-potential, thermotropic phase behavior, yield and stability. A central composite face-centered design was performed followed by multiple linear regression analysis. The size, PDI, enthalpy of the phase transition and yield were successfully modeled, whereas the models for the zeta-potential and the stability were poor. Cryo-transmission electron microscopy revealed that the main structural effect on the nanoparticle architecture is caused by the use of PVA, and two different morphologies were identified: i) A PLGA core coated with one or several concentric lipid bilayers, and ii) a PLGA nanoshell encapsulating lipid membrane structures. The optimal formulation, identified from the OOS, was evaluated in vivo. The hybrid NPs induced antibody and Th1/Th17 immune responses that were similar in quality and magnitude to the response induced by DDA/TDB liposomes, showing that the adjuvant properties of DDA/TDB are maintained in the PLGA hybrid matrix. This study demonstrates the complexity of formulation design for the engineering of a hybrid lipid-polymer nanoparticle adjuvant. Copyright © 2015 Elsevier B.V. All rights reserved.

Optimized self nano-emulsifying systems of ezetimibe with enhanced bioavailability potential using long chain and medium chain triglycerides.

PubMed

Bandyopadhyay, Shantanu; Katare, O P; Singh, Bhupinder

2012-12-01

The objective of the current work is to develop systematically optimized self-nanoemulsifying drug delivery systems (SNEDDS) using long chain triglycerides (LCT's) and medium chain triglycerides (MCT's) of ezetimibe employing Formulation by Design (FbD), and evaluate their in vitro and in vivo performance. Equilibrium solubility studies indicated the choice of Maisine 35-1 and Capryol 90 as lipids, and of Labrasol and Tween 80 as emulgents for formulating the LCT and MCT systems, respectively. Ternary phase diagrams were constructed to select the areas of nanoemulsion, and the amounts of lipid (X(1)) and emulgent (X(2)) as the critical factor variables. The SNEDDS were systematically optimized using 3(2) central composite design and the optimized formulations located using overlay plot. TEM studies on reconstituted SNEDDS demonstrated uniform shape and size of globules. The nanometer size range and high negative values of zeta potential depicted non-coalescent nature of the optimized SNEDDS. Thermodynamic studies, cloud point determination and accelerated stability studies ascertained the stability of optimized formulations. In situ perfusion (SPIP) studies in Sprague Dawley (SD) rats construed remarkable enhancement in the absorptivity and permeability parameters of SNEDDS vis-à-vis the conventional marketed product. In vivo pharmacodynamic studies in SD rats indicated significantly superior modification in plasma lipid levels of optimized SNEDDS vis-à-vis marketed product, inclusion complex and pure drug. The studies, therefore, indicate the successful formulation development of self-nanoemulsifying systems with distinctly improved bioavailability potential of ezetimibe. Copyright © 2012 Elsevier B.V. All rights reserved.

Simple and efficient liposomal encapsulation of topotecan by ammonium sulfate gradient: stability, pharmacokinetic and therapeutic evaluation.

PubMed

Liu, Jun-Jen; Hong, Ruey-Long; Cheng, Wen-Fang; Hong, Keelung; Chang, Fu-Hsiung; Tseng, Yun-Long

2002-08-01

Topotecan (TPT), a topoisomerase I inhibitor, is presently undergoing clinical evaluation worldwide. Previous studies have shown that entrapping TPT within multi-lamellar vesicle liposome can stabilize the lactone moiety, which is structurally important for biological activity. However, low drug:lipid ratios due to the amphipathic character and small entrapment volume in the unilamellar vesicle limits the development of pharmaceutically acceptable liposomal formulation. With an aim to improve on this drawback, we herein describe a method that utilizes the ammonium sulfate gradient to entrap TPT into liposomes. By this method, the encapsulation efficiency was over 90% and a drug:lipid molar ratio as high as 1:5.4 was reached. In comparison with free drug, liposome-encapsulated TPT is more stable in physiological conditions and shows higher in vitro cytotoxicity. Because of increased blood circulation time, the initial plasma concentration and area under the plasma concentration of liposomal drugs were 14 and 40 times, respectively, of those of free drug. Furthermore, liposome encapsulation enhanced the antitumor activity of TPT in syngeneic murine C-26 and human HTB-9 xenograft models in vivo. At a dose of 5 mg/kg, the tumor growth delay of liposomal formulation was significantly than that of free TPT. Based on these results, we believe that this liposomal TPT formulation is worthy of further clinical study. Copyright 2002 Lippincott Williams & Wilkins.

Enhanced topical delivery of finasteride using glyceryl monooleate-based liquid crystalline nanoparticles stabilized by cremophor surfactants.

PubMed

Madheswaran, Thiagarajan; Baskaran, Rengarajan; Yong, Chul Soon; Yoo, Bong Kyu

2014-02-01

The aim of this study was to investigate the capability of two surfactants, Cremophor RH 40 (RH) and Cremophor EL (EL), to prepare liquid crystalline nanoparticles (LCN) and to study its influence on the topical delivery of finasteride (FNS). FNS-loaded LCN was formulated with the two surfactants and characterized for size distribution, morphology, entrapment efficiency, in vitro drug release, and skin permeation/retention. Influence of FNS-loaded LCN on the conformational changes on porcine skin was also studied using attenuated total reflectance Fourier-transform infrared spectroscopy. Transmission electron microscopical image confirmed the formation of LCN. The average particle size of formulations was in the range of 165.1-208.6 and 153.7-243.0 nm, respectively. The formulations prepared with higher surfactant concentrations showed faster release and significantly increased skin permeation. Specifically, LCN prepared with RH 2.5% presented higher permeation flux (0.100 ± 0.005 μgcm(-2)h(-1)) compared with lower concentration (0.029 ± 0.007 μgcm(-2)h(-1)). Typical spectral bands of lipid matrix of porcine skin were shifted to higher wavenumber, indicating increased degree of disorder of the lipid acyl chains which might cause fluidity increase of stratum corneum. Taken together, Cremophor surfactants exhibited a promising potential to stabilize the LCN and significantly augmented the skin permeation of FNS.

Lipids as a principle for the identification of Archaebacteria

NASA Technical Reports Server (NTRS)

Tornabene, T. G.; Lloyd, R. E.; Holzer, G.; Oro, J.

1980-01-01

The 'Archaebacteria' consist of several distinct subgroups including methanogens, extreme halophiles and specific thermoacidophiles. These bacteria are distinct from other bacteria with respect to their characteristic RNA compositions, the absence of muramic acid in the cell walls and the predominance of nonsaponifable lipids. The lipid composition of the Archaebacteria consists of isoprenoid and hydroisoprenoid hydrocarbons and isopranyl glycerol ether lipids. The pathways for the biosynthesis of the lipid components are those shared by most microorganisms and demonstrate a close relationship; however, an independent line of descent is indicated by the formation of the isopranyl glycerol ether lipids. This discontinuity formulates a point for delineating the early stages of biological evolution and for dividing bacteria into two subgroups.

Development and evaluation of nanostructured lipid carrier-based hydrogel for topical delivery of 5-fluorouracil

PubMed Central

Rajinikanth, Paruvathanahalli Siddalingam; Chellian, Jestin

2016-01-01

The aim of this study was to develop a nanostructured lipid carrier (NLC)-based hydrogel and study its potential for the topical delivery of 5-fluorouracil (5-FU). Precirol® ATO 5 (glyceryl palmitostearate) and Labrasol® were selected as the solid and liquid lipid phases, respectively. Poloxamer 188 and Solutol® HS15 (polyoxyl-15-hydroxystearate) were selected as surfactants. The developed lipid formulations were dispersed in 1% Carbopol® 934 (poly[acrylic acid]) gel medium in order to maintain the topical application consistency. The average size, zeta potential, and polydispersity index for the 5-FU-NLC were found to be 208.32±8.21 nm, −21.82±0.40 mV, and 0.352±0.060, respectively. Transmission electron microscopy study revealed that 5-FU-NLC was <200 nm in size, with a spherical shape. In vitro drug permeation studies showed a release pattern with initial burst followed by sustained release, and the rate of 5-FU permeation was significantly improved for 5-FU-NLC gel (10.27±1.82 μg/cm2/h) as compared with plain 5-FU gel (2.85±1.12 μg/cm2/h). Further, skin retention studies showed a significant retention of 5-FU from the NLC gel (91.256±4.56 μg/cm2) as compared with that from the 5-FU plain gel (12.23±3.86 μg/cm2) in the rat skin. Skin irritation was also significantly reduced with 5-FU-NLC gel as compared with 5-FU plain gel. These results show that the prepared 5-FU-loaded NLC has high potential to improve the penetration of 5-FU through the stratum corneum, with enormous retention and with minimal skin irritation, which is the prerequisite for topically applied formulations. PMID:27785014

Modelling of microalgal growth and lipid production in Dunaliella tertiolecta using nitrogen-phosphorus-potassium fertilizer medium in sintered disk chromatographic glass bubble column.

PubMed

Kumar, Anup; Guria, Chandan; Chitres, G; Chakraborty, Arunangshu; Pathak, A K

2016-10-01

A comprehensive mathematical model involving NPK-10:26:26 fertilizer, NaCl, NaHCO3, light and temperature operating variables for Dunaliella tertiolecta cultivation is formulated to predict microalgae-biomass and lipid productivity. Proposed model includes Monod/Andrews kinetics for the absorption of essential nutrients into algae-biomass and Droop model involving internal nutrient cell quota for microalgae growth, assuming algae-biomass is composed of sugar, functional-pool and neutral-lipid. Biokinetic model parameters are determined by minimizing the residual-sum-of-square-errors between experimental and computed microalgae-biomass and lipid productivity using genetic algorithm. Developed model is validated with the experiments of Dunaliella tertiolecta cultivation using air-agitated sintered-disk chromatographic glass-bubble column and the effects of operating variables on microalgae-biomass and lipid productivity is investigated. Finally, parametric sensitivity analysis is carried out to know the sensitivity of model parameters on the obtained results in the input parameter space. Proposed model may be helpful in scale-up studies and implementation of model-based control strategy in large-scale algal cultivation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Characterization of Sodium Mobility and Binding by 23 Na NMR Spectroscopy in a Model Lipoproteic Emulsion Gel for Sodium Reduction.

PubMed

Okada, Kyle S; Lee, Youngsoo

2017-07-01

The effects of formulation and processing parameters on sodium availability in a model lipid/protein-based emulsion gel were studied for purposes of sodium reduction. Heat-set model gels were prepared with varying levels of protein, lipid, and NaCl contents and high pressure homogenization treatments. Single quantum and double quantum-filtered 23 Na NMR spectroscopy experiments were used to characterize sodium mobility, structural order around "bound" (restricted mobility) sodium, and sodium binding, which have been correlated to saltiness perception in food systems previously. Total sodium mobility was lower in gels with higher protein or fat content, and was not affected by changes in homogenization pressure. The gels with increased protein, fat, or homogenization pressure had increased structure surrounding "bound" sodium and more relative "bound" sodium due to increased interfacial protein interactions. The data obtained in this study provide information on factors affecting sodium availability, which can be applied towards sodium reduction in lipid/protein-based foods. © 2017 Institute of Food Technologists®.

Drug Release and Skin Permeation from Lipid Liquid Crystalline Phases

NASA Astrophysics Data System (ADS)

Costa-Balogh, F. O.; Sparr, E.; Sousa, J. J. S.; Pais, A. A. C. C.

We have studied drug release and skin permeation from several different liquid crystalline lipid formulations that may be used to control the respective release rates. We have studied the release and permeation through human skin of a water-soluble and amphiphilic drug, propranolol hydrochloride, from several formulations prepared with monoolein and phytantriol as permeation enhancers and controlled release excipients. Diolein and cineol were added to selected formulations. We observed that viscosity decreases with drug load, wich is compatible with the occurrence of phase changes. Diolein stabilizes the bicontinuous cubic phases leading to an increase in viscosity and sustained release of the drug. The slowest release was found for the cubic phases with higher viscosity. Studies on skin permeation showed that these latter formulations also presented lower permeability than the less viscous monoolein lamellar phases. Formulations containing cineol originated higher permeability with higher enhancement ratios. Thus, the various formulations are adapted to different circumstances and delivery routes. While a slow release is usually desired for drug sustained delivery, the transdermal route may require a faster release. Lamellar phases, which are less viscous, are more adapted to transdermal applications. Thus, systems involving lamellar phases of monoolein and cineol are good candidates to be used as skin permeation enhancers for propranolol hydrochloride.

Lipid nanostructured Hydrogels for Topical Delivery of Anti-inflammatory Drugs: Preparation and Characterization

NASA Astrophysics Data System (ADS)

Acevedo-Robles, Noelia

Diclofenac sodium is a nonsteroidal anti-inflammatory drugs (NSAID) used to treat sign or symptoms of osteoarthritis and rheumatoid arthritis. However, its clinical usage is limited to some extent due to its toxicity and systemic side effects, including gastrointestinal lesions. The development of lipid nanostructured hydrogel for topical application will solve the problems of first pass metabolism minimize systemic side effect of the anti-inflammatory drugs. Two types of nanotechnologies were used: Lipid Nanostructured Lipid carrier (NLC) and Solid Lipid Nanoparticles (SLN). The difference between both nanotechnologies is that NLC carrier contain liquid and solid lipid, however, the SLN contains solid lipid. Both nanostructured lipid carrier is prepared by high pressure micro-fluidizer technology avoiding solvents use. The use of liquid lipid with solid lipid leads us to imperfection in the matrix which can provide more space for the accommodation of the drug, therefore NLC is the more efficient formulation in drug entrapment.

Lipid Nanoparticles Enabling Gene Therapies: From Concepts to Clinical Utility.

PubMed

Kulkarni, Jayesh A; Cullis, Pieter R; van der Meel, Roy

2018-04-23

Genetic drugs based on RNA or DNA have remarkable therapeutic potential as virtually any disease can be treated by silencing a pathological gene, expressing a beneficial protein, or by editing defective genes. However, therapies based on nucleic acid polymers require sophisticated delivery systems to deliver these macromolecules to the interior of target cells. In this study, we review progress in developing nonviral lipid nanoparticle (LNP) delivery systems that have attractive properties, including ease of manufacture, reduced immune responses, multidosing capabilities, larger payloads, and flexibility of design. LNP systems represent the most advanced delivery systems for genetic drugs as it is expected that an LNP-short interfering RNA (siRNA) formulation will receive clinical approval from the Food and Drug Administration (FDA) in 2018 for treatment of the hereditary condition transthyretin-mediated amyloidosis, a fatal condition for which there is currently no treatment. This achievement is largely due to the development of optimized ionizable cationic lipids, arguably the most important factor in the clinical success of LNP-siRNA. In addition, we highlight potential LNP applications, including targeting tissues beyond the liver and therapeutic approaches based on messenger RNA or Clustered Regularly Interspaced Short Palindromic Repeats/Cas.

Transdermal solid delivery of epigallocatechin-3-gallate using self-double-emulsifying drug delivery system as vehicle: Formulation, evaluation and vesicle-skin interaction.

PubMed

Hu, Caibiao; Gu, Chengyu; Fang, Qiao; Wang, Qiang; Xia, Qiang

2016-02-01

The present study investigated a self-double-emulsifying drug delivery system loaded with epigallocatechin-3-gallate to improve epigallocatechin-3-gallate skin retention. The long chain solid lipids (cetostearyl alcohol) and macadamia oil were utilized as a carrier to deliver the bioactive ingredient. Response surface methodology was used to optimize the formulation, and the solid lipid to total lipid weight ratio, concentration of epigallocatechin-3-gallate and hydrophilic surfactant on skin retention were found to be the principal factors. The optimum formulation with high encapsulation efficiency (95.75%), self-double-emulsification performance (99.58%) and skin retention (87.24%) were derived from the fitted models and experimentally examined, demonstrating a reasonable agreement between experimental and predicted values. Epigallocatechin-3-gallate-self-double-emulsifying drug delivery system was found to be stable for 3 months. Transdermal studies could explain a higher skin diffusion of epigallocatechin-3-gallate from the self-double-emulsifying drug delivery system compared with EGCG aqueous solution. In vitro cytotoxicity showed that epigallocatechin-3-gallate-self-double-emulsifying drug delivery system did not exert hazardous effect on L929 cells up to 1:10. © The Author(s) 2015.

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential.

PubMed

Singh, Bhupinder; Khurana, Lalit; Bandyopadhyay, Shantanu; Kapil, Rishi; Katare, O O P

2011-11-01

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.

Polycation nanostructured lipid carrier, a novel nonviral vector constructed with triolein for efficient gene delivery.

PubMed

Zhang, Zhiwen; Sha, Xianyi; Shen, Anle; Wang, Yongzhong; Sun, Zhaogui; Gu, Zheng; Fang, Xiaoling

2008-06-06

A novel nonviral gene transfer vector was developed by modifying nanostructured lipid carrier (NLC) with cetylated polyethylenimine (PEI). Polycation nanostructured lipid carrier (PNLC) was prepared using the emulsion-solvent evaporation method. Its in vitro gene transfer properties were evaluated in the human lung adenocarcinoma cell line SPC-A1 and Chinese Hamster Ovary (CHO) cells. Enhanced transfection efficiency of PNLC was observed after the addition of triolein to the PNLC formulation and the transfection efficiency of the optimized PNLC was comparable to that of Lipofectamine 2000. In the presence of 10% serum the transfection efficiency of the optimal PNLC was not significantly changed in either cell line, whereas that of Lipofectamine 2000 was greatly decreased in both. Thus, PNLC is an effective nonviral gene transfer vector and the gene delivery activity of PNLC was enhanced after triolein was included into the PNLC formulation.

Lipid nanoparticle vectorization of indocyanine green improves fluorescence imaging for tumor diagnosis and lymph node resection.

PubMed

Navarro, Fabrice P; Berger, Michel; Guillermet, Stéphanie; Josserand, Véronique; Guyon, Laurent; Neumann, Emmanuelle; Vinet, Françoise; Texier, Isabelle

2012-10-01

Fluorescence imaging is opening a new era in image-guided surgery and other medical applications. The only FDA approved contrast agent in the near infrared is IndoCyanine Green (ICG), which despites its low toxicity, displays poor chemical and optical properties for long-term and sensitive imaging applications in human. Lipid nanoparticles are investigated for improving ICG optical properties and in vivo fluorescence imaging sensitivity. 30 nm diameter lipid nanoparticles (LNP) are loaded with ICG. Their characterization and use for tumor and lymph node imaging are described. Nano-formulation benefits dye optical properties (6 times improved brightness) and chemical stability (>6 months at 4 degrees C in aqueous buffer). More importantly, LNP vectorization allows never reported sensitive and prolonged (>1 day) labeling of tumors and lymph nodes. Composed of human-use approved ingredients, this novel ICG nanometric formulation is foreseen to expand rapidly the field of clinical fluorescence imaging applications.

Nanoengineered drug delivery systems for enhancing antibiotic therapy.

PubMed

Kalhapure, Rahul S; Suleman, Nadia; Mocktar, Chunderika; Seedat, Nasreen; Govender, Thirumala

2015-03-01

Formulation scientists are recognizing nanoengineered drug delivery systems as an effective strategy to overcome limitations associated with antibiotic drug therapy. Antibiotics encapsulated into nanodelivery systems will contribute to improved management of patients with various infectious diseases and to overcoming the serious global burden of antibiotic resistance. An extensive review of several antibiotic-loaded nanocarriers that have been formulated to target drugs to infectious sites, achieve controlled drug release profiles, and address formulation challenges, such as low-drug entrapment efficiencies, poor solubility and stability is presented in this paper. The physicochemical properties and the in vitro/in vivo performances of various antibiotic-loaded delivery systems, such as polymeric nanoparticles, micelles, dendrimers, liposomes, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, nanohybirds, nanofibers/scaffolds, nanosheets, nanoplexes, and nanotubes/horn/rods and nanoemulsions, are highlighted and evaluated. Future studies that will be essential to optimize formulation and commercialization of these antibiotic-loaded nanosystems are also identified. The review presented emphasizes the significant formulation progress achieved and potential that novel nanoengineered antibiotic drug delivery systems have for enhancing the treatment of patients with a range of infections. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Tadalafil-loaded nanostructured lipid carriers using permeation enhancers.

PubMed

Baek, Jong-Suep; Pham, Cuong Viet; Myung, Chang-Seon; Cho, Cheong-Weon

2015-11-30

Tadalafil is a phosphodiesterase-5 inhibitor indicated for the treatment of erectile dysfunction. In this study, we prepared and evaluated transdermal nanostructured lipid carriers (NLC) to improve the skin permeability of tadalafil. Tadalafil-loaded NLC dispersions were prepared using glyceryl monostearate as a solid lipid, oleic acid as a liquid lipid, and Tween 80 as a surfactant. We characterized the dispersions according to particle size, polydispersity index, zeta potential, encapsulation efficiency, and transmission electron microscopy. In vitro skin permeation studies were carried out using Franz diffusion cells, and cytotoxicity was examined using HaCaT keratinocyte cell lines. Tadalafil skin permeability increased for all tadalafil-loaded NLC formulations. The tadalafil-loaded NLC dispersion with ethanol and limonene as skin permeation enhancers exhibited the highest flux (∼4.8-fold) compared to that observed with tadalafil solution alone. Furthermore, a tadalafil-loaded NLC gel with selected permeation enhancers showed tolerance against toxicity in HaCaT cells. These results suggest that the NLC formulations with ethanol and limonene as skin permeation enhancers could be a promising dermal delivery carrier for tadalafil. Copyright © 2015 Elsevier B.V. All rights reserved.

Biophysical aspects of using liposomes as delivery vehicles.

PubMed

Ulrich, Anne S

2002-04-01

Liposomes are used as biocompatible carriers of drugs, peptides, proteins, plasmic DNA, antisense oligonucleotides or ribozymes, for pharmaceutical, cosmetic, and biochemical purposes. The enormous versatility in particle size and in the physical parameters of the lipids affords an attractive potential for constructing tailor-made vehicles for a wide range of applications. Some of the recent literature will be reviewed here and presented from a biophysical point of view, thus providing a background for the more specialized articles in this special issue on liposome technology. Different properties (size, colloidal behavior, phase transitions, and polymorphism) of diverse lipid formulations (liposomes, lipoplexes, cubic phases, emulsions, and solid lipid nanoparticles) for distinct applications (parenteral, transdermal, pulmonary, and oral administration) will be rationalized in terms of common structural, thermodynamic and kinetic parameters of the lipids. This general biophysical basis helps to understand pharmaceutically relevant aspects such as liposome stability during storage and towards serum, the biodistribution and specific targeting of cargo, and how to trigger drug release and membrane fusion. Methods for the preparation and characterization of liposomal formulations in vitro will be outlined, too.

Design of an inhalable dry powder formulation of DOTAP-modified PLGA nanoparticles loaded with siRNA.

PubMed

Jensen, Ditte Krohn; Jensen, Linda Boye; Koocheki, Saeid; Bengtson, Lasse; Cun, Dongmei; Nielsen, Hanne Mørck; Foged, Camilla

2012-01-10

Matrix systems based on biocompatible and biodegradable polymers like the United States Food and Drug Administration (FDA)-approved polymer poly(DL-lactide-co-glycolide acid) (PLGA) are promising for the delivery of small interfering RNA (siRNA) due to favorable safety profiles, sustained release properties and improved colloidal stability, as compared to polyplexes. The purpose of this study was to design a dry powder formulation based on cationic lipid-modified PLGA nanoparticles intended for treatment of severe lung diseases by pulmonary delivery of siRNA. The cationic lipid dioleoyltrimethylammoniumpropane (DOTAP) was incorporated into the PLGA matrix to potentiate the gene silencing efficiency. The gene knock-down level in vitro was positively correlated to the weight ratio of DOTAP in the particles, and 73% silencing was achieved in the presence of 10% (v/v) serum at 25% (w/w) DOTAP. Optimal properties were found for nanoparticles modified with 15% (w/w) DOTAP, which reduced the gene expression with 54%. This formulation was spray-dried with mannitol into nanocomposite microparticles of an aerodynamic size appropriate for lung deposition. The spray-drying process did not affect the physicochemical properties of the readily re-dispersible nanoparticles, and most importantly, the in vitro gene silencing activity was preserved during spray-drying. The siRNA content in the powder was similar to the theoretical loading and the siRNA was intact, suggesting that the siRNA is preserved during the spray-drying process. Finally, X-ray powder diffraction analysis demonstrated that mannitol remained in a crystalline state upon spray-drying with PLGA nanoparticles suggesting that the sugar excipient might exert its stabilizing effect by sterical inhibition of the interactions between adjacent nanoparticles. This study demonstrates that spray-drying is an excellent technique for engineering dry powder formulations of siRNA nanoparticles, which might enable the local delivery of biologically active siRNA directly to the lung tissue. Copyright © 2011 Elsevier B.V. All rights reserved.

Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come

PubMed Central

Yingchoncharoen, Phatsapong; Kalinowski, Danuta S.

2016-01-01

Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number of cytotoxic chemotherapeutics are highly hydrophobic, which limits their utility in cancer therapy. Finally, many chemotherapeutic agents exhibit short half-lives that curtail their efficacy. As a result of these deficiencies, many current treatments lead to side effects, noncompliance, and patient inconvenience due to difficulties in administration. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems known commonly as nanoparticles. Among these delivery systems, lipid-based nanoparticles, particularly liposomes, have shown to be quite effective at exhibiting the ability to: 1) improve the selectivity of cancer chemotherapeutic agents; 2) lower the cytotoxicity of anticancer drugs to normal tissues, and thus, reduce their toxic side effects; 3) increase the solubility of hydrophobic drugs; and 4) offer a prolonged and controlled release of agents. This review will discuss the current state of lipid-based nanoparticle research, including the development of liposomes for cancer therapy, different strategies for tumor targeting, liposomal formulation of various anticancer drugs that are commercially available, recent progress in liposome technology for the treatment of cancer, and the next generation of lipid-based nanoparticles. PMID:27363439

Preparation and Characterization of Three Tilmicosin-loaded Lipid Nanoparticles: Physicochemical Properties and in-vitro Antibacterial Activities.

PubMed

Al-Qushawi, Alwan; Rassouli, Ali; Atyabi, Fatemeh; Peighambari, Seyed Mostafa; Esfandyari-Manesh, Mehdi; Shams, Gholam Reza; Yazdani, Azam

2016-01-01

Tilmicosin (TLM) is an important antibiotic in veterinary medicine with low bioavailability and safety. This study aimed to formulate and evaluate physicochemical properties, storage stability after lyophilization, and antibacterial activity of three TLM-loaded lipid nanoparticles (TLM-LNPs) including solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid-core nanocapsules (LNCs). Physicochemical parameters such as particle size-mean diameter, polydispersity index, zeta potential, drug encapsulation efficiency (EE), loading capacity, and morphology of the formulations were evaluated and the effects of various cryoprotectants during lyophilization and storage for 8 weeks were also studied. The profiles of TLM release and the antibacterial activities of these TLM-LNPs suspensions (against Escherichia coli and Staphylococcus aureus ) were tested in comparison with their corresponding powders. TLM-LNPs suspensions were in nano-scale range with mean diameters of 186.3 ± 1.5, 149.6 ± 3.0, and 85.0 ± 1.0nm, and also EE, 69.1, 86.3, and 94.3% for TLM- SLNs, TLM-NLCs, and TLM- LNCs respectively. TLM-LNCs gave the best results with significantly low particle size and high EE (p<0.05). Mannitol was the most effective cryoprotectant for lyophilization and storage of TLM-LNPs. The drug release profiles were biphasic and the release times were longer at pH 7.4 where TLM-NLCs and TLM-LNCs powders showed longer release times. In microbiological tests, S. aureus was about 4 times more sensitive than E. coli to TLM-LNPs with minimum inhibitory concentration ranges of 0.5-1.0 and 2-4 µg/mL respectively, and TLM-LNCs exhibited the best antibacterial activities. In conclusion, TLM-LNP formulations especially TLM-LNCs and TLM-NLCs are promising carriers for TLM with better drug encapsulation capacity, release behavior, and antibacterial activity.

Nanostructured lipid carriers to enhance transdermal delivery and efficacy of diclofenac.

PubMed

Nguyen, Chien Ngoc; Nguyen, Thi Thuy Trang; Nguyen, Hanh Thuy; Tran, Tuan Hiep

2017-10-01

Lipid carrier-mediated transdermal drug delivery offers several advantages because it is non-irritating and non-toxic, provides effective control of drug release, and forms an adhesive film that hydrates the outer skin layers. However, to penetrate the deeper skin layers, these formulations need to overcome several barriers in the stratum corneum. This study evaluates factors influencing particle size and drug-loading capacity, which play a key role in drug permeation and efficacy. Diclofenac sodium was chosen as the model drug. The fabrication of diclofenac sodium-loaded lipid nanoparticles was optimized by modulating several parameters, including the lipids and surfactants employed, the drug/lipid ratio, and the pH of the aqueous phase. The physical properties and loading efficiencies of the nanoparticles were characterized. The optimized formulation was then dispersed into a polymer solution to form a gel, which demonstrated a sustained ex vivo permeation of diclofenac sodium over 24 h through excised rat skin and a higher drug penetrating capacity than that of a commercially available gel. In vivo anti-inflammatory activity was assessed in a rat carrageenan-induced paw edema model; the anti-edema effects of the prepared gel and commercially available gel over 24 h were comparable. The present findings indicate the effects of particle size and drug loading on the ability of nanostructured lipid carrier preparations to provide transdermal drug delivery.

HPLC-APCI-MS analysis of triacylglycerols (TAGs) in historical pharmaceutical ointments from the eighteenth century.

PubMed

Saliu, Francesco; Modugno, Francesca; Orlandi, Marco; Colombini, Maria Perla

2011-10-01

The lipid fractions of residues from historical pharmaceutical ointments were analysed by reversed-phase liquid chromatography coupled with atmospheric pressure chemical ionization and mass spectrometer detection. The residues were contained in a series of historical apothecary jars, dating from the eighteenth century and conserved at the "Aboca Museum" in Sansepolcro (Arezzo, Italy) and at the pharmacy of the "Real Cartuja de Valldemossa" in Palma de Majorca (Spain). The analytical protocol was set up using a comparative study based on the evaluation of triacylglycerol (TAG) compositions in raw natural lipid materials and in laboratory-reproduced ointments. These ointments were prepared following pharmaceutical recipes reported in historical treatises and used as reference materials. The reference materials were also subjected to stress treatments in order to evaluate the modification occurring in the TAG profiles as an effect of ageing. TAGs were successfully detected in the reproduced formulations even in mixtures of up to ten ingredients and after harsh degradative treatments, and also in real historical samples. No particular interferences were detected from other non-lipid ingredients of the formulations. The TAG compositions detected in the historical ointments indicated a predominant use of olive oil and pig adipose material as lipid ingredients. The detection of a high level of tristearine and myristyl-palmitoyl-stearyl glycerol in two of the samples suggested the presence of a fatty material of a different origin (maybe a ruminant). On the basis of the positional isomer ratio, sn-PPO/sn-POP, it was possible to hypothesize an exclusive use of pig fat in one sample. We also evaluated the application of principal component analysis of TAG profiles as an approach for the multivariate statistical comparison of the reference and historical ointments.

Minimal food effect for eicosapentaenoic acid and docosahexaenoic acid bioavailability from omega-3-acid ethyl esters with an Advanced Lipid TechnologiesTM (ALT®)-based formulation.

PubMed

Lopez-Toledano, Miguel A; Thorsteinsson, Thorsteinn; Daak, Ahmed A; Maki, Kevin C; Johns, Colleen; Rabinowicz, Adrian L; Sancilio, Frederick D

The absorption of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) omega-3-acid ethyl esters (EEs) is influenced by food. There is a need for a formulation of EE that is less impacted by food effect. SC401 is a novel Advanced Lipid Technologies-based formulation of EPA-EE and DHA-EE. In the presence of an aqueous medium, Advanced Lipid Technologies forms stable micelles in situ independent of bile salt secretion. This effect is hypothesized to improve EPA-EE and DHA-EE bioavailability while it helps mitigate the food effect associated with their consumption. The aim of the article was to assess the effect of food on the bioavailability of DHA and EPA after a single oral dose of 1530 mg omega-3 fatty acids EE (SC401) in 24 healthy subjects under fasted and low-fat (9% of total calories from fat) and high-fat (50% of total calories from fat) meal conditions. This was a randomized, open-label, single-dose, 3-period, 3-way crossover study. Blood samples for pharmacokinetic analyses were taken at predose and at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12 and 24 hours postdose. To assess the safety of the intervention, active monitoring of adverse events, physical examinations, vital signs, clinical laboratory assessments (chemistry, hematology, and urinalysis), and 12-lead electrocardiograms were conducted. SC401 showed high bioavailability of both EPA and DHA in fasted, low-fat meal, and high-fat meal conditions. No differences were found in SC401 DHA AUC 0-t (t = 24 hours) among the 3 conditions (91.69% high-fat/fasted, 97.12% low-fat/fasted, and 105.92% low-fat/high-fat; P > .05 in all cases). In contrast, SC401 EPA AUC 0-t was affected by food intake (179.06% high-fat/fasted, P < .0001; 150.05% low-fat/fasted, P < .0001) and the amount of fat taken with SC401 (83.80% low-fat/high-fat; P = .0009). SC401 was safe and well tolerated. A single dose of SC401 resulted in high levels of EPA and DHA total lipids in plasma in fasting and fed conditions. SC401 overcame the food effect for DHA and partially ameliorated it for EPA. SC401 represents a convenient option for treatment of severe hypertriglyceridemia, especially for patients under a restricted intake of dietary fat. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery.

PubMed

Chan, Juliana M; Zhang, Liangfang; Yuet, Kai P; Liao, Grace; Rhee, June-Wha; Langer, Robert; Farokhzad, Omid C

2009-03-01

Current approaches to encapsulate and deliver therapeutic compounds have focused on developing liposomal and biodegradable polymeric nanoparticles (NPs), resulting in clinically approved therapeutics such as Doxil/Caelyx and Genexol-PM, respectively. Our group recently reported the development of biodegradable core-shell NP systems that combined the beneficial properties of liposomal and polymeric NPs for controlled drug delivery. Herein we report the parameters that alter the biological and physicochemical characteristics, stability, drug release properties and cytotoxicity of these core-shell NPs. We further define scalable processes for the formulation of these NPs in a reproducible manner. These core-shell NPs consist of (i) a poly(D,L-lactide-co-glycolide) hydrophobic core, (ii) a soybean lecithin monolayer, and (iii) a poly(ethylene glycol) shell, and were synthesized by a modified nanoprecipitation method combined with self-assembly. Preparation of the NPs showed that various formulation parameters such as the lipid/polymer mass ratio and lipid/lipid-PEG molar ratio controlled NP physical stability and size. We encapsulated a model chemotherapy drug, docetaxel, in the NPs and showed that the amount of lipid coverage affected its drug release kinetics. Next, we demonstrated a potentially scalable process for the formulation, purification, and storage of NPs. Finally, we tested the cytotoxicity using MTT assays on two model human cell lines, HeLa and HepG2, and demonstrated the biocompatibility of these particles in vitro. Our data suggest that the PLGA-lecithin-PEG core-shell NPs may be a useful new controlled release drug delivery system.

