Rostami, Elham; Kashanian, Soheila; Azandaryani, Abbas H; Faramarzi, Hossain; Dolatabadi, Jafar Ezzati Nazhad; Omidfar, Kobra
The present review aims to show the features of solid lipid nanoparticles (SLNs) which are at the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery and research. Because of some unique features of SLNs such as their unique size dependent properties it offers possibility to develop new therapeutics. A common denominator of all these SLN-based platforms is to deliver drugs into specific tissues or cells in a pathological setting with minimal adverse effects on bystander cells. SLNs are capable to incorporate drugs into nanocarriers which lead to a new prototype in drug delivery which maybe used for drug targeting. Hence solid lipid nanoparticles hold great promise for reaching the goal of controlled and site specific drug delivery and hence attracted wide attention of researchers. This review presents a broad treatment of targeted solid lipid nanoparticles discussing their types such as antibody SLN, magnetic SLN, pH sensitive SLN and cationic SLN.
Patel, Mandar R; San Martin-Gonzalez, M Fernanda
The use of solid lipid nanoparticles (SLNs) is a technique that has been widely used in the pharmaceutical industry for the last 2 decades and has become of increasing interest to food scientists due to its potential for encapsulation and controlled release. Ergocalciferol (vitamin D₂) is a bioactive compound whose deficiency may lead to rickets in children and osteomalacia in adults. In this study, ergocalciferol was encapsulated in tripalmitin SLNs stabilized by polysorbate 20 (Tween 20). SLN dispersions (5% w/w) were prepared by hot homogenization technique using a nozzle-type high-pressure homogenizer. Ergocalciferol at 0%, 5%, 10%, 15%, and 20% (w/w of lipid) was dissolved in the molten lipid at 80 °C, mixed with a 5% (w/w) aqueous solution of polysorbate 20 and homogenized at 138 MPa at 80 °C. Particle size, thermal properties, and microstructure were evaluated by dynamic light scattering (DLS), differential scanning calorimetry (DSC), and transmission electron microscopy (TEM) respectively. As the proportion of ergocalciferol in the SLN increased from 0% to 20%, the Z-average values of the particles gradually decreased (P≤ 0.05) from approximately 120 nm to approximately 65 nm. DSC analysis of freeze dried SLN samples showed gradual decrease in enthalpies of fusion and crystallization for stable β-subcell whereas for SLN dispersions, the enthalpy of fusion of unstable α-subcell crystal increased with increased ergocalciferol loading. The TEM images of the ergocalciferol loaded SLN samples showed the presence of spherical as well as rod-shaped nanoparticles. It was also observed that the turbidity of the SLN dispersions reduced noticeably with increased ergocalciferol loading. This finding could be useful in terms of fortification of clear juices with ergocalciferol. Solid lipid nanoparticles (SLNs) were used in this study to encapsulate vitamin D₂, a vitamin important for bone health. It was found that as the concentration of vitamin D₂ increased
Jourghanian, Parisa; Ghaffari, Solmaz; Ardjmand, Mehdi; Haghighat, Setareh; Mohammadnejad, Mahdieh
Purpose: curcumin is poorly water soluble drug with low bioavailability. Use of lipid systems in lipophilic substances increases solubility and bioavailability of poorly soluble drugs. The aim of this study was to prepare curcumin loaded Solid Lipid Nanoparticles (SLNs) with high loading efficiency, small particle size and prolonged release profile with enhanced antibacterial efficacy. Methods: to synthesize stable SLNs, freeze- Drying was done using mannitol as cryoprotectant. Cholesterol was used as carrier because of good tolerability and biocompatibility. SLNs were prepared using high pressure homogenization method. Results: optimized SLNs had 112 and 163 nm particle size before and after freeze drying, respectively. The prepared SLNs had 71% loading efficiency. 90% of loaded curcumin was released after 48 hours. Morphologic study for formulation was done by taking SEM pictures of curcumin SLNs. Results show the spherical shape of curcumin SLNs. DSC studies were performed to determine prolonged release mechanism. Antimicrobial studies were done to compare the antimicrobial efficacy of curcumin SLNs with free curcumin. DSC studies showed probability of formation of hydrogen bonds between cholesterol and curcumin which resulted in prolonged release of curcumin. Lipid structure of cholesterol could cause enhanced permeability in studied bacteria to increase antibacterial characteristics of curcumin. Conclusion: the designed curcumin SLNs could be candidate for formulation of different dosage forms or cosmeceutical products. PMID:27123413
Shidhaye, S S; Vaidya, Reshma; Sutar, Sagar; Patwardhan, Arati; Kadam, V J
The first generation of solid lipid carrier systems in nanometer range, Solid Lipid Nanoparticles (SLN), was introduced as an alternative to liposomes. SLN are aqueous colloidal dispersions, the matrix of which comprises of solid biodegradable lipids. SLN are manufactured by techniques like high pressure homogenization, solvent diffusion method etc. They exhibit major advantages such as modulated release, improved bioavailability, protection of chemically labile molecules like retinol, peptides from degradation, cost effective excipients, improved drug incorporation and wide application spectrum. However there are certain limitations associated with SLN, like limited drug loading capacity and drug expulsion during storage, which can be minimized by the next generation of solid lipids, Nanostructured lipid carriers (NLC). NLC are lipid particles with a controlled nanostructure that improves drug loading and firmly incorporates the drug during storage. Owing to their properties and advantages, SLN and NLC may find extensive application in topical drug delivery, oral and parenteral administration of cosmetic and pharmaceutical actives. Cosmeceuticals is emerging as the biggest application target of these carriers. Carrier systems like SLN and NLC were developed with a perspective to meet industrial needs like scale up, qualification and validation, simple technology, low cost etc. This paper reviews present status of SLN and NLC as carrier systems with special emphasis on their application in Cosmeceuticals; it also gives an overview about various manufacturing techniques of SLN and NLC.