Natural lipids in nanostructured lipid carriers and its cytotoxicity

NASA Astrophysics Data System (ADS)

Lima, Paula A.; Rampazo, Caroline A. D.; Costa, Amanda F.; Rodrigues, Tiago; Watashi, Carolina M.; Durán, Nelson

2017-06-01

Nanostructured lipid carriers (NLCs) are active carrier systems which modulate the sustained release of actives and protect unstable compounds against degradation. NLCs can also protect skin from sun light, due to its particulates nature, which gives them intrinsic scattering properties. In this work, we present the preparation of NLCs using natural lipids and its cytotoxicity profile. It was used a vegetal butter with melting point (m.p.) ~32-40°C, an animal wax (m.p. 35-40°C) and a vegetal oil (boiling point ~120-150°C). NLCs were prepared by hot high pressure homogenization method and particles were characterized by average size (Zave), polydispersity index (PDI) and zeta potential (PZ) (Fig.1). The thermal behavior of the NLCs was studied using Differential Scanning Calorimetry (DSC). All the formulations were followed up for 60 days in order to evaluate their stability. NLCs exhibited a Zave around 150-200 nm, PDI less than 0.2 and PZ varying from -25 to -40 mV. The m.p. for the lyophilized NLCs was about 40-56°C. Cytotoxicity of the formulations were evaluated for human keratinocytes (HaCaT) and melanocytes (Melan-A) in the exponential growth phase. Cell viability was used as indicator of cytotoxicity and determined after 4 days of culture by MTT assay. It was found that the NLC formulations were not toxic against HaCaT and Melan-A cells. Results showed that the NLCs produced are potential carriers for nanocosmetics and sunscreen products.

Design of a nanostructured lipid carrier intended to improve the treatment of tuberculosis

PubMed Central

Pinheiro, Marina; Ribeiro, Ricardo; Vieira, Alexandre; Andrade, Fernanda; Reis, Salette

2016-01-01

This work aimed to design, develop, and characterize a lipid nanocarrier system for the selective delivery of rifabutin (RFB) to alveolar macrophages. Lipid nanoparticles, specifically nanostructured lipid carriers (NLC), were synthetized by the high-shear homogenization and ultrasonication techniques. These nanoparticles were designed to exhibit both passive and active targeting strategies to be efficiently internalized by the alveolar macrophages, traffic to the acidified phagosomes and phagolysosomes, and release bactericidal concentrations of the antituberculosis drug intracellularly. NLC that could entrap RFB were prepared, characterized, and further functionalized with mannose. Particles’ diameter, zeta potential, morphology, drug% entrapping efficiency, and drug release kinetics were evaluated. The mannose coating process was confirmed by Fourier transform infrared. Further, the cytotoxicity of the formulations was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay in A549, Calu-3, and Raw 264.7 cells. The diameter of NLC formulations was found to be in the range of 175–213 nm, and drug entrapping efficiency was found to be above 80%. In addition, high storage stability for the formulations was expected since they maintained the initial characteristics for 6 months. Moreover, the drug release was pH-sensitive, with a faster drug release at acidic pH than at neutral pH. These results pose a strong argument that the developed nanocarrier can be explored as a promising carrier for safer and more efficient management of tuberculosis by exploiting the pulmonary route of administration. PMID:27536067

Novel formulations for antimicrobial peptides.

PubMed

Carmona-Ribeiro, Ana Maria; de Melo Carrasco, Letícia Dias

2014-10-09

Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy.

Novel Formulations for Antimicrobial Peptides

PubMed Central

Carmona-Ribeiro, Ana Maria; Carrasco, Letícia Dias de Melo

2014-01-01

Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy. PMID:25302615

Impact of Lipid Components and Emulsifiers on Plant Sterols Bioaccessibility from Milk-Based Fruit Beverages.

PubMed

Alvarez-Sala, Andrea; Garcia-Llatas, Guadalupe; Cilla, Antonio; Barberá, Reyes; Sánchez-Siles, Luis Manuel; Lagarda, María Jesús

2016-07-20

Sterol bioaccessibility (BA) of three plant sterol (PS)-enriched milk-based fruit beverages (MFb) with different fat contents (1.1-2.4%), lipid sources (animal or vegetable), and without or with emulsifiers (whey proteins enriched with milk fat globule membrane (MFGM) or soy lecithin) was evaluated after simulated gastrointestinal digestion. The BA of total PS followed the order 31.4% (MFbM containing milk fat and whey proteins enriched with MFGM) = 28.2% (MFbO containing extra virgin olive oil and soy lecithin) > 8.7% (MFb without fat addition). Total and individual PS content in the bioaccessible fractions followed the order MFbM > MFbO > MFb. Consequently, formulation with MFGM is proposed in beverages of this kind to ensure optimum bioavailability of PS. Our results suggest that the BA of PS is influenced by the type and quantity of fat and the emulsifier type involved.

A protocol describing the use of a recombinant protein-based, animal product-free medium (APEL) for human embryonic stem cell differentiation as spin embryoid bodies.

PubMed

Ng, Elizabeth S; Davis, Richard; Stanley, Edouard G; Elefanty, Andrew G

2008-01-01

In order to promote the uniform and reproducible differentiation of human embryonic stem cells (HESCs) in response to exogenously added growth factors, we have developed a method (spin embryoid bodies (EBs)) that uses a recombinant protein-based, animal product-free medium in which HESCs are aggregated by centrifugation to form EBs. In this protocol we describe the formulation of this medium, denoted APEL (Albumin Polyvinylalcohol Essential Lipids), and its use in spin EB differentiation of HESCs. We also describe a more economical variant, BPEL (Bovine Serum Albumin (BSA) Polyvinylalchohol Essential Lipids), in which BSA replaces the recombinant human albumin. The integration of a medium that includes only defined and recombinant components with a defined number of cells to initiate EB formation results in a generally applicable, robust platform for growth factor-directed HESC differentiation.

Solid lipid nanoparticles for enhancing vinpocetine's oral bioavailability.

PubMed

Luo, YiFan; Chen, DaWei; Ren, LiXiang; Zhao, XiuLi; Qin, Jing

2006-08-10

An ultrasonic-solvent emulsification technique was adopted to prepare vinpocetine loaded Glyceryl monostearate (GMS) nanodispersions with narrow size distribution. To increase the lipid load the process was conducted at 50 degrees C, and in order to prepare nanoparticle using an ultrasonic-solvent emulsification technique. The mean particle size and droplet size distribution, drug loading capacity, drug entrapment efficiency (EE%), zeta potential, and long-term physical stability of the SLNs were investigated in detail respectively. Drug release from two sorts of VIN-SLN was studied using a dialysis bag method. A pharmacokinetic study was conducted in male rats after oral administration of 10 mg kg(-1) VIN in different formulations, it was found that the relative bioavailability of VIN in SLNs was significantly increased compared with that of the VIN solution. The amount of surfactant also had a marked effect on the oral absorption of VIN with SLN formulations. The absorption mechanism of the SLN formulations was also discussed. These results indicated that VIN absorption is enhanced significantly by employing SLN formulations. SLNs offer a new approach to improve the oral bioavailability of poorly soluble drugs.

Single-Dose Intracardiac Injection of Pro-Regenerative MicroRNAs Improves Cardiac Function After Myocardial Infarction.

PubMed

Lesizza, Pierluigi; Prosdocimo, Giulia; Martinelli, Valentina; Sinagra, Gianfranco; Zacchigna, Serena; Giacca, Mauro

2017-04-14

Recent evidence indicates that a few human microRNAs (miRNAs), in particular hsa-miR-199a-3p and hsa-miR-590-3p, stimulate proliferation of cardiomyocytes and, once expressed in the mouse heart using viral vectors, induce cardiac regeneration after myocardial infarction. Viral vectors, however, are not devoid of safety issues and, more notably, drive expression of the encoded miRNAs for indefinite periods of time, which might not be desirable in light of human therapeutic application. As an alternative to the use of viral vectors, we wanted to assess the efficacy of synthetic miRNA mimics in inducing myocardial repair after single intracardiac injection using synthetic lipid formulations. We comparatively analyzed the efficacy of different lipid formulations in delivering hsa-miR-199a-3p and hsa-miR-590-3p both in primary neonatal mouse cardiomyocytes and in vivo. We established a transfection protocol allowing persistence of these 2 mimics for at least 12 days after a single intracardiac injection, with minimal dispersion to other organs and long-term preservation of miRNA functional activity, as assessed by monitoring the expression of 2 mRNA targets. Administration of this synthetic formulation immediately after myocardial infarction in mice resulted in marked reduction of infarct size and persistent recovery of cardiac function. A single administration of synthetic miRNA-lipid formulations is sufficient to stimulate cardiac repair and restoration of cardiac function. © 2017 American Heart Association, Inc.

An isocratic HPLC method for the simultaneous determination of cholesterol, cardiolipin, and DOPC in lyophilized lipids and liposomal formulations.

PubMed

Simonzadeh, Ninus

2009-04-01

Phospholipids, such as 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 1,1',2,2'-tetramyristoyl cardiolipin, along with cholesterol, form liposomes in aqueous media and have been investigated at NeoPharm (Lake Bluff, IL) as drug-delivery systems. To accurately assess the effectiveness of various formulations involving the use of aforementioned phospholipids and cholesterol, their quantitative determination is essential. An isocratic high-performance liquid chromatographic method for the simultaneous determination of cholesterol, cardiolipin, and DOPC in various pharmaceutical formulations containing the active drug substance has consequently been developed and is presented here. The current method utilizes an ASTEC-diol analytical column and is shown to be stability-indicating and free from interference from any of the formulation excipients, such as sucrose, sodium chloride, and sodium lactate. The analytes are detected using an evaporative light scattering detector (Alltech or Polymer Laboratories). The quantitation of each lipid component is performed using non-linear regression analysis. The retention characteristics of the analytes are examined as a function of eluent composition (e.g., pH, salt content, organic to aqueous phase ratio) and column temperature. The method was validated and was found to be sensitive, specific, rugged, and cost-effective. The current method provides enhanced chromatographic separation for lipid components as well as degradation products as compared to similar methods reported in the literature. It is also inherently simpler than other similar methods reported in the literature that typically use complex gradient elution.

Ocular Dorzolamide Nanoliposomes for Prolonged IOP Reduction: in-vitroand in-vivo Evaluation in Rabbits

PubMed Central

Kouchak, Maryam; Bahmandar, Reza; Bavarsad, Neda; Farrahi, Fereydoun

2016-01-01

Dorzolamide ophthalmic drop is one of the most common glaucoma medications but it has a short residence time in the eye. The aim of this study is to develop ocular dorzolamide HCl nanoliposomes (DRZ – nanoliposomes) and to evaluate their potential use for the treatment of ocular hypertension. Nanoliposomes were prepared using Reverse-phase evaporation vesicle (REV) and thin layer hydration (TLH) method with 7:3 and 7:4 molar ratios of phosphatidylcholine:cholesterol. The physicochemical properties of the formulations were investigated. Formulations with 7:4 lipid ratios were evaluated in terms of drug release, physical stability and ex-vivo permeation through the excised albino rabbit cornea. The rabbits in groups of 6 were treated with selected DRZ – nanoliposomes or dorzolamide solution or marketed dorzolamid preparation (Biosopt®) and intraocular pressure (IOP) was monitored. Formulations with 7:4 molar ratio entrapped greater amount of drug compared to those with 7:3 lipid components ratio. DRZ – nanoliposomes with 7:4 lipid ratio showed more transcorneal permeation than Dorzolamide solution (p<0.05); and the formulation prepared by TLH method exhibited higher permeability than that prepared by REV method (p<0.05). The selected DRZ – nanoliposomes showed greater IOP lowering activity and a more prolonged effect compared to dorzolamide solution and Biosopt®. DRZ – nanoliposomes prepared by TLH method with 7:4 ratios showed promising results as a candidate for the treatment of ocular hypertension. PMID:27610160

Co-liposomes having anisamide tagged lipid and cholesteryl tryptophan trigger enhanced gene transfection in sigma receptor positive cells.

PubMed

Misra, Santosh K; Moitra, Parikshit; Kondaiah, Paturu; Bhattacharya, Santanu

2016-06-01

Selective gene transfection could be strategy of interest for reducing off-target gene expression and toxicity. In this respect, sigma receptors are found to be over-expressed in many human tumors and liposomal formulations with ability to target these sigma receptors may improve the transfection efficiency to a significant level. To this direction, six novel lipids have been synthesized with different hydrophobic segments such as a long hydrophobic chain or a cholesteryl group and L-tryptophan as the head group. Three of them, Lipid 1, 3 and 5 possessed cationic Me3N(+) moiety at the distal end. In contrast each of the other three Lipid 2, 4 and 6 possessed sigma receptor targeting anisamide group with no cationic charge. Mixing of cationic and anisamide counterparts of the same lipid in a molar ratio of 1:1 produced co-liposomes L-M-1 (Lipid 1+2), L-M-2 (Lipid 3+4) and L-M-3 (Lipid 5+6). These co-liposomes, while keeping the sigma targeting anisamide tag intact, showed good DNA binding and release which were optimized from EB intercalation and gel electrophoresis assays. Inclusion of a zwitterionic, fusogenic natural lipid, DOPE, into the co-liposomes further improved the binding efficiencies of the lipid mixtures with DNA. These co-liposomes having cationic and anisamide lipids and DOPE were highly selective toward sigma positive HEK293 and HEK293T cells compared to the sigma negative HeLa cells. As evidenced from both FACS and luciferase assay, a lipid mixture comprising Lipid 3, 4 and DOPE in a molar ratio of 1:1:1 (L-M-2D1) was the best for transfection of reporter pEGFP-C3 and functional pCEP4-p53 gene plasmids. Anisamide mediated sigma receptor selectivity was further probed by pre-incubating the transfecting cells with lipids possessing anisamide and by quantification of the un-transfected plasmid DNA. Also each formulation was highly non-toxic in the cell lines examined. Copyright © 2016. Published by Elsevier B.V.

The safety of ethambutol dihydrochloride dry powder formulations containing chitosan for the possibility of treating lung tuberculosis.

PubMed

Ahmad, Md Iftekhar; Nakpheng, Titpawan; Srichana, Teerapol

2014-12-01

The aim of this study was to conduct in vitro studies of a dry powder formulation of ethambutol dihydrochloride (EDH) to determine if it was an acceptable candidate for further in vivo studies to target alveolar macrophages for the treatment of lung tuberculosis. Nanosized drug particles were prepared by optimizing the spray drying conditions. The cell toxicities were determined by interacting the formulations with respiratory cell lines (A549, calu-3 and NR8383 cell lines), and phagocytosis of the formulations was tested on a macrophage cell line. Permeations of the EDH formulations across a lipid bilayer were studied using the Ussing chamber and HPLC. Bioactivity tests of the formulations were carried out by using the resazurin method on M. bovis cells. Spray rate and inlet temperature were the two most important factors that affected the size and % yield of the product. The % cell viability of A549 cells with all EDH formulations, pure EDH and chitosan carrier was higher than 80%, the calu-3 cell line had % viabilities of between 85 and 99%, and the % viability of NR8383 cells was between 81 and 100%. The pure EDH had a minimum inhibitory concentration (MIC) of 2 µg/mL while the EDH formulations had MIC values of less than 1 µg/mL when tested against M. bovis. The formulation was completely phagocytized by the macrophage cells after 30 min. The permeability of pure EDH across lipid bilayer was 48.7% after 2 h while in the EDH formulations it was enhanced to 71%. The EDH formulations showed a lower toxicity, higher potency and better permeation than the pure EDH. Thus, EDH DPI formulations could help to minimize the duration of treatment and the risk of developing multidrug resistance tuberculosis compared to the non-formulated EDH.

Diclofenac salts, part 6: release from lipid microspheres.

PubMed

Fini, Adamo; Cavallari, Cristina; Rabasco Alvarez, Antonio M; Rodriguez, Marisa Gonzalez

2011-08-01

The release of diclofenac (20%, w/w) was studied from lipidic solid dispersions using three different chemical forms (acid, sodium salt, and pyrrolidine ethanol salt) and two different lipid carriers (Compritol 888 ATO or Carnauba wax) either free or together with varying amounts (10%-30%, w/w) of stearic acid. Microspheres were prepared by ultrasound-assisted atomization of the molten dispersions and analyzed by scanning electron microscopy, differential scanning calorimetry, and hot stage microscopy. The effects of different formulations on the resulting drug release profiles as a function of pH were studied and the results were discussed. The formulation of the 18 systems and the chemical form of the drug were found to strongly affect the mode of the drug release. The solubility of the chemical forms in the lipid mixture is in the following order: pyrrolidine ethanol salt ≫ acid > sodium salt (according to the solubility parameters), and the nature of the systems thus obtained ranges from a matrix, for mutually soluble drug/carrier pairs, to a microcapsule, for pairs wherein mutual solubility is poor. Drug release from microspheres prepared by pure lipids was primarily controlled by diffusion, whereas the release from microspheres containing stearic acid was diffusion/erosion controlled at pH 7.4. Copyright © 2011 Wiley-Liss, Inc.

Effectiveness of supersaturation promoting excipients on albendazole concentrations in upper gastrointestinal lumen of fasted healthy adults.

PubMed

Kourentas, Alexandros; Vertzoni, Maria; Symillides, Mira; Goumas, Konstantinos; Gibbon, Robert; Butler, James; Reppas, Christos

2016-08-25

To evaluate the impact of dosage form relevant levels of a polymeric precipitation inhibitor and of lipid excipients on supersaturation of upper gastrointestinal contents with albendazole, a lipophilic weak base. Albendazole concentrations in stomach and in duodenum were evaluated after administration of 1) a suspension in water (Susp-Control), 2) a suspension in water in which hydroxyprolylmethylcellulose E5 (HPMC E5) had been pre-dissolved (Susp-HPMC), and 3) and 4) two contrasting designs of lipid based suspensions dispersed in water (Susp-IIIA and Susp-IV), on a cross-over basis to fasted healthy adults. Limited, but statistically significant supersaturation of duodenal contents was observed after Susp-HPMC, Susp-IIIA, and Susp-IV; supersaturation was more consistent after Susp-HPMC administration. Based on total albendazole amount per volume, gastric secretions did not significantly alter volumes of bulk gastric contents during the first 40min post administration of a glass of non-caloric water-based fluid. Αlbendazole gastric concentrations were higher than in the administered suspensions, but similar for all four formulations. Gastric emptying of albendazole after administration of Susp-Control or Susp-HPMC was slower than after administration of Susp-IIIA or Susp-IV. Small amounts of HPMC E5 were as effective as lipid excipients in achieving supersaturation of duodenal contents with albendazole, a fast precipitating weak base, in fasted adults. However, compared with the effect of HPMC E5 the effect of lipid excipients was delayed and variable. Copyright © 2016 Elsevier B.V. All rights reserved.

Reduction in blood pressure and serum lipids by lycosome formulation of dark chocolate and lycopene in prehypertension

PubMed Central

Petyaev, Ivan M; Dovgalevsky, Pavel Y; Chalyk, Natalia E; Klochkov, Victor; Kyle, Nigel H

2014-01-01

Twenty-nine healthy volunteers aged 47–69 years old were randomly assigned to a 28-day oral intake of different dark chocolate (DC) formulations. The main group received daily 30 g of proprietary lycopene-containing (L-tug) lycosome formulation of DC with enhanced bioavailability of cocoa flavanols. Two control groups daily consumed either 30 g of regular DC alone or along with 7 mg of lycopene, which corresponds to the amount of lycopene ingested with L-tug formulation. It was found that L-tug was more efficient in reducing diastolic blood pressure (mean value of −6.22 mmHg, 95% CI: 5.00, 8.00) when compared with the regular DC group (−3.00 mmHg, P < 0.05) or the group which ingested the DC and lycopene as two separate formulations (mean reduction of −4 mmHg, 95% CI: 2.47, 6.00, P = 0.0262). Only marginal superiority for L-tug formulation in the reduction in systolic blood pressure was seen. However, the L-tug formulation was the only formulation of DC which affected serum lipids. There was a reduction in total cholesterol (from median 228.00 mg/dL [95% CI: 206.2, 242.5] to 187.00 mg/dL [95% CI: 166.2, 202.2, P < 0.05]) with corresponding decline of low-density lipoprotein (LDL) cholesterol (from a median of 166.00 mg/dL [95% CI: 130.8, 177.0] to 151.00 mg/dL [95% CI: 122.8, 167.4; P < 0.05]) at the end of the intervention period. Similar decline was seen in serum triglycerides (P < 0.05). Serum high-density lipoprotein (HDL) cholesterol, glucose levels, and C-reactive protein (CRP) values remained statistically unchanged in all study groups throughout the intervention period. A superior biological activity of the L-tug lycosome formulation of DC extending beyond its antihypertensive effect to lipid-lowering ability opens up new possibilities for the use of DC for health purposes helping to reduce daily caloric intake without compromising on the health benefits of DC consumption. PMID:25493193

Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids

DOE PAGES

Kieler-Ferguson, Heidi M.; Chan, Darren; Sockolosky, Jonathan; ...

2017-03-03

Here, we employed a recently introduced class of sterol-modified lipids (SML) to produce m-PEG-DSPE containing liposome compositions with a range of cis-platinum content release rates. SML have a cholesterol succinate attached to the phosphatidylglycerol head group and a fatty acid at the 2 position. These compositions were compared to the well-studied liposome phospholipid compositions: mPEG-DSPE/Hydrogenated Soy PC/cholesterol or mPEG-DSPE/POPC/cholesterol to determine the effect of the cis-platinum release extent on C26 tumor proliferation in the BALB/c colon carcinoma mouse model. The release rates of cis-platinum from liposomes composed of SML are a function of the acyl chain length. SML-liposomes with shortermore » acyl chain lengths C-8 provided more rapid cisplatin release, lower in vitro IC50, and were easier to formulate compared to liposomes using traditional phospholipid compositions. Similar to other liposome cis-platinum formulations, the half-life of m-PEG-DSPE SML liposome cisplatin is substantially longer than the free drug. This resulted in a higher tumor cisplatin concentration at 48 h post-dosing compared to the free drug and higher Pt-DNA adducts in the tumor. Moreover, the maximum tolerated dose of the liposome formulations where up to four fold greater than the free drug. Using X-ray fluorescence spectroscopy on tumor sections, we compared the location of platinum, to the location of a fluorescence lipid incorporated in the liposomes. The liposome platinum co-localized with the fluorescent lipid and both were non-uniformly distributed in the tumor. Non-encapsulated Cis-platinum, albeit at a low concentration, was more uniformly distributed thorough the tumor. Three liposome formulations, including the well studied hydrogenated HSPC composition, had better antitumor activity in the murine colon 26 carcinoma model as compared to the free drug at the same dose but the SML liposome platinum formulations did not perform better than the HSPC formulation.« less

Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kieler-Ferguson, Heidi M.; Chan, Darren; Sockolosky, Jonathan

Here, we employed a recently introduced class of sterol-modified lipids (SML) to produce m-PEG-DSPE containing liposome compositions with a range of cis-platinum content release rates. SML have a cholesterol succinate attached to the phosphatidylglycerol head group and a fatty acid at the 2 position. These compositions were compared to the well-studied liposome phospholipid compositions: mPEG-DSPE/Hydrogenated Soy PC/cholesterol or mPEG-DSPE/POPC/cholesterol to determine the effect of the cis-platinum release extent on C26 tumor proliferation in the BALB/c colon carcinoma mouse model. The release rates of cis-platinum from liposomes composed of SML are a function of the acyl chain length. SML-liposomes with shortermore » acyl chain lengths C-8 provided more rapid cisplatin release, lower in vitro IC50, and were easier to formulate compared to liposomes using traditional phospholipid compositions. Similar to other liposome cis-platinum formulations, the half-life of m-PEG-DSPE SML liposome cisplatin is substantially longer than the free drug. This resulted in a higher tumor cisplatin concentration at 48 h post-dosing compared to the free drug and higher Pt-DNA adducts in the tumor. Moreover, the maximum tolerated dose of the liposome formulations where up to four fold greater than the free drug. Using X-ray fluorescence spectroscopy on tumor sections, we compared the location of platinum, to the location of a fluorescence lipid incorporated in the liposomes. The liposome platinum co-localized with the fluorescent lipid and both were non-uniformly distributed in the tumor. Non-encapsulated Cis-platinum, albeit at a low concentration, was more uniformly distributed thorough the tumor. Three liposome formulations, including the well studied hydrogenated HSPC composition, had better antitumor activity in the murine colon 26 carcinoma model as compared to the free drug at the same dose but the SML liposome platinum formulations did not perform better than the HSPC formulation.« less

An X-ray transparent microfluidic platform for screening of the phase behavior of lipidic mesophases

PubMed Central

Khvostichenko, Daria S.; Kondrashkina, Elena; Perry, Sarah L.; Pawate, Ashtamurthy S.; Brister, Keith

2013-01-01

Lipidic mesophases are a class of highly ordered soft materials that form when certain lipids are mixed with water. Understanding the relationship between the composition and the microstructure of mesophases is necessary for fundamental studies of self-assembly in amphiphilic systems and for applications, such as crystallization of membrane proteins. However, the laborious formulation protocol for highly viscous mesophases and the large amounts of material required for sample formulation are significant obstacles in such studies. Here we report a microfluidic platform that facilitates investigations of the phase behavior of mesophases by reducing sample consumption, and automating and parallelizing sample formulation. The mesophases were formulated on-chip using less than 40 nL of material per sample and their microstructure was analyzed in situ using small-angle X-ray scattering (SAXS). The 220 μm-thick X-ray compatible platform was comprised of thin polydimethylsiloxane (PDMS) layers sandwiched between cyclic olefin copolymer (COC) sheets. Uniform mesophases were prepared using an active on-chip mixing strategy coupled with periodic cooling of the sample to reduce the viscosity. We validated the platform by preparing and analyzing mesophases of lipid monoolein (MO) mixed with aqueous solutions of different concentrations of β-octylglucoside (βOG), a detergent frequently used in membrane protein crystallization. Four samples were prepared in parallel on chip, by first metering and automatically diluting βOG to obtain detergent solutions of different concentration, then metering MO, and finally mixing by actuation of pneumatic valves. Integration of detergent dilution and subsequent mixing significantly reduced the number of manual steps needed for sample preparation. Three different types of mesophases typical for monoolein were successfully identified in SAXS data from on-chip samples. Microstructural parameters of identical samples formulated in different chips showed excellent agreement. Phase behavior observed on-chip corresponded well with that of samples prepared via the traditional coupled-syringe method (“off-chip”) using 300-fold larger amount of material, further validating the utility of the microfluidic platform for on-chip characterization of mesophase behavior. PMID:23882463

Oral delivery of BCG Moreau Rio de Janeiro gives equivalent protection against tuberculosis but with reduced pathology compared to parenteral BCG Danish vaccination.

PubMed

Clark, Simon O; Kelly, Dominic L F; Badell, Edgar; Castello-Branco, Luiz Roberto; Aldwell, Frank; Winter, Nathalie; Lewis, David J M; Marsh, Philip D

2010-10-08

There is a need for an improved vaccine to better control human tuberculosis (TB), as the only currently available TB vaccine, bacillus Calmette-Guerin (BCG) delivered parenterally, offers variable levels of efficacy. Therefore, recombinant strains expressing additional antigens are being developed alongside alternative routes to parenteral delivery. There is strong evidence that BCG Moreau (RdJ) is a safe and effective vaccine in humans when given by the oral route. This study compared the efficacy of a single oral dose of wild type BCG Moreau Rio de Janeiro (RdJ), or a recombinant RdJ strain expressing Ag85B-ESAT6 fusion protein, formulated with and without lipid to enhance oral delivery, with subcutaneous BCG Danish 1331 and saline control groups in a guinea pig aerosol infection model of pulmonary tuberculosis. Protection was measured as survival at 30 weeks post-challenge and reduced bacterial load and histopathology in lungs and spleen. Results showed that a single oral dose of BCG Moreau (RdJ) or recombinant BCG Moreau (RdJ)-Ag85B-ESAT6, formulated with or without lipid, gave protection equivalent to subcutaneously delivered BCG Danish in the 30 weeks post-challenge survival study. The orally delivered vaccines gave reduced pathology scores in the lungs (three of the four formulations) and spleens (all four formulations) compared to subcutaneously delivered BCG Danish. The oral wild type BCG Moreau (RdJ) in lipid and the unformulated oral wild type BCG Moreau (RdJ) vaccine also gave statistically lower bacterial loads in the lungs and spleens, respectively, compared to subcutaneously delivered BCG Danish. This study provides further evidence to show that lipid formulation does not impair vaccine efficacy and may enhance the delivery and stability of oral vaccines intended for use in countries with poor health infrastructure. Oral delivery also avoids needles (and associated cross-infection risks) and immunisation without the need for specially trained medical professional staff. Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

Enhanced skin penetration of lidocaine through encapsulation into nanoethosomes and nanostructured lipid carriers: a comparative study.

PubMed

Babaei, S; Ghanbarzadeh, S; Adib, Z M; Kouhsoltani, M; Davaran, S; Hamishehkar, H

2016-05-01

Lipid based nanoparticles have become a major research object in topical drug delivery to enable drugs to pass the stratum corneum and reach the desired skin layer. The present investigation deals with the encapsulation of lidoacine into nanostructured lipid carriers (NLCs) and nanoethosomes for improving its dermal delivery and consequently local anesthetic efficacy. Concurrently these two topical delivery systems were compared. Lidocaine-loaded NLCs and nanoethosomes were characterized by various techniques and used for an in vitro skin penetration study using excised rat skin and Franz diffusion cells. The nanoparticles were tracked in the skin by following the Rhodamine-labled nanocarriers under fluorescent microscopy. Optimized lidocaine-loaded NLCs (size 96 nm, zeta potential -13.7 mV, encapsulation efficiency (EE) % 69.86% and loading capacity (LC) % 10.47%) and nanoethosomes (size 105.4 nm, zeta potential -33.6 mV, EE 40.14% and LC 8.02%) were chosen for a skin drug delivery study. Higher skin drug deposition of NLCs and nanoethosomal formulations compared to lidocaine hydroalcoholic solution represented a better localization of the drug in the skin. NLC formulation showed the lowest entered drug in the receptor phase of Franz diffusion cell in comparison with nanoethosomes and hydroalcoholic solution confirming the highest skin accumulation of drug. Both colloidal systems showed superiority over the drug solution for dermal delivery of lidocaine, however, NLC exhibited more promising characteristics than nanoethosomes regarding drug loading and skin targeted delivery.

Phyto-mediated nanostructured carriers based on dual vegetable actives involved in the prevention of cellular damage.

PubMed

Istrati, D; Lacatusu, I; Bordei, N; Badea, G; Oprea, O; Stefan, L M; Stan, R; Badea, N; Meghea, A

2016-07-01

The growing scientific interest in exploitation of vegetable bioactives has raised a number of questions regarding their imminent presence in pharmaceutical formulations. This study intends to demonstrate that a dual combination between vegetable oil (e.g. thistle oil, safflower oil, sea buckthorn oil) and a carrot extract represents an optimal approach to formulate safe carrier systems that manifest cell regeneration effect and promising antioxidant and anti-inflammatory activity. Inclusion of both natural actives into lipid carriers imparted a strong negative charge on the nanocarrier surface (up to -45mV) and displayed average sizes of 70nm to 140nm. The entrapment efficiency of carrot extract into nanostructured carriers ranged between 78.3 and 88.3%. The in vitro release study has demonstrated that the entrapment of the extract represents a viable way for an equilibrated release of carotenoids. Besides the excellent antioxidant properties (e.g. scavenging up to 98% of the free oxygen radicals), the results of cellular integrity (e.g. cell viability of 133%) recommend these nanocarriers based on dual carrot extract-bioactive oil as a promising trend for the treatment of certain disorders in which oxidative stress plays a prominent role. In addition, the lipid nanocarriers based on safflower oil and sea buckthorn oil demonstrated an anti-inflammatory effect on LPS induced THP-1 macrophages, by inhibiting the secretion of two pro-inflammatory cytokines, IL-6 and TNF-α. Copyright © 2016 Elsevier B.V. All rights reserved.

Liposome-containing Hibiscus sabdariffa calyx extract formulations with increased antioxidant activity, improved dermal penetration and reduced dermal toxicity.

PubMed

Pinsuwan, Sirirat; Amnuaikit, Thanaporn; Ungphaiboon, Suwipa; Itharat, Arunporn

2010-12-01

Hibiscus sabdariffa Linn, or Roselle, is a medicinal plant used extensively in traditional Thai medicine since ancient times. The extracts of Roselle calyces possess antioxidant activity and have potential for development as active ingredients in cosmetic products. However the limitations of using Roselle extracts in cosmetics are its low skin permeation and dermal irritation. Liposome technology is an obvious approach that might overcome these problems. Liposome formulations of standardized Roselle extracts were developed with various lipid components. The formulation showing the highest entrapment efficiency was selected for stability, skin permeation and dermal irritability studies. The liposome formulation with the highest entrapment efficiency (83%) and smalôlest particle size (332 mm) was formulated with phosphatidylcholine from soybean (SPC): Tween 80: deoxycholic acid (DA); 84:16:2.5 weight ratio, total lipid of 200 g/mL and 10% w/v Roselle extract in final liposomal preparation. This liposome formulation was found to be stable after storage at 4 degrees C, protected from light, for 2 months. The in vitro skin permeation studies, using freshly excised pig skin and modified Franz-diffusion cells, showed that the liposome formulation was able to considerably increased the rate of permeation of active compounds in Roselle extracts compared to the Roselle extract solution. The in vivo dermal irritability testing on rabbit skin showed that the liposome formulation dramatically decreased skin irritability compared to the unformulated extract. These results showed that the liposomes containing Roselle extracts had good stability, high entrapment efficacy, increased skin permeation and low skin irritation.

Synthesis and characterization of canola oil-stearic acid-based trans-free structured lipids for possible margarine application.

PubMed

Lumor, Stephen E; Jones, Kerby C; Ashby, Rick; Strahan, Gary D; Kim, Byung Hee; Lee, Guan-Chiun; Shaw, Jei-Fu; Kays, Sandra E; Chang, Shu-Wei; Foglia, Thomas A; Akoh, Casimir C

2007-12-26

Incorporation of stearic acid into canola oil to produce trans-free structured lipid (SL) as a healthy alternative to partially hydrogenated fats for margarine formulation was investigated. Response surface methodology was used to study the effects of lipozyme RM IM from Rhizomucor miehei and Candida rugosa lipase isoform 1 (LIP1) and two acyl donors, stearic acid and ethyl stearate, on the incorporation. Lipozyme RM IM and ethyl stearate gave the best result. Gram quantities of SLs were synthesized using lipozyme RM IM, and the products were compared to SL made by chemical catalysis and fat from commercial margarines. After short-path distillation, the products were characterized by GC and RPHPLC-MS to obtain fatty acid and triacylglycerol profiles, 13C NMR spectrometry for regiospecific analysis, X-ray diffraction for crystal forms, and DSC for melting profile. Stearic acid was incorporated into canola oil, mainly at the sn-1,3 positions, for the lipase reaction, and no new trans fatty acids formed. Most SL products did not have adequate solid fat content or beta' crystal forms for tub margarine, although these may be suitable for light margarine formulation.