Shah, M.; Agrawal, Y. K.; Garala, K.; Ramkishan, A.
The aim of this study was to understand and investigate the relationship between experimental factors and their responses in the preparation of ciprofloxacin hydrochloride based solid lipid nanoparticles. A quadratic relationship was studied by developing central composite rotatable design. Amount of lipid and drug, stirring speed and stirring time were selected as experimental factors while particle size, zeta potential and drug entrapment were used as responses. Prior to the experimental design, a qualitative prescreening study was performed to check the effect of various solid lipids and their combinations. Results showed that changing the amount of lipid, stirring speed and stirring time had a noticeable influence on the entrapment efficiencies and particle size of the prepared solid lipid nanoparticles. The particle size of a solid lipid nanoparticle was in the range of 159-246 nm and drug encapsulation efficiencies were marginally improved by choosing a binary mixture of physically incompatible solid lipids. Release of ciprofloxacin hydrochloride from solid lipid nanoparticle was considerably slow, and it shows Higuchi matrix model as the best fitted model. Study of solid lipid nanoparticle suggested that the lipid based carrier system could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release for water soluble actives. PMID:23716872
Kumar, Sacheen; Randhawa, Jaspreet Kaur
Poor solubility of newly developed drug molecules is the main problem in recent drug discovery research, so novel drug delivery approaches are being used to deliver these molecular entities for pharmacological action. Colloidal carriers (emulsion, suspensions, liposomes, polymer nanoparticles and solid lipid nanoparticles) have been used to administer poorly soluble drugs, but solid lipid nanoparticles are found to be the most reliable carriers for this type of drugs due to its advantages over other carriers. Solid lipid nanoparticles have the potential to solve the drug delivery problems with safe excipients used in its formulation. In this review all the aspects of solid lipid nanoparticles production, stability, characterization, differentiation based on route, preservation and storage have been discussed.
Noack, Andreas; Hause, Gerd; Mäder, Karsten
Curcuminoid-loaded solid lipid nanoparticles (SLN) were produced by melt-homogenization. The used lipid matrices were medium chain triglycerides, trimyristin and tristearin. The resulting nanoparticles had an anisometric shape and a platelet-like structure. Curcuminoid-loaded trimyristin particles did not solidify when stored at room temperature. The supercooled state of trimyristin was studied by DSC and (1)H NMR experiments. A partial recrystallization of the lipid matrix was detected but no change of the mobility of the lipid was noted. Nanoparticles based on tristearin had an α- and β-modification which was subsequently converted into the stable β-phase. Curcuminoids did neither influence the melting behavior nor the crystalline or geometric structure of the particles. The interactions between the curcuminoids and the lipid matrix were investigated by Raman and fluorescence spectroscopy. The shape of the curcuminoid bands in the Raman spectra suggested that the drug was in an amorphous state. The fluorescence spectra showed an effect of the lipid matrix on fluorescence properties of the curcuminoids. It was further demonstrated that the drug was not secluded by the solid lipid matrix, but it was influenced by the surrounding aqueous environment. Fluorescence anisotropy measurements revealed a decreased mobility of the curcuminoids within the nanodispersions. From the results of Raman and fluorescence measurements it was concluded that the drug was mainly located on the surface of the crystalline particles.