Pharmacodynamic evaluation of self micro-emulsifying formulation of standardized extract of Lagerstroemia speciosa for antidiabetic activity.

PubMed

Agarwal, Vipin Kumar; Amresh, Gupta; Chandra, Phool

Lagerstroemia speciosa (SEL) leaves are a popular folk medicine for diabetes treatment due to presence of corosolic acid. It has low water solubility resulting poor absorption after oral administration. Self micro-emulsified drug delivery system is the way by which we can improve the oral absorption of drug. The objective of this study was to develop the self micro-emulsifying formulation of standardized extract of SEL leaves and evaluate its pharmacodynamic performance for antidiabetic activity. The SME formulation was prepared by using sefsol-218 as oil, cremophor-EL as surfactant and transcutol-P as co-surfactant. The ratio of surfactant and co-surfactant was determined by pseudoternary phase diagram. SME formulations were characterized for dilution at different pH, self emulsification, optical clarity, globule size and thermodynamic stability. Pharmacodynamic evaluation of formulations was assessed in Wistar rats by using parameters viz. blood glucose level and serum lipid profile. SEL loaded SME formulation was successfully developed by using sefsol-218, cremophor-EL and transcutol-P with a droplet size 23.53 nm. Pharmacodynamic results showed a higher reduction in blood glucose by SME formulation than SEL without SMES respectively at 50 mg/kg dose while reduction produced at dose of 100 mg/kg was found significant and better on 15th day of study. The percentage reduction produced by SME formulation on serum lipid profile was also significant and was more prominent than SEL. This study confirms that the formulation elevates the pharmacodynamic performance of SEL approximately two fold. Copyright © 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

Formulation and Evaluation of Morin-Loaded Solid Lipid Nanoparticles.

PubMed

Ikeuchi-Takahashi, Yuri; Ishihara, Chizuko; Onishi, Hiraku

2016-09-01

In this study, solid lipid nanoparticle (SLN) suspensions were prepared using a base of hard fat with or without ethylcellulose (EC) and polyvinyl alcohols (PVA) and polysorbate (Tween) 60 surfactants. Commercially available PVAs vary in their degree of saponification and polymerization, and the appropriate PVAs to form SLNs from hard fat with or without EC were investigated. A relatively low-saponification-degree PVA was required to reproducibly form SLN suspensions without EC and relatively high-saponification-degree PVAs were suitable for SLNs with EC. The release of morin from SLNs with EC was more sustained than that from SLNs without EC. The maximum plasma concentration (Cmax) of SLNs with and without EC were almost the same, and both were higher than that of a morin suspension. The area under the curve for 0 to 360 min (AUC0-360) of SLNs with EC was increased compared with those of a morin suspension and SLNs without EC. The median diameter of SLNs with EC and a very low-saponification-degree PVA was decreased compared to other formulation, and morin release was more sustained for this formulation. SLNs with EC and a very low-saponification-degree PVA showed higher Cmax and AUC0-360 than SLNs with EC lacking a very low-saponification-degree PVA. The optimized SLNs with EC and a very low-saponification-degree PVA improved bioavailability via increased accessibility to the enterocyte surface by decreased particle size and increased permeation of SLN encapsulated morin through the intestinal membrane by sustained release properties.

Dropwise additive manufacturing of pharmaceutical products for amorphous and self emulsifying drug delivery systems.

PubMed

Içten, Elçin; Purohit, Hitesh S; Wallace, Chelsey; Giridhar, Arun; Taylor, Lynne S; Nagy, Zoltan K; Reklaitis, Gintaras V

2017-05-30

The improvements in healthcare systems and the advent of the precision medicine initiative have created the need to develop more innovative manufacturing methods for the delivery and production of individualized dosing and personalized treatments. In accordance with the changes observed in healthcare systems towards more innovative therapies, this paper presents dropwise additive manufacturing of pharmaceutical products (DAMPP) for small scale, distributed manufacturing of individualized dosing as an alternative to conventional manufacturing methods A dropwise additive manufacturing process for amorphous and self-emulsifying drug delivery systems is reported, which utilizes drop-on-demand printing technology for automated and controlled deposition of melt-based formulations onto inert tablets. The advantages of drop on demand technology include reproducible production of droplets with adjustable sizing and high placement accuracy, which enable production of individualized dosing even for low dose and high potency drugs. Flexible use of different formulations, such as lipid-based formulations, allows enhancement of the solubility of poorly water soluble and highly lipophilic drugs with DAMPP. Here, DAMPP is used to produce solid oral dosage forms from melts of an active pharmaceutical ingredient and a surfactant. The dosage forms are analyzed to show the amorphous nature, self-emulsifying drug delivery system characteristics and dissolution behavior of these formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of liposomal and microemulsion formulations for transdermal delivery of clonazepam: effect of randomly methylated β-cyclodextrin.

PubMed

Mura, Paola; Bragagni, Marco; Mennini, Natascia; Cirri, Marzia; Maestrelli, Francesca

2014-11-20

Transdermal administration of clonazepam, a poorly water-soluble benzodiazepine, is an interesting strategy for overcoming the drawbacks of its oral administration. With this aim, two nano-carrier formulations, based on ultra-deformable liposomes and microemulsions, have been developed to favour clonazepam transdermal delivery. Considering the solubilizing power of methyl-βcyclodextrin (Me-βCD) toward clonazepam and its potential positive influence on transdermal drug delivery, the effect of its addition to these formulations was investigated. Artificial lipophilic membranes simulating the skin allowed a rapid evaluation of the drug permeation properties from the systems, compared with those from an aqueous drug suspension, with or without Me-βCD. The best formulations were further characterized by permeation through excised rabbit ear skin. All the formulations increased drug permeability, ranging from 2-fold (liposomes without Me-βCD), up to over 4-fold (microemulsions containing Me-βCD). The different formulations allowed for pointing out different possible permeation enhancing mechanisms of Me-βCD: increase in drug solubility and thermodynamic activity in the vehicle, when added to the drug aqueous suspension; interactions with the vesicle bilayer, in case of liposomal formulations; interactions with the skin membrane lipids, as evidenced in experiments with excised rabbit ear for microemulsions containing Me-βCD, that were then selected for further in vivo studies. Copyright © 2014. Published by Elsevier B.V.

Minimal-length Synthetic shRNAs Formulated with Lipid Nanoparticles are Potent Inhibitors of Hepatitis C Virus IRES-linked Gene Expression in Mice

PubMed Central

Dallas, Anne; Ilves, Heini; Shorenstein, Joshua; Judge, Adam; Spitler, Ryan; Contag, Christopher; Wong, Suet Ping; Harbottle, Richard P; MacLachlan, Ian; Johnston, Brian H

2013-01-01

We previously identified short synthetic shRNAs (sshRNAs) that target a conserved hepatitis C virus (HCV) sequence within the internal ribosome entry site (IRES) of HCV and potently inhibit HCV IRES-linked gene expression. To assess in vivo liver delivery and activity, the HCV-directed sshRNA SG220 was formulated into lipid nanoparticles (LNP) and injected i.v. into mice whose livers supported stable HCV IRES-luciferase expression from a liver-specific promoter. After a single injection, RNase protection assays for the sshRNA and 3H labeling of a lipid component of the nanoparticles showed efficient liver uptake of both components and long-lasting survival of a significant fraction of the sshRNA in the liver. In vivo imaging showed a dose-dependent inhibition of luciferase expression (>90% 1 day after injection of 2.5 mg/kg sshRNA) with t1/2 for recovery of about 3 weeks. These results demonstrate the ability of moderate levels of i.v.-injected, LNP-formulated sshRNAs to be taken up by liver hepatocytes at a level sufficient to substantially suppress gene expression. Suppression is rapid and durable, suggesting that sshRNAs may have promise as therapeutic agents for liver indications. PMID:24045712

Lipid nanoparticles for cancer therapy: state of the art and future prospects.

PubMed

Lasa-Saracibar, Beatriz; Estella-Hermoso de Mendoza, Ander; Guada, Melissa; Dios-Vieitez, Carmen; Blanco-Prieto, María J

2012-10-01

Cancer is a leading cause of death worldwide and it is estimated that deaths from this disease will rise to over 11 million in 2030. Most cases of cancer can be cured with surgery, radiotherapy or chemotherapy if they are detected at an early stage. However, current cancer therapies are commonly associated with undesirable side effects, as most chemotherapy treatments are cytotoxic and present poor tumor targeting. Lipid nanoparticles (LN) are one of the most promising options in this field. LN are made up of biodegradable generally recognized as safe (GRAS) lipids, their formulation includes different techniques, and most are easily scalable to industrial manufacture. LN overcome the limitations imposed by the need for intravenous administration, as they are mainly absorbed via the lymphatic system when they are administered orally, which improves drug bioavailability. Furthermore, depending on their composition, LN present the ability to cross the blood-brain barrier, thus opening up the possibility of targeting brain tumors. The drawbacks of chemotherapeutic agents make it necessary to invest in research to find safer and more effective therapies. Nanotechnology has opened the door to new therapeutic options through the design of formulations that include a wide range of materials and formulations at the nanometer range, which improve drug efficacy through direct or indirect tumor targeting, increased bioavailability and diminished toxicity.

Nanostructured Lipid Carriers Loaded with Baicalin: An Efficient Carrier for Enhanced Antidiabetic Effects

PubMed Central

Shi, Feng; Wei, Zheng; Zhao, Yingying; Xu, Ximing

2016-01-01

Context: Recent studies have demonstrated that baicalin has antihyperglycemic effects by inhibiting lipid peroxidation. Baicalin is low hydrophilic and poorly absorbed after oral administration. Thus, a suitable formulation is highly desired to overcome the disadvantages of baicalin. Objective: The objective of this work was to prepare baicalin-loaded nanostructured lipid carriers (B-NLCs) for enhanced antidiabetic effects. Materials and Methods: B-NLCs were prepared by high-pressure homogenization method using Precirol as the solid lipid and Miglyol as the liquid lipid. The properties of the NLCs, such as particle size, zeta potential (ZP), and drug encapsulation efficiency (EE), were investigated. The morphology of NLCs was observed by transmission electron microscopy. In addition, drug release and antidiabetic activity were also studied. Results: The results revealed that B-NLCs particles were uniformly in the nanosize range and of spherical morphology with a mean size of 92 ± 3.1 nm, a ZP of −31.35 ± 3.08 mV, and an EE of 85.29 ± 3.42%. Baicalin was released from NLCs in a sustained manner. In addition, B-NLCs showed a significantly higher antidiabetic efficacy compared with baicalin. Conclusion: B-NLCs described in this study are well-suited for the delivery of baicalin. SUMMARY Currently, herbal medicines have attracted increasing attention as a complementary approach for type 2 diabetesBaicalin has antihyperglycemic effects by inhibiting lipid peroxidationA suitable formulation is highly desired to overcome the disadvantages (poor solubility and low bioavailability) of baicalinNanostructured lipid carriers could enhance the antidiabetic effects of baicalin. Abbreviations used: B-NLCs: Baicalin-Loaded Nanostructured Lipid Carriers, B-SUS: Baicalin Water Suspension, EE: Encapsulation Efficiency, FBG: Fasting Blood Glucose, HbAlc: Glycosylated Hemoglobin, HPLC: High-performance Liquid Chromatography; NLCs: Nanostructured Lipid Carriers, PI: Polydispersity Index, SD: Sprague-Dawley, SLNs: Solid lipid nanoparticles, STZ: Streptozotocin, TC: Total cholesterol, TEM: Transmission Electron Microscope, TG: Total Triglyceride, ZP: Zeta Potential. PMID:27601850

Nanostructured Lipid Carriers Loaded with Baicalin: An Efficient Carrier for Enhanced Antidiabetic Effects.

PubMed

Shi, Feng; Wei, Zheng; Zhao, Yingying; Xu, Ximing

2016-01-01

Recent studies have demonstrated that baicalin has antihyperglycemic effects by inhibiting lipid peroxidation. Baicalin is low hydrophilic and poorly absorbed after oral administration. Thus, a suitable formulation is highly desired to overcome the disadvantages of baicalin. The objective of this work was to prepare baicalin-loaded nanostructured lipid carriers (B-NLCs) for enhanced antidiabetic effects. B-NLCs were prepared by high-pressure homogenization method using Precirol as the solid lipid and Miglyol as the liquid lipid. The properties of the NLCs, such as particle size, zeta potential (ZP), and drug encapsulation efficiency (EE), were investigated. The morphology of NLCs was observed by transmission electron microscopy. In addition, drug release and antidiabetic activity were also studied. The results revealed that B-NLCs particles were uniformly in the nanosize range and of spherical morphology with a mean size of 92 ± 3.1 nm, a ZP of -31.35 ± 3.08 mV, and an EE of 85.29 ± 3.42%. Baicalin was released from NLCs in a sustained manner. In addition, B-NLCs showed a significantly higher antidiabetic efficacy compared with baicalin. B-NLCs described in this study are well-suited for the delivery of baicalin. Currently, herbal medicines have attracted increasing attention as a complementary approach for type 2 diabetesBaicalin has antihyperglycemic effects by inhibiting lipid peroxidationA suitable formulation is highly desired to overcome the disadvantages (poor solubility and low bioavailability) of baicalinNanostructured lipid carriers could enhance the antidiabetic effects of baicalin. Abbreviations used: B-NLCs: Baicalin-Loaded Nanostructured Lipid Carriers, B-SUS: Baicalin Water Suspension, EE: Encapsulation Efficiency, FBG: Fasting Blood Glucose, HbAlc: Glycosylated Hemoglobin, HPLC: High-performance Liquid Chromatography; NLCs: Nanostructured Lipid Carriers, PI: Polydispersity Index, SD: Sprague-Dawley, SLNs: Solid lipid nanoparticles, STZ: Streptozotocin, TC: Total cholesterol, TEM: Transmission Electron Microscope, TG: Total Triglyceride, ZP: Zeta Potential.

Alpha-lipoic acid-stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study.

PubMed

Dhaundiyal, Ankit; Jena, Sunil K; Samal, Sanjaya K; Sonvane, Bhavin; Chand, Mahesh; Sangamwar, Abhay T

2016-12-01

This study was designed to demonstrate the potential of novel α-lipoic acid-stearylamine (ALA-SA) conjugate-based solid lipid nanoparticles in modulating the pharmacokinetics and hepatotoxicity of tamoxifen (TMX). α-lipoic acid-stearylamine bioconjugate was synthesized via carbodiimide chemistry and used as a lipid moiety for the generation of TMX-loaded solid lipid nanoparticles (TMX-SLNs). TMX-SLNs were prepared by solvent emulsification-diffusion method and optimized for maximum drug loading using rotatable central composite design. The optimized TMX-SLNs were stabilized using 10% w/w trehalose as cryoprotectant. In addition, pharmacokinetics and hepatotoxicity of freeze-dried TMX-SLNs were also evaluated in Sprague Dawley rats. Initial characterization with transmission electron microscopy revealed spherical morphology with smooth surface having an average particle size of 261.08 ± 2.13 nm. The observed entrapment efficiency was 40.73 ± 2.83%. In-vitro release study showed TMX release was slow and pH dependent. Pharmacokinetic study revealed a 1.59-fold increase in relative bioavailability as compared to TMX suspension. A decrease in hepatotoxicity of TMX is evidenced by the histopathological evaluation of liver tissues. α-lipoic acid-stearylamine conjugate-based SLNs have a great potential in enhancing the oral bioavailability of poorly soluble drugs like TMX. Moreover, this ALA-SA nanoparticulate system could be of significant value in long-term anticancer therapy with least side effects. © 2016 Royal Pharmaceutical Society.

Core hydrophobicity tuning of a self-assembled particle results in efficient lipid reduction and favorable organ distribution.

PubMed

Banik, Bhabatosh; Wen, Ru; Marrache, Sean; Kumar, Anil; Kolishetti, Nagesh; Howerth, Elizabeth W; Dhar, Shanta

2017-12-21

Atherosclerosis, the deadliest disease in the United States, arises due to the build up of plaques in the arteries as a result of excessive cholesterol deposition and an impaired cholesterol removal process. High density lipoproteins (HDL), popularly known as "good cholesterol", are naturally occurring nano-sized particles that, along with apolipoproteins, are deployed to maintain cholesterol homeostasis in the body. Both cholesterol efflux, from the fat-laden macrophages in the arteries, and intracellular lipid transport, to deliver cholesterol to the mitochondria of liver cells for metabolism, hold key responsibilities to maintain healthy lipid levels inside the body. We designed a library of nine mitochondria targeted polymer-lipid hybrid nanoparticles (NPs), comprised of completely synthetic yet biodegradable components, that are capable of performing HDL-like functions. Using this library, we optimized a superior mitochondria targeted NP candidate, which can show favourable organ distribution, therapeutic potential, and non-toxic properties. Two targeted NP formulations with optimum NP size, zeta potential, and cholesterol binding and release properties were identified. Lipid reduction and anti-oxidative properties of these two NPs demonstrated cholesterol removal ability. In vivo therapeutic evaluation of the targeted-NP formulations in apolipoprotein E knockout (apoE - / - ) mice indicated lipid reduction and anti-inflammatory properties compared to non-targeted NPs. This synthetic targeted NP with potential abilities to participate in both extra- and intracellular cholesterol transport might potentiate therapeutic interventions for heart diseases.

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for application of ascorbyl palmitate.

PubMed

Uner, M; Wissing, S A; Yener, G; Müller, R H

2005-08-01

The aim of this study was to improve the chemical stability of ascorbyl palmitate (AP) in a colloidal lipid carrier for its topical use. For this purpose, AP-loaded solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and for comparison, a nanoemulsion (NE) were prepared employing the high pressure homogenization technique and stored at room temperature (RT), 4 degrees C and 40 degrees C. During 3 months, physical stability of these formulations compared to placebo formulations which were prepared by the same production method, was studied including recrystallization behaviour of the lipid with differential scanning calorimetry (DSC), particle size distribution and storage stability with photon correlation spectroscopy (PCS) and laser diffractometry (LD). After evaluating data indicating excellent physical stability, AP-loaded SLN, NLC and NE were incorporated into a hydrogel by the same production method as the next step. Degradation of AP by HPLC and physical stability in the same manner were investigated at the same storage temperatures during 3 months. As a result, AP was found most stable in both the NLC and SLN stored at 4 degrees C (p > 0.05) indicating the importance of storage temperature. Nondegraded AP content in NLC, SLN and NE was found to be 71.1% +/- 1.4, 67.6% +/- 2.9 and 55.2% +/- 0.3 after 3 months, respectively. Highest degradation was observed with NE at all the storage temperatures indicating even importance of the carrier structure.

Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come.

PubMed

Yingchoncharoen, Phatsapong; Kalinowski, Danuta S; Richardson, Des R

2016-07-01

Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number of cytotoxic chemotherapeutics are highly hydrophobic, which limits their utility in cancer therapy. Finally, many chemotherapeutic agents exhibit short half-lives that curtail their efficacy. As a result of these deficiencies, many current treatments lead to side effects, noncompliance, and patient inconvenience due to difficulties in administration. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems known commonly as nanoparticles. Among these delivery systems, lipid-based nanoparticles, particularly liposomes, have shown to be quite effective at exhibiting the ability to: 1) improve the selectivity of cancer chemotherapeutic agents; 2) lower the cytotoxicity of anticancer drugs to normal tissues, and thus, reduce their toxic side effects; 3) increase the solubility of hydrophobic drugs; and 4) offer a prolonged and controlled release of agents. This review will discuss the current state of lipid-based nanoparticle research, including the development of liposomes for cancer therapy, different strategies for tumor targeting, liposomal formulation of various anticancer drugs that are commercially available, recent progress in liposome technology for the treatment of cancer, and the next generation of lipid-based nanoparticles. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

The Addition of Medium-Chain Triglycerides to a Purified Fish Oil Based Diet Alters Inflammatory Profiles in Mice

PubMed Central

Carlson, SJ; Nandivada, P; Chang, MI; Mitchell, PD; O’Loughlin, A; Cowan, E; Gura, KM; Nose, V; Bistrian, B; Puder, M

2014-01-01

Objective Parenteral nutrition associated liver disease (PNALD) is a deadly complication of long term parenteral nutrition (PN) use in infants. Fish oil-based lipid emulsion has been shown in recent years to effectively treat PNALD. Alternative fat sources free of essential fatty acids have recently been investigated for health benefits related to decreased inflammatory response. We hypothesized that the addition of medium-chain triglycerides (MCT) to a purified fish oil-based diet would decrease the response to inflammatory challenge in mice, while allowing for sufficient growth and development. Materials/Methods Six groups of ten adult male C57/Bl6 mice were pair-fed different dietary treatments for a period of twelve weeks, varying only in fat source (percent calories by weight): 10.84% soybean oil (SOY), 10% coconut oil (HCO), 10% medium-chain triglycerides (MCT), 3% purified fish oil (PFO), 3% purified fish oil with 3% medium-chain triglycerides (50:50 MCT:PFO) and 3% purified fish oil with 7.59% medium-chain triglycerides (70:30 MCT:PFO). An endotoxin challenge was administered to half of the animals in each group at the completion of dietary treatment. Results All groups demonstrated normal growth throughout the study period. Groups fed MCT and HCO diets demonstrated biochemical essential fatty acid deficiency and decreased IL-6 and TNF-α response to endotoxin challenge. Groups containing PFO had increased inflammatory response to endotoxin challenge, and the addition of MCT to PFO mitigated this inflammatory response. Conclusion These results suggest that the addition of MCT to PFO formulations may decrease the host response to inflammatory challenge, which may pose potential for optimized PN formulations. Inclusion of MCT in lipid emulsions given with PN formulations may be of use in therapeutic interventions for disease states resulting from chronic inflammation. PMID:25458829

The addition of medium-chain triglycerides to a purified fish oil-based diet alters inflammatory profiles in mice.

PubMed

Carlson, Sarah J; Nandivada, Prathima; Chang, Melissa I; Mitchell, Paul D; O'Loughlin, Alison; Cowan, Eileen; Gura, Kathleen M; Nose, Vania; Bistrian, Bruce R; Puder, Mark

2015-02-01

Parenteral nutrition associated liver disease (PNALD) is a deadly complication of long term parenteral nutrition (PN) use in infants. Fish oil-based lipid emulsion has been shown in recent years to effectively treat PNALD. Alternative fat sources free of essential fatty acids have recently been investigated for health benefits related to decreased inflammatory response. We hypothesized that the addition of medium-chain triglycerides (MCT) to a purified fish oil-based diet would decrease the response to inflammatory challenge in mice, while allowing for sufficient growth and development. Six groups of ten adult male C57/Bl6 mice were pair-fed different dietary treatments for a period of twelve weeks, varying only in fat source (percent calories by weight): 10.84% soybean oil (SOY), 10% coconut oil (HCO), 10% medium-chain triglycerides (MCT), 3% purified fish oil (PFO), 3% purified fish oil with 3% medium-chain triglycerides (50:50 MCT:PFO) and 3% purified fish oil with 7.59% medium-chain triglycerides (70:30 MCT:PFO). An endotoxin challenge was administered to half of the animals in each group at the completion of dietary treatment. All groups demonstrated normal growth throughout the study period. Groups fed MCT and HCO diets demonstrated biochemical essential fatty acid deficiency and decreased IL-6 and TNF-α response to endotoxin challenge. Groups containing PFO had increased inflammatory response to endotoxin challenge, and the addition of MCT to PFO mitigated this inflammatory response. These results suggest that the addition of MCT to PFO formulations may decrease the host response to inflammatory challenge, which may pose potential for optimized PN formulations. Inclusion of MCT in lipid emulsions given with PN formulations may be of use in therapeutic interventions for disease states resulting from chronic inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

Formulation and evaluation of chitosan solid lipid nanoparticles of carbamazepine.

PubMed

Nair, Rahul; Kumar, Ashok C K; Priya, Vishnu K; Yadav, Chakrapani M; Raju, Prasanna Y

2012-06-13

The present work aims at preparing aqueous suspension of Solid lipid Nanoparticles containing Chitosan (CT) which is a biopolymer that exhibits a number of interesting properties which include controlled drug delivery. Carbamezapine (CBZ) is a lipophilic drug which shows it antiepileptic activity by inactivating sodium channels. The solid lipid Nanoparticles (SLN) of Chitosan-CBZ were prepared by using solvent injection method using ethanol as organic solvent. The prepared SLN formulations exhibited high encapsulation efficiency, high physical stability. The drug incorporated SLNs have demonstrated that the controlled release patterns of the drug for prolonged period. The prepared SLNs were characterized for surface morphology by SEM analysis, entrapment efficiency, zeta potential, FTIR, DSC and In-vitro diffusion studies. The hydrodynamic mean diameter and zeta potential were 168.7 ± 1.8 nm and -28.9 ± 2.0 mV for SLN-chitosan-CBZ respectively. Therefore chitosan-SLN can be good candidates to encapsulate CBZ and to increase its therapeutic efficacy in the treatment of Epilepsy.

Formulation and evaluation of chitosan solid lipid nanoparticles of carbamazepine

PubMed Central

2012-01-01

The present work aims at preparing aqueous suspension of Solid lipid Nanoparticles containing Chitosan (CT) which is a biopolymer that exhibits a number of interesting properties which include controlled drug delivery. Carbamezapine (CBZ) is a lipophilic drug which shows it antiepileptic activity by inactivating sodium channels. The solid lipid Nanoparticles (SLN) of Chitosan-CBZ were prepared by using solvent injection method using ethanol as organic solvent. The prepared SLN formulations exhibited high encapsulation efficiency, high physical stability. The drug incorporated SLNs have demonstrated that the controlled release patterns of the drug for prolonged period. The prepared SLNs were characterized for surface morphology by SEM analysis, entrapment efficiency, zeta potential, FTIR, DSC and In-vitro diffusion studies. The hydrodynamic mean diameter and zeta potential were 168.7 ±1.8 nm and −28.9 ±2.0 mV for SLN-chitosan-CBZ respectively. Therefore chitosan-SLN can be good candidates to encapsulate CBZ and to increase its therapeutic efficacy in the treatment of Epilepsy. PMID:22695222

Liposomal lipid and plasmid DNA delivery to B16/BL6 tumors after intraperitoneal administration of cationic liposome DNA aggregates.

PubMed

Reimer, D L; Kong, S; Monck, M; Wyles, J; Tam, P; Wasan, E K; Bally, M B

1999-05-01

The transfer of plasmid expression vectors to cells is essential for transfection after administration of lipid-based DNA formulations (lipoplexes). A murine i.p. B16/BL6 tumor model was used to characterize DNA delivery, liposomal lipid delivery, and gene transfer after regional (i.p.) administration of free plasmid DNA and DNA lipoplexes. DNA lipoplexes were prepared using cationic dioleoyldimethylammonium chloride/dioleoylphosphatidylethanolamine (50:50 mol ratio) liposomes mixed with plasmid DNA (1 microgram DNA/10 nmol lipid). The plasmid used contained the chloramphenicol acetyltransferase gene and chloramphenicol acetyltransferase expression (mU/g tumor) was measured to estimate transfection efficiency. Tumor-associated DNA and liposomal lipid levels were measured to estimate the efficiency of lipid-mediated DNA delivery to tumors. Plasmid DNA delivery was estimated using [3H]-labeled plasmid as a tracer, dot blot analysis, and/or Southern analysis. Liposomal lipid delivery was estimated using [14C]-dioleoylphosphatidylethanolamine as a liposomal lipid marker. Gene expression in the B16/BL6 tumors was highly variable, with values ranging from greater than 2,000 mU/g tumor to less than 100 mU/g tumor. There was a tendency to observe enhanced transfection in small (<250 mg) tumors. Approximately 18% of the injected dose of DNA was associated with these small tumors 2 h after i.p. administration. Southern analysis of extracted tumor DNA indicated that plasmid DNA associated with tumors was intact 24 h after administration. DNA and associated liposomal lipid are efficiently bound to tumors after regional administration; however, it is unclear whether delivery is sufficient to abet internalization and appropriate subcellular localization of the expression vector.

Form(ul)ation of adipocytes by lipids.

PubMed

Lapid, Kfir; Graff, Jonathan M

2017-07-03

Lipids have the potential to serve as bio-markers, which allow us to analyze and to identify cells under various experimental settings, and to serve as a clinical diagnostic tool. For example, diagnosis according to specific lipids that are associated with diabetes and obesity. The rapid development of mass-spectrometry techniques enables identification and profiling of multiple types of lipid species. Together, lipid profiling and data interpretation forge the new field of lipidomics. Lipidomics can be used to characterize physiologic and pathophysiological processes in adipocytes, since lipid metabolism is at the core of adipocyte physiology and energy homeostasis. A significant bulk of lipids are stored in adipocytes, which can be released and used to produce energy, used to build membranes, or used as signaling molecules that regulate metabolism. In this review, we discuss how exhaust of lipidomes can be used to study adipocyte differentiation, physiology and pathophysiology.

Benzocaine loaded solid lipid nanoparticles: Formulation design, in vitro and in vivo evaluation of local anesthetic effect.

PubMed

Basha, Mona; Abd El-Alim, Sameh Hosam; Kassem, Ahmed Alaa; El Awdan, Sally; Awad, Gamal

2015-01-01

The aim of the present work is the development and evaluation of solid lipid nanoparticles (SLNs) as carrier system for topical delivery of benzocaine (BZC) improving its local anesthesia aiming to produce a fast acting and long lasting topical formulation. BZC loaded SLNs were prepared using a full factorial design to study the influence of the type of polyoxyethylene sorbitan ester surfactants as well as their concentration as independent variables on the particle size, entrapment efficacy and zeta potential selected as dependent variables. Design of experiment (DOE) and the analysis of variance (ANOVA) were conducted to assess the optimization of the developed formulations. The results indicated that the fatty acid chain length of tested surfactants and their concentration had a significant effect on the studied responses. The optimized formulations were spherical in shape of mean particle diameters<350 nm with negatively charged surface <-20mV. Particles were characterized using differential scanning calorimetry and X-ray powder diffraction confirming the amorphous nature and the uniformity of drug inclusion in the lipid matrix. Optimized BZC-SLNs were incorporated into hydrogels characterized by a pseudoplastic non-Newtonian behavior. In vitro release study revealed an apparently biphasic release process with sustained release profile following Higuchi kinetics. BZC loaded SLNs hydrogels showed more potent anesthetic effect compared to BZC hydrogel evaluated using tail-flick analgesimeter, confirming significant improvement in both the intensity and duration of anesthetic effect. The above results proved that SLNs represent good candidates to encapsulate BZC improving its therapeutic efficacy for the topical treatment of pain.

Nutritional Profile and Chemical Stability of Pasta Fortified with Tilapia (Oreochromis niloticus) Flour

PubMed Central

Monteiro, Maria Lúcia G.; Mársico, Eliane T.; Soares, Manoel S.; Magalhães, Amanda O.; Canto, Anna Carolina V. C. S.; Costa-Lima, Bruno R. C.; Alvares, Thiago S.; Conte, Carlos A.

2016-01-01

Physicochemical parameters of pasta enriched with tilapia (Oreochromis niloticus) flour were investigated. Five formulations were prepared with different concentrations of tilapia flour as partial substitute of wheat flour: pasta without tilapia flour (PTF0%), pasta with 6% (PTF6%), 12% (PTF12%), 17% (PTF17%), and 23% (PTF23%) of tilapia flour. The formulations were assessed for proximate composition, fatty acid and amino acid profile on day 1 whereas, instrumental color parameters (L*, a* and b* values), pH, water activity (aw), and lipid and protein oxidation were evaluated on days 1, 7, 14, and 21 of storage at 25°C. Fortification with tilapia flour increased (p < 0.05) protein, lipid, ash, total essential amino acids, and total polyunsaturated fatty acids contents. In addition, supplementation of pasta with tilapia flour decreased (p < 0.05) lightness and water activity while redness, yellowness, pH values, and lipid oxidation were increased (p < 0.05) in a level-dependent manner. Nevertheless, all formulations were exhibited storage stability at 25°C. In general, protein oxidation was greater (p < 0.05) in the pasta containing 12%, 17%, and 23% of tilapia flour than their counterparts, and the storage promoted an increase (p < 0.05) on the carbonyl content in all formulations. Thus, pasta with 6% of tilapia flour has the potential to be a technological alternative to food industry for the nutritional enrichment of traditional pasta with negligible negative effects on the chemical stability of the final product during 21 days at 25°C. PMID:27973565

Nutritional Profile and Chemical Stability of Pasta Fortified with Tilapia (Oreochromis niloticus) Flour.

PubMed

Monteiro, Maria Lúcia G; Mársico, Eliane T; Soares, Manoel S; Magalhães, Amanda O; Canto, Anna Carolina V C S; Costa-Lima, Bruno R C; Alvares, Thiago S; Conte, Carlos A

2016-01-01

Physicochemical parameters of pasta enriched with tilapia (Oreochromis niloticus) flour were investigated. Five formulations were prepared with different concentrations of tilapia flour as partial substitute of wheat flour: pasta without tilapia flour (PTF0%), pasta with 6% (PTF6%), 12% (PTF12%), 17% (PTF17%), and 23% (PTF23%) of tilapia flour. The formulations were assessed for proximate composition, fatty acid and amino acid profile on day 1 whereas, instrumental color parameters (L*, a* and b* values), pH, water activity (aw), and lipid and protein oxidation were evaluated on days 1, 7, 14, and 21 of storage at 25°C. Fortification with tilapia flour increased (p < 0.05) protein, lipid, ash, total essential amino acids, and total polyunsaturated fatty acids contents. In addition, supplementation of pasta with tilapia flour decreased (p < 0.05) lightness and water activity while redness, yellowness, pH values, and lipid oxidation were increased (p < 0.05) in a level-dependent manner. Nevertheless, all formulations were exhibited storage stability at 25°C. In general, protein oxidation was greater (p < 0.05) in the pasta containing 12%, 17%, and 23% of tilapia flour than their counterparts, and the storage promoted an increase (p < 0.05) on the carbonyl content in all formulations. Thus, pasta with 6% of tilapia flour has the potential to be a technological alternative to food industry for the nutritional enrichment of traditional pasta with negligible negative effects on the chemical stability of the final product during 21 days at 25°C.

Structural characterization of a new lipid/DNA complex showing a selective transfection efficiency in ovarian cancer cells

NASA Astrophysics Data System (ADS)

Caracciolo, G.; Pozzi, D.; Caminiti, R.; Congiu Castellano, A.

2003-04-01

We investigated, for the first time, by using Energy Dispersive X-ray Diffraction, the structure of a new ternary cationic liposome formulated with dioleoyl trimethylammonium propane (DOTAP), 1,2-dioleoyl-3-phosphatidylethanolamine (DOPE) and cholesterol (Chol) (DDC) which has been recently found to have a selective high gene transfer ability in ovarian cancer cells. Our structural results provide a further experimental support to the widely accepted statement that there is not a simple and direct correlation between structure and transfection efficiency and that the factors controlling cationic lipid/DNA (CL-DNA) complexes-mediated gene transfer depend not only on the formulations of the cationic liposomes and their thermodynamic phase, but also significantly on the cell properties.

Solid-State Characterization of Novel Propylene Glycol Ester Solvates Isolated from Lipid Formulations.

PubMed

Chakravarty, Paroma; Kothari, Sanjeev; Deese, Alan; Lubach, Joseph W

2015-07-06

The purpose of this study was to identify and characterize precipitates obtained from a liquid formulation of GNE068.HCl, a Genentech developmental compound, and lipophilic excipients, such as propylene glycol monocaprylate, and monolaurate. Precipitates were characterized using powder X-ray diffractometry (PXRD), differential scanning calorimetry, thermogravimetry, microscopy, nuclear magnetic resonance spectroscopy (NMR; solution and solid-state) and water sorption analysis. PXRD and NMR revealed the precipitates to be crystalline solvates of propylene glycol esters. The solvates (capryolate and lauroglycolate) were isomorphic and stable up to 70 °C, beyond which melting of the lattice occurred with subsequent dissolution of the active ingredient in the melt (microscopy and variable temperature PXRD). They were found to be mechanically stable (no change in PXRD pattern upon compression) and were nonhygroscopic up to ∼70% RH (25 °C). Our results highlight the outcome of inadvertent drug-excipient interactions in two separate lipid solution formulations with good solid-state properties and, thus, potential for further development.

Buparvaquone Nanostructured Lipid Carrier: Development of an Affordable Delivery System for the Treatment of Leishmaniases.

PubMed

Monteiro, Lis Marie; Löbenberg, Raimar; Cotrim, Paulo Cesar; Barros de Araujo, Gabriel Lima; Bou-Chacra, Nádia

2017-01-01

Buparvaquone (BPQ), a veterinary drug, was formulated as nanostructured lipid carriers (NLC) for leishmaniases treatment. The formulation design addressed poor water solubility of BPQ and lack of human drug delivery system. The DSC/TG and microscopy methods were used for solid lipids screening. Softisan® 154 showed highest BPQ solubility in both methods. The BPQ solubility in liquid lipids using HPLC revealed Miglyol® 812 as the best option. Response surface methodology (RSM) was used to identify the optimal Softisan154 : Miglyol 812 ratios (7 : 10 to 2 : 1) and Kolliphor® P188 and Tween® 80 concentration (>3.0% w/w) aiming for z -average in the range of 100-300 nm for macrophage delivery. The NLC obtained by high-pressure homogenization showed low z -averages (<350 nm), polydispersity (<0.3), and encapsulation efficiency close to 100%. DSC/TG and microscopy in combination proved to be a powerful tool to select the solid lipid. The relationship among the variables, demonstrated by a linear mathematical model using RSM, allowed generating a design space. This design space showed the limits in which changes in the variables influenced the z -average. Therefore, these drug delivery systems have the potential to improve the availability of affordable medicines due to the low cost of raw materials, using well established, reliable, and feasible scale-up technology.

Sucrose ester stabilized solid lipid nanoparticles and nanostructured lipid carriers. II. Evaluation of the imidazole antifungal drug-loaded nanoparticle dispersions and their gel formulations.

PubMed

Das, Surajit; Ng, Wai Kiong; Tan, Reginald B H

2014-03-14

This study focused on: (i) feasibility of the previously developed sucrose ester stabilized SLNs and NLCs to encapsulate different imidazole antifungal drugs and (ii) preparation and evaluation of topical gel formulations of those SLNs and NLCs. Three imidazole antifungal drugs; clotrimazole, ketoconazole and climbazole were selected for this study. The results suggested that size, size distribution and drug encapsulation efficiency depend on the drug molecule and type of nanoparticles (SLN/NLC). The drug release experiment always showed faster drug release from NLCs than SLNs when the same drug molecule was loaded in both nanoparticles. However, drug release rate from both SLNs and NLCs followed the order of climbazole > ketoconazole > clotrimazole. NLCs demonstrated better physicochemical stability than SLNs in the case of all drugs. The drug release rate from ketoconazole- and clotrimazole-loaded SLNs became faster after three months than a fresh formulation. There was no significant change in drug release rate from climbazole-loaded SLNs and all drug-loaded NLCs. Gel formulations of SLNs and NLCs were prepared using polycarbophil polymer. Continuous flow measurements demonstrated non-Newtonian flow with shear-thinning behavior and thixotropy. Oscillation measurements depicted viscoelasticity of the gel formulations. Similar to nanoparticle dispersion, drug release rate from SLN- and NLC-gel was in the order of climbazole > ketoconazole > clotrimazole. However, significantly slower drug release was noticed from all gel formulations than their nanoparticle counterparts. Unlike nanoparticle dispersions, no significant difference in drug release from gel formulations containing SLNs and NLCs was observed for each drug. This study concludes that gel formulation of imidazole drug-loaded SLNs and NLCs can be used for sustained/prolonged topical delivery of the drugs.

Development of amino acid substituted gemini surfactant-based mucoadhesive gene delivery systems for potential use as noninvasive vaginal genetic vaccination.

PubMed

Singh, Jagbir; Michel, Deborah; Getson, Heather M; Chitanda, Jackson M; Verrall, Ronald E; Badea, Ildiko

2015-02-01

Recently, we synthesized amino acid- and peptide-substituted gemini surfactants, 'biolipids' that exhibited high transfection efficiency in vitro. In this study, we developed these plasmid DNA and gemini surfactant lipid particles for noninvasive administration in vaginal cavity. Novel formulations of these gene delivery systems were prepared with poloxamer 407 to induce in situ gelling of the formulation and diethylene glycol monoethyl ether to improve their penetration across mucosal tissue. Poloxamer at 16% w/v concentration in diethylene glycol monoethyl ether aqueous solution produced dispersions that gelled near body temperature and had a high yield value, preventing leakage of the formulation from the vaginal cavity. Intravaginal administration in rabbits showed that the glycyl-lysine-substituted gemini surfactant led to a higher gene expression compared with the parent unsubstituted gemini surfactant. This provides a proof-of-concept that amino acid substituted gemini surfactants can be used as noninvasive mucosal (vaginal) gene delivery systems to treat diseases associated with mucosal epithelia.

Solid lipid nanoparticles for delivery of Calendula officinalis extract.

PubMed

Arana, Lide; Salado, Clarisa; Vega, Sandra; Aizpurua-Olaizola, Oier; de la Arada, Igor; Suarez, Tatiana; Usobiaga, Aresatz; Arrondo, José Luis R; Alonso, Alicia; Goñi, Félix M; Alkorta, Itziar

2015-11-01

Solid lipid nanoparticles (SLN) composed of long-chain fatty acids (palmitic acid, stearic acid or arachidic acid), Epikuron 200 (purified phosphatidylcholine), and bile salts (cholate, taurocholate or taurodeoxycholate) have been prepared by dilution of a microemulsion. A total of five different systems were prepared, and characterized by photon correlation spectroscopy, transmission electron microscopy, differential scanning calorimetry, and infrared spectroscopy. The SLN formulation showing optimal properties (lowest size and polydispersity index and highest zeta potential) was obtained with stearic acid and taurodeoxycholate as cosurfactant. This formulation was loaded with Calendula officinalis extract, a natural compound used on ophthalmic formulations given its anti-inflammatory, emollient, and wound repairing activity. Calendula-loaded SLN preparations were characterized in order to determine loading capacity and entrapment efficiency. In vitro cytotoxicity and wound healing efficacy of Calendula-loaded SLN compared to that of a free plant extract were evaluated on a conjunctival epithelium cell line WKD. Our results suggest that this SLN formulation is a safe and solvent-free Calendula extract delivery system which could provide a controlled therapeutic alternative for reducing disease-related symptoms and improving epithelium repair in ocular surface. Copyright © 2015 Elsevier B.V. All rights reserved.

Dorzolamide Loaded Niosomal Vesicles: Comparison of Passive and Remote Loading Methods.

PubMed

Hashemi Dehaghi, Mohadeseh; Haeri, Azadeh; Keshvari, Hamid; Abbasian, Zahra; Dadashzadeh, Simin

2017-01-01

Glaucoma is a common progressive eye disorder and the treatment strategies will benefit from nanoparticulate delivery systems with high drug loading and sustained delivery of intraocular pressure lowering agents. Niosomes have been reported as a novel approach to improve drug low corneal penetration and bioavailability characteristics. Along with this, poor entrapment efficiency of hydrophilic drug in niosomal formulation remains as a major formulation challenge. Taking this perspective into consideration, dorzolamide niosomes were prepared employing two different loading methodologies (passive and remote loading methods) and the effects of various formulation variables (lipid to drug ratio, cholesterol percentage, drug concentration, freeze/thaw cycles, TPGS content, and external and internal buffer molarity and pH) on encapsulation efficiency were assessed. Encapsulation of dorzolamide within niosomes increased remarkably by the incorporation of higher cholesterol percentage as well as increasing the total lipid concentration. Remote loading method showed higher efficacy for drug entrapment compared to passive loading technique. Incorporation of TPGS in bilayer led to decrease in EE; however, retarded drug release rate. Scanning electron microscopy (SEM) studies confirmed homogeneous particle distribution, and spherical shape with smooth surface. In conclusion, the highest encapsulation can be obtained using phosphate gradient method and 50% cholesterol in Span 60 niosomal formulation.

Full replacement of menhaden fish meal protein by low-gossypol cottonseed flour protein in the diet of juvenile black sea bass Centropristis striata

USDA-ARS?s Scientific Manuscript database

Eight iso-nitrogeneous (46% crude protein) and iso-lipidic (14% crude lipid) diets were formulated and prepared to replace menhaden fish meal (FM) protein (59.5% CP) by low-gossypol glandless meal (GCSM) protein (50.4% CP), solvent-extracted cottonseed meal (SCSM) protein (53.8% protein) and high go...

Enhanced liposomal vaccine formulation and performance: simple physicochemical and immunological approaches.

PubMed

de Almeida Silva, Vanessa; Sayoko Takata, Célia; Sant'Anna, Osvaldo A; Carlos Lopes, Antônio; Soares de Araujo, Pedro; Helena Bueno da Costa, Maria

2006-01-01

The Dtxd (Diphtheria toxoid) was the first antigen encapsulated within liposomes, their adjuvant properties were discovered (their capacity to enhance the vaccine immunogenicity). The point here is not to propose a new method to prepare this lipossomal vaccine. The central idea is to give new dresses for old vaccines by using classical and well-established liposome preparation method changing only the encapsulation pH and the immunization protocol. The most appropriate method of Dtxd encapsulation within liposome was based on lipid film hydration in 100 mM citrate buffer, pH 4.0. This was accompanied by changes on protein hydrophobicity, observed by CD and fluorescence spectroscopies. Whenever the Dtxd exposed its hydrophobic residues at pH 4.0, it interacted better with the lipossomal (observed by electrophoretic mobility) film than when its hydrophobic residues were buried (pH 9.0). The Dtxd partition coefficient in Triton-X114 and the acrylamide fluorescence quenching were also pH dependent. Both were bigger at pH 4.0 than at pH 9.0. The relationship protein structure and lipid interaction was pH dependent and now it can be easily maximized to enhance encapsulation of antigens in vaccine development. Mice were primed with formulations containing 5 mug of Dtxd within liposomes prepared in pH 4.0 or 7.0 or 9.0. The boosters were done 38 or 138 days after the first immunization. The IgM produced by immediate response of all lipossomal formulations were higher than the control (free protein). The response patterns and the immune maturity were measured by IgG1 and IgG2a titrations. The IgG1 titers produced by both formulations at pH 4.0 and 7.0 were at least 22 higher than those produced by mice injected lipossomal formulation at pH 9.0. When the boosters were done, 138 days after priming the mice produced a IgG2a titer of 29 and the group that received the booster 30 days after priming produced a titer of 25. The strongest antibody production was the neutralizing antibody (245 higher than the control) produced by those mice injected with lipossomal formulation at pH 4.0 with the booster done 138 days after priming. The simple change on lipossomal pH formulation and timing of the booster enhanced both antibody production and selectivity.

Orodispersible tablets containing taste-masked solid lipid pellets with metformin hydrochloride: Influence of process parameters on tablet properties.

PubMed

Petrovick, Gustavo Freire; Kleinebudde, Peter; Breitkreutz, Jörg

2018-01-01

Compaction of multiparticulates into tablets, particularly into orodispersible tablets (ODTs), is challenging. The compression of pellets, made by solid lipid extrusion/spheronization processes, presents peculiar difficulties since solid lipids usually soften or melt at relatively low temperature ranges and due to applied mechanical forces. Until now, there are no reports in literature about the development of ODTs based on solid lipid pellets. To investigate the feasibility of producing such tablets, a design of experiment (DoE) approach was performed to elucidate the influence of compression force and amount of two co-processed excipients (Ludiflash ® and Parteck ® ODT) on properties of the tablets (friability, tensile strength, and disintegration time). ODTs (15 mm, flat-faced) with solid lipid pellets (250-1000 µm in diameter) containing 500 mg of metformin HCl, presenting immediate drug release profile and taste-masked properties, were targeted. During compression, a strong lamination of the tablets containing Parteck ® ODT was observed. This phenomenon was prominently observed when high compression forces (≥5 kN) and high excipient amounts (≥40%; w/w) were used. On the other hand, the DoE focused on tablets with Ludiflash ® showed better results regarding the production of ODTs. A positive influence of the compression force on the tensile strength and disintegration time of the tablets, regarding specifications of the Ph. Eur., was observed. The increase in the amount of this excipient resulted in fast disintegrating tablets, however, a negative influence on the tensile strength was noticed. After optimization of the parameters and formulation, based on the DoE results and considering the Ph. Eur. specifications for tablets, ODTs based on lipid pellets containing metformin HCl presenting immediate release profile (85% drug release in less than 30 min) and taste-masked properties (determined by an electronic tongue) were successfully obtained. Copyright © 2017 Elsevier B.V. All rights reserved.

Investigation of nano lipid vesicles of methotrexate for anti-rheumatoid activity

PubMed Central

Prabhu, Prabhakara; Shetty, Rakshith; Koland, Marina; Vijayanarayana, K; Vijayalakshmi, KK; Nairy, M Harish; Nisha, GS

2012-01-01

Background The purpose of this study was to formulate and evaluate nano lipid vesicles of methotrexate (MTX) for its anti-rheumatoid activity. Methods In this study the principle of both active as well as passive targeting using MTX-loaded stealth liposomes as per the magic gun approach was followed. Stealth liposomes of MTX were prepared by thin-film hydration method using a PEGylated phospholipid-like DSPE-MPEG 2000. Similarly, conventional liposomes were prepared using phospholipids like DPPC and DSPC. Conventional liposomes were coated with a hydrophilic biocompatible polymer like chitosan. They were investigated for their physical properties and in vitro release profile. Further, in vivo screening of the formulations for their anti-rheumatoid efficacy was carried out in rats. Rheumatoid arthritis was induced in male Wistar-Lewis rats using complete Freund’s adjuvant (1 mg/mL Mycobacterium tuberculosis, heat killed in mineral oil). Results It was found that chitosan coating of the conventional liposomes increased the physical stability of the liposomal suspension as well as its entrapment efficiency. The size of the unsonicated lipid vesicles was found to be in the range of 8–10 μm, and the sonicated lipid vesicles in the range of 210–260 nm, with good polydispersity index. Further, chitosan-coated conventional liposomes and the PEGylated liposomes released the drug for a prolonged period of time, compared to the uncoated conventional liposomes. It was found that there was a significant reduction in edema volume in the rat group administered with the test stealth liposomal formulations and chitosan-coated conventional liposomes (PEGylated and chitosan-coated conventional) compared to that of the control and standard (administered with free MTX) group of rats. PEGylated liposomes showed almost equal efficacy as that of the chitosan-coated conventional liposomes. Conclusion Lipid nano vesicles of MTX can be administered by intravenous route, whereby the drug selectively reaches the target site with reduced toxicity to other organs. PMID:22275833

Preparation and Characterization of Three Tilmicosin-loaded Lipid Nanoparticles: Physicochemical Properties and in-vitro Antibacterial Activities

PubMed Central

Al-Qushawi, Alwan; Rassouli, Ali; Atyabi, Fatemeh; Peighambari, Seyed Mostafa; Esfandyari-Manesh, Mehdi; Shams, Gholam Reza; Yazdani, Azam

2016-01-01

Tilmicosin (TLM) is an important antibiotic in veterinary medicine with low bioavailability and safety. This study aimed to formulate and evaluate physicochemical properties, storage stability after lyophilization, and antibacterial activity of three TLM-loaded lipid nanoparticles (TLM-LNPs) including solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid-core nanocapsules (LNCs). Physicochemical parameters such as particle size-mean diameter, polydispersity index, zeta potential, drug encapsulation efficiency (EE), loading capacity, and morphology of the formulations were evaluated and the effects of various cryoprotectants during lyophilization and storage for 8 weeks were also studied. The profiles of TLM release and the antibacterial activities of these TLM-LNPs suspensions (against Escherichia coli and Staphylococcus aureus) were tested in comparison with their corresponding powders. TLM-LNPs suspensions were in nano-scale range with mean diameters of 186.3 ± 1.5, 149.6 ± 3.0, and 85.0 ± 1.0nm, and also EE, 69.1, 86.3, and 94.3% for TLM- SLNs, TLM-NLCs, and TLM- LNCs respectively. TLM-LNCs gave the best results with significantly low particle size and high EE (p<0.05). Mannitol was the most effective cryoprotectant for lyophilization and storage of TLM-LNPs. The drug release profiles were biphasic and the release times were longer at pH 7.4 where TLM-NLCs and TLM-LNCs powders showed longer release times. In microbiological tests, S. aureus was about 4 times more sensitive than E. coli to TLM-LNPs with minimum inhibitory concentration ranges of 0.5-1.0 and 2-4 µg/mL respectively, and TLM-LNCs exhibited the best antibacterial activities. In conclusion, TLM-LNP formulations especially TLM-LNCs and TLM-NLCs are promising carriers for TLM with better drug encapsulation capacity, release behavior, and antibacterial activity. PMID:28261309

Effect of squalane on mebendazole-loaded Compritol® nanoparticles.

PubMed

Graves, Richard A; Ledet, Grace A; Nation, Cedric A; Pramar, Yashoda V; Bostanian, Levon A; Mandal, Tarun K

2015-01-01

The objective of this study is to develop nanostructured lipid formulations of Compritol for the delivery of mebendazole. The formulations were prepared with Compritol 888 ATO, squalane, and Pluronic F68. Nine batches with different amounts of modifier, squalane, and drug were prepared. The formulations were characterized by evaluating particle size, morphology, and zeta potential. The thermal properties of the formulations were analyzed by differential scanning calorimetry (DSC). The encapsulation efficiency of each formulation and the drug release rates from each formulation were quantified by UPLC. The particles were spherical and had median particle sizes between 300 and 600 nm (50th percentile). A linear relationship was observed between Compritol/squalane composition and the melting point of the mixture. The DSC scans of the formulations revealed some recrystallization of the drug from the formulations, and the amount of recrystallization correlated with the amount of squalane in the formulation. Approximately, 70% efficiency of encapsulation was observed in the formulations with 30% (w/w) squalane, and these formulations also had faster dissolution rates compared to the other formulations. Overall, the formulations with 30% squalane are the preferred formulation for future testing.

Solid lipid nanoparticles suspension versus commercial solutions for dermal delivery of minoxidil.

PubMed

Padois, Karine; Cantiéni, Céline; Bertholle, Valérie; Bardel, Claire; Pirot, Fabrice; Falson, Françoise

2011-09-15

Solid lipid nanoparticles have been reported as possible carrier for skin drug delivery. Solid lipid nanoparticles are produced from biocompatible and biodegradable lipids. Solid lipid nanoparticles made of semi-synthetic triglycerides stabilized with a mixture of polysorbate and sorbitan oleate were loaded with 5% of minoxidil. The prepared systems were characterized for particle size, pH and drug content. Ex vivo skin penetration studies were performed using Franz-type glass diffusion cells and pig ear skin. Ex vivo skin corrosion studies were realized with a method derived from the Corrositex(®) test. Solid lipid nanoparticles suspensions were compared to commercial solutions in terms of skin penetration and skin corrosion. Solid lipid nanoparticles suspensions have been shown as efficient as commercial solutions for skin penetration; and were non-corrosive while commercial solutions presented a corrosive potential. Solid lipid nanoparticles suspensions would constitute a promising formulation for hair loss treatment. Copyright © 2011 Elsevier B.V. All rights reserved.

Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo

PubMed Central

Feng, Lan; Wu, Huali; Ma, Ping; Mumper, Russell J; Benhabbour, S Rahima

2011-01-01

Three docetaxel (DX) lipid conjugates: 2′-lauroyl-docetaxel (C12-DX), 2′-stearoyl-docetaxel (C18-DX), and 2′-behenoyl-docetaxel (C22-DX) were synthesized to enhance drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The three conjugates showed ten-fold higher solubility in the liquid oil phase Miglyol 808 than DX. To further increase the drug entrapment efficiency in NPs, orthogonal design was performed. The optimized formulation was composed of Miglyol 808, Brij 78, and Vitamin E tocopheryl polyethylene glycol succinate (TPGS). The conjugates were successfully entrapped in the reduced-surfactant NPs with entrapment efficiencies of about 50%–60% as measured by gel permeation chromatography (GPC) at a final concentration of 0.5 mg/mL. All three conjugates showed 45% initial burst release in 100% mouse plasma. Whereas C12-DX showed another 40% release over the next 8 hours, C18-DX and C22-DX in NPs showed no additional release after the initial burst of drug. All conjugates showed significantly lower cytotoxicity than DX in human DU-145 prostate cancer cells. The half maximal inhibitory concentration values (IC50) of free conjugates and conjugate NPs were comparable except for C22-DX, which was nontoxic in the tested concentration range and showed only vehicle toxicity when entrapped in NPs. In vivo, the total area under the curve (AUC0–∞) values of all DX conjugate NPs were significantly greater than that of Taxotere, demonstrating prolonged retention of drug in the blood. The AUC0–∞ value of DX in Taxotere was 8.3-fold, 358.0-fold, and 454.5-fold lower than that of NP-formulated C12-DX, C18-DX, and C22-DX, respectively. The results of these studies strongly support the idea that the physical/chemical properties of DX conjugates may be fine-tuned to influence the affinity and retention of DX in oil-filled lipid NPs, which leads to very different pharmacokinetic profiles and blood exposure of an otherwise potent chemo-therapeutic agent. These studies and methodologies may allow for improved and more potent nanoparticle-based formulations. PMID:22072889

Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo.

PubMed

Feng, Lan; Wu, Huali; Ma, Ping; Mumper, Russell J; Benhabbour, S Rahima

2011-01-01

THREE DOCETAXEL (DX) LIPID CONJUGATES: 2'-lauroyl-docetaxel (C12-DX), 2'-stearoyl-docetaxel (C18-DX), and 2'-behenoyl-docetaxel (C22-DX) were synthesized to enhance drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The three conjugates showed ten-fold higher solubility in the liquid oil phase Miglyol 808 than DX. To further increase the drug entrapment efficiency in NPs, orthogonal design was performed. The optimized formulation was composed of Miglyol 808, Brij 78, and Vitamin E tocopheryl polyethylene glycol succinate (TPGS). The conjugates were successfully entrapped in the reduced-surfactant NPs with entrapment efficiencies of about 50%-60% as measured by gel permeation chromatography (GPC) at a final concentration of 0.5 mg/mL. All three conjugates showed 45% initial burst release in 100% mouse plasma. Whereas C12-DX showed another 40% release over the next 8 hours, C18-DX and C22-DX in NPs showed no additional release after the initial burst of drug. All conjugates showed significantly lower cytotoxicity than DX in human DU-145 prostate cancer cells. The half maximal inhibitory concentration values (IC(50)) of free conjugates and conjugate NPs were comparable except for C22-DX, which was nontoxic in the tested concentration range and showed only vehicle toxicity when entrapped in NPs. In vivo, the total area under the curve (AUC(0-∞)) values of all DX conjugate NPs were significantly greater than that of Taxotere, demonstrating prolonged retention of drug in the blood. The AUC(0-∞) value of DX in Taxotere was 8.3-fold, 358.0-fold, and 454.5-fold lower than that of NP-formulated C12-DX, C18-DX, and C22-DX, respectively. The results of these studies strongly support the idea that the physical/chemical properties of DX conjugates may be fine-tuned to influence the affinity and retention of DX in oil-filled lipid NPs, which leads to very different pharmacokinetic profiles and blood exposure of an otherwise potent chemo-therapeutic agent. These studies and methodologies may allow for improved and more potent nanoparticle-based formulations.

Stability and compatibility assessment techniques for total parenteral nutrition admixtures: setting the bar according to pharmacopeial standards.

PubMed

Driscoll, David F

2005-05-01

The stability and compatibility of total parenteral nutrition mixtures compounded for patients requiring nutritional support is paramount to their safety on intravenous infusion. The most significant pharmaceutical issues associated with mixing total parenteral nutrition formulations affecting their safety involve the stability of lipid-injectable emulsions and the compatibility of calcium and phosphate salts. Methods of analysis for stability and compatibility have varied, and the assessments have mostly been largely qualitative. Although pharmacopeial standards have been primarily applicable to pharmaceutical manufacturers, recent efforts by the United States Pharmacopeia have been directed at standardizing pharmacy practices involved in the safe mixing of compounded sterile preparations. The adoption of chapter 797 entitled 'Pharmaceutical compounding - sterile preparations' on 1 January 2004 has had a dramatic impact on pharmacy practice in the United States. More recently, the United States Pharmacopeia has also proposed a new chapter 729 entitled 'Globule size distribution in lipid-injectable emulsions', setting specific limits on the sizes and concentrations of lipid droplets in the formulation, which may have implications for all-in-one mixtures. Finally, new efforts are under way to establish limits on the level of acceptable amounts of particulates intrinsically introduced by the manufacturer, and thus may have ramifications for particulates extrinsically introduced or initiated during compounding by the pharmacist. With careful monitoring and the development of appropriate pharmacopeial-based specifications that limit the size and concentration of large-diameter fat globules and eliminate the possibility of dibasic calcium phosphate precipitates, improved patient outcomes may be achieved.

Design and in vivo evaluation of solid lipid nanoparticulate systems of Olanzapine for acute phase schizophrenia treatment: Investigations on antipsychotic potential and adverse effects.

PubMed

Joseph, Emil; Reddi, Satish; Rinwa, Vibhu; Balwani, Garima; Saha, Ranendra

2017-06-15

The present paper discusses the design, characterization and in vivo evaluation of glyceryl monostearate nanoparticles of Olanzapine, an atypical antipsychotic drug for acute schizophrenia treatment, during which hospitalization is mandatory and adverse effects are at its peak. The solid lipid nanoparticulate system was obtained by emulsification-ultra sonication technique wherein three factors such as solid lipid content, concentration of surfactant and drug: solid lipid ratio were selected at three different levels in order to study their influence on significant characteristic responses such as particle size, encapsulation efficiency and drug content. A Box Behnken design with 17 runs involving whole factors at three levels was employed for the study. The optimized formulation was further coated with Polysorbate 80 in order to enhance its brain targeting potential through endocytosis transport process via blood brain barrier. The designed formulations were pre-clinically tested successfully in Wistar rat model for in vivo antipsychotic efficacy (apomorphine induced psychosis) and adverse effects (weight gain study for 28days). The results obtained indicated that solid lipid nanoparticles had very narrow size distribution (151.29±3.36nm) with very high encapsulation efficiency (74.51±1.75%). Morphological studies by SEM have shown that solid lipid nanoparticles were spherical in shape with smooth surface. Olanzapine-loaded nanoparticles prepared from solid lipid, extended the release of drug for 48h, as found by the in vitro release studies. The formulations also exhibited high redispersibility after freeze-drying and stability study results demonstrated good stability, with no significant change for a period of 6months. In vivo evaluation and adverse effects studies of Olanzapine-loaded nanoparticulate systems in animal model have demonstrated an improved therapeutic efficacy than pure Olanzapine. The antipsychotic effect of drug loaded nanoparticulate systems was maintained for 48h as compared to 8h antipsychotic action of pure Olanzapine solution. The weight gain studies for 28days demonstrated a significant inhibition in weight gain for Olanzapine-loaded nanoparticulate systems as compared to the pure Olanzapine. The present research findings indicate that OLN-loaded nanoparticulate systems may be highly promising for effective delivery of Olanzapine with better efficacy and minimum adverse effects. Copyright © 2017 Elsevier B.V. All rights reserved.

Nanoemulsion: for improved oral delivery of repaglinide.

PubMed

Akhtar, Juber; Siddiqui, Hefazat Hussain; Fareed, Sheeba; Badruddeen; Khalid, Mohammad; Aqil, Mohammed

2016-07-01

Repaglinide (RPG) is a fast-acting prandial glucose regulator. It acts by stimulating insulin release from pancreatic β-cells. Recurrent dosing of RPG before each meal is burdensome remedy. Hence the plan of the present study was to evaluate nanoemulsion as a hopeful carrier for RPG for persistent hypoglycemic effect. The drug was incorporated into oil phase of nanoemulsion to give improved biopharmaceutical properties as compared to the lipid-based systems. Pseudo ternary phase diagrams were prepared by aqueous titration method. Formulations were selected at a difference of 5% w/w of oil from the o/w nanoemulsion region of phase diagrams. The optimized nanoemulsion formulation constituted sefsol-218 (5% v/v) as an oil phase, 30% v/v of Tween-80 and transcutol as a surfactant and co-surfactant to restrain nanodroplet size and low viscosity and distilled water (65%). In vitro dissolution studies showed higher drug release (98.22%), finest droplet size (76.23 nm), slightest polydispersity value (0.183), least viscosity (21.45 cps) and immeasurable dilution capability from the nanoemulsion as compared with existing oral tablet formulation. The optimized RPG nanoemulsion formulation showed better hypoglycemic effect in comparison to tablet formulation in experimental diabetic rats. No significant variations were also observed in the optimized formulation when subjected to accelerated stability study at different temperature and relative humidity over a period of 3 months.

In vitro gastrointestinal lipolysis of four formulations of piroxicam and cinnarizine with the self emulsifying excipients Labrasol and Gelucire 44/14.

PubMed

Fernandez, Sylvie; Chevrier, Stéphanie; Ritter, Nicolas; Mahler, Bruno; Demarne, Frédéric; Carrière, Frédéric; Jannin, Vincent

2009-08-01

Labrasol and Gelucire 44/14 are defined admixtures of acylglycerols and PEG esters which are substrates for digestive lipases. We investigated their in vitro gastrointestinal lipolysis to understand which compounds are, after digestion, responsible for keeping poorly water-soluble drugs in solution. The precipitation of piroxicam and cinnarizine formulated in these excipients during the gastrointestinal lipolysis was also studied. Monoacylglycerols and PEG monoesters are the largest compounds present at the end of gastric phase whereas PEG-monoesters are the largest compounds after the duodenal phase. The precipitation of piroxicam is mainly due to the gastric lipolysis. In the control experiments performed without digestive lipases, cinnarizine formulated in Labrasol was found to precipitate upon dilution of the gastric medium to form the solution mimicking the duodenal medium. In the presence of gastric lipase, Labrasol was hydrolyzed and the precipitation of cinnarizine was not observed in this case. When the cinnarizine was formulated with Gelucire 44/14 the precipitation was only due to the dilution of the gastric medium. Our study highlights the importance of the gastrointestinal lipolysis and the associated phenomena such as the dilution of chyme by biliary and pancreatic secretions in vivo, on the solubilisation of poorly water-soluble drugs formulated with lipid-based excipients.

Molecular adjuvants based on nonpyrogenic lipophilic derivatives of norAbuMDP/GMDP formulated in nanoliposomes: stimulation of innate and adaptive immunity.

PubMed

Knotigová, Pavlína Turánek; Zyka, Daniel; Mašek, Josef; Kovalová, Anna; Křupka, Michal; Bartheldyová, Eliška; Kulich, Pavel; Koudelka, Štěpán; Lukáč, Róbert; Kauerová, Zuzana; Vacek, Antonín; Horynová, Milada Stuchlová; Kozubík, Alois; Miller, Andrew D; Fekete, Ladislav; Kratochvílová, Irena; Ježek, Jan; Ledvina, Miroslav; Raška, Milan; Turánek, Jaroslav

2015-04-01

The aim of this work was to demonstrate an immunostimulatory and adjuvant effect of new apyrogenic lipophilic derivatives of norAbuMDP and norAbuGMDP formulated in nanoliposomes. Nanoliposomes and metallochelating nanoliposomes were prepared by lipid film hydration and extrusion methods. The structure of the liposomal formulation was studied by electron microscopy, AF microscopy, and dynamic light scattering. Sublethal and lethal γ-irradiation mice models were used to demonstrate stimulation of innate immune system. Recombinant Hsp90 antigen (Candida albicans) bound onto metallochelating nanoliposomes was used for immunisation of mice to demonstrate adjuvant activities of tested compounds. Safety and stimulation of innate and adaptive immunity were demonstrated on rabbits and mice. The liposomal formulation of norAbuMDP/GMDP was apyrogenic in rabbit test and lacking any side effect in vivo. Recovery of bone marrow after sublethal γ-irradiation as well as increased survival of mice after lethal irradiation was demonstrated. Enhancement of specific immune response was demonstrated for some derivatives incorporated in metallochelating nanoliposomes with recombinant Hsp90 protein antigen. Liposomal formulations of new lipophilic derivatives of norAbuMDP/GMDP proved themselves as promising adjuvants for recombinant vaccines as well as immunomodulators for stimulation of innate immunity and bone-marrow recovery after chemo/radio therapy of cancer.

Standardised neonatal parenteral nutrition formulations – an Australasian group consensus 2012

PubMed Central

2014-01-01

Standardised parenteral nutrition formulations are routinely used in the neonatal intensive care units in Australia and New Zealand. In 2010, a multidisciplinary group was formed to achieve a consensus on the formulations acceptable to majority of the neonatal intensive care units. Literature review was undertaken for each nutrient and recommendations were developed in a series of meetings held between November 2010 and April 2011. Three standard and 2 optional amino acid/dextrose formulations and one lipid emulsion were agreed by majority participants in the consensus. This has a potential to standardise neonatal parenteral nutrition guidelines, reduce costs and prescription errors. PMID:24548745

Incorporation of paramagnetic, fluorescent and PET/SPECT contrast agents into liposomes for multimodal imaging

PubMed Central

Mitchell, Nick; Kalber, Tammy L.; Cooper, Margaret S.; Sunassee, Kavitha; Chalker, Samantha L.; Shaw, Karen P.; Ordidge, Katherine L.; Badar, Adam; Janes, Samuel M.; Blower, Philip J.; Lythgoe, Mark F.; Hailes, Helen C.; Tabor, Alethea B.