Ye, Jiesheng; Wang, Aihua; Liu, Chunxi; Chen, Zhijin; Zhang, Na
The objective of this study was to design novel anionic ternary nanoparticles for gene delivery. These ternary nanoparticles were equipped with protamine/DNA binary complexes (150-200 nm) as the support, and the anionic formation was achieved by absorption of anionic solid lipid nanoparticles (<=20 nm) onto the surface of the binary complexes. The small solid lipid nanoparticles (SLNs) were prepared by a modified film dispersion-ultrasonication method, and adsorption of the anionic SLNs onto the binary complexes was typically carried out in water via electrostatic interaction. The formulated ternary nanoparticles were found to be relatively uniform in size (257.7 ± 10.6 nm) with a 'bumpy' surface, and the surface charge inversion from 19.28 ± 1.14 mV to -17.16 ± 1.92 mV could be considered as evidence of the formation of the ternary nanoparticles. The fluorescence intensity measurements from three batches of the ternary nanoparticles gave a mean adsorption efficiency of 96.75 ± 1.13%. Circular dichroism spectra analysis showed that the protamine/DNA complexes had been coated by small SLNs, and that the anionic ternary nanoparticles formed did not disturb the construction of the binary complexes. SYBR Green I analysis suggested that the ternary nanoparticles could protect the DNA from nuclease degradation, and cell viability assay results showed that they exhibit lower cytotoxicity to A549 cells compared with the binary complexes and lipofectamine. The transfection efficiency of the ternary nanoparticles was better than that of naked DNA and the binary complexes, and almost equal to that of lipofectamine/DNA complexes, as revealed by inversion fluorescence microscope observation. These results indicated that the anionic ternary nanoparticles could facilitate gene transfer in cultured cells, and might alleviate the drawbacks of the conventional cationic vector/DNA complexes for gene delivery in vivo.
Naseri, Neda; Valizadeh, Hadi; Zakeri-Milani, Parvin
Lipid nanoparticles (LNPs) have attracted special interest during last few decades. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are two major types of Lipid-based nanoparticles. SLNs were developed to overcome the limitations of other colloidal carriers, such as emulsions, liposomes and polymeric nanoparticles because they have advantages like good release profile and targeted drug delivery with excellent physical stability. In the next generation of the lipid nanoparticle, NLCs are modified SLNs which improve the stability and capacity loading. Three structural models of NLCs have been proposed. These LNPs have potential applications in drug delivery field, research, cosmetics, clinical medicine, etc. This article focuses on features, structure and innovation of LNPs and presents a wide discussion about preparation methods, advantages, disadvantages and applications of LNPs by focusing on SLNs and NLCs. PMID:26504751
Qi, Jianping; Lu, Yi; Wu, Wei
Solid lipid nanoparticles (SLNs) are primarily composed of solid lipids, which thus impart to them some of the fundamental properties of these lipids, including biocompatibility, biodegradability and low-toxicity. SLNs represent a unique class of colloidal drug delivery systems that possess the advantages of both the "soft" drug carriers such as emulsions and liposomes and polymeric nanoparticles. In this review, we will provide an overview on the absorption, disposition and pharmacokinetics of SLNs. The lipidic nature, as well as the relatively small particle size, of SLNs ensures sufficient affinity with the biomembranes, and results in improved absorption by either of the oral, transdermal, pulmonary, nasal, ocular, rectal or buccal route. One special aspect of oral SLNs is the enhanced lymphatic absorption by either the chylomicron-association pathway or the M cell uptaking pathway. Intravenous SLNs are predominantly uptaken by the liver or spleen following opsonization by the complementary system. Modification of SLN surface with PEGs chains will mask the hydrophobic surface and divert SLNs to non-hepatic and non-splenic organs, while ligand-modification will achieve active targeting to specific tissues or organs. Degradation of SLNs is primarily based on the degradation of the lipids themselves by lipase. Pharmacokinetics reflects the effect of the lipidic vehicles of SLNs on in vivo disposition of the loaded drugs.
Mao, Shi-rui; Wang, Yan-zhi; Ji, Hong-yu; Bi, Dian-zhou
To prepare solid lipid nanoparticles by microemulsion technique. Stearic acid was used as the oil phase, lecithin as surfactant, alcohol as cosurfactant and distilled water as the aqueous phase. Microemulsion was prepared by mixing the above component in proper ratio. The corresponding pseudoternary phase diagram monitored Microemulsion formation field of different lecithin/alcohol. Solid lipid nanoparticles (SLN) were prepared by dispersing warm microemulsion in cold water under magnetic stirring. Then appropriate microemulsions that can contain more water phase and suitable oil phase were selected to prepare SLN. The influence of formulation, process variables on the preparation and quality of SLN were studied. Based on the investigation of single factors, orthogonal design was used to optimize SLN formulation and preparation process, and more, the reproducibility of the optimized results were studied. The results showed that the device temperature (Ti), water temperature (Tw), and delivery rate (Rd) were the key factors that influence the preparation process of SLN, and Tw was extremely important. The ratio of microemulsion formulation, the ratio of microemulsion and distilled water had also influence on its quality. Microemulsion technique can be used to prepare solid lipid nanoparticles.