2013-01-01

A series of metal-chelating lipid conjugates has been designed and synthesized. Each member of the series bears a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) macrocycle attached to the lipid head group, using short n-ethylene glycol (n-EG) spacers of varying length. Liposomes incorporating these lipids, chelated to Gd3+, 64Cu2+, or 111In3+, and also incorporating fluorescent lipids, have been prepared, and their application in optical, magnetic resonance (MR) and single-photon emission tomography (SPECT) imaging of cellular uptake and distribution investigated in vitro and in vivo. We have shown that these multimodal liposomes can be used as functional MR contrast agents as well as radionuclide tracers for SPECT, and that they can be optimized for each application. When shielded liposomes were formulated incorporating 50% of a lipid with a short n-EG spacer, to give nanoparticles with a shallow but even coverage of n-EG, they showed good cellular internalization in a range of tumour cells, compared to the limited cellular uptake of conventional shielded liposomes formulated with 7% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethyleneglycol)2000] (DSPE-PEG2000). Moreover, by matching the depth of n-EG coverage to the length of the n-EG spacers of the DOTA lipids, we have shown that similar distributions and blood half lives to DSPE-PEG2000-stabilized liposomes can be achieved. The ability to tune the imaging properties and distribution of these liposomes allows for the future development of a flexible tri-modal imaging agent. PMID:23131536

Effect of shrimp ( Litopenaeus vannamei) farming waste on the growth, digestion, ammonium-nitrogen excretion of sea cucumber ( Stichopus monotuberculatus)

NASA Astrophysics Data System (ADS)

Chen, Yanfeng; Luo, Peng; Hu, Chaoqun; Ren, Chunhua

2015-06-01

In this study, specific growth rate (SGR), ingestion rate (IR), food conversion ratio (FCR), apparent digestion ratio (ADR) and ammonium-nitrogen excretion were determined for sea cucumber ( Stichopus monotuberculatus) reared in plastic containers (70 L; 4 containers each diet treatment). Sea cucumbers were fed with five diets containing different amounts of farming waste from shrimp ( Litopenaeus vannamei) (100%, 75%, 50%, 25% and 0) and a formulated compound (20% sea mud and 80% powdered algae). Sea cucumbers grew faster when they were fed with diet D (25% shrimp waste and 75% formulated compound) than those fed with other diets. Although IR value of sea cucumber fed with diet A (shrimp waste) was higher than those fed with other diets, both the lowest SGR and the highest FCR occurred in this diet group. The highest and the lowest ADR occurred in diet E (formulated compound) and diet A group, respectively, and the same to ammonium-nitrogen excretion. The contents of crude protein, crude lipid and total organic matter (TOM) in feces decreased in comparison with corresponding diets. In the feces from different diet treatments, the contents of crude protein and TOM increased gradually as the contents of crude protein and TOM in diets increased, while crude lipid content decreased gradually as the crude lipid content in diets increased.

Formulation optimization, characterization, and evaluation of in vitro cytotoxic potential of curcumin loaded solid lipid nanoparticles for improved anticancer activity.

PubMed

Rompicharla, Sri Vishnu Kiran; Bhatt, Himanshu; Shah, Aashma; Komanduri, Neeraja; Vijayasarathy, Dhanya; Ghosh, Balaram; Biswas, Swati

2017-11-01

The aim of the present research was to develop a novel, biocompatible, amenable to industrial scale up and affordable solid lipid nanoparticles (SLN) preparation of curcumin and evaluate the therapeutic efficacy in vitro using cancer cells. We have incorporated cholesterol as the lipid to prepare SLN along with the Poloxamer-188 as stabilizer. High shear homogenization was used to prepare the SLN and formulation was optimized using Quality by Design The optimized Chol CUR SLN exhibited a narrow size distribution with a particle size of 166.4±3.5nm. Percentage encapsulation (%EE) was found to be 76.9±1.9%. The SLN were further characterized by DSC, FTIR, XRD and drug release. In vitro cell studies in MDA-MB-231 (Human Breast cancer) cell line revealed that the Chol CUR SLN showed superior cytotoxicity and uptake in comparison to the free curcumin. Furthermore, Chol CUR SLN induced a significantly higher apoptosis compared to free CUR treatment. These results indicated that the curcumin encapsulated in Chol SLN was able to significantly improve the cytotoxic potential and induction of apoptosis in MDA-MB-231 cells. The promising result from our study could lead a further exploration of this nanoparticle formulation to be utilized clinically for cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Topical Formulation Containing Naringenin: Efficacy against Ultraviolet B Irradiation-Induced Skin Inflammation and Oxidative Stress in Mice

PubMed Central

Martinez, Renata M.; Pinho-Ribeiro, Felipe A.; Steffen, Vinicius S.; Silva, Thais C. C.; Caviglione, Carla V.; Bottura, Carolina; Fonseca, Maria J. V.; Vicentini, Fabiana T. M. C.; Vignoli, Josiane A.; Baracat, Marcela M.; Georgetti, Sandra R.; Verri, Waldiceu A.; Casagrande, Rubia

2016-01-01

Naringenin (NGN) exhibits anti-inflammatory and antioxidant activities, but it remains undetermined its topical actions against ultraviolet B (UVB)-induced inflammation and oxidative stress in vivo. The purpose of this study was to evaluate the physicochemical and functional antioxidant stability of NGN containing formulations, and the effects of selected NGN containing formulation on UVB irradiation-induced skin inflammation and oxidative damage in hairless mice. NGN presented ferric reducing power, ability to scavenge 2,2′-azinobis (3-ethylbenzothiazoline- 6-sulfonic acid) (ABTS) and hydroxyl radical, and inhibited iron-independent and dependent lipid peroxidation. Among the three formulations containing NGN, only the F3 kept its physicochemical and functional stability over 180 days. Topical application of F3 in mice protected from UVB-induced skin damage by inhibiting edema and cytokine production (TNF-α, IL-1β, IL-6, and IL-10). Furthermore, F3 inhibited superoxide anion and lipid hydroperoxides production and maintained ferric reducing and ABTS scavenging abilities, catalase activity, and reduced glutathione levels. In addition, F3 maintained mRNA expression of cellular antioxidants glutathione peroxidase 1, glutathione reductase and transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), and induced mRNA expression of heme oxygenase-1. In conclusion, a formulation containing NGN may be a promising approach to protecting the skin from the deleterious effects of UVB irradiation. PMID:26741806

Construction and cellular uptake behavior of redox-sensitive docetaxel prodrug-loaded liposomes.

PubMed

Ren, Guolian; Jiang, Mengjuan; Guo, Weiling; Sun, Bingjun; Lian, He; Wang, Yongjun; He, Zhonggui

2018-01-01

A redox-responsive docetaxel (DTX) prodrug consisting of a disulfide linkage between DTX and vitamin E (DTX-SS-VE) was synthesized in our laboratory and was successfully formulated into liposomes. The aim of this study was to optimize the formulation and investigate the cellular uptake of DTX prodrug-loaded liposomes (DPLs). The content of DTX-SS-VE was determined by ultrahigh-performance liquid chromatography (UPLC). The formulation and process were optimized using entrapment efficiency (EE), drug-loading (DL), particle size and polydispersity index (PDI) as the evaluation indices. The optimal formulation was as follows: drug/lipid ratio of 1:12, cholesterol/lipid ratio of 1:10, hydration temperature of 40 °C, sonication power and time of 400 W and 5 min. The EE, DL and particle size of the optimized DPLs were 97.60 ± 0.03%, 7.09 ± 0.22% and 93.06 ± 0.72 nm, respectively. DPLs had good dilution stability under the physiological conditions over 24 h. In addition, DPLs were found to enter tumor cells via different pathways and released DTX from the prodrug to induce apoptosis. Taken together, the optimized formulation and process were found to be a simple, stable and applicable method for the preparation of DPLs that could successfully escape from lysosomes.

Anacardic acid enhances the anticancer activity of liposomal mitoxantrone towards melanoma cell lines – in vitro studies

PubMed Central

Legut, Mateusz; Lipka, Dominik; Filipczak, Nina; Piwoni, Adriana; Kozubek, Arkadiusz; Gubernator, Jerzy

2014-01-01

This paper describes a novel formulation of antineoplastic drug: mitoxantrone loaded into liposomal carriers enriched with encapsulated anacardic acid in the liposomal bilayer using a vitamin C gradient. Anacardic acid is a potent epigenetic agent with anticancer activity. This is the first liposomal formulation to combine an actively encapsulated drug and anacardic acid. The liposomes were characterized in terms of basic parameters, such as size, zeta potential, optimal drug-to-lipid ratio, loading time and temperature, and stability at 4°C and in human plasma in vitro. The formulation was found to be stable, and the loading process was rapid and efficient (drug-to-lipid ratio of up to 0.3 with over 90% efficiency in 5 minutes). The cytotoxicity of these formulations was assessed using the human melanoma cell lines A375 and Hs294T and the normal human dermal fibroblast line. The results showed that anacardic acid and to a smaller extent vitamin C significantly increased the cytotoxicity of the drug towards melanoma compared to ammonium sulfate liposomes. On the other hand, vitamin C and anacardic acid both protected normal cells from damage caused by the drug. The formulation combining anacardic acid, vitamin C, and mitoxantrone showed promising results in terms of cytotoxicity and cytoprotection. Therefore, it has potential for anticancer treatment. PMID:24489469

IVABRADINE LOADED SOLID LIPID MICROPARTICLES: FORMULATION, CHARACTERIZATION AND OPTIMIZATION BY CENTRAL COMPOSITE ROTATABLE DESIGN.

PubMed

Hanif, Muhammad; Khan, Hafeez Ullah; Afzal, Samina; Sher, Muhammad

2017-01-01

The current research focused on improvement of oral bioavailability and decrease in dosing frequency of ivabradine (Iva) in order to enhance patient compliance by formulating novel sustained release Iva loaded solid lipid microparticles (SLMs) with the help of melt emulsification technique. SLMs formulations were designed with the help of three level central composite rotatable design (CCRD) to study the impact of independent variables like lipid concentration, surfactant concentration and stirring speed on responses - percentage yield (Y,) and entrapment efficiency (Y2). Compatibility between the drug and bees wax (BW) was checked by conducting Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRD). SLMs were further evaluated for rheological behavior, zeta potential, particle size and for morphology by scanning'electron microscope (SEM). The release of drug from SLMs was conducted by USP type-Il apparatus at pH 1.2, pH 6.8 and data were analyzed by different kinetic models like zero order, first order, Higuchi model, Korsmeyer-Peppas and Hixon-Crowell models. The rheo- logical studies approved the good flow behavior of SLMs and spherical smooth surface of SLMs was observed from SEM. DSC, FTIR and XRD studies concluded the lack of any possible interaction between formulation components. The size-of SLMs ranged from 300 to 500 pm and zeta potential study showed the presence of higher negative charge (-30 to -52 mV). Response Y, varied from 53 to 90% and response Y2 ranged from 29 to 78% indicating the effect of formulation variables. The obtained outcomes were analyzed by second order polynomial equation and suggested quadratic model was also validated. SLMs released Iva from 54 to 90% at pH 6.8 and was significantly (p 0.05) affected by BW concentration. The release mechanism followed the zero order and Korsmeyer-Peppas (n 0.85) kinetic models suggesting slow erosion along with diffusion mechanism for Iva release.

Process optimization involving critical evaluation of oxygen transfer, oxygen uptake and nitrogen limitation for enhanced biomass and lipid production by oleaginous yeast for biofuel application.

PubMed

Chopra, Jayita; Sen, Ramkrishna

2018-04-20

Lipid accumulation in oleaginous yeast is generally induced by nitrogen starvation, while oxygen saturation can influence biomass growth. Systematic shake flask studies that help in identifying the right nitrogen source and relate its uptake kinetics to lipid biosynthesis under varying oxygen saturation conditions are very essential for addressing the bioprocessing-related issues, which are envisaged to occur in the fermenter scale production. In the present study, lipid bioaccumulation by P. guilliermondii at varying C:N ratios and oxygen transfer conditions (assessed in terms of k L a) was investigated in shake flasks using a pre-optimized N-source and a two-stage inoculum formulated in a hybrid medium. A maximum lipid concentration of 10.8 ± 0.5 g L -1 was obtained in shake flask study at the optimal condition with an initial C:N and k L a of 60:1 and 0.6 min -1 , respectively, at a biomass specific growth rate of 0.11 h -1 . Translating these optimal shake flask conditions to a 3.7 L stirred tank reactor resulted in biomass and lipid concentrations of 16.74 ± 0.8 and 8 ± 0.4 g L -1 . The fatty acid methyl ester (FAME) profile of lipids obtained by gas chromatography was found to be suitable for biodiesel application. We strongly believe that the rationalistic approach-based design of experiments adopted in the study would help in achieving high cell density with improved lipid accumulation and also minimize the efforts towards process optimization during bioreactor level operations, consequently reducing the research and development-associated costs.

Quantitative In Vitro Assessment of Liposome Stability and Drug Transfer Employing Asymmetrical Flow Field-Flow Fractionation (AF4).

PubMed

Holzschuh, Stephan; Kaeß, Kathrin; Fahr, Alfred; Decker, Christiane

2016-04-01

In the present study we introduce an efficient approach for a size-based separation of liposomes from plasma proteins employing AF4. We investigated vesicle stability and release behavior of the strongly lipophilic drug temoporfin from liposomes in human plasma for various incubation times at 37°C. We used the radioactive tracer cholesteryl oleyl ether (COE) or dipalmitoyl-phosphocholine (DPPC) as lipid markers and (14)C-labeled temoporfin. First, both lipid labels were examined for their suitability as liposome markers. Furthermore, the influence of plasma origin on liposome stability and drug transfer was investigated. The effect of membrane fluidity and PEGylation on vesicle stability and drug release characteristics was also analyzed. Surprisingly, we observed an enzymatic transfer of (3)H-COE to lipoproteins due to the cholesterol ester transfer protein (CETP) in human plasma in dependence on membrane rigidity and were able to inhibit this transfer by plasma preincubation with the CETP inhibitor torcetrapib. This effect was not seen when liposomes were incubated in rat plasma. DPPC labels suffered from hydrolysis effects during preparation and/or storage. Fluid liposomes were less stable in human plasma than their PEGylated analogues or a rigid formulation. In contrast, the transfer of the incorporated drug to lipoproteins was higher for the rigid formulations. The observed effects render COE-labels questionable for in vivo studies using CEPT-rich species. Here, choline labelled (14)C-DPPC was found to be the most promising alternative. Bilayer composition has a high influence on stability and drug release of a liposomal formulation in human plasma.

Comparative Analysis of Amphotericin B Lipid Complex and Liposomal Amphotericin B Kinetics of Lung Accumulation and Fungal Clearance in a Murine Model of Acute Invasive Pulmonary Aspergillosis▿

PubMed Central

Lewis, Russell E.; Liao, Guangling; Hou, Jinggou; Chamilos, Georgios; Prince, Randall A.; Kontoyiannis, Dimitrios P.

2007-01-01

The reformulation of amphotericin B (AMB) into a lipid complex (AMB lipid complex [ABLC]) or liposomal carrier (liposomal AMB [L-AMB]) changes the rate and extent of drug distribution to the lung. The importance of pharmacokinetic differences among the various lipid AMB formulations in the treatment of invasive pulmonary aspergillosis (IPA) remains unknown. We compared the kinetics of AMB lung accumulation and fungal clearance of ABLC- and L-AMB-treated mice with acute IPA. BALB/c mice were immunosuppressed with cyclophosphamide and cortisone before intranasal inoculation with 1.5 × 106 Aspergillus fumigatus 293 conidia. ABLC or L-AMB was administered in daily intravenous doses (1, 5, or 10 mg/kg of body weight), starting 12 h after infection and continuing until day 5. At predetermined times (0, 24, 72, and 120 h), mice were euthanized, and lungs were harvested for determinations of lung fungal burdens (quantitative PCR) and total AMB lung tissue concentrations. Both ABLC and L-AMB were effective at reducing lung fungal burdens at doses of ≥5 mg/kg/day. Clearance of A. fumigatus during the first 24 h was associated with AMB tissue concentrations of >4 μg/g. At 5 mg/kg/day, ABLC produced a more rapid fungal clearance than did L-AMB, but at the end of therapy, fungal burden reductions were similar for both formulations and were not improved with higher dosages. These data suggest that ABLC delivers active AMB to the lung more rapidly than does L-AMB, resulting in faster Aspergillus clearance in an experimental model of IPA. However, pharmacodynamic differences between the two formulations were less apparent when mice were dosed at 10 mg/kg/day. PMID:17261624

COMPARATIVE EFFECTIVENESS AND SAFETY BETWEEN AMPHOTERICIN B LIPID-FORMULATIONS: A SYSTEMATIC REVIEW.

PubMed

Grazziotin, Luiza Raquel; Moreira, Leila Beltrami; Ferreira, Maria Angelica Pires

2018-06-13

It is not yet established the advantages between amphotericin B lipid complex (ABLC) and liposomal (L-AmB) in patients with invasive fungal infections refractory to usual doses of conventional AmB (d-AmB), previous renal impairment, or unacceptable d-AmB renal toxicity. This systematic review aims to compare ABLC and L-AmB effectiveness and safety outcomes in these subgroups of patients. The search was performed on Medline, Cochrane Library, EMBASE, and LILACS databases. treatment comparing L-AmB with ABLC; patients who had (i) refractory infection after being treated with d-AmB, (ii) previous renal impairment, or (iii) unacceptable d-AmB toxicity. Two investigators independently screened the search results, assessed trial quality, and extracted data. A total of 1,054 articles were identified in the literature. Among those, eleven were selected for full-text reading and five met the inclusion criteria. The five articles included reported on four separate observational studies. Overall, no significant difference was found in clinical relevant outcomes as new-onset dialysis, length of hospital stay, or mortality when comparing both lipid formulations. The studies reported a trend toward lower nephrotoxicity in patients treated with L-AmB. However, the results were imprecise and heterogeneous and the studies presented important methodological biases. The studies included in this systematic review pointed toward less nephrotoxicity events in the L-AmB group. However, due to low quality of evidence and no statistically significant differences in other clinical relevant outcomes, there is no definitive evidence of overall superiority in effectiveness or safety outcomes regarding one lipid formulation or another in this population subgroup.

Release of Cyclic Phosphatidic Acid from Gelatin-based Hydrogels Inhibit Colon Cancer Cell Growth and Migration

PubMed Central

Tsukahara, Tamotsu; Murakami-Murofushi, Kimiko

2012-01-01

Microparticle and nanoparticle formulations are widely used to improve the bioavailability of low-solubility drugs and as vehicles for organ- and tissue-specific targeted drug delivery. We investigated the effect of a novel, controlled-release form of a bioactive lipid, cyclic phosphatidic acid (cPA), on human colon cancer cell line functions. We encapsulated cPA in gelatin-based hydrogels and examined its ability to inhibit the viability and migration of HT-29 and DLD-1 cells in vitro and the LPA-induced activity of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). The hydrogel delivery system prolonged cPA release into the culture medium. Accordingly, cPA-hydrogel microspheres substantially inhibited LPA-induced PPARγ activity and cell growth and migration compared with that of cells cultured with cPA alone. Thus, hydrogel microspheres are a potential system for stable and efficient delivery of bioactive lipids such as cPA and may offer a new strategy for targeted colon cancer treatment. PMID:23008752

Development of self-microemulsifying drug delivery system for oral delivery of poorly water-soluble nutraceuticals.

PubMed

Shah, Ankita V; Desai, Heta H; Thool, Prajwal; Dalrymple, Damon; Serajuddin, Abu T M

2018-06-01

The objective of the study was to develop a self-microemulsifying drug delivery system (SMEDDS), also known as microemulsion preconcentrate, for oral delivery of five poorly water-soluble nutraceuticals or bioactive agents, namely, vitamin A, vitamin K2, coenzyme Q 10 , quercetin and trans-resveratrol. The SMEDDS contained a 1:1 mixture (w/w) of Capmul MCM NF (a medium chain monoglyceride) and Captex 355 EP/NF (a medium chain triglyceride) as the hydrophobic lipid and Tween 80 (polysorbate 80) as the hydrophilic surfactant. The lipid and surfactant were mixed at 50:50 w/w ratio. All three of the SMEDDS components have GRAS or safe food additive status. The solubility of nutraceuticals was determined in Capmul MCM, Captex 355, Tween 80, and the SMEDDS (microemulsion preconcentrate mixture). The solubility values of vitamin A palmitate, vitamin K2, coenzyme Q 10 , quercetin, and trans-resveratrol per g of SMEDDS were, respectively, 500, 12, 8, 56, and 87 mg. Appropriate formulations of nutraceuticals were prepared and filled into hard gelatin capsules. They were then subjected to in vitro dispersion testing using 250 mL of 0.01 N HCl in USP dissolution apparatus II. The dispersion test showed that all SMEDDS containing nutraceuticals dispersed spontaneously to form microemulsions after disintegration of capsule shells with globule size in the range of 25 to 200 nm. From all formulations, except that of vitamin K2, >80-90% nutraceuticals dispersed in 5-10 min and there was no precipitation of compounds during the test period of 120 min. Some variation in dispersion of vitamin K2 was observed due to the nature of the material used (vitamin K2 pre-adsorbed onto calcium phosphate). The present report provides a simple and organic cosolvent-free lipid-based SMEDDS for the oral delivery of poorly water-soluble nutraceuticals. Although a 50:50 w/w mixture of lipid to surfactant was used, the lipid content may be increased to 70:30 without compromising the formation of microemulsion.

The effect of formulative parameters on the size and physical stability of SLN based on "green" components.

PubMed

Soddu, Elena; Rassu, Giovanna; Cossu, Massimo; Giunchedi, Paolo; Cerri, Guido; Gavini, Elisabetta

2016-01-01

Cocoa butter (CB) is a largely used excipient in pharmaceutical field. Aim of this work was to set formulative parameters for the preparation of SLN based on "green" lipid matrix for drug delivery as natural, both human and environmental safe systems. Double emulsion technique (w1/o/w2) was selected for SLN preparation. The effect on the dimensional properties of different surfactants (Tween 80 and PEG 40 monostearate) and co-surfactants (PEG400 monostearate, Emulium® Kappa2 and Plurol®Stearique) at different concentrations was evaluated. Stability tests were performed. SLN dispersions were exsiccated and the effect of the dried process on SLN size was evaluated. The influence of temperature on SLN dimensions was investigated at 37 °C. MTT test was performed on raw materials and formulations. The w1/o/w2 is suitable, rapid and economic technique for the preparation of CB SLN. Tween 80-Plurol Stearique combination gives the best results: particles size less than 400 nm and PI of about 0.4 are obtained when PS 2% is used. Both raw materials and formulations are safe. The importance to evaluate the effect of different surfactant and/or co-surfactant on the dimensional properties of SLN is evident by selecting substances with preferable safety profiles, and favorable environmental properties to develop stable "green" SLN.

Performance of structured lipids incorporating selected phenolic and ascorbic acids.

PubMed

Gruczynska, Eliza; Przybylski, Roman; Aladedunye, Felix

2015-04-15

Conditions applied during frying require antioxidant which is stable at these conditions and provides protection for frying oil and fried food. Novel structured lipids containing nutraceuticals and antioxidants were formed by enzymatic transesterification, exploring canola oil and naturally occurring antioxidants such as ascorbic and selected phenolic acids as substrates. Lipozyme RM IM lipase from Rhizomucor miehei was used as biocatalyst. Frying performance and oxidative stability of the final transesterification products were evaluated. The novel lipids showed significantly improved frying performance compared to canola oil. Oxidative stability assessment of the structured lipids showed significant improvement in resistance to oxidative deterioration compared to original canola oil. Interestingly, the presence of ascorbic acid in an acylglycerol structure protected α-tocopherol against thermal degradation, which was not observed for the phenolic acids. Developed structured lipids containing nutraceuticals and antioxidants may directly affect nutritional properties of lipids also offering nutraceutical ingredients for food formulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Intravenous Lipid Emulsions in Parenteral Nutrition123

PubMed Central

Fell, Gillian L; Nandivada, Prathima; Gura, Kathleen M; Puder, Mark

2015-01-01

Fat is an important macronutrient in the human diet. For patients with intestinal failure who are unable to absorb nutrients via the enteral route, intravenous lipid emulsions play a critical role in providing an energy-dense source of calories and supplying the essential fatty acids that cannot be endogenously synthesized. Over the last 50 y, lipid emulsions have been an important component of parenteral nutrition (PN), and over the last 10–15 y many new lipid emulsions have been manufactured with the goal of improving safety and efficacy profiles and achieving physiologically optimal formulations. The purpose of this review is to provide a background on the components of lipid emulsions, their role in PN, and to discuss the lipid emulsions available for intravenous use. Finally, the role of parenteral fat emulsions in the pathogenesis and management of PN-associated liver disease in PN-dependent pediatric patients is reviewed. PMID:26374182

Studies on self-nanoemulsifying drug delivery system of flurbiprofen employing long, medium and short chain triglycerides.

PubMed

Daar, Junaid; Khan, Ahmad; Khan, Jallat; Khan, Amjad; Khan, Gul Majid

2017-03-01

The aim of the study was to successfully design, formulate and evaluate self-nanoemulsifying drug delivery system (SNEDDS) of poorly aqueous soluble drug viz. flurbiprofen using long (LCT), medium (MCT) and short chain triglycerides (SCT). The SNEDDS are thermodynamically stable lipid based drug delivery systems which consist of mixture of oil, surfactant and co-surfactant. Upon aqueous dilution, this mixture produces nano-emulsion spontaneously on slight agitation. The excipients intended to be used were screened for their potential to dissolve the drug and to form clear dispersion upon aqueous dilution. Labrafil M 1944 CS, capryol-90 and triacetin were selected as long, medium and short chain triglycerides, respectively, as lipids while tween-80 and polyethylene glycol-400 (PEG-400)/ethanol (3:1 ratio) were selected as surfactant and co-surfactant, respectively. The excipients were studied at every possible combination ratios using pseudo-ternary diagram. The LCT, MCT and SCT-SNEDDS were optimized using thermodynamic studies, percentage transmittance value, viscosity, refractive index (RI), electrical conductivity, globule size analysis and in-vitro drug release studies. The drug release profiles of optimized SNEDDS were then compared with market product at different pH mediums. The LCT-SNEDDS was considered to be superior for enhancement of the drug bioavailability when compared with other SNEDDS formulations and market product.

Reverse micelle-loaded lipid nano-emulsions: new technology for nano-encapsulation of hydrophilic materials.

PubMed

Anton, Nicolas; Mojzisova, Halina; Porcher, Emilien; Benoit, Jean-Pierre; Saulnier, Patrick

2010-10-15

This study presents novel, recently patented technology for encapsulating hydrophilic species in lipid nano-emulsions. The method is based on the phase-inversion temperature method (the so-called PIT method), which follows a low-energy and solvent-free process. The nano-emulsions formed are stable for months, and exhibit droplet sizes ranging from 10 to 200 nm. Hydrophilic model molecules of fluorescein sodium salt are encapsulated in the oily core of these nano-emulsion droplets through their solubilisation in the reverse micellar system. As a result, original, multi-scaled nano-objects are generated with a 'hydrophilic molecule in a reverse-micelles-in-oil-in-water' structure. Once fluorescein has been encapsulated it remains stable, for thermodynamic reasons, and the encapsulation yields can reach 90%. The reason why such complex objects can be formed is due to the soft method used (PIT method) which allows the conservation of the structure of the reverse micelles throughout the formulation process, up to their entrapment in the nano-emulsion droplets. In this study, we focus the investigation on the process itself, revealing its potential and limits. Since the formulation of nanocarriers for the encapsulation of hydrophilic substances still remains a challenge, this study may constitute a significant advance in this field. Copyright 2010 Elsevier B.V. All rights reserved.

Drug transport mechanism of oral antidiabetic nanomedicines.

PubMed

Gundogdu, Evren; Yurdasiper, Aysu

2014-01-01

Over the last few decades, extensive efforts have been made worldwide to develop nanomedicine delivery systems, especially via oral route for antidiabetic drugs. Absorption of insulin is hindered by epithelial cells of gastrointestinal tract, acidic gastric pH and digestive enzymes. Recent reports have identified and explained the beneficial role of several structural molecules like mucoadhesive polymers (polyacrylic acid, sodium alginate, chitosan) and other copolymers for the efficient transport and release of insulin to its receptors. Insulin nanomedicines based on alginate-dextran sulfate core with a chitosan-polyethylene glycol-albumin shell reduced glycaemia in a dose dependent manner. Orally available exendin-4 formulations exerted their effects in a time dependent manner. Insulin nanoparticles formed by using alginate and dextran sulfate nucleating around calcium and binding to poloxamer, stabilized by chitosan, and subsequently coated with albumin showed a threefold increase of the hypoglycemic effect in comparison to free insulin in animal models. Solid lipid nanoparticles showed an enhancement of the bioavailability of repaglinide (RG) within optimized solid lipid nanoparticle formulations when compared with RG alone. Nanoparticles represent multiparticulate delivery systems designed to obtain prolonged or controlled drug delivery and to improve bioavailability as well as stability. Nanoparticles can also offer advantages like limiting fluctuations within therapeutic range, reducing side effects, protecting drugs from degradation, decreasing dosing frequency, and improving patient compliance and convenience.

Lipid Nanoparticles Decorated with TNF-Related Aptosis-Inducing Ligand (TRAIL) Are More Cytotoxic than Soluble Recombinant TRAIL in Sarcoma.

PubMed

Gallego-Lleyda, Ana; De Miguel, Diego; Anel, Alberto; Martinez-Lostao, Luis

2018-05-13

Sarcomas are rare and heterogeneous cancers classically associated with a poor outcome. Sarcomas are 1% of the cancer but recent estimations indicate that sarcomas account for 2% of the estimated cancer-related deaths. Traditional treatment with surgery, radiotherapy, and chemotherapy has improved the outcome for some types of sarcomas. However, novel therapeutic strategies to treat sarcomas are necessary. TNF-related apoptosis-inducing ligand (TRAIL) is a death ligand initially described as capable of inducing apoptosis on tumor cell while sparing normal cells. Only few clinical trials have used TRAIL-based treatments in sarcoma, but they show only low or moderate efficacy of TRAIL. Consequently, novel TRAIL formulations with an improved TRAIL bioactivity are necessary. Our group has developed a novel TRAIL formulation based on tethering this death ligand on a lipid nanoparticle surface (LUV-TRAIL) resembling the physiological secretion of TRAIL as a trasmembrane protein inserted into the membrane of exosomes. We have already demonstrated that LUV-TRAIL shows an improved cytotoxic activity when compared to soluble recombinant TRAIL both in hematological malignancies and epithelial-derived cancers. In the present study, we have tested LUV-TRAIL in several human sarcoma tumor cell lines with different sensitivity to soluble recombinant TRAIL, finding that LUV-TRAIL was more efficient than soluble recombinant TRAIL. Moreover, combined treatment of LUV-TRAIL with distinct drugs proved to be especially effective, sensitizing even more resistant cell lines to TRAIL.

Dextran and protamine-based solid lipid nanoparticles as potential vectors for the treatment of X-linked juvenile retinoschisis.

PubMed

Delgado, Diego; del Pozo-Rodríguez, Ana; Solinís, Maria Ángeles; Avilés-Triqueros, Marcelino; Weber, Bernhard H F; Fernández, Eduardo; Gascón, Alicia R

2012-04-01

The goal of the present study was to analyze the potential application of nonviral vectors based on solid lipid nanoparticles (SLN) for the treatment of ocular diseases by gene therapy, specifically X-linked juvenile retinoschisis (XLRS). Vectors were prepared with SLN, dextran, protamine, and a plasmid (pCMS-EGFP or pCEP4-RS1). Formulations were characterized and the in vitro transfection capacity as well as the cellular uptake and the intracellular trafficking were studied in ARPE-19 cells. Formulations were also tested in vivo in Wistar rat eyes, and the efficacy was studied by monitoring the expression of enhanced green fluorescent protein (EGFP) after intravitreal, subretinal, and topical administration. The presence of dextran and protamine in the SLN improved greatly the expression of retinoschisin and EGFP in ARPE-19 cells. The nuclear localization signals of protamine, its ability to protect the DNA, and a shift in the entry mechanism from caveola-mediated to clathrin-mediated endocytosis promoted by the dextran, justify the increase in transfection. After ocular administration of the dextran-protamine-DNA-SLN complex to rat eyes, we detected the expression of EGFP in various types of cells depending on the administration route. Our vectors were also able to transfect corneal cells after topical application. We have demonstrated the potential usefulness of our nonviral vectors loaded with XLRS1 plasmid and provided evidence for their potential application for the management or treatment of degenerative retinal disorders as well as ocular surface diseases.

Atorvastatin calcium encapsulated eudragit nanoparticles with enhanced oral bioavailability, safety and efficacy profile.

PubMed

Kumar, Nagendra; Chaurasia, Sundeep; Patel, Ravi R; Khan, Gayasuddin; Kumar, Vikas; Mishra, Brahmeshwar

2017-03-01

Atorvastatin calcium (ATR), a second generation statin drug, was encapsulated in eudragit RSPO-based polymeric nanoparticles. The effect of independent variables (polymer content, stabilizer concentration, volume of chloroform and homogenization speed) on response variables (mean diameter particle size and entrapment efficiency) were investigated by employing central composite experimental design. All the independent variables were found to be significant for determining the response variables. Solid-state characterization study indicated the absence of physicochemical interaction between drug and polymer in formulation. Morphological study exhibited homogenous spherical shape of formulated nanoparticles. In vitro release study in phosphate buffer (pH 7.4) demonstrated sustained release profile over 24 h. Pharmacokinetic study in Charles Foster rats showed significant enhancement in oral bioavailability as compared to pure drug suspension. Efficacy study (lipid profile and blood glucose level) significantly justified the effectiveness of formulation having 50% less dose of ATR as compared to pure drug suspension. The effectiveness of formulation was further justified with an improved plasma safety profile of treated rats. Hence, ATR encapsulated eudragit RSPO nanoparticles can serve as potential drug delivery approach to enhance drug bioavailability, efficacy and safety profiles to alter existing marketed drug products.

A double-blind, randomized clinical trial comparing soybean oil–based versus olive oil–based lipid emulsions in adult medical–surgical intensive care unit patients requiring parenteral nutrition

PubMed Central

Spiegelman, Ronnie; Zhao, Vivian; Smiley, Dawn D.; Pinzon, Ingrid; Griffith, Daniel P.; Peng, Limin; Morris, Timothy; Luo, Menghua; Garcia, Hermes; Thomas, Christopher; Newton, Christopher A.; Ziegler, Thomas R.

2013-01-01

Objective Parenteral nutrition has been associated with metabolic and infectious complications in intensive care unit patients. The underlying mechanism for the high risk of complications is not known but may relate to the proinflammatory effects of soybean oil–based lipid emulsions, the only Food and Drug Administration–approved lipid formulation for clinical use. Design Prospective, double-blind, randomized, controlled trial. Setting Medical–surgical intensive care units from a major urban teaching hospital and a tertiary referral university hospital. Patients Adult medical–surgical intensive care unit patients. Intervention Parenteral nutrition containing soybean oil–based (Intralipid) or olive oil–based (ClinOleic) lipid emulsions. Measurements Differences in hospital clinical outcomes (nosocomial infections and noninfectious complications), hospital length of stay, glycemic control, inflammatory and oxidative stress markers, and granulocyte and monocyte functions between study groups. Results A total of 100 patients were randomized to either soybean oil–based parenteral nutrition or olive oil–based parenteral nutrition for up to 28 days. A total of 49 patients received soybean oil–based parenteral nutrition (age 51 ± 15 yrs, body mass index 27 ± 6 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.5 ± 7 [±SD]), and a total of 51 patients received olive oil–based lipid emulsion in parenteral nutrition (age 46 ± 19 yrs, body mass index 27 ± 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 ± 6 [±SD]) for a mean duration of 12.9 ± 8 days. The mean hospital blood glucose concentration during parenteral nutrition was 129 ± 14 mg/dL, without differences between groups. Patients treated with soybean oil–based and olive oil–based parenteral nutrition had a similar length of stay (47 ± 47 days and 41 ± 36 days, p = .49), mortality (16.3% and 9.8%, p = .38), nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34). In addition, there were no differences in inflammatory and oxidative stress markers or in granulocyte and monocyte functions between groups. Conclusion The administration of parenteral nutrition containing soybean oil–based and olive oil–based lipid emulsion resulted in similar rates of infectious and noninfectious complications and no differences in glycemic control, inflammatory and oxidative stress markers, and immune function in critically ill adults. PMID:22488002

Evaluation of conformity of a first prescription of lipid-based formulation of amphotericin B in a university-teaching pediatric hospital.

PubMed

Agogué, Claire; Bussières, Jean-François; Dehaut, Catherine; Lebel, Denis; Brochet, Marie-Sophie

2006-04-01

Invasive fungal infections are an important cause of morbidity and mortality in immunodeficient children. Amphotericin B is an important therapeutic agent for the treatment of invasive fungal infections but is associated with significant toxicities and high acquisition costs. The purpose of this study was to evaluate physician adherence to a local guideline for the use of lipid-based amphotericin B. The study was approved through Pharmacology & Therapeutics (P&T) committee activities. A retrospective drug utilization review (DUR) was conducted. All orders written between January 1, 2003, and December 31, 2004, were reviewed. Demographic and descriptive clinical data were collected as well as variables related to the drug order process. Conformity rates were calculated for the primary objective criteria (authorized prescribers - infectious disease members; recommended drug of choice-Abelcet; accepted indications; and presence of underlying conditions). A total of 109 orders for 70 patients were reviewed by a single research assistant for a 2-year period. Global conformity rate for all four criteria was calculated at 7.3%. Non-conformity was mostly associated with the absence of underlying conditions (e.g., prerenal insufficiency or presence of nephrotoxicity due to amphotericin B desoxycholate) in 84.5% of the cases. Infusionrelated adverse drug reactions partly explained a switch to a non-formulary lipid-based amphotericin B product. External factors (newly published results since the adoption of the guideline and continuous marketing practices) and internal factors (availability of non-formulary process, inefficient DUR process) could have contributed to non-adherence to a local guideline. This study shows low adherence to P&T committee drug guidelines on lipid-based amphotericin B. Continuous and efficient DUR processes should be in place to monitor drug guideline adherence.

Novel Solid Lipid Nanocarrier Of Glibenclamide: A Factorial Design Approach With Response Surface Methodology.

PubMed

Pandey, Sonia; Patel, Payal; Gupta, Arti

2018-05-21

In the present investigation a factorial design approach attempt was applied to develop the solid lipid nanoparticles (SLN) of Glibenclamide (GLB) a poorly water-soluble drug (BCS -II) used in the treatment of type 2 diabetes. Prime objectives of this experiment are to optimize the SLN formulation of Glibenclamide and improve the therapeutic effectiveness of the developed formulation. Glibenclamide loaded SLNs (GLB-SLN) were fabricated by High speed homogenization technique. A 32-factorial design approach has been employed to assess the influence of two independent variables, namely amount of Poloxamer 188 and Glyceryl Monostearate on entrapment efficiency (% EE) (Y1), Particle Size (nm) (Y2), % drug release at 8hr Q8 (Y3) and 24 hr Q24 (Y4) of prepared SLNs. Differential scanning calorimetry analysis revealed the compatibility of the drug into lipid matrix with surfactant, while Transmission electron and Scanning electron microscopy studies indicated the size and shape of SLN. The entrapment efficiency, particle size, Q8 and Q24 of the optimized SLNs were 88.93%, 125 nm, 31.12±0.951% and 86.07±1.291% respectively. Optimized GLB-SLN formula was derived from an overlay plot. Three dimensional response surface plots and regression equations confirmed the corresponding influence of selected independent variables on measured responses. In vivo testing of the GLB-SLN in diabetic albino rats demonstrated significant antidiabetic effect of GLB-SLN. The hypoglycemic effect obtained by GLB-SLN remained significantly higher than that given by drug alone and marketed formulation, further confirming the higher therapeutic effectiveness of the GLB-SLN formulation. Our findings suggested the feasibility of investigated system for oral administration of Glibenclamide. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The effectiveness of styrene-maleic acid (SMA) copolymers for solubilisation of integral membrane proteins from SMA-accessible and SMA-resistant membranes.

PubMed

Swainsbury, David J K; Scheidelaar, Stefan; Foster, Nicholas; van Grondelle, Rienk; Killian, J Antoinette; Jones, Michael R

2017-10-01

Solubilisation of biological lipid bilayer membranes for analysis of their protein complement has traditionally been carried out using detergents, but there is increasing interest in the use of amphiphilic copolymers such as styrene maleic acid (SMA) for the solubilisation, purification and characterisation of integral membrane proteins in the form of protein/lipid nanodiscs. Here we survey the effectiveness of various commercially-available formulations of the SMA copolymer in solubilising Rhodobacter sphaeroides reaction centres (RCs) from photosynthetic membranes. We find that formulations of SMA with a 2:1 or 3:1 ratio of styrene to maleic acid are almost as effective as detergent in solubilising RCs, with the best solubilisation by short chain variants (<30kDa weight average molecular weight). The effectiveness of 10kDa 2:1 and 3:1 formulations of SMA to solubilise RCs gradually declined when genetically-encoded coiled-coil bundles were used to artificially tether normally monomeric RCs into dimeric, trimeric and tetrameric multimers. The ability of SMA to solubilise reaction centre-light harvesting 1 (RC-LH1) complexes from densely packed and highly ordered photosynthetic membranes was uniformly low, but could be increased through a variety of treatments to increase the lipid:protein ratio. However, proteins isolated from such membranes comprised clusters of complexes in small membrane patches rather than individual proteins. We conclude that short-chain 2:1 and 3:1 formulations of SMA are the most effective in solubilising integral membrane proteins, but that solubilisation efficiencies are strongly influenced by the size of the target protein and the density of packing of proteins in the membrane. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Twin-screw extruded lipid implants containing TRP2 peptide for tumour therapy.

PubMed

Even, Marie-Paule; Bobbala, Sharan; Gibson, Blake; Hook, Sarah; Winter, Gerhard; Engert, Julia

2017-05-01

Much effort has been put in the development of specific anti-tumour immunotherapies over the last few years, and several studies report on the use of liposomal carriers for tumour-associated antigens. In this work, the use of lipid implants, prepared using two different extruders, was investigated for sustained delivery in tumour therapy. The implants consisted of cholesterol, soybean lecithin, Dynasan 114, trehalose, ovalbumin (OVA) or a TRP2 peptide, and Quil-A. Implants were first produced on a Haake Minilab extruder, and then a scale-down to minimal quantities of material on a small scale ZE mini extruder was performed. All formulations were characterised in terms of extrudability, implant properties and in vitro release behaviour of the model antigen ovalbumin. The type of extruder used to produce the implants had a major influence on implant properties and the release behaviour, demonstrating that extrusion parameters and lipid formulations have to be individually adapted to each extrusion device. Subsequently, lipid implants containing TRP-2 peptide were extruded on the ZE mini extruder and investigated in vitro and in vivo. The in vivo study showed that mice having received TRP2 loaded implants had delayed tumour growth for 3days compared to groups having received no TRP2. Copyright © 2017 Elsevier B.V. All rights reserved.

Box-Behnken study design for optimization of bicalutamide-loaded nanostructured lipid carrier: stability assessment.

PubMed

Kudarha, Ritu; Dhas, Namdev L; Pandey, Abhijeet; Belgamwar, Veena S; Ige, Pradum P

2015-01-01

Bicalutamide (BCM) is an anti-androgen drug used to treat prostate cancer. In this study, nanostructured lipid carriers (NLCs) were chosen as a carrier for delivery of BCM using Box-Behnken (BB) design for optimizing various quality attributes such as particle size and entrapment efficiency which is very critical for efficient drug delivery and high therapeutic efficacy. Stability of formulated NLCs was assessed with respect to storage stability, pH stability, hemolysis, protein stability, serum protein stability and accelerated stability. Hot high-pressure homogenizer was utilized for formulation of BCM-loaded NLCs. In BB response surface methodology, total lipid, % liquid lipid and % soya lecithin was selected as independent variable and particle size and %EE as dependent variables. Scanning electron microscopy (SEM) was done for morphological study of NLCs. Differential scanning calorimeter and X-ray diffraction study were used to study crystalline and amorphous behavior. Analysis of design space showed that process was robust with the particle size less than 200 nm and EE up to 78%. Results of stability studies showed stability of carrier in various storage conditions and in different pH condition. From all the above study, it can be concluded that NLCs may be suitable carrier for the delivery of BCM with respect to stability and quality attributes.

Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential.

PubMed

Telange, Darshan R; Patil, Arun T; Pethe, Anil M; Fegade, Harshal; Anand, Sridhar; Dave, Vivek S

2017-10-15

The apigenin-phospholipid phytosome (APLC) was developed to improve the aqueous solubility, dissolution, in vivo bioavailability, and antioxidant activity of apigenin. The APLC synthesis was guided by a full factorial design strategy, incorporating specific formulation and process variables to deliver an optimized product. The design-optimized formulation was assayed for aqueous solubility, in vitro dissolution, pharmacokinetics, and antioxidant activity. The pharmacological evaluation was carried out by assessing its effects on carbon tetrachloride-induced elevation of liver function marker enzymes in a rat model. The antioxidant activity was assessed by studying its effects on the liver antioxidant marker enzymes. The developed model was validated using the design-optimized levels of formulation and process variables. The physical-chemical characterization confirmed the formation of phytosomes. The optimized formulation demonstrated over 36-fold higher aqueous solubility of apigenin, compared to that of pure apigenin. The formulation also exhibited a significantly higher rate and extent of apigenin release in dissolution studies. The pharmacokinetic analysis revealed a significant enhancement in the oral bioavailability of apigenin from the prepared formulation, compared to pure apigenin. The liver function tests indicated that the prepared phytosome showed a significantly improved restoration of all carbon tetrachloride-elevated rat liver function marker enzymes. The prepared formulation also exhibited antioxidant potential by significantly increasing the levels of glutathione, superoxide dismutase, catalase, and decreasing the levels of lipid peroxidase. The study shows that phospholipid-based phytosome is a promising and viable strategy for improving the delivery of apigenin and similar phytoconstituents with low aqueous solubility. Copyright © 2016 Elsevier B.V. All rights reserved.

Preparation of Salicylic Acid Loaded Nanostructured Lipid Carriers Using Box-Behnken Design: Optimization, Characterization and Physicochemical Stability.

PubMed

Pantub, Ketrawee; Wongtrakul, Paveena; Janwitayanuchit, Wicharn

2017-01-01

Nanostructured lipid carriers loaded salicylic acid (NLCs-SA) were developed and optimized by using the design of experiment (DOE). Box-Behnken experimental design of 3-factor, 3-level was applied for optimization of nanostructured lipid carriers prepared by emulsification method. The independent variables were total lipid concentration (X 1 ), stearic acid to Lexol ® GT-865 ratio (X 2 ) and Tween ® 80 concentration (X 3 ) while the particle size was a dependent variable (Y). Box-Behnken design could create 15 runs by setting response optimizer as minimum particle size. The optimized formulation consists of 10% of total lipid, a mixture of stearic acid and capric/caprylic triglyceride at a 4:1 ratio, and 25% of Tween ® 80 which the formulation was applied in order to prepare in both loaded and unloaded salicylic acid. After preparation for 24 hours, the particle size of loaded and unloaded salicylic acid was 189.62±1.82 nm and 369.00±3.37 nm, respectively. Response surface analysis revealed that the amount of total lipid is a main factor which could affect the particle size of lipid carriers. In addition, the stability studies showed a significant change in particle size by time. Compared to unloaded nanoparticles, the addition of salicylic acid into the particles resulted in physically stable dispersion. After 30 days, sedimentation of unloaded lipid carriers was clearly observed. Absolute values of zeta potential of both systems were in the range of 3 to 18 mV since non-ionic surfactant, Tween ® 80, providing steric barrier was used. Differential thermograms indicated a shift of endothermic peak from 55°C for α-crystal form in freshly prepared samples to 60°C for β´-crystal form in storage samples. It was found that the presence of capric/caprylic triglyceride oil could enhance encapsulation efficiency up to 80% and facilitate stability of the particles.

Development of HIV-1 Rectal-Specific Microbicides and Colonic Tissue Evaluation

PubMed Central

Dezzutti, Charlene S.; Russo, Julie; Wang, Lin; Abebe, Kaleab Z.; Li, Jie; Friend, David R.; McGowan, Ian M.; Rohan, Lisa C.

2014-01-01

The gastrointestinal tract is structurally and functionally different from the vagina. Thus, the paradigm of topical microbicide development and evaluation has evolved to include rectal microbicides (RMs). Our interest was to create unique RM formulations to safely and effectively deliver antiretroviral drugs to mucosal tissue. RMs were designed to include those that spread and coat all surfaces of the rectum and distal colon rapidly (liquid) and those that create a deformable, erodible barrier and remain localized at the administration site (gel). Tenofovir (TFV) (1%) was formulated as an aqueous thermoreversible fluid and a carbopol-based aqueous hydrogel. Lipid-based liquid and gel formulations were prepared for UC781 (0.1%) using isopropyl myristate and GTCC (Caprylic/Capric Triglycerides), respectively. Formulations were characterized for pH, viscosity, osmolality, and drug content. Pre-clinical testing incorporated ex vivo colonic tissue obtained through surgical resections and flexible sigmoidoscopy (flex sig). As this was the first time using tissue from both sources side-by-side, the ability to replicate HIV-1 was compared. Efficacy of the RM formulations was tested by applying the products with HIV-1 directly to polarized colonic tissue and following viral replication. Safety of the formulations was determined by MTT assay and histology. All products had a neutral pH and were isoosmolar. While HIV-1BaL and HIV-1JR-CSF alone and in the presence of semen had similar replication trends between surgically resected and flex sig tissues, the magnitude of viral replication was significantly better in flex sig tissues. Both TFV and UC781 formulations protected the colonic tissue, regardless of tissue source, from HIV-1 and retained tissue viability and architecture. Our in vitro and ex vivo results show successful formulation of unique RMs. Moreover, the results of flex sig and surgically resected tissues were comparable suggesting the incorporation of both in pre-clinical testing algorithms. PMID:25025306

Development of HIV-1 rectal-specific microbicides and colonic tissue evaluation.

PubMed

Dezzutti, Charlene S; Russo, Julie; Wang, Lin; Abebe, Kaleab Z; Li, Jie; Friend, David R; McGowan, Ian M; Rohan, Lisa C

2014-01-01

The gastrointestinal tract is structurally and functionally different from the vagina. Thus, the paradigm of topical microbicide development and evaluation has evolved to include rectal microbicides (RMs). Our interest was to create unique RM formulations to safely and effectively deliver antiretroviral drugs to mucosal tissue. RMs were designed to include those that spread and coat all surfaces of the rectum and distal colon rapidly (liquid) and those that create a deformable, erodible barrier and remain localized at the administration site (gel). Tenofovir (TFV) (1%) was formulated as an aqueous thermoreversible fluid and a carbopol-based aqueous hydrogel. Lipid-based liquid and gel formulations were prepared for UC781 (0.1%) using isopropyl myristate and GTCC (Caprylic/Capric Triglycerides), respectively. Formulations were characterized for pH, viscosity, osmolality, and drug content. Pre-clinical testing incorporated ex vivo colonic tissue obtained through surgical resections and flexible sigmoidoscopy (flex sig). As this was the first time using tissue from both sources side-by-side, the ability to replicate HIV-1 was compared. Efficacy of the RM formulations was tested by applying the products with HIV-1 directly to polarized colonic tissue and following viral replication. Safety of the formulations was determined by MTT assay and histology. All products had a neutral pH and were isoosmolar. While HIV-1BaL and HIV-1JR-CSF alone and in the presence of semen had similar replication trends between surgically resected and flex sig tissues, the magnitude of viral replication was significantly better in flex sig tissues. Both TFV and UC781 formulations protected the colonic tissue, regardless of tissue source, from HIV-1 and retained tissue viability and architecture. Our in vitro and ex vivo results show successful formulation of unique RMs. Moreover, the results of flex sig and surgically resected tissues were comparable suggesting the incorporation of both in pre-clinical testing algorithms.

Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a Box-Behnken design.

PubMed

Hao, Jifu; Fang, Xinsheng; Zhou, Yanfang; Wang, Jianzhu; Guo, Fengguang; Li, Fei; Peng, Xinsheng

2011-01-01

The purpose of the present study was to optimize a solid lipid nanoparticle (SLN) of chloramphenicol by investigating the relationship between design factors and experimental data using response surface methodology. A Box-Behnken design was constructed using solid lipid (X(1)), surfactant (X(2)), and drug/lipid ratio (X(3)) level as independent factors. SLN was successfully prepared by a modified method of melt-emulsion ultrasonication and low temperature-solidification technique using glyceryl monostearate as the solid lipid, and poloxamer 188 as the surfactant. The dependent variables were entrapment efficiency (EE), drug loading (DL), and turbidity. Properties of SLN such as the morphology, particle size, zeta potential, EE, DL, and drug release behavior were investigated, respectively. As a result, the nanoparticle designed showed nearly spherical particles with a mean particle size of 248 nm. The polydispersity index of particle size was 0.277 ± 0.058 and zeta potential was -8.74 mV. The EE (%) and DL (%) could reach up to 83.29% ± 1.23% and 10.11% ± 2.02%, respectively. In vitro release studies showed a burst release at the initial stage followed by a prolonged release of chloramphenicol from SLN up to 48 hours. The release kinetics of the optimized formulation best fitted the Peppas-Korsmeyer model. These results indicated that the chloramphenicol-loaded SLN could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release.

Buparvaquone Nanostructured Lipid Carrier: Development of an Affordable Delivery System for the Treatment of Leishmaniases

PubMed Central

Löbenberg, Raimar; Cotrim, Paulo Cesar

2017-01-01

Buparvaquone (BPQ), a veterinary drug, was formulated as nanostructured lipid carriers (NLC) for leishmaniases treatment. The formulation design addressed poor water solubility of BPQ and lack of human drug delivery system. The DSC/TG and microscopy methods were used for solid lipids screening. Softisan® 154 showed highest BPQ solubility in both methods. The BPQ solubility in liquid lipids using HPLC revealed Miglyol® 812 as the best option. Response surface methodology (RSM) was used to identify the optimal Softisan154 : Miglyol 812 ratios (7 : 10 to 2 : 1) and Kolliphor® P188 and Tween® 80 concentration (>3.0% w/w) aiming for z-average in the range of 100–300 nm for macrophage delivery. The NLC obtained by high-pressure homogenization showed low z-averages (<350 nm), polydispersity (<0.3), and encapsulation efficiency close to 100%. DSC/TG and microscopy in combination proved to be a powerful tool to select the solid lipid. The relationship among the variables, demonstrated by a linear mathematical model using RSM, allowed generating a design space. This design space showed the limits in which changes in the variables influenced the z-average. Therefore, these drug delivery systems have the potential to improve the availability of affordable medicines due to the low cost of raw materials, using well established, reliable, and feasible scale-up technology. PMID:28255558

Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a Box-Behnken design

PubMed Central

Hao, Jifu; Fang, Xinsheng; Zhou, Yanfang; Wang, Jianzhu; Guo, Fengguang; Li, Fei; Peng, Xinsheng

2011-01-01

The purpose of the present study was to optimize a solid lipid nanoparticle (SLN) of chloramphenicol by investigating the relationship between design factors and experimental data using response surface methodology. A Box-Behnken design was constructed using solid lipid (X1), surfactant (X2), and drug/lipid ratio (X3) level as independent factors. SLN was successfully prepared by a modified method of melt-emulsion ultrasonication and low temperature-solidification technique using glyceryl monostearate as the solid lipid, and poloxamer 188 as the surfactant. The dependent variables were entrapment efficiency (EE), drug loading (DL), and turbidity. Properties of SLN such as the morphology, particle size, zeta potential, EE, DL, and drug release behavior were investigated, respectively. As a result, the nanoparticle designed showed nearly spherical particles with a mean particle size of 248 nm. The polydispersity index of particle size was 0.277 ± 0.058 and zeta potential was −8.74 mV. The EE (%) and DL (%) could reach up to 83.29% ± 1.23% and 10.11% ± 2.02%, respectively. In vitro release studies showed a burst release at the initial stage followed by a prolonged release of chloramphenicol from SLN up to 48 hours. The release kinetics of the optimized formulation best fitted the Peppas–Korsmeyer model. These results indicated that the chloramphenicol-loaded SLN could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release. PMID:21556343

Gelatin modified lipid nanoparticles for anti- viral drug delivery.

PubMed

K S, Joshy; S, Snigdha; Kalarikkal, Nandakumar; Pothen, Laly A; Thomas, Sabu

2017-10-01

The major challenges to clinical application of zidovudine are its moderate aqueous solubility and relative short half-life and serious side effects due to frequent administrations. We investigated the preparation of zidovudine-loaded nanoparticles based on lipids which were further modified with the polymer gelatin. Formulation and stability of the modified nanoparticles were analysed from the physico-chemical characterizations. The interactions of nanoparticles with blood components were tested by haemolysis and aggregation studies. The drug content and entrapment efficiencies were assessed by UV analysis. The effect of nanoparticles on protein adsorption was assessed by native polyacrylamide gel electrophoresis (PAGE). In vitro release studies showed a sustained release profile of zidovudine. In vitro cytotoxicity and cellular uptake of the zidovudine-loaded nanoparticles were performed in MCF-7 and neuro 2a brain cells. The enhanced cellular internalization of drug loaded modified nanoparticles in both the cell lines were revealed by fluorescence microscopy. Hence the present study focuses on the feasibility of zidovudine-loaded polymer modified lipid nanoparticles as carriers for safe and efficient HIV/AIDS therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of ibuprofen-loaded nanostructured lipid carrier-based gels: characterization and investigation of in vitro and in vivo penetration through the skin

PubMed Central

Sütő, Blanka; Berkó, Szilvia; Kozma, Gábor; Kukovecz, Ákos; Budai-Szűcs, Mária; Erős, Gábor; Kemény, Lajos; Sztojkov-Ivanov, Anita; Gáspár, Róbert; Csányi, Erzsébet

2016-01-01

An ibuprofen-loaded nanostructured lipid carrier (IBU-NLC) was developed for enhanced skin penetration to improve the treatment of osteoarthritis and other musculoskeletal diseases. The mean particle size was 106 nm, with a spherical morphology, a smooth surface, and a zeta potential of −18.4 mV. X-ray diffraction studies revealed the amorphous state of the lipid matrix. Both Raman spectroscopy and Fourier transformation infrared analysis indicated no major shifts in the spectra of the formulations, which suggest rapid drug dissolution from the nanoparticles. The drug loading was 9.85%, and the entrapment efficiency was 98.51%. In vitro release of the NLC dispersion, in vitro permeation, and in vivo animal studies of IBU-NLC gel all confirmed that the permeation of IBU was significantly better than that of a reference after 6 hours. In conclusion, IBU-NLC gel is of great potential to enhance drug permeation through the skin and hence the efficacy of the treatment of chronic joint inflammation. PMID:27099487

Lipid Multilayer Grating Arrays Integrated by Nanointaglio for Vapor Sensing by an Optical Nose

PubMed Central

Lowry, Troy W.; Prommapan, Plengchart; Rainer, Quinn; Van Winkle, David; Lenhert, Steven

2015-01-01

Lipid multilayer gratings are recently invented nanomechanical sensor elements that are capable of transducing molecular binding to fluid lipid multilayers into optical signals in a label free manner due to shape changes in the lipid nanostructures. Here, we show that nanointaglio is suitable for the integration of chemically different lipid multilayer gratings into a sensor array capable of distinguishing vapors by means of an optical nose. Sensor arrays composed of six different lipid formulations are integrated onto a surface and their optical response to three different vapors (water, ethanol and acetone) in air as well as pH under water is monitored as a function of time. Principal component analysis of the array response results in distinct clustering indicating the suitability of the arrays for distinguishing these analytes. Importantly, the nanointaglio process used here is capable of producing lipid gratings out of different materials with sufficiently uniform heights for the fabrication of an optical nose. PMID:26308001

Sustained release biodegradable solid lipid microparticles: Formulation, evaluation and statistical optimization by response surface methodology.

PubMed

Hanif, Muhammad; Khan, Hafeez Ullah; Afzal, Samina; Mahmood, Asif; Maheen, Safirah; Afzal, Khurram; Iqbal, Nabila; Andleeb, Mehwish; Abbas, Nazar

2017-12-20

For preparing nebivolol loaded solid lipid microparticles (SLMs) by the solvent evaporation microencapsulation process from carnauba wax and glyceryl monostearate, central composite design was used to study the impact of independent variables on yield (Y1), entrapment efficiency (Y2) and drug release (Y3). SLMs having a 10-40 μm size range, with good rheological behavior and spherical smooth surfaces, were produced. Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffractometry pointed to compatibility between formulation components and the zeta-potential study confirmed better stability due to the presence of negative charge (-20 to -40 mV). The obtained outcomes for Y1 (29-86 %), Y2 (45-83 %) and Y3 (49-86 %) were analyzed by polynomial equations and the suggested quadratic model were validated. Nebivolol release from SLMs at pH 1.2 and 6.8 was significantly (p < 0.05) affected by lipid concentration. The release mechanism followed Higuchi and zero order models, while n > 0.85 value (Korsmeyer- Peppas) suggested slow erosion along with diffusion. The optimized SLMs have the potential to improve nebivolol oral bioavailability.

Infrared study of structural characteristics of Frankfurters formulated with olive oil-in-water emulsions stabilized with casein as pork backfat replacer.

PubMed

Carmona, P; Ruiz-Capillas, C; Jiménez-Colmenero, F; Pintado, T; Herrero, A M

2011-12-28

This article reports an infrared spectroscopic (FT-IR) study on lipids and protein structural characteristics in frankfurters as affected by an emulsified olive oil stabilizing system used as a pork backfat replacer. The oil-in-water emulsions were stabilized with sodium caseinate, without (F/SC) and with microbial transglutaminase (F/SC+MTG). Proximate composition and textural characteristics were also evaluated. Frankfurters F/SC+MTG showed the highest (P < 0.05) hardness and lowest (P < 0.05) adhesiveness. These products also showed the lowest (P < 0.05) half-bandwidth of the 2922 cm(-1) band, which could be related to the fact that the lipid chain was more orderly than that in the frankfurters formulated with animal fat and F/SC. The spectral results revealed modifications in the amide I band profile when the olive oil-in-water emulsion replaced animal fat. This fact is indicative of a greater content of aggregated intermolecular β-sheets. Structural characteristics in both proteins and lipids could be associated with the specific textural properties of frankfurters.

Preservation of anthocyanins in solid lipid nanoparticles: Optimization of a microemulsion dilution method using the Placket-Burman and Box-Behnken designs.

PubMed

Ravanfar, Raheleh; Tamaddon, Ali Mohammad; Niakousari, Mehrdad; Moein, Mahmoud Reza

2016-05-15

Anthocyanins are the main polyphenol components from red cabbage (Brassica oleracea L. Var. Capitata f. Rubra) extracts that have inherent antioxidant activities. Anthocyanins are effectively stable in acidic gastric digestion conditions, with nearly 100% phenol content recovery. However, the total phenol content recovery after simulated pancreatic digestion was approximately 25%. To protect anthocyanins against harsh environmental conditions (e.g., pH and temperature), solid lipid nanoparticles were prepared by the dilution of water in oil (w/o) microemulsions containing anthocyanins in aqueous media. The formulations were characterized for particle size and encapsulation efficiency. The formulation parameters (e.g., volume of the internal aqueous phase, homogenization time and the percentages of total lipid, total surfactant or stabilizer) were optimized using the Placket-Burman and Box-Behnken experimental designs. Entrapment efficiency (89.2 ± 0.3%) was calculated when the mean particle size was 455 ± 2 nm. A scanning electron microscopy study revealed the spherical morphology of the particles. Copyright © 2015 Elsevier Ltd. All rights reserved.

Novel Nanostructured Solid Materials for Modulating Oral Drug Delivery from Solid-State Lipid-Based Drug Delivery Systems.

PubMed

Dening, Tahnee J; Rao, Shasha; Thomas, Nicky; Prestidge, Clive A

2016-01-01

Lipid-based drug delivery systems (LBDDS) have gained significant attention in recent times, owing to their ability to overcome the challenges limiting the oral delivery of poorly water-soluble drugs. Despite the successful commercialization of several LBDDS products over the years, a large discrepancy exists between the number of poorly water-soluble drugs displaying suboptimal in vivo performances and the application of LBDDS to mitigate their various delivery challenges. Conventional LBDDS, including lipid solutions and suspensions, emulsions, and self-emulsifying formulations, suffer from various drawbacks limiting their widespread use and commercialization. Accordingly, solid-state LBDDS, fabricated by adsorbing LBDDS onto a chemically inert solid carrier material, have attracted substantial interest as a viable means of stabilizing LBDDS whilst eliminating some of the various limitations. This review describes the impact of solid carrier choice on LBDDS performance and highlights the importance of appropriate solid carrier material selection when designing hybrid solid-state LBDDS. Specifically, emphasis is placed on discussing the ability of the specific solid carrier to modulate drug release, control lipase action and lipid digestion, and enhance biopharmaceutical performance above the original liquid-state LBDDS. To encourage the interested reader to consider their solid carrier choice on a higher level, various novel materials with the potential for future use as solid carriers for LBDDS are described. This review is highly significant in guiding future research directions in the solid-state LBDDS field and fostering the translation of these delivery systems to the pharmaceutical marketplace.

Stratum corneum lipid liposome-encapsulated panomycocin: preparation, characterization, and the determination of antimycotic efficacy against Candida spp. isolated from patients with vulvovaginitis in an in vitro human vaginal epithelium tissue model.

PubMed

İzgü, Fatih; Bayram, Günce; Tosun, Kübra; İzgü, Demet

2017-01-01

In this study, a liposomal lyophilized powder formulation of panomycocin was developed for therapeutic purposes against vulvovaginal candidiasis which affects 80% of women worldwide. Panomycocin is a potent antimycotic protein secreted by the yeast Wickerhamomyces anomalus NCYC 434. This study involved the preparation of panomycocin-loaded stratum corneum lipid liposomes (SCLLs), characterization of the SCLLs, and determination of antimycotic efficacy of the formulation against Candida albicans and Candida glabrata clinical vaginal isolates in a human vaginal epithelium tissue model. The encapsulation and loading efficiencies of SCLLs were 73% and 76.8%, respectively. In transmission electron microscopy images, the SCLLs appeared in the submicron size range. Dynamic light scattering analyses showed that the SCLLs had uniform size distribution. Zeta potential measurements revealed stable and positively charged SCLLs. In Fourier transform infrared spectroscopy analyses, no irreversible interactions between the encapsulated panomycocin and the SCLLs were detected. The SCLLs retained >98% of encapsulated panomycocin in aqueous solution up to 12 hours. The formulation was fungicidal at the same minimum fungicidal concentration values for non-formulated pure panomycocin when tested on an in vitro model of vaginal candidiasis. This is the first study in which SCLLs and a protein as an active ingredient have been utilized together in a formulation. The results obtained in this study led us to conduct further preclinical trials of this formulation for the development of an effective topical anti-candidal drug with improved safety.

Stratum corneum lipid liposome-encapsulated panomycocin: preparation, characterization, and the determination of antimycotic efficacy against Candida spp. isolated from patients with vulvovaginitis in an in vitro human vaginal epithelium tissue model

PubMed Central

İzgü, Fatih; Bayram, Günce; Tosun, Kübra; İzgü, Demet

2017-01-01

In this study, a liposomal lyophilized powder formulation of panomycocin was developed for therapeutic purposes against vulvovaginal candidiasis which affects 80% of women worldwide. Panomycocin is a potent antimycotic protein secreted by the yeast Wickerhamomyces anomalus NCYC 434. This study involved the preparation of panomycocin-loaded stratum corneum lipid liposomes (SCLLs), characterization of the SCLLs, and determination of antimycotic efficacy of the formulation against Candida albicans and Candida glabrata clinical vaginal isolates in a human vaginal epithelium tissue model. The encapsulation and loading efficiencies of SCLLs were 73% and 76.8%, respectively. In transmission electron microscopy images, the SCLLs appeared in the submicron size range. Dynamic light scattering analyses showed that the SCLLs had uniform size distribution. Zeta potential measurements revealed stable and positively charged SCLLs. In Fourier transform infrared spectroscopy analyses, no irreversible interactions between the encapsulated panomycocin and the SCLLs were detected. The SCLLs retained >98% of encapsulated panomycocin in aqueous solution up to 12 hours. The formulation was fungicidal at the same minimum fungicidal concentration values for non-formulated pure panomycocin when tested on an in vitro model of vaginal candidiasis. This is the first study in which SCLLs and a protein as an active ingredient have been utilized together in a formulation. The results obtained in this study led us to conduct further preclinical trials of this formulation for the development of an effective topical anti-candidal drug with improved safety. PMID:28831255

Potential of insulin nanoparticle formulations for oral delivery and diabetes treatment.

PubMed

Wong, Chun Y; Al-Salami, Hani; Dass, Crispin R

2017-10-28

Nanoparticles have demonstrated significant advancements in potential oral delivery of insulin. In this publication, we review the current status of polymeric, inorganic and solid-lipid nanoparticles designed for oral administration of insulin. Firstly, the structure and physiological function of insulin are examined. Then, the efficiency and shortcomings of insulin nanoparticle are discussed. These include the susceptibility to digestive enzyme degradation, instability in the acidic pH environment, poor mucus diffusion and inadequate permeation through the gastrointestinal epithelium. In order to optimise the nanocarriers, the following considerations, including polymer nature, surface charge, size, polydispersity index and morphology of nanoparticles, have to be taken into account. Some novel designs such as chitosan-based glucose-responsive nanoparticles, layer by layer technique-based nanoparticles and zwitterion nanoparticles are being adopted to overcome the physiological challenges. The review ends with some future directions and challenges to be addressed for the success of oral delivery of insulin-loaded nanoparticle formulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Canned bluefin tuna, an in vitro cardioprotective functional food potentially safer than commercial fish oil based pharmaceutical formulations.