Madureira, Ana Raquel; Campos, Débora; Gullon, Beatriz; Marques, Cláudia; Rodríguez-Alcalá, Luís M; Calhau, Conceição; Alonso, Jose Luis; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Manuela
Solid lipid nanoparticles (SLNs) can be used for oral delivery of phenolic compounds in order to protect them from the harsh conditions of digestion and improve their bioavailability in the intestinal epithelium. Recently, the production and characterization of SLNs loaded with rosmarinic acid (RA) and herbal extracts was performed for future use as functional food ingredients. Diet components have been shown to have a huge impact on gut microbiota viability and metabolic activity. Hence, SLNs loaded with RA, sage and savoury extracts have been evaluated for their effect on intestinal microbiota growth and the metabolic products generated. Fermentations in anaerobic batch cultures using volunteer human faeces were performed during 24 h. Dynamic bacterial population changes were analysed using PCR-real time, as well as the generation of fatty acids and the quantification of phenolic compounds by analytical methods. Solid lipid nanoparticles released phenolic compounds at non-inhibitory bacterial growth concentrations. Released herbal extract phenolic compounds showed a beneficial effect on gut microbiota growth (e.g. bifidogenic effects) and were used as substrates. Acetate, formate, lactate and butyrate were produced in higher concentrations. The released phenolic compounds also induced PUFA and trans fatty acids metabolic activity, the production of saturated fatty acids, as well of potential beneficial conjugated linoleic acid isomers. Solid lipid nanoparticles modulate gut microbiota and metabolic activities.
Dingler, A; Gohla, S
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.
Mukherjee, S.; Ray, S.; Thakur, R. S.
Solid lipid nanoparticles are at the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery, clinical medicine and research, as well as in other varied sciences. Due to their unique size-dependent properties, lipid nanoparticles offer the possibility to develop new therapeutics. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could be used for secondary and tertiary levels of drug targeting. Hence, solid lipid nanoparticles hold great promise for reaching the goal of controlled and site specific drug delivery and hence have attracted wide attention of researchers. This review presents a broad treatment of solid lipid nanoparticles discussing their advantages, limitations and their possible remedies. The different types of nanocarriers which were based on solid lipid like solid lipid nanoparticles, nanostructured lipid carriers, lipid drug conjugates are discussed with their structural differences. Different production methods which are suitable for large scale production and applications of solid lipid nanoparticles are described. Appropriate analytical techniques for characterization of solid lipid nanoparticles like photon correlation spectroscopy, scanning electron microscopy, differential scanning calorimetry are highlighted. Aspects of solid lipid nanoparticles route of administration and their biodistribution are also incorporated. If appropriately investigated, solid lipid nanoparticles may open new vistas in therapy of complex diseases. PMID:20502539
Padois, Karine; Cantiéni, Céline; Bertholle, Valérie; Bardel, Claire; Pirot, Fabrice; Falson, Françoise
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.
Upadhyay, S U; Patel, J K; Patel, V A; Saluja, A K
Tamoxifen Citrate (TC) is an estrogen receptor antagonist and drug of choice for hormone sensitive breast cancer. Solid Lipid Nanoparticles loaded with TC were prepared by High Shear Homogenization followed by Ultrasonication. The aim of the present work is to study the effect of four different Solid Lipids and three Surfactants on Formulation and Stability of SLN. They were characterized for Particle size, Polydispersity Index and Zeta Potential by Zetasizer Nano. SLN prepared by Solid Lipid Compritol 888 (Glyceryldibehenate) and Tween 80 (1%) showed desired Particle Size of 206.9 nm, PDI of 0.046 and Zeta Potential of 9.32 mV.
Breidenich, Jennifer; Patrone, Julia; Kelly, Lisa; Benkoski, Jason; Le, Huong; Sample, Jennifer
We report the synthesis and characterization of a novel nanoparticle formulation designed for skin penetration for the purpose of skin imaging. Solid lipid nanoparticles (SLNs), a drug delivery vehicle, were used as the matrix for targeted delivery of peroxide-sensitive chemiluminescent compounds to the epidermis. Luminol and oxalate were chosen as the chemiluminescent test systems, and a formulation was determined based upon non-toxic components, lotion-like properties, and longevity/visibility of a chemiluminescent signal. The luminescence lifetime was extended in the lipid formulation in comparison to the chemiluminescent system in solution. When applied to porcine skin, our formulation remained detectable relative to negative and positive controls. Initial MTT toxicity testing using HepG2 cells have indicated that this formulation is relatively non-toxic. This formulation could be used to image native peroxides present in tissue that may be indicative of skin disease.
Thukral, Dipti Kakkar; Dumoga, Shweta; Mishra, Anil K
Development of colloidal delivery systems has opened new avenues/frontiers for improving drug delivery. Solid lipid nanoparticles have come up as the latest development in the arena of lipid based colloidal delivery systems after nanoemulsion and liposomes ever since their introduction in the early 1990s. In this review, the authors have made efforts to bring forth the essential and practically relevant aspects of SLNs. This review gives an overview of the preparation methods of solid lipid nanoparticles while mainly focussing on their biological applications including their projected applications in drug delivery. This review critically examines the influential factors governing the formation of SLNs and then discussing in detail the several techniques being utilized for their characterization. This review discusses the drug loading and drug release aspects of SLNs as these are useful biocompatible carriers of lipophilic and to a certain extent hydrophilic drugs. An updated list of drugs encapsulated into various lipids to prepare SLN formulations has been provided. Other relevant aspects pertaining to the clinical use of SLN formulations like their sterilization and storage stability have also been explained. A unique facet of this review is the discussion on the challenging issues of in vivo applications and recent progresses in overcoming these challenges which follows in the end.
Priyanka, K; Sathali, A Abdul Hasan
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
Attama, Anthony A; Umeyor, Chukwuebuka E
Novel solid lipid drug delivery systems such as solid lipid nanoparticles (SLN) have attracted wide and increasing attention in recent years. It has been sought as an interesting alternative drug delivery carrier system for bioactives for a variety of delivery routes. They show major advantages such as sustained release, improved bioavailability, improved drug incorporation and very wide application. This paper presents a discussion on the production protocols of SLN, lyophilization of SLN and delivery of SLN across the blood-brain barrier. Special attention was also paid to entrapment and release of drugs from SLN and strategies to enhance drug entrapment in SLN for sustained release. Analytical methods for the characterization of SLN were also discussed. Various routes of administration of SLN were presented as well as a consideration of the ethical issues and future prospects in the production and use of SLN for sustained release of bioactives.
Patil, Hemlata; Kulkarni, Vijay; Majumdar, Soumyajit; Repka, Michael A
Solid lipid nanoparticles (SLN) can either be produced by hot homogenization of melted lipids at higher temperatures or by a cold homogenization process. This paper proposes and demonstrates the formulation of SLN for pharmaceutical applications by combining two processes: hot melt extrusion (HME) technology for melt-emulsification and high-pressure homogenization (HPH) for size reduction. This work aimed at developing continuous and scalable processes for SLN by mixing a lipid and aqueous phase containing an emulsifier in the extruder barrel at temperatures above the melting point of the lipid and further reducing the particle size of emulsion by HPH linked to HME in a sequence. 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 (for 60 mg/ml lipid solution at a flow rate of 100ml/min). Among the several process parameters investigated, the lipid concentration, residence time and screw design played major roles in influencing the size of the SLN. This new process demonstrates the potential use of hot melt extrusion technology for continuous and large-scale production of SLN.
Kathe, Niranjan; Henriksen, Brian; Chauhan, Harsh
Solid lipid nanoparticles (SLNs) are gaining importance due to numerous advantages they offer as a drug delivery system. SLN incorporate poorly soluble drugs, proteins, biologicals, etc. SLN are prepared by techniques like high-pressure homogenization, sonication and employs a wide range of lipids and surfactants. Physicochemical characterization techniques include particle size analysis, zeta potential and determination of crystallinity/polymorphism. Furthermore, drug loading and drug entrapment efficiency are common parameters used to test the efficiency of SLN. Most importantly, the functionality assay of SLN is essential to predict the activity and performance in vivo. The review presented discusses the importance of SLN in drug delivery with emphasis on principles and limitations associated with their physicochemical characterization.
Sandri, Giuseppina; Motta, Simona; Bonferoni, Maria Cristina; Brocca, Paola; Rossi, Silvia; Ferrari, Franca; Rondelli, Valeria; Cantù, Laura; Caramella, Carla; Del Favero, Elena
Solid Lipid Nanoparticles (SLNs) composed of biodegradable physiological lipids have been widely proposed as efficient drug delivery systems, also for ophthalmic administration. Recently, chitosan-associated-SLNs have been developed to further improve the residence time of these colloidal systems in the precorneal area by means of mucoadhesive interaction. In the present study, a one-step preparation protocol was used aiming both at scale-up ease and at stronger coupling between chitosan and SLNs. The resulting particles were chitosan associated-SLNs (CS-SLNs). These nanoparticles were characterized, as compared to both the chitosan-free and the usual chitosan-coated ones, by applying a multi-technique approach: light, neutron and X-ray scattering, Zeta-potential, AFM, calorimetry. It was assessed that, while keeping the features of nano-size and surface-charge required for an efficient vector, these new nanoparticles display a strong and intimate interaction between chitosan and SLNs, far more settled than the usual simple coverage. Moreover, this one-step preparation method allows to obtain a strong and intimate interaction between chitosan and SLNs, firmer than the usual simple coating. This confers to the CS-SLNs an improved mucoadhesion, opening the way for a high-performing ophthalmic formulation.