PubMed

Tenore, Gian Carlo; Calabrese, Giorgio; Ritieni, Alberto; Campiglia, Pietro; Giannetti, Daniela; Novellino, Ettore

2014-09-01

Commercial canned fish species typical in the Italian market were evaluated for their lipid profile. Bluefin tuna samples showed the highest content in omega-3 fatty acids (n-3 PUFA) among the canned fish samples analyzed. Tests on H9C2 cardiomyocytes revealed that bluefin tuna n-3 PUFA may responsible for a significant cell protection against both physiological and doxorubicin-induced oxidative stress. Analogous tests performed by incubating cardiac cells with n-3 PUFA ethyl esters, of which most of fish oil pharmaceutical formulations (FOPF) are based, showed cytotoxicity at high doses. Our results highlighted that n-3 PUFA contents in a 50 g canned bluefin tuna portion would be almost equivalent to and potentially safer than those of 1 FOPF capsule (1000 mg)/die usually suggested for hyperlipidaemic subjects. Thus, Italian commercial canned bluefin tuna could be indicated as a functional food with potential health benefits for the prevention and care of cardiovascular disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

Multilayer engineered nanoliposomes as a novel tool for oral delivery of lipopeptide-based vaccines against group A Streptococcus.

PubMed

Marasini, Nirmal; Giddam, Ashwini K; Ghaffar, Khairunnisa A; Batzloff, Michael R; Good, Michael F; Skwarczynski, Mariusz; Toth, Istvan

2016-05-01

To develop an oral nanovaccine delivery system for lipopeptide-based vaccine candidate against group A Streptococcus. Lipid-core peptide-1-loaded nanoliposomes were prepared as a template and coated with opposite-charged polyelectrolytes to produce particles with size <200 nm. Efficacy of this oral nanovaccine delivery system was evaluated in mice model. Polymer-coated liposomes produced significantly higher antigen-specific mucosal IgA and systemic IgG titers in comparison to vaccine formulated with a strong mucosal adjuvant upon oral immunization in mice. Moreover, high levels of systemic antibody titers were retained even at day 185 postprimary immunization. Efficient oral delivery platform for lipopeptide-based vaccines has been developed.

Methodology for AACT evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning.

PubMed

Gosselin, Sophie; Morris, Martin; Miller-Nesbitt, Andrea; Hoffman, Robert S; Hayes, Bryan D; Turgeon, Alexis F; Gilfix, Brian M; Grunbaum, Ami M; Bania, Theodore C; Thomas, Simon H L; Morais, José A; Graudins, Andis; Bailey, Benoit; Mégarbane, Bruno; Calello, Diane P; Levine, Michael; Stellpflug, Samuel J; Hoegberg, Lotte C G; Chuang, Ryan; Stork, Christine; Bhalla, Ashish; Rollins, Carol J; Lavergne, Valéry

2015-07-01

Intravenous lipid emulsion (ILE) therapy is a novel treatment that was discovered in the last decade. Despite unclear understanding of its mechanisms of action, numerous and diverse publications attested to its clinical use. However, current evidence supporting its use is unclear and recommendations are inconsistent. To assist clinicians in decision-making, the American Academy of Clinical Toxicology created a workgroup composed of international experts from various clinical specialties, which includes representatives of major clinical toxicology associations. Rigorous methodology using the Appraisal of Guidelines for Research and Evaluation or AGREE II instrument was developed to provide a framework for the systematic reviews for this project and to formulate evidence-based recommendations on the use of ILE in poisoning. Systematic reviews on the efficacy of ILE in local anesthetic toxicity and non-local anesthetic poisonings as well as adverse effects of ILE are planned. A comprehensive review of lipid analytical interferences and a survey of ILE costs will be developed. The evidence will be appraised using the GRADE system. A thorough and transparent process for consensus statements will be performed to provide recommendations, using a modified Delphi method with two rounds of voting. This process will allow for the production of useful practice recommendations for this therapy.

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38.

PubMed

Bala, Vaskor; Rao, Shasha; Boyd, Ben J; Prestidge, Clive A

2013-11-28

SN38 (7-ethyl-10-hydroxy camptothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents; therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines. © 2013 Elsevier B.V. All rights reserved.

Efficient co-delivery of immiscible hydrophilic/hydrophobic chemotherapeutics by lipid emulsions for improved treatment of cancer

PubMed Central

Zhang, Bo; Song, Yunmei; Wang, Tianqi; Yang, Shaomei; Zhang, Jing; Liu, Yongjun; Zhang, Na; Garg, Sanjay

2017-01-01

Combinational nanomedicine is becoming a topic of much interest in cancer therapy, although its translation into the clinic remains extremely challenging. One of the main obstacles lies in the difficulty to efficiently co-deliver immiscible hydrophilic/hydrophobic drugs into tumor sites. The aim of this study was to develop co-loaded lipid emulsions (LEs) to co-deliver immiscible hydrophilic/hydrophobic drugs to improve cancer therapy and to explore the co-delivery abilities between co-loaded LEs and mixture formulation. Multiple oxaliplatin/irinotecan drug–phospholipid complexes (DPCs) were formulated. Co-loaded LEs were prepared using DPC technique to efficiently encapsulate both drugs. Co-loaded LEs exhibited uniform particle size distribution, desired stability and synchronous release profiles in both drugs. Co-loaded LEs demonstrated superior anti-tumor activity compared with the simple solution mixture and the mixture of single-loaded LEs. Furthermore, co-loaded nanocarriers could co-deliver both drugs into the same cells more efficiently and exhibited the optimized synergistic effect. These results indicate that co-loaded LEs could be a desired formulation for enhanced cancer therapy with potential application prospects. The comparison between co-loaded LEs and mixture formulation is significant for pharmaceutical designs aimed at co-delivery of multiple drugs. PMID:28435264

Efficient co-delivery of immiscible hydrophilic/hydrophobic chemotherapeutics by lipid emulsions for improved treatment of cancer.

PubMed

Zhang, Bo; Song, Yunmei; Wang, Tianqi; Yang, Shaomei; Zhang, Jing; Liu, Yongjun; Zhang, Na; Garg, Sanjay

2017-01-01

Combinational nanomedicine is becoming a topic of much interest in cancer therapy, although its translation into the clinic remains extremely challenging. One of the main obstacles lies in the difficulty to efficiently co-deliver immiscible hydrophilic/hydrophobic drugs into tumor sites. The aim of this study was to develop co-loaded lipid emulsions (LEs) to co-deliver immiscible hydrophilic/hydrophobic drugs to improve cancer therapy and to explore the co-delivery abilities between co-loaded LEs and mixture formulation. Multiple oxaliplatin/irinotecan drug-phospholipid complexes (DPCs) were formulated. Co-loaded LEs were prepared using DPC technique to efficiently encapsulate both drugs. Co-loaded LEs exhibited uniform particle size distribution, desired stability and synchronous release profiles in both drugs. Co-loaded LEs demonstrated superior anti-tumor activity compared with the simple solution mixture and the mixture of single-loaded LEs. Furthermore, co-loaded nanocarriers could co-deliver both drugs into the same cells more efficiently and exhibited the optimized synergistic effect. These results indicate that co-loaded LEs could be a desired formulation for enhanced cancer therapy with potential application prospects. The comparison between co-loaded LEs and mixture formulation is significant for pharmaceutical designs aimed at co-delivery of multiple drugs.

Impacts of chemical enhancers on skin permeation and deposition of terbinafine.

PubMed

Erdal, Meryem Sedef; Peköz, Ayca Yıldız; Aksu, Buket; Araman, Ahmet

2014-08-01

The addition of chemical enhancers into formulations is the most commonly employed approach to overcome the skin barrier. The objective of this work was to evaluate the effect of vehicle and chemical enhancers on the skin permeation and accumulation of terbinafine, an allylamine antifungal drug. Terbinafine (1% w/w) was formulated as a Carbopol 934 P gel formulation in presence and absence of three chemical enhancers, nerolidol, dl-limonene and urea. Terbinafine distribution and deposition in stratum corneum (SC) and skin following 8-h ex vivo permeation study was determined using a sequential tape stripping procedure. The conformational order of SC lipids was investigated by ATR-FTIR spectroscopy. Nerolidol containing gel formulation produced significantly higher enhancement in terbinafine permeation through skin and its skin accumulation was increased. ATR-FTIR results showed enhancer induced lipid bilayer disruption in SC. Urea resulted in enhanced permeation of terbinafine across the skin and a balanced distribution to the SC was achieved. But, dl-limonene could not minimize the accumulation of terbinafine in the upper SC. Nerolidol dramatically improved the skin permeation and deposition of terbinafine in the skin that might help to optimize targeting of the drug to the epidermal sites as required for both of superficial and deep cutaneous fungal infections.

Dorzolamide Loaded Niosomal Vesicles: Comparison of Passive and Remote Loading Methods

PubMed Central

Hashemi Dehaghi, Mohadeseh; Haeri, Azadeh; Keshvari, Hamid; Abbasian, Zahra; Dadashzadeh, Simin

2017-01-01

Glaucoma is a common progressive eye disorder and the treatment strategies will benefit from nanoparticulate delivery systems with high drug loading and sustained delivery of intraocular pressure lowering agents. Niosomes have been reported as a novel approach to improve drug low corneal penetration and bioavailability characteristics. Along with this, poor entrapment efficiency of hydrophilic drug in niosomal formulation remains as a major formulation challenge. Taking this perspective into consideration, dorzolamide niosomes were prepared employing two different loading methodologies (passive and remote loading methods) and the effects of various formulation variables (lipid to drug ratio, cholesterol percentage, drug concentration, freeze/thaw cycles, TPGS content, and external and internal buffer molarity and pH) on encapsulation efficiency were assessed. Encapsulation of dorzolamide within niosomes increased remarkably by the incorporation of higher cholesterol percentage as well as increasing the total lipid concentration. Remote loading method showed higher efficacy for drug entrapment compared to passive loading technique. Incorporation of TPGS in bilayer led to decrease in EE; however, retarded drug release rate. Scanning electron microscopy (SEM) studies confirmed homogeneous particle distribution, and spherical shape with smooth surface. In conclusion, the highest encapsulation can be obtained using phosphate gradient method and 50% cholesterol in Span 60 niosomal formulation. PMID:28979296

Effect of apitherapy formulations against carbon tetrachloride-induced toxicity in Wistar rats after three weeks of treatment.

PubMed

Andritoiu, Calin Vasile; Ochiuz, Lacramioara; Andritoiu, Vasile; Popa, Marcel

2014-08-29

The human body is exposed nowadays to increasing attacks by toxic compounds in polluted air, industrially processed foods, alcohol and drug consumption that increase liver toxicity, leading to more and more severe cases of hepatic disorders. The present paper aims to evaluate the influence of the apitherapy diet in Wistar rats with carbon tetrachloride-induced hepatotoxicity, by analyzing the biochemical determinations (enzymatic, lipid and protein profiles, coagulation parameters, minerals, blood count parameters, bilirubin levels) and histopathological changes at the level of liver, spleen and pancreas. The experiment was carried out on six groups of male Wistar rats. Hepatic lesions were induced by intraperitoneal injection of carbon tetrachloride (dissolved in paraffin oil, 10% solution). Two mL per 100 g were administered, every 2 days, for 2 weeks. Hepatoprotection was achieved with two apitherapy diet formulations containing honey, pollen, propolis, Apilarnil, with/without royal jelly. Biochemical results reveal that the two apitherapy diet formulations have a positive effect on improving the enzymatic, lipid, and protein profiles, coagulation, mineral and blood count parameters and bilirubin levels. The histopathological results demonstrate the benefits of the two apitherapy diet formulations on reducing toxicity at the level of liver, spleen and pancreas in laboratory animals.

Encapsulation of Naproxen in Lipid-Based Matrix Microspheres: Characterization and Release Kinetics

PubMed Central

Bhoyar, PK; Morani, DO; Biyani, DM; Umekar, MJ; Mahure, JG; Amgaonkar, YM

2011-01-01

The objective of this study was to microencapsulate the anti-inflammatory drug (naproxen) to provide controlled release and minimizing or eliminating local side effect by avoiding the drug release in the upper gastrointestinal track. Naproxen was microencapsulated with lipid-like carnauba wax, hydrogenated castor oil using modified melt dispersion (modified congealable disperse phase encapsulation) technique. Effect of various formulation and process variables such as drug-lipid ratio, concentration of modifier, concentration of dispersant, stirring speed, stirring time, temperature of external phase, on evaluatory parameters such as size, entrapment efficiency, and in vitro release of naproxen were studied. The microspheres were characterized for particle size, scanning electron microscopy (SEM), FT-IR spectroscopy, drug entrapment efficiency, in vitro release studies, for in vitro release kinetics. The shape of microspheres was found to be spherical by SEM. The drug entrapment efficiency of various batches of microspheres was found to be ranging from 60 to 90 %w/w. In vitro drug release studies were carried out up to 24 h in pH 7.4 phosphate buffer showing 50-65% drug release. In vitro drug release from all the batches showed better fitting with the Korsmeyer-Peppas model, indicating the possible mechanism of drug release to be by diffusion and erosion of the lipid matrix. PMID:21731354

Encapsulation of naproxen in lipid-based matrix microspheres: characterization and release kinetics.

PubMed

Bhoyar, P K; Morani, D O; Biyani, D M; Umekar, M J; Mahure, J G; Amgaonkar, Y M

2011-04-01

The objective of this study was to microencapsulate the anti-inflammatory drug (naproxen) to provide controlled release and minimizing or eliminating local side effect by avoiding the drug release in the upper gastrointestinal track. Naproxen was microencapsulated with lipid-like carnauba wax, hydrogenated castor oil using modified melt dispersion (modified congealable disperse phase encapsulation) technique. Effect of various formulation and process variables such as drug-lipid ratio, concentration of modifier, concentration of dispersant, stirring speed, stirring time, temperature of external phase, on evaluatory parameters such as size, entrapment efficiency, and in vitro release of naproxen were studied. The microspheres were characterized for particle size, scanning electron microscopy (SEM), FT-IR spectroscopy, drug entrapment efficiency, in vitro release studies, for in vitro release kinetics. The shape of microspheres was found to be spherical by SEM. The drug entrapment efficiency of various batches of microspheres was found to be ranging from 60 to 90 %w/w. In vitro drug release studies were carried out up to 24 h in pH 7.4 phosphate buffer showing 50-65% drug release. In vitro drug release from all the batches showed better fitting with the Korsmeyer-Peppas model, indicating the possible mechanism of drug release to be by diffusion and erosion of the lipid matrix.

Chitosan-Coated Cinnamon/Oregano-Loaded Solid Lipid Nanoparticles to Augment 5-Fluorouracil Cytotoxicity for Colorectal Cancer: Extract Standardization, Nanoparticle Optimization, and Cytotoxicity Evaluation.

PubMed

Kamel, Kamel M; Khalil, Islam A; Rateb, Mostafa E; Elgendy, Hosieny; Elhawary, Seham

2017-09-13

This study aimed to coat lipid-based nanocarriers with chitosan to encapsulate nutraceuticals, minimize opsonization, and facilitate passive-targeting. Phase one was concerned with standardization according to the World Health Organization. Qualitative analysis using liquid chromatography-high-resolution mass spectrometry (LC-HRMS/MS) investigated the active constituents, especially reported cytotoxic agents. Cinnamaldehyde and rosmarinic acid were selected to be quantified using high-performance liquid chromatography. Phase two was aimed to encapsulate both extracts in solid lipid nanoparticles (core) and chitosan (shell) to gain the advantages of both materials properties. The developed experimental model suggested an optimum formulation with 2% lipid, 2.3% surfactant, and 0.4% chitosan to achieve a particle size of 254.77 nm, polydispersity index of 0.28, zeta potential of +15.26, and entrapment efficiency percentage of 77.3% and 69.1% for cinnamon and oregano, respectively. Phase three was focused on the evaluation of cytotoxic activity unencapsulated/encapsulated cinnamon and oregano extracts with/without 5-fluorouracil on HCT-116 cells. This study confirmed the success of the suggested combination with 5-fluorouracil for treating human colon carcinoma with a low dose leading to decreasing side effects and allowing uninterrupted therapy.

Structural recovery of the retina in a retinoschisin-deficient mouse after gene replacement therapy by solid lipid nanoparticles.

PubMed

Apaolaza, P S; Del Pozo-Rodríguez, A; Solinís, M A; Rodríguez, J M; Friedrich, U; Torrecilla, J; Weber, B H F; Rodríguez-Gascón, A

2016-06-01

X-linked juvenile retinoschisis (XLRS) is a retinal degenerative disorder caused by mutations in the RS1 gene encoding a protein termed retinoschisin. The disease is an excellent candidate for gene replacement therapy as the majority of mutations have been shown to lead to a complete deficiency of the secreted protein in the retinal structures. In this work, we have studied the ability of non-viral vectors based on solid lipid nanoparticles (SLN) to induce the expression of retinoschisin in photoreceptors (PR) after intravitreal administration to Rs1h-deficient mice. We designed two vectors prepared with SLN, protamine, and dextran (DX) or hyaluronic acid (HA), bearing a plasmid containing the human RS1 gene under the control of the murin opsin promoter (mOPS). In vitro, the nanocarriers were able to induce the expression of retinoschisin in a PR cell line. After injection into the murine vitreous, the formulation prepared with HA induced a higher transfection level in PR than the formulation prepared with DX. Moreover, the level of retinoschisin in the inner nuclear layer (INL), where bipolar cells are located, was also higher. Two weeks after vitreal administration into Rs1h-deficient mice, both formulations showed significant improvement of the retinal structure by inducing a decrease of cavities and PR loss, and an increase of retinal and outer nuclear layer (ONL) thickness. HA-SLN resulted in a significant higher increase in the thickness of both retina and ONL, which can be explained by the higher transfection level of PR. In conclusion, we have shown the structural improvement of the retina of Rs1h-deficient mice with PR specific expression of the RS1 gene driven by the specific promoter mOPS, after successful delivery via SLN-based non-viral vectors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Trilysinoyl oleylamide-based cationic liposomes for systemic co-delivery of siRNA and an anticancer drug.

PubMed

Shim, Gayong; Han, Su-Eun; Yu, Yong-Hee; Lee, Sangbin; Lee, Han Young; Kim, Kwangmeyung; Kwon, Ick Chan; Park, Tae Gwan; Kim, Young Bong; Choi, Yong Seok; Kim, Chan-Wha; Oh, Yu-Kyoung

2011-10-10

Oligolysine-based cationic lipid derivatives were synthesized for delivery of siRNA, and formulated into cationic liposomes. Among various oligolysine-based lipid derivatives differing in lysine residue number and lipid moiety, trilysinoyl oleylamide (TLO)-based liposomes (TLOL) showed the highest delivery efficiency combined with minimal cytotoxicity. Delivery of siRNA using TLOL silenced target genes both in vitro and in vivo. In green fluorescent protein (GFP)-expressing tumor tissue, a significant reduction of fluorescence was observed after intratumoral administration of siGFP using TLOL compared with control siGL2. Intravenous administration of siMcl1 employing pegylated TLOL (pTLOL) reduced the expression of human Mcl1 protein in KB-xenografted tumor tissue. Despite the reduction in target protein Mcl1 expression following such systemic delivery, tumor growth was only slightly reduced compared to a siGL2-treated control group. To potentiate the anticancer activity of siMcl1, the anticancer drug suberoylanilide hydroxamic acid (SAHA) was additionally encapsulated in pTLOL. After intravenous administration of siMcl1 using SAHA-loaded pTLOL (pSTLOL), a significant reduction in tumor growth was observed compared to that seen in animals treated with free SAHA or siGL2 complexed with pSTLOL. The results indicate that pTLOL could be further developed as a systemic delivery system for synergistic anticancer siRNA and a drug. Copyright © 2010 Elsevier B.V. All rights reserved.

A Novel ω-3 Acid Ethyl Ester Formulation Incorporating Advanced Lipid TechnologiesTM (ALT®) Improves Docosahexaenoic Acid and Eicosapentaenoic Acid Bioavailability Compared with Lovaza®.

PubMed

Lopez-Toledano, Miguel A; Thorsteinsson, Thorsteinn; Daak, Ahmed; Maki, Kevin C; Johns, Colleen; Rabinowicz, Adrian L; Sancilio, Frederick D

2017-03-01

The US Food and Drug Administration has approved several highly purified ω-3 fatty acid prescription drugs for the treatment of severe hypertriglyceridemia. These differ in the amounts and forms of docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA). This study compared the bioavailability of SC401 (1530 mg EPA-ethyl esters [EEs] and DHA-EEs plus Advanced Lipid Technologies ⁎ [ALT † ], a proprietary lipid-delivery platform to improve absorption), with. Lovaza ‡ (3600 mg ω-3, primarily EPA-EEs and DHA-EEs) under low-fat feeding conditions. This was a Phase I, randomized, open-label, single-dose, 2-way crossover study in healthy participants housed from day -3 to day 2 in each treatment period. Blood samples for pharmacokinetic measurements were collected before and after dosing, and safety profile and tolerability were assessed. In unadjusted analyses, SC401 had 5% lower C max and approximately the same AUC 0-last of EPA + DHA total lipids compared with Lovaza. When adjusted for baseline, SC401 had ~6% higher C max and 18% higher AUC 0-last for EPA + DHA total lipids, and dose- and baseline-adjusted analyses found that SC401 had ~149% higher C max and 178% higher AUC 0-last than Lovaza for EPA + DHA total lipids. The T max was also substantially longer with Lovaza (~10 hours) than with SC401 (~6 hours). These results indicate that SC401, an ω-3 acid EE formulation containing ALT † achieved high bioavailability of EPA and DHA, at a lower dose (1530 mg) than Lovaza (3600 mg), under low-fat feeding conditions. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Functionalized nanoparticles for AMF-induced gene and drug delivery

NASA Astrophysics Data System (ADS)

Biswas, Souvik

The properties and broad applications of nano-magnetic colloids have generated much interest in recent years. Specially, Fe3O4 nanoparticles have attracted a great deal of attention since their magnetic properties can be used for hyperthermia treatment or drug targeting. For example, enhanced levels of intracellular gene delivery can be achieved using Fe3O4 nano-vectors in the presence of an external magnetic field, a process known as 'magnetofection'. The low cytotoxicity, tunable particle size, ease of surface functionalization, and ability to generate thermal energy using an external alternating magnetic field (AMF) are properties have propelled Fe3O4 research to the forefront of nanoparticle research. The strategy of nanoparticle-mediated, AMF-induced heat generation has been used to effect intracellular hyperthermia. One application of this 'magnetic hyperthermia' is heat activated local delivery of a therapeutic effector (e.g.; drug or polynucleotide). This thesis describes the development of a magnetic nano-vector for AMF-induced, heat-activated pDNA and small molecule delivery. The use of heat-inducible vectors, such as heat shock protein ( hsp) genes, is a promising mode of gene therapy that would restrict gene expression to a local region by focusing a heat stimulus only at a target region. We thus aimed to design an Fe3O4 nanoparticle-mediated gene transfer vehicle for AMF-induced localized gene expression. We opted to use 'click' oximation techniques to assemble the magnetic gene transfer vector. Chapter 2 describes the synthesis, characterization, and transfection studies of the oxime ether lipid-based nano-magnetic vectors MLP and dMLP. The synthesis and characterization of a novel series of quaternary ammonium aminooxy reagents (2.1--2.4) is described. These cationic aminooxy compounds were loaded onto nanoparticles for ligation with carbonyl groups and also to impart a net positive charge on the nanoparticle surface. Our studies indicated that the non-toxic magnetoplexes (magnetic nanoparticle + pDNA complex) derived from dMLP deliver pDNA into mammalian cells even without external magnetic assistance. To date, dMLP is the only polymer-free magnetic gene delivery system that can deliver pDNA without any magnetic assistance. Chapter 3 of this thesis outlines the synthesis and characterization of other oxime ether lipids and details studies using derived-lipoplexes. These lipids were evaluated in pDNA and siRNA transfection studies in various mammalian cell lines. This work constitutes the first use of an oxime ether as the linking domain in cationic transfection lipids. These biocompatible oxime ether lipids can be readily assembled by click chemistry through ligation of hydrophobic aldehydes with quaternary ammonium aminooxy salts. Our studies showed that the oxime ether lipids transfected pDNA and siRNA efficiently in MCF-7, H 1792, and in PAR C10 cells comparable to and in some cases better than commercial transfection lipids. Chapter 4 describes the design and characterization of a nano-magnetic delivery system for AMF-induced drug (doxorubicin) release. In efforts to develop a magnetic formulation free from thermosensitive materials, such as hydrogels, we synthesized three nanoparticle-based doxorubicin formulations using charge interactions as the key associative force. To do so, we synthesized and characterized a novel cationic oxime ether conjugate at C-13 of doxorubicin. Our investigation indicated that the positive charge of the oxime ether drug conjugate tended to bind better to the negatively charged nanoparticle than did the other formulations prepared in stepwise manner. Our findings show that the nano-magnetic formulations remained essestially inactive at body temperature (37.5 °C) and released a majority of the cargo only when exposed to an external AMF. Our designed magnetic drug delivery platform is the first example of an AMF-inducible system that does not depend on the inclusion of thermosensitive materials. Finally, we have developed a bioanalytical application of the highly chemoselective oximation chemistry using aminooxy reagent 2.1. Chapter 5 describes a silica microchip containing micropillars coated with cationic aminooxy reagent 2.1. The microchip captures gaseous ketones and aldehydes from exhaled human breath. A brief description of microchip fabricated breath analyzer and breath analysis is described in Chapter 5. Our studies showed that the acetone capture efficiency of the aminooxy-loaded microchip was 98%.

Development of a liposome microbicide formulation for vaginal delivery of octylglycerol for HIV prevention

PubMed Central

Wang, Lin; Sassi, Alexandra Beumer; Patton, Dorothy; Isaacs, Charles; Moncla, B. J.; Gupta, Phalguni; Rohan, Lisa Cencia

2015-01-01

The feasibility of using a liposome drug delivery system to formulate octylglycerol (OG) as a vaginal microbicide product was explored. A liposome formulation was developed containing 1% OG and phosphatidyl choline in a ratio that demonstrated in vitro activity against Neisseria gonorrhoeae, HSV-1, HSV-2 and HIV-1 while sparing the innate vaginal flora, Lactobacillus. Two conventional gel formulations were prepared for comparison. The OG liposome formulation with the appropriate OG/lipid ratio and dosing level had greater efficacy than either conventional gel formulation and maintained this efficacy for at least 2 months. No toxicity was observed for the liposome formulation in ex vivo testing in a human ectocervical tissue model or in vivo testing in the macaque safety model. Furthermore, minimal toxicity was observed to lactobacilli in vitro or in vivo safety testing. The OG liposome formulation offers a promising microbicide product with efficacy against HSV, HIV and N. gonorrhoeae. PMID:22149387

Design, Synthesis of Novel Lipids as Chemical Permeation Enhancers and Development of Nanoparticle System for Transdermal Drug Delivery

PubMed Central

Shah, Punit P.; Etukala, Jagan Reddy; Vemuri, Adithi; Singh, Mandip

2013-01-01

In the present study, we designed and developed novel lipids that include (Z)-1-(Octadec-9-en-1-yl)-pyrrolidine (Cy5T), 1, 1-Di-((Z)-octadec-9-en-1-yl)pyrrolidin-1-ium iodide (Cy5), (Z)-1-(Octadec-9-en-1-yl)-piperidine (Cy6T), and 1, 1-Di-((Z)-octadec-9-en-1-yl) piperidin-1-ium iodide (Cy6) to enhance the transdermal permeation of some selected drugs. Firstly, we evaluated the transdermal permeation efficacies of these lipids as chemical permeation enhancers in vehicle formulations for melatonin, ß-estradiol, caffeine, α-MSH, and spantide using franz diffusion cells. Among them Cy5 lipid was determined to be the most efficient by increasing the transdermal permeation of melatonin, ß-estradiol, caffeine, α-MSH, and spantide by 1.5 to 3.26-fold more at the epidermal layer and 1.3 to 2.5-fold more at the dermal layer, in comparison to either NMP or OA. Hence we developed a nanoparticle system (cy5 lipid ethanol drug nanoparticles) to evaluate any further improvement in the drug penetration. Cy5 lipid formed uniformly sized nanoparticles ranging from 150–200 nm depending on the type of drug. Further, Cy5 based nanoparticle system significantly (p<0.05) increased the permeation of all the drugs in comparison to the lipid solution and standard permeation enhancers. There were about 1.54 to 22-fold more of drug retained in the dermis for the Cy5 based nanoparticles compared to OA/NMP standard enhancers and 3.87 to 66.67-fold more than lipid solution. In addition, epifluorescent microscopic analysis in rhodamine-PE permeation studies confirmed the superior permeation enhancement of LEDs (detection of fluorescence up to skin depth of 340 μm) more than lipid solution, which revealed fluorescence up to skin depth of only 260 μm. In summary the present findings demonstrate that i) cationic lipid with 5 membered amine heterocyclic ring has higher permeating efficacy than the 6 membered amine hertocyclic ring. ii) The nanoparticle system prepared with Cy5 showed significant (p<0.05) increase in the permeation of the drugs than the control penetration enhancers, oleic acid and NMP. PMID:24349315

Surface coating of siRNA-peptidomimetic nano-self-assemblies with anionic lipid bilayers: enhanced gene silencing and reduced adverse effects in vitro

NASA Astrophysics Data System (ADS)

Zeng, Xianghui; de Groot, Anne Marit; Sijts, Alice J. A. M.; Broere, Femke; Oude Blenke, Erik; Colombo, Stefano; van Eden, Willem; Franzyk, Henrik; Nielsen, Hanne Mørck; Foged, Camilla

2015-11-01

Cationic vectors have demonstrated the potential to facilitate intracellular delivery of therapeutic oligonucleotides. However, enhanced transfection efficiency is usually associated with adverse effects, which also proves to be a challenge for vectors based on cationic peptides. In this study a series of proteolytically stable palmitoylated α-peptide/β-peptoid peptidomimetics with a systematically varied number of repeating lysine and homoarginine residues was shown to self-assemble with small interfering RNA (siRNA). The resulting well-defined nanocomplexes were coated with anionic lipids giving rise to net anionic liposomes. These complexes and the corresponding liposomes were optimized towards efficient gene silencing and low adverse effects. The optimal anionic liposomes mediated a high silencing effect, which was comparable to that of the control (cationic Lipofectamine 2000), and did not display any noticeable cytotoxicity and immunogenicity in vitro. In contrast, the corresponding nanocomplexes mediated a reduced silencing effect with a more narrow safety window. The surface coating with anionic lipid bilayers led to partial decomplexation of the siRNA-peptidomimetic nanocomplex core of the liposomes, which facilitated siRNA release. Additionally, the optimal anionic liposomes showed efficient intracellular uptake and endosomal escape. Therefore, these findings suggest that a more efficacious and safe formulation can be achieved by surface coating of the siRNA-peptidomimetic nano-self-assemblies with anionic lipid bilayers.Cationic vectors have demonstrated the potential to facilitate intracellular delivery of therapeutic oligonucleotides. However, enhanced transfection efficiency is usually associated with adverse effects, which also proves to be a challenge for vectors based on cationic peptides. In this study a series of proteolytically stable palmitoylated α-peptide/β-peptoid peptidomimetics with a systematically varied number of repeating lysine and homoarginine residues was shown to self-assemble with small interfering RNA (siRNA). The resulting well-defined nanocomplexes were coated with anionic lipids giving rise to net anionic liposomes. These complexes and the corresponding liposomes were optimized towards efficient gene silencing and low adverse effects. The optimal anionic liposomes mediated a high silencing effect, which was comparable to that of the control (cationic Lipofectamine 2000), and did not display any noticeable cytotoxicity and immunogenicity in vitro. In contrast, the corresponding nanocomplexes mediated a reduced silencing effect with a more narrow safety window. The surface coating with anionic lipid bilayers led to partial decomplexation of the siRNA-peptidomimetic nanocomplex core of the liposomes, which facilitated siRNA release. Additionally, the optimal anionic liposomes showed efficient intracellular uptake and endosomal escape. Therefore, these findings suggest that a more efficacious and safe formulation can be achieved by surface coating of the siRNA-peptidomimetic nano-self-assemblies with anionic lipid bilayers. Electronic supplementary information (ESI) available: Non-fusogenic liposomes; cytotoxicity of naked siRNA and the empty vector; immunogenicity; low-magnification images; DOPE/DPPC liposomes. See DOI: 10.1039/c5nr04807a

Effect of different polysorbates on development of self-microemulsifying drug delivery systems using medium chain lipids.

PubMed

Shah, Ankita; Thool, Prajwal; Sorathiya, Komal; Prajapati, Hetal; Dalrymple, Damon; Serajuddin, Abu T M

2018-02-01

The primary objective of this study was to develop lipid-based self-microemulsifying drug delivery systems (SMEDDS) without using any organic cosolvents that would spontaneously form microemulsions upon dilution with water. Cosolvents were avoided to prevent possible precipitation of drug upon dilution and other stability issues. Different polysorbates, namely, Tween 20, Tween 40, Tween 60, and Tween 80, were used as surfactants, and Captex 355 EP/NF (glycerol tricaprylate/caprate) or its 1:1 mixture with Capmul MCM NF (glycerol monocaprylocaprate) were used as lipids. Captex 355-Tween-water ternary phase diagrams showed that oil-in-water microemulsions were formed only when the surfactant content was high (80-90%) and the lipid content low (10-20%). Thus, mixtures of Tweens with Captex 355 alone were not suitable to prepare SMEDDS with substantial lipid contents. However, when Captex 355 was replaced with the 1:1 mixture of Captex 355 and Capmul MCM, clear isotropic microemulsion regions in phase diagrams with sizes in the increasing order of Tween 20 < Tween 40 < Tween 60 < Tween 80 were obtained. Tween 80 had the most profound effect among all surfactants as microemulsions were formed with lipid to surfactant ratios as high as 7:3, which may be attributed to the presence of double bond in its side chain that increased the curvature of surfactant layer. Thus, lipid-surfactant mixtures containing 1:1 mixture of medium chain triglyceride (Captex 355) and monoglyceride (Capmul MCM) and as low as 30% Tween 80 were identified as organic cosolvent-free systems for the preparation of SMEDDS. Formulations with a model drug, probucol, dispersed spontaneously and rapidly upon dilution with water to form microemulsions without any drug precipitation.

Systematic Development of Transethosomal Gel System of Piroxicam: Formulation Optimization, In Vitro Evaluation, and Ex Vivo Assessment.