Tiyaboonchai, Waree; Tungpradit, Watcharaphorn; Plianbangchang, Pinyupa
Curcuminoids loaded solid lipid nanoparticles (SLNs) have been successfully developed using a microemulsion technique at approximately 75 degrees C. It was found that variation in the amount of ingredients had profound effects on the curcuminoid loading capacity, the mean particle size, and size distribution. At optimized process conditions, lyophilized curcuminoids loaded SLNs showed spherical particles with a mean particle size of approximately 450nm and a polydispersity index of 0.4. Up to 70% (w/w) curcuminoids incorporation efficacy was achieved. In vitro release studies showed a prolonged release of the curcuminoids from the solid lipid nanoparticles up to 12h following the Higuchi's square root model. After 6-month storage at room temperature in the absence of sunlight, the physical and chemical stabilities of the lyophilized curcuminoids loaded SLNs could be maintained, i.e. the mean particle size and the amount of curcuminoids showed no significant changes (P>0.05) compared to the freshly prepared SLNs. In addition, the chemical stability of curcuminoids incorporated into SLNs was further investigated by dispersing them into a model cream base. The results revealed that after storage in the absence of sunlight for 6 months, the percentages of the remaining curcumin, bisdemethoxycurcumin and demethoxycurcumin were 91, 96 and 88, respectively.
Aboutaleb, Ehsan; Noori, Massoumeh; Gandomi, Narges; Atyabi, Fatemeh; Fazeli, Mohammad Reza; Jamalifar, Hossein; Dinarvand, Rassoul
Rifampin (RIF) is one of the front-line drugs in therapy of tuberculosis (TB). The emergence of multidrug-resistant strains of mycobacteria has greatly contributed to the increased incidence of TB. Nano-based formulation of several antimicrobials has been shown to improve either antibacterial efficacy or pharmacokinetic behavior. In this study, RIF-loaded solid lipid nanoparticles (SLNs) were prepared by a modified microemulsion-based method and their particle size, zeta potential, encapsulation efficiency, morphology, and antibacterial activity against Mycobacterium fortuitum were evaluated. The resulting SLNs were spherical with diameter of about 100 nm, with low negative zeta potential, and an encapsulation efficiency of 82%. The formulation also sustained the drug release for 72 h. The antimycobacterial efficacy was greatly improved against M. fortuitum, and the minimum inhibitory concentration of drug-loaded SLNs was eight times less than free RIF. Drug-free SLNs and the ingredients showed no antibacterial effect. It can be concluded that as expected, solid lipid nanoparticles are promising vehicles for enhanced antimycobacterial effect of rifampin.
Subedi, Robhash Kusam; Kang, Keon Wook; Choi, Hoo-Kyun
Solid lipid nanoparticles (SLN) loaded with doxorubicin were prepared by solvent emulsification-diffusion method. Glyceryl caprate (Capmul)MCM C10) was used as lipid core, and curdlan as the shell material. Dimethyl sulfoxide (DMSO) was used to dissolve both lipid and drug. Polyethylene glycol 660 hydroxystearate (Solutol)HS15) was employed as surfactant. Major formulation parameters were optimized to obtain high quality nanoparticles. The mean particle size measured by photon correlation spectroscopy (PCS) was 199nm. The entrapment efficiency (EE) and drug loading capacity (DL), determined with fluorescence spectroscopy, were 67.5+/-2.4% and 2.8+/-0.1%, respectively. The drug release behavior was studied by in vitro method. Cell viability assay showed that properties of SLN remain unchanged during the process of freeze-drying. Stability study revealed that lyophilized SLN were equally effective (p<0.05) after 1 year of storage at 4 degrees C. In conclusion, SLN with small particle size, high EE, and relatively high DL for doxorubicin can be obtained by this method.
Helgason, Thrandur; Salminen, Hanna; Kristbergsson, Kristberg; McClements, David Julian; Weiss, Jochen
This study investigated the influence of liquid-solid transition and particle size on the optical properties of nanoemulsions. The hypothesis was that the crystallization of lipid droplets influences the nanoemulsion appearance. Liquid and solid nanoemulsions (10 wt% octadecane, 1-5 wt% sodium dodecylsulfate) were formed by high-pressure microfluidization (5000-28,500 psi) at 45 °C. Solid lipid nanoparticles were formed by cooling the nanoemulsions to 5 °C and then heating to ambient temperature, whereas liquid nanoemulsions were formed by maintaining them at 25 °C. Results indicated that lipid nanoparticles ranging from 136 nm down to 36 nm were generated, and were stable to particle aggregation. The melting and onset temperatures of the nanoparticles decreased with decreasing particle diameter. Upon crystallization of the lipid, the absorbance increased by about 140% for nanoemulsions with 136 nm particle diameter, but only 5% for nanoemulsions with 36 nm particle diameter. These results were explained in terms of changes in refractive index upon droplet solidification that alter their scattering behavior. These results show that solidification of nanoemulsions results in a shift of the transparent-to-turbid transition regime. The practical consequences for emulsion manufacturers are that solid nanoemulsions must be smaller than liquid nanoemulsions to remain transparent. Copyright © 2015 Elsevier Inc. All rights reserved.
Chuan, Junlan; Li, Yanzhen; Yang, Likai; Sun, Xun; Zhang, Qiang; Gong, Tao; Zhang, Zhirong
The present study aimed at developing a drug delivery system targeting the densest site of tuberculosis infection, the alveolar macrophages (AMs). Rifampicin (RFP)-loaded solid lipid nanoparticles (RFP-SLNs) with an average size of 829.6 ± 16.1 nm were prepared by a modified lipid film hydration method. The cytotoxicity of RFP-SLNs to AMs and alveolar epithelial type II cells (AECs) was examined using MTT assays. The viability of AMs and AECs was above 80 % after treatment with RFP-SLNs, which showed low toxicity to both AMs and AECs. Confocal Laser Scanning Microscopy was employed to observe the interaction between RFP-SLNs and both AMs and AECs. After incubating the cells with RFP-SLNs for 2 h, the fluorescent intensity in AMs was more and remained longer (from 0.5 to 12 h) when compared with that in AECs (from 0.5 to 8 h). In vitro uptake characteristics of RFP-SLNs in AMs and AECs were also investigated by detection of intracellular RFP by High performance liquid chromatography. Results showed that RFP-SLNs delivered markedly higher RFP into AMs (691.7 ng/mg in cultured AMs, 662.6 ng/mg in primary AMs) than that into AECs (319.2 ng/mg in cultured AECs, 287.2 ng/mg in primary AECs). Subsequently, in vivo delivery efficiency and the selectivity of RFP-SLNs were further verified in Sprague-Dawley rats. Under pulmonary administration of RFP-SLNs, the amount of RFP in AMs was significantly higher than that in AECs at each time point. Our results demonstrated that solid lipid nanoparticles are a promising strategy for the delivery of rifampicin to alveolar macrophages selectively.
Gaur, Praveen Kumar; Mishra, Shikha; Purohit, Suresh
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.
Gaur, Praveen Kumar; Mishra, Shikha; Purohit, Suresh
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
Jensen, Louise B; Magnussson, Emily; Gunnarsson, Linda; Vermehren, Charlotte; Nielsen, Hanne M; Petersson, Karsten
Solid lipid nanoparticles (SLN) show promise as a drug delivery system for skin administration. The solid state of the lipid particle enables efficient drug encapsulation and controlled drug release. The present study addresses the influence of lipid composition and drug substance lipid solubility on the in vitro release profile of corticosteroids from SLN for topical administration. Firstly, the effect of lipid composition on the lipid solubility and in vitro release of betamethasone-17-valerate (BMV) was determined by varying the lipid monoglyceride content and the chain length of the fatty acid moiety. Secondly, the effect of drug substance physicochemical properties was determined by studying five different corticosteroid derivatives with different lipophilicity. A high concentration of monoglyceride in SLN increased the amount of BMV released. The corticosteroid release rate depended on the drug substance lipophilicity and it was clear that the release profiles depended on drug partitioning to the aqueous phase as indicated by zero order kinetics. The results emphasize that the corticosteroid solubility in the lipid phase greatly influence drug distribution in the lipid particles and release properties. Thus knowledge of drug substance solubility and lipid polarity contributes to optimize SLN release properties. Copyright 2009 Elsevier B.V. All rights reserved.
Fang, Jia-You; Fang, Chia-Lang; Liu, Chi-Hsien; Su, Yu-Han
Solid lipid nanoparticles (SLN) were developed by using Precirol ATO 5 as the solid core of the particles for topical psoralen delivery. Nanostructured lipid carriers (NLC) consisting of Precirol and squalene, a liquid lipid, were also prepared for comparison. SLN and NLC showed respective mean particle sizes of approximately 300 and 200nm, respectively. Viscosity, polarity, and differential scanning calorimetry (DSC) studies were performed to characterize the physicochemical properties of the SLN and NLC. The viscosity of all nanoparticulate systems exhibited Newtonian behavior except the NLC with Tween 80 and soybean phospholipids as the emulsifiers (NLC-Tw). According to the DSC thermograms, the melting peak of Precirol shifted from 58 to 55 degrees C after incorporating squalene into the solid lipid cores (of NLC), which suggests defects in the crystalline lattice of the lipid cores and smaller particle sizes. Three psoralen derivatives for psoriasis treatments were loaded in SLN and NLC to examine their ability to permeate skin. The permeability of psoralens increased in the order of 8-methoxypsoralen (8-MOP)>5-methoxypsoralen (5-MOP)>4,5,8-trimethylpsoralen (TMP). Enhanced permeation and controlled release of psoralen delivery were both achieved using the NLC. The in vitro permeation results showed that NLC-Tw increased the 8-MOP flux 2.8 times over that of a conventional emulsion. Hyperproliferative or psoriasis-like skin produced by repeated strippings in the dorsal skin of nude mouse was also used as a permeation barrier. The results showed that the entrapment of 8-MOP in nanoparticulate systems could minimize the permeation differentiation between normal and hyperproliferative skin compared to the free drug in an aqueous control.