PubMed

Garg, Varun; Singh, Harmanpreet; Bhatia, Amit; Raza, Kaisar; Singh, Sachin Kumar; Singh, Bhupinder; Beg, Sarwar

2017-01-01

Piroxicam is used in the treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory diseases. Upon oral administration, it is reported to cause ulcerative colitis, gastrointestinal irritation, edema and peptic ulcer. Hence, an alternative delivery system has been designed in the form of transethosome. The present study describes the preparation, optimization, characterization, and ex vivo study of piroxicam-loaded transethosomal gel using the central composite design. On the basis of the prescreening study, the concentration of lipids and ethanol was kept in the range of 2-4% w/v and 0-40% v/v, respectively. Formulation was optimized by measuring drug retention in the skin, drug permeation, entrapment efficiency, and vesicle size. Optimized formulation was incorporated in hydrogel and compared with other analogous vesicular (liposomes, ethosomes, and transfersomes) gels for the aforementioned responses. Among the various lipids used, soya phosphatidylcholine (SPL 70) and ethanol in various percentages were found to affect drug retention in the skin, drug permeation, vesicle size, and entrapment efficiency. The optimized batch of transethosome has shown 392.730 μg cm -2 drug retention in the skin, 44.312 μg cm -2  h -1 drug permeation, 68.434% entrapment efficiency, and 655.369 nm vesicle size, respectively. It was observed that the developed transethosomes were found superior in all the responses as compared to other vesicular formulations with improved stability and highest elasticity. Similar observations were noted with its gel formulation.

Formulation, Characterization and Pulmonary Deposition of Nebulized Celecoxib Encapsulated Nanostructured Lipid Carriers

PubMed Central

Patlolla, Ram R.; Chougule, Mahavir; Patel, Apurva R.; Jackson, Tanise; Tata, Prasad NV; Singh, Mandip

2010-01-01

The aim of the current study was to encapsulate celecoxib (Cxb) in the Nanostructured Lipid Carrier (Cxb-NLC) nanoparticles and evaluate the lung disposition of nanoparticles following nebulization in Balb/c mice. Cxb-NLC nanoparticles were prepared with Cxb, Compritol, Miglyol and sodium taurocholate using high-pressure homogenization. Cxb-NLC nanoparticles were characterized for physical and aerosol properties. In-vitro cytotoxicity studies were performed with A549 cells. The lung deposition and pharmacokinetic parameters of Cxb-NLC and Cxb solution (Cxb-Soln) formulations were determined using Inexpose™ system and Pari LC star jet nebulizer. The particle size and entrapment efficiency of Cxb-NLC formulation were 217 ± 20 nm and > 90%, respectively. The Cxb-NLC released the drug in controlled fashion, and in vitro aersolization of Cxb-NLC formulation showed FPF of 75.6 ± 4.6 %, MMAD of 1.6 ±0.13 μm and GSD of 1.2 ± 0.21. Cxb-NLC showed dose and time dependent cytotoxicity against A549 cells. Nebulization of Cxb-NLC demonstrated 4 fold higher AUCt/D in lung tissues compared to Cxb-Soln. The systemic clearance of Cxb-NLC was slower (0.93 L/h) compared to Cxb-Soln (20.03 L/h). Cxb encapsulated NLC were found to be stable and aerodynamic properties were within the respirable limits. Aerosolization of Cxb-NLC improved the Cxb pulmonary bioavailability compared to solution formulation which will potentially lead to better patient compliance with minimal dosing intervals. PMID:20153385

Formulation and characterization of liquid crystal systems containing azelaic acid for topical delivery.

PubMed

Aytekin, Merve; Gursoy, R Neslihan; Ide, Semra; Soylu, Elif H; Hekimoglu, Sueda

2013-02-01

The aim of this study is to prepare and characterize azelaic acid (AzA) containing liquid crystal (LC) drug delivery systems for topical use. Two ternary phase diagrams, containing liquid paraffin as the oil component and a mixture of two nonionic surfactants (Brij 721P and Brij 72), were constructed. Formulations chosen from the phase diagrams were characterized by polarized light microscopy, rheological analyses, differential scanning calorimetry (DSC), and small angle x-ray scattering spectroscopy. Polarized light microscopy proved that except the oil/water emulsion (O/W E), other formulations showed lamellar LC structure. In vitro release studies indicated that the fastest release was achieved by the Lamellar LC (LLC) and O/W E systems, whereas slower release was obtained from the emulsion containing lamellar LC (E-LLC) and distorted lamellar LC (D-LLC) systems. Results of rheological measurements both supported the results of in vitro release studies and showed that the emulsion containing the LC (E-LLC) system had the most stable structure. The formulations and their effect on stratum corneum (SC) were evaluated by DSC studies. The lamellar LC (LLC), emulsion containing lamellar liquid crystal (E-LLC), and O/W E formulations had an effect on both lipid and protein components of SC, whereas distorted lamellar liquid crystal (D-LLC) system had an effect on only the lipid components of SC. LLC systems could be considered promising for the topical delivery of AzA.

Evidence does not support absorption of intact solid lipid nanoparticles via oral delivery

NASA Astrophysics Data System (ADS)

Hu, Xiongwei; Fan, Wufa; Yu, Zhou; Lu, Yi; Qi, Jianping; Zhang, Jian; Dong, Xiaochun; Zhao, Weili; Wu, Wei

2016-03-01

Whether and to what extent solid lipid nanoparticles (SLNs) can be absorbed integrally via oral delivery should be clarified because it is the basis for elucidation of absorption mechanisms. To address this topic, the in vivo fate of SLNs as well as their interaction with biomembranes is investigated using water-quenching fluorescent probes that can signal structural variations of lipid-based nanocarriers. Live imaging indicates prolonged retention of SLNs in the stomach, whereas in the intestine, SLNs can be digested quickly. No translocation of intact SLNs to other organs or tissues can be observed. The in situ perfusion study shows bioadhesion of both SLNs and simulated mixed micelles (SMMs) to intestinal mucus, but no evidence of penetration of integral nanocarriers. Both SLNs and SMMs exhibit significant cellular uptake, but fail to penetrate cell monolayers. Confocal laser scanning microscopy reveals that nanocarriers mainly concentrate on the surface of the monolayers, and no evidence of penetration of intact vehicles can be obtained. The mucous layer acts as a barrier to the penetration of both SLNs and SMMs. Both bile salt-decoration and SMM formulation help to strengthen the interaction with biomembranes. It is concluded that evidence does not support absorption of intact SLNs via oral delivery.Whether and to what extent solid lipid nanoparticles (SLNs) can be absorbed integrally via oral delivery should be clarified because it is the basis for elucidation of absorption mechanisms. To address this topic, the in vivo fate of SLNs as well as their interaction with biomembranes is investigated using water-quenching fluorescent probes that can signal structural variations of lipid-based nanocarriers. Live imaging indicates prolonged retention of SLNs in the stomach, whereas in the intestine, SLNs can be digested quickly. No translocation of intact SLNs to other organs or tissues can be observed. The in situ perfusion study shows bioadhesion of both SLNs and simulated mixed micelles (SMMs) to intestinal mucus, but no evidence of penetration of integral nanocarriers. Both SLNs and SMMs exhibit significant cellular uptake, but fail to penetrate cell monolayers. Confocal laser scanning microscopy reveals that nanocarriers mainly concentrate on the surface of the monolayers, and no evidence of penetration of intact vehicles can be obtained. The mucous layer acts as a barrier to the penetration of both SLNs and SMMs. Both bile salt-decoration and SMM formulation help to strengthen the interaction with biomembranes. It is concluded that evidence does not support absorption of intact SLNs via oral delivery. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07474f

Anti-Inflammatory Effects of Novel Standardized Solid Lipid Curcumin Formulations.

PubMed

Nahar, Pragati P; Slitt, Angela L; Seeram, Navindra P

2015-07-01

Inflammation and the presence of pro-inflammatory cytokines are associated with numerous chronic diseases such as type-2 diabetes mellitus, cardiovascular disease, Alzheimer's disease, and cancer. An overwhelming amount of data indicates that curcumin, a polyphenol obtained from the Indian spice turmeric, Curcuma longa, is a potential chemopreventive agent for treating certain cancers and other chronic inflammatory diseases. However, the low bioavailability of curcumin, partly due to its low solubility and stability in the digestive tract, limits its therapeutic applications. Recent studies have demonstrated increased bioavailability and health-promoting effects of a novel solid lipid particle formulation of curcumin (Curcumin SLCP, Longvida(®)). The goal of this study was to evaluate the aqueous solubility and in vitro anti-inflammatory effects of solid lipid curcumin particle (SLCP) formulations using lipopolysaccharide (LPS)-stimulated RAW 264.7 cultured murine macrophages. SLCPs treatment significantly decreased nitric oxide (NO) and prostaglandin-E2 (PGE2) levels at concentrations ranging from 10 to 50 μg/mL, and reduced interleukin-6 (IL-6) levels in a concentration-dependent manner. Transient transfection experiments using a nuclear factor-kappa B (NF-κB) reporter construct indicate that SLCPs significantly inhibit the transcriptional activity of NF-κB in macrophages. Taken together, these results show that in RAW 264.7 murine macrophages, SLCPs have improved solubility over unformulated curcumin, and significantly decrease the LPS-induced pro-inflammatory mediators NO, PGE2, and IL-6 by inhibiting the activation of NF-κB.

Anti-Inflammatory Effects of Novel Standardized Solid Lipid Curcumin Formulations

PubMed Central

Nahar, Pragati P.

2015-01-01

Abstract Inflammation and the presence of pro-inflammatory cytokines are associated with numerous chronic diseases such as type-2 diabetes mellitus, cardiovascular disease, Alzheimer's disease, and cancer. An overwhelming amount of data indicates that curcumin, a polyphenol obtained from the Indian spice turmeric, Curcuma longa, is a potential chemopreventive agent for treating certain cancers and other chronic inflammatory diseases. However, the low bioavailability of curcumin, partly due to its low solubility and stability in the digestive tract, limits its therapeutic applications. Recent studies have demonstrated increased bioavailability and health-promoting effects of a novel solid lipid particle formulation of curcumin (Curcumin SLCP, Longvida®). The goal of this study was to evaluate the aqueous solubility and in vitro anti-inflammatory effects of solid lipid curcumin particle (SLCP) formulations using lipopolysaccharide (LPS)-stimulated RAW 264.7 cultured murine macrophages. SLCPs treatment significantly decreased nitric oxide (NO) and prostaglandin-E2 (PGE2) levels at concentrations ranging from 10 to 50 μg/mL, and reduced interleukin-6 (IL-6) levels in a concentration-dependent manner. Transient transfection experiments using a nuclear factor-kappa B (NF-κB) reporter construct indicate that SLCPs significantly inhibit the transcriptional activity of NF-κB in macrophages. Taken together, these results show that in RAW 264.7 murine macrophages, SLCPs have improved solubility over unformulated curcumin, and significantly decrease the LPS-induced pro-inflammatory mediators NO, PGE2, and IL-6 by inhibiting the activation of NF-κB. PMID:25490740

Preparation, characterization and pharmacokinetics of enrofloxacin-loaded solid lipid nanoparticles: influences of fatty acids.

PubMed

Xie, Shuyu; Zhu, Luyan; Dong, Zhao; Wang, Xiaofang; Wang, Yan; Li, Xihe; Zhou, WenZhong

2011-04-01

Enrofloxacin-loaded solid lipid nanoparticles (SLN) were prepared using fatty acids (tetradecanoic acid, palmitic acid, stearic acid) as lipid matrix by hot homogenization and ultrasonication method. The effect of fatty acids on the characteristics and pharmacokinetics of the SLN were investigated. The results showed that the encapsulation efficiency and loading capacity of nanoparticles varied with fatty acids in the order of stearic acid>palmitic acid>tetradecanoic acid. Furthermore, stearic acid-SLN had larger particle size, bigger polydispersity index (PDI) and higher zeta potential compared with the other two fatty acid formulated SLN. The SLN showed sustained releases in vitro and the released enrofloxacin had the same antibacterial activity as that of the native enrofloxacin. Although in vitro release exhibited similar patterns, within 24 h the releasing rates of the three formulations were significantly different (tetradecanoic acid-SLN>palmitic acid-SLN>stearic acid-SLN). Pharmacokinetic study after a single dose of intramuscular administration to mice demonstrated that tetradecanoic acid-SLN, palmitic acid-SLN, and stearic acid-SLN increased the bioavailability by 6.79, 3.56 and 2.39 folds, and extended the mean residence time (MRT) of the drug from 10.60 h to 180.36, 46.26 and 19.09 h, respectively. These results suggest that the enrofloxacin-fatty acid SLN are promising formulations for sustained release while fatty acids had significant influences on the characteristics and performances of the SLN. Copyright © 2010 Elsevier B.V. All rights reserved.

Characterization of cationic liposome formulations designed to exhibit extended plasma residence times and tumor vasculature targeting properties.

PubMed

Ho, Emmanuel A; Ramsay, Euan; Ginj, Mihaela; Anantha, Malathi; Bregman, Isaiah; Sy, Jonathan; Woo, Janet; Osooly-Talesh, Maryam; Yapp, Donald T; Bally, Marcel B

2010-06-01

Cationic liposomes exhibit a propensity to selectively target tumor-associated blood vessels demonstrating potential value as anti-cancer drug delivery vehicles. Their utility however, is hampered by their biological instability and rapid elimination following i.v. administration. Efforts to circumvent rapid plasma elimination have, to date, focused on decreasing cationic lipid content and incorporating polyethylene glycol (PEG)-modified lipids. In this study we wanted to determine whether highly charged cationic liposomes with surface-associated PEG could be designed to exhibit extended circulation lifetimes, while retaining tumor vascular targeting properties in an HT29 colorectal cancer xenograft model. Cationic liposomes prepared of DSPC, cationic lipids (DODAC, DOTAP, or DC-CHOL), and DSPE-PEG(2000) were studied. Our results demonstrate that formulations prepared with 50 mol% DODAC or DC-CHOL, and 20 mol% DSPE-PEG(2000) exhibited circulation half-lives ranging from 6.5 to 12.5 h. Biodistribution studies demonstrated that DC-CHOL formulations prepared with DSPE-PEG(2000) accumulated threefold higher in s.c. HT29 tumors than its PEG-free counterpart. Fluorescence microscopy studies suggested that the presence of DSPE-PEG(2000) did not adversely affect liposomal tumor vasculature targeting. We show for the first time that it is achievable to design highly charged, highly pegylated (20 mol% DSPE-PEG(2000)) cationic liposomes which exhibit both extended circulation lifetimes and tumor vascular targeting properties. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association

The rational design of biomimetic skin barrier lipid formulations using biophysical methods.

PubMed

Bulsara, P A; Varlashkin, P; Dickens, J; Moore, D J; Rawlings, A V; Clarke, M J

2017-04-01

The focus of this communication was to study phospholipid-structured emulsions whose phase behaviour is modified with monoalkyl fatty amphiphiles. Ideally, these systems would mimic key physical and structural attributes observed in human stratum corneum (SC) so that they better alleviate xerotic skin conditions. Phosphatidylcholine-structured emulsions were prepared, and their phase behaviour modified with monoalkyl fatty amphiphiles. The effect of molecular volume, acyl chain length and head-group interactions was studied using a combination of physical methods. Water vapour transmission rate (WVTR) was used as a primary test to assess occlusive character. Changes in the vibrational modes observed in Fourier transform infrared (FTIR) spectroscopy and bilayer spacing measured by X-ray diffraction (XRD) were then applied to elucidate the lateral and lamellar microstructural characteristics in the systems. Water vapour transmission rate demonstrated that as the phosphatidylcholine acyl chain length increased from C14, to C18, to C22, there was a corresponding increase in occlusive character. The addition of monoalkyl fatty amphiphiles such as behenic acid, behenyl alcohol or cetostearyl alcohol to a base formulation incorporating dipalmitoyl and distearoylphosphatidylcholine (C18) was seen to further increase barrier characteristics of the emulsions. FTIR methods used to probe lipid-chain conformational ordering demonstrated that as phosphatidylcholine acyl chain lengths increased, there was a corresponding improvement in acyl chain ordering, with an increase in thermal transition temperatures. The addition of a monoalkyl fatty amphiphile resulted in conformational order and thermal transition temperature improvements trending towards those observed in stratum corneum. FTIR also demonstrated that systems containing behenic acid or behenyl alcohol exhibited features associated with orthorhombic character. X-ray diffraction data showed that addition of monoalkyl fatty amphiphile also resulted in thicker lamellar structures than when those agents are not present. The generalized approach described herein is shown to mechanistically describe the occlusive character of phospholipid-structured formulations in the presence of long-chain fatty acids or alcohols and that they exhibit characteristics mimicking those found in human SC lipids. © 2016 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Formulation and shelf life stability of water-borne lecithin nanoparticles for potential application in dietary supplements field.

PubMed

Edris, Amr E

2012-09-01

ABSTRACT The objective of the present investigation is to formulate commercial soybean lecithin as nanoparticles in solvent-free aqueous system for potential supplementary applications. A mechanical method, which involved two major steps, was used for that purpose. First, lecithin submicron particles (~ 0.5 μm) have been prepared by gradual hydration of lecithin powder using mechanical agitation. Finally, the size of these particles was further reduced to < 100 nm by using high-pressure microfluidization. The physical stability (appearance, particle size distribution, ζ-potential) and the chemical stability (lipid oxidation) of the dispersions carrying lecithin nanoparticles were assessed every 15 days during the 3-month shelf life period at two different temperatures. Results showed that the final particle size of lecithin in the freshly prepared aqueous dispersion was 79.8 ± 1.0 nm and the amount of peroxide detected was 3.5 ± 0.2 meq/kg lipid. At the end of the storage period, dispersions stored at 4°C exhibited physical and chemical stability as evident from the translucent appearance, the small change in particle size (84.1 ± 1.3 nm), and the small amount of generated peroxides (4.1 ± 0.2 meq/kg lipid). On the other hand, dispersions stored at 25°C were physically stable up to 60 days. Over that period, samples became turbid and the particle size increased to 145.0 ± 1.7 nm with a bimodal distribution pattern. This behavior was due to phospholipids (PLs) degradation and hydrolysis under acidic conditions, which proceeds faster at a relatively high temperature (25°C) than at (4°C). The outcome of this investigation may help in developing water-based dispersions carrying lecithin nanoparticles for dietary supplement of PLs.

Novel tretinoin formulations: a drug-in-cyclodextrin-in-liposome approach.

PubMed

Ascenso, Andreia; Cruz, Mariana; Euletério, Carla; Carvalho, Filomena A; Santos, Nuno C; Marques, Helena C; Simões, Sandra

2013-09-01

The aims of this experimental work were the incorporation and full characterization of the system Tretinoin-in-dimethyl-beta-cyclodextrin-in-ultradeformable vesicles (Tretinoin-CyD-UDV) and Tretinoin-in-ultradeformable vesicles (Tretinoin-UDV). The Tretinoin-CyD complex was prepared by kneading and the UDV by adding soybean phosphatidylcholine (SPC) to Tween® 80 followed by an appropriate volume of sodium phosphate buffer solution to make a 10%-20% lipid suspension. The resulting suspension was brought to the final mean vesicles size, of approximately 150 nm, by sequential filtration. The physicochemical characterization was based on: the evaluation of mean particle size and polydispersity index (PI) measured by photon correlation spectroscopy (PCS) and atomic force microscopy (AFM) topographic imaging; zeta potential (ζ-potential) and the SPC concentration determined by Laser-Doppler anemometry and an enzymatic-colorimetric test, respectively. The quantification of the incorporated Tretinoin and its chemical stability (during preparation and storage) was assayed by a HPLC at 342 nm. It was possible to obtain the system Tretinoin-CyD-UDV. The mean vesicle size was the most stable parameter during experiments time course. AFM showed that Tretinoin-CyD-UDV samples were very heterogeneous in size, having three distinct subpopulations, while Tretinoin-UDV samples had only one homogeneous size population. The results of the ζ-potential measurements have shown that vesicle surface charge was low, as expected, presenting negative values. The incorporation efficiency was high, and no significant differences between Tretinoin-CyD-UDV and Tretinoin-UDV were observed. However, only Tretinoin-UDV with 20% lipid concentration formulation remained chemically stable during the evaluation period. According to our results, Tretinoin-UDV with 20% lipid concentration seems to be a better approach than Tretinoin-CyD-UDV, attending to the higher chemical stability.

Propagation of Cutaneous Thermal Injury: A Mathematical Model

PubMed Central

Xue, Chuan; Chou, Ching-Shan; Kao, Chiu-Yen; Sen, Chandan K.; Friedman, Avner

2012-01-01

Cutaneous burn wounds represent a significant public health problem with 500,000 patients per year in the U.S. seeking medical attention. Immediately after skin burn injury, the volume of the wound burn expands due to a cascade of chemical reactions, including lipid peroxidation chain reactions. Based on these chemical reactions, the present paper develops for the first time a three-dimensional mathematical model to quantify the propagation of tissue damage within 12 hours post initial burn. We use the model to investigate the effect of supplemental antioxidant vitamin E for stopping the propagation. We show, for example, that if the production rate of vitamin E is increased, post burn, by five times the natural production in a healthy tissue, then this would slow down the lipid peroxide propagation by at least 50%. Our model is formulated in terms of differential equations, and sensitivity analysis is performed on the parameters to ensure the robustness of the results. PMID:22211391

Preparation and characterization of dutasteride-loaded nanostructured lipid carriers coated with stearic acid-chitosan oligomer for topical delivery.

PubMed

Noor, Norhayati Mohamed; Sheikh, Khalid; Somavarapu, Satyanarayana; Taylor, Kevin M G

2017-08-01

Dutasteride, used for treating benign prostate hyperplasia (BPH), promotes hair growth. To enhance delivery to the hair follicles and reduce systemic effects, in this study dutasteride has been formulated for topical application, in a nanostructured lipid carrier (NLC) coated with chitosan oligomer-stearic acid (CSO-SA). CSO-SA has been successfully synthesized, as confirmed using 1 H NMR and FTIR. Formulation of dutasteride-loaded nanostructured lipid carriers (DST-NLCs) was optimized using a 2 3 full factorial design. This formulation was coated with different concentrations of stearic acid-chitosan solution. Coating DST-NLCs with 5% SA-CSO increased mean size from 187.6±7.0nm to 220.1±11.9nm, and modified surface charge, with zeta potentials being -18.3±0.9mV and +25.8±1.1mV for uncoated and coated DST-NLCs respectively. Transmission electron microscopy showed all formulations comprised approximately spherical particles. DST-NLCs, coated and uncoated with CSO-SA, exhibited particle size stability over 60days, when stored at 4-8°C. However, NLCs coated with CSO (without conjugation) showed aggregation when stored at 4-8°C after 30days. The measured particle size for all formulations stored at 25°C suggested aggregation, which was greatest for DST-NLCs coated with 10% CSO-SA and 5% CSO. All nanoparticle formulations exhibited rapid release in an in vitro release study, with uncoated NLCs exhibiting the fastest release rate. Using a Franz diffusion cell, no dutasteride permeated through pig ear skin after 48h, such that it was not detected in the receptor chamber for all samples. The amount of dutasteride in the skin was significantly different (p<0.05) for DST-NLCs (6.09±1.09μg/cm 2 ) without coating and those coated with 5% CSO-SA (2.82±0.40μg/cm 2 ), 10% CSO-SA (2.70±0.35μg/cm 2 ) and CSO (2.11±0.64μg/cm 2) . There was a significant difference (p<0.05) in the cytotoxicity (IC 50 ) between dutasteride alone and in the nanoparticles. DST-NLCs coated and uncoated with CSO-SA increased the maximum non-toxic concentration by 20-fold compared to dutasteride alone. These studies indicate that a stearic acid-chitosan conjugate was successfully prepared, and modified the surface charge of DST-NLCs from negative to positive. These stable, less cytotoxic, positively-charged dutasteride-loaded nanostructured lipid carriers, with stearic acid-chitosan oligomer conjugate, are appropriate for topical delivery and have potential for promotion of hair growth. Copyright © 2017. Published by Elsevier B.V.

Factorial design applied to the optimization of lipid composition of topical antiherpetic nanoemulsions containing isoflavone genistein

PubMed Central

Argenta, Débora Fretes; de Mattos, Cristiane Bastos; Misturini, Fabíola Dallarosa; Koester, Leticia Scherer; Bassani, Valquiria Linck; Simões, Cláudia Maria Oliveira; Teixeira, Helder Ferreira

2014-01-01

The aim of this study was to optimize topical nanoemulsions containing genistein, by means of a 23 full factorial design based on physicochemical properties and skin retention. The experimental arrangement was constructed using oil type (isopropyl myristate or castor oil), phospholipid type (distearoylphosphatidylcholine [DSPC] or dioleylphosphaditylcholine [DOPC]), and ionic cosurfactant type (oleic acid or oleylamine) as independent variables. The analysis of variance showed effect of third order for particle size, polydispersity index, and skin retention of genistein. Nanoemulsions composed of isopropyl myristate/DOPC/oleylamine showed the smallest diameter and highest genistein amount in porcine ear skin whereas the formulation composed of isopropyl myristate/DSPC/oleylamine exhibited the lowest polydispersity index. Thus, these two formulations were selected for further studies. The formulations presented positive ζ potential values (>25 mV) and genistein content close to 100% (at 1 mg/mL). The incorporation of genistein in nanoemulsions significantly increased the retention of this isoflavone in epidermis and dermis, especially when the formulation composed by isopropyl myristate/DOPC/oleylamine was used. These results were supported by confocal images. Such formulations exhibited antiherpetic activity in vitro against herpes simplex virus 1 (strain KOS) and herpes simplex virus 22 (strain 333). Taken together, the results show that the genistein-loaded nanoemulsions developed in this study are promising options in herpes treatment. PMID:25336951

A stable and practical etoposide-containing intravenous long-/medium-chain triglycerides-based lipid emulsion formulation: pharmacokinetics, biodistribution, toxicity, and antitumor efficacy.

PubMed

Dong, Wenna; Zhang, Luna; Niu, Yantao; Fan, Dongjiao; Wu, Xiaorong; Tang, Xing; Cai, Cuifang

2013-05-01

This work aimed to evaluate pharmacokinetics, biodistribution, toxicity, and antitumor activities of a highly stable long-/medium-chain triglycerides (LCT/MCT)-based etoposide parenteral emulsion (EPE) in comparison to etoposide parenteral solution (EPS). Using high-pressure homogenization method, EPE was prepared and sterilized at 121°C for 10 min by autoclaving. The biological samples were analyzed using the UPLC-ESI-MS/MS method. Superior stability of EPE was verified with no significant changes in physicochemical properties in the accelerating and long-term stability tests. Similar pharmacokinetic behavior in beagle dogs was obtained and the AUC 0 - 12h values were 1196.73 ± 320.85 and 1505.56 ± 617.93 µg.h/L for EPE and EPS (p > 0.5), respectively. Likewise, no remarkable difference in biodistribution profiles in mice was found for both formulations. Safety assessment studies including hemolysis test, rabbit ear vein test and injection anaphylaxis were undertaken and the EPE was proven to be safe for intravenous administration. Specifically, after consecutive 12 weeks administration in rats, systematic and local toxicity induced by EPE were alleviated relative to that of EPS. Furthermore, significant and comparable antitumor activities to EPS were also demonstrated by EPE with tumor suppression rate (TSR) of 66.63, 55.94, and 60.16% against H460, Hep G2, and BCAP-37 human cancer cell lines in nude mice at the dose of 15 mg/kg, respectively. These results suggest that this LCT/MCT-based lipid emulsion is a promising alternative intravenous carrier for etoposide with high stability, improved convenience, alleviated toxicity, and noncompromised antitumor efficacy.

Supramolecular nano-engineered lipidic carriers based on diflunisal-phospholipid complex for transdermal delivery: QbD based optimization, characterization and preclinical investigations for management of rheumatoid arthritis.

PubMed

Kaur, Amanpreet; Bhoop, Bhupinder Singh; Chhibber, Sanjay; Sharma, Gajanand; Gondil, Vijay Singh; Katare, Om Prakash

2017-11-25

Diflunisal (DIF) is used for treatment of rheumatoid arthritis, osteoarthritis etc. DIF-phospholipid complex (DIF-PL complex) was prepared by solvent-evaporation method and characterized by molecular docking studies, SEM, FTIR, DSC, PXRD studies. Further, the DIF-PL complex was incorporated into supramolecular nano-engineered lipidic carriers (SNLCs) for transdermal delivery. The optimization exercise was done using Face centered cubic design (FCCD) after screening of variables by L8 Taguchi orthogonal array design. The optimized SNLC formulation depicted average particle size (188.1nm), degree of entrapment (86.77±3.33%), permeation flux (5.47±0.48μg/cm 2 /h) and skin retention (17.72±0.68μg/cm 2 ). The dermatokinetic studies revealed the higher concentration of DIF in dermis. The Confocal laser scanning microscopy (CSLM) studies revealed penetration of SNLCs into the deeper layers of skin. The results of mice ear edema depicted significant inhibition of ear edema (76.37±12.52%; p<0.05). In CFA induced rheumatoid arthritis model, the inhibition of paw edema was significantly higher (73.85±14.5%). The levels of TNF-α were reduced in synovial fluid (146.74±1.69pg/mL) and serum (132.43±2.70pg/mL). Furthermore, the licking and biting time was reduced in formalin induced hyperalgesia model. Hence, it can be concluded that dual formulation strategy based SNLCs were promising in treatment of pain and inflammation associated with rheumatoid arthritis. Copyright © 2017 Elsevier B.V. All rights reserved.

New Updates Pertaining to Drug Delivery of Local Anesthetics in Particular Bupivacaine Using Lipid Nanoparticles

NASA Astrophysics Data System (ADS)

Beiranvand, Siavash; Eatemadi, Ali; Karimi, Arash

2016-06-01

Lipid nanoparticles (liposomes) were first described in 1965, and several work have led to development of important technical advances like triggered release liposomes and drug-loaded liposomes. These advances have led to numerous clinical trials in such diverse areas such as the delivery of anti-cancer, antifungal, and antibiotic drugs; the delivery of gene medicines; and most importantly the delivery of anesthesia drugs. Quite a number of liposomes are on the market, and many more are still in developmental stage. Lipid nanoparticles are the first nano-medicine delivery system to be advanced from laboratory concept to clinical application with high considerable clinical acceptance. Drug delivery systems for local anesthetics (LAs) have caught the interest of many researchers because there are many biomedical advantages connected to their application. There have been several formulation techniques to systemically deliver LA that include encapsulation in liposomes and complexation in cyclodextrins, nanoparticles, and to a little extent gold nanoparticles. The proposed formulations help to decrease the LA concentration utilized, increase its permeability, and most importantly increase the localization of the LA for a long period of time thereby leading to increase in the duration of the LA effect and finally to reduce any local and systemic toxicity. In this review, we will highlight on new updates pertaining to drug delivery of local anesthetics in particular bupivacaine using lipid nanoparticles.

New Updates Pertaining to Drug Delivery of Local Anesthetics in Particular Bupivacaine Using Lipid Nanoparticles.

PubMed

Beiranvand, Siavash; Eatemadi, Ali; Karimi, Arash

2016-12-01

Lipid nanoparticles (liposomes) were first described in 1965, and several work have led to development of important technical advances like triggered release liposomes and drug-loaded liposomes. These advances have led to numerous clinical trials in such diverse areas such as the delivery of anti-cancer, antifungal, and antibiotic drugs; the delivery of gene medicines; and most importantly the delivery of anesthesia drugs. Quite a number of liposomes are on the market, and many more are still in developmental stage. Lipid nanoparticles are the first nano-medicine delivery system to be advanced from laboratory concept to clinical application with high considerable clinical acceptance. Drug delivery systems for local anesthetics (LAs) have caught the interest of many researchers because there are many biomedical advantages connected to their application. There have been several formulation techniques to systemically deliver LA that include encapsulation in liposomes and complexation in cyclodextrins, nanoparticles, and to a little extent gold nanoparticles. The proposed formulations help to decrease the LA concentration utilized, increase its permeability, and most importantly increase the localization of the LA for a long period of time thereby leading to increase in the duration of the LA effect and finally to reduce any local and systemic toxicity. In this review, we will highlight on new updates pertaining to drug delivery of local anesthetics in particular bupivacaine using lipid nanoparticles.

Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles

PubMed Central

Elnaggar, Yosra SR; El-Massik, Magda A; Abdallah, Ossama Y

2011-01-01

Although sildenafil citrate (SC) is used extensively for erectile dysfunction, oral delivery of SC encounters many obstacles. Furthermore, the physicochemical characteristics of this amphoteric drug are challenging for delivery system formulation and transdermal permeation. This article concerns the assessment of the potential of nanomedicine for improving SC delivery and transdermal permeation. SC-loaded nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) were fabricated using a modified high-shear homogenization technique. Nanoparticle optimization steps included particle size analysis, entrapment efficiency (EE) determination, freeze-drying and reconstitution, differential scanning calorimetry, in vitro release, stability study and high-performance liquid chromatography analysis. Transdermal permeation of the nanocarriers compared with SC suspension across human skin was assessed using a modified Franz diffusion cell assembly. Results revealed that SLNs and NLCs could be optimized in the nanometric range (180 and 100 nm, respectively) with excellent EE (96.7% and 97.5%, respectively). Nanoparticles have significantly enhanced in vitro release and transdermal permeation of SC compared with its suspensions. Furthermore, transdermal permeation of SC exhibited higher initial release from both SLN and NLC formulations followed by controlled release, with promising implications for faster onset and longer drug duration. Nanomedicines prepared exhibited excellent physical stability for the study period. Solid nanoparticles optimized in this study successfully improved SC characteristics, paving the way for an efficient topical Viagra® product. PMID:22238508

Cholesterol derived cationic lipids as potential non-viral gene delivery vectors and their serum compatibility.

PubMed

Ju, Jia; Huan, Meng-Lei; Wan, Ning; Hou, Yi-Lin; Ma, Xi-Xi; Jia, Yi-Yang; Li, Chen; Zhou, Si-Yuan; Zhang, Bang-Le

2016-05-15

Cholesterol derivatives M1-M6 as synthetic cationic lipids were designed and the biological evaluation of the cationic liposomes based on them as non-viral gene delivery vectors were described. Plasmid pEGFP-N1, used as model gene, was transferred into 293T cells by cationic liposomes formed with M1-M6 and transfection efficiency and GFP expression were tested. Cationic liposomes prepared with cationic lipids M1-M6 exhibited good transfection activity, and the transfection activity was parallel (M2 and M4) or superior (M1 and M6) to that of DC-Chol derived from the same backbone. Among them, the transfection efficiency of cationic lipid M6 was parallel to that of the commercially available Lipofectamine2000. The optimal formulation of M1 and M6 were found to be at a mol ratio of 1:0.5 for cationic lipid/DOPE, and at a N/P charge mol ratio of 3:1 for liposome/DNA. Under optimized conditions, the efficiency of M1 and M6 is greater than that of all the tested commercial liposomes DC-Chol and Lipofectamine2000, even in the presence of serum. The results indicated that M1 and M6 exhibited low cytotoxicity, good serum compatibility and efficient transfection performance, having the potential of being excellent non-viral vectors for gene delivery. Copyright © 2016 Elsevier Ltd. All rights reserved.