Butani, Dhruv; Yewale, Chetan; Misra, Ambikanandan
The present work is focused on design and development of topical Amphotericin B solid lipid nanoparticles (SLNs) to improve the therapeutic antifungal activity. Amphotericin B loaded SLNs were prepared by novel solvent diffusion method and were characterized for particle size, zeta potential, drug entrapment, surface morphology, in vitro antifungal activity, ex vivo permeation, retention and skin-irritation. Optimized SLNs were spherical with average size of 111.1±2.2nm, zeta potential of -23.98±1.36mV and 93.8±1.8% of drug entrapment. Characterization of Amphotericin B SLNs by differential scanning calorimetry, Fourier transform infrared spectroscopy and Powder X-ray diffraction studies revealed absence of interaction between Amphotericin B and lipid. Amphotericin B is well dispersed in the lipid matrix without any crystallization. The SLNs were lyophilized with and without cryoprotectants to evaluate the stability and it was observed that the particle size of the SLNs significantly increased in SLN formulations lyophilized without cryoprotectant. The optimized SLN 5 formulation exhibited 2 fold higher drug permeation as compared to plain drug dispersion and higher zone of inhibition in Trichophyton rubrum fungal species. Formulation was found to be stable at 2-8°C and 25±2°C for the period of three months. Results of present study indicate that SLNs are suitable carriers for entrapment of poorly water soluble drugs and for enhancement of therapeutic efficacy of antifungal drug.
Varshosaz, J.; Ghaffari, S.; Mirshojaei, S. F.; Jafarian, A.; Atyabi, F.; Kobarfard, F.; Azarmi, S.
The main purpose of the present work was studying the biodistribution of amikacin solid lipid nanoparticles (SLNs) after pulmonary delivery to increase its concentration in the lungs for treatment of cystic fibrosis lung infections and also providing a new method for clinical application of amikacin. To achieve this aim, 99mTc labelled amikacin was loaded in cholesterol SLNs and after in vitro optimization, the desired SLNs and free drug were administered through pulmonary and i.v. routes to male rats and qualitative and biodistribution studies were done. Results showed that pulmonary delivery of SLNs of amikacin by microsprayer caused higher drug concentration in lungs than kidneys while i.v. administration of free drug caused reverse conditions. It seems that pulmonary delivery of SLNs may improve patients' compliance due to reduction of drug side effects in kidneys and elongation of drug dosing intervals due to the sustained drug release from SLNs. PMID:23984315
de Jesus, Marcelo B; Radaic, Allan; Hinrichs, Wouter L J; Ferreira, Carmen V; de Paula, Eneida; Hoekstra, Dick; Zuhorn, Inge S
Solid lipid nanoparticles (SLNs) are a promising system for the delivery of lipophilic and hydrophilic drugs. They consist of a solid lipid core that is stabilized by a layer of surfactants. By the incorporation of cationic lipids in the formulation, positively charged SLNs can be generated, that are suitable carriers for nucleic acids (DNA, siRNA). Considering the beneficial effect of helper lipids on the transfection efficiency with cationic liposomes, the effect of the helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) on transfection with cationic lipid-containing solid lipid nanoparticles was investigated in PC3 prostate cancer cells. The inclusion of DOPE in SLN formulations, instead of promoted, strongly inhibited SLN transfection efficiency, by frustrating the accommodation of DNA by the particles, as was revealed by biochemical analysis. SLNs devoid of DOPE maintained a homogenous size distribution of approximately 150 nm following lipoplex assembly and cellular delivery, and showed transfection efficiency comparable to that of Lipofectamine 2000' (LF2k). Moreover, the SLNs maintain their high transfection efficiency after lyophilization and long-term storage (1-2 years), an important asset for biomedical applications. There is even the possibility to lyophilize the SLN carrier together with its DNA cargo, which represents an interesting pharmaceutical advantage of the SLN formulations over LF2k. These results reflect marked differences between the physicochemical properties of cationic liposomes and SLNs, the latter requiring more critical lipid-depending properties for effective 'packaging' of DNA but displaying a higher storage stability than cationic lipid based carriers like LF2k.
Sutthanut, Khaetthareeya; Lu, Xiuling; Jay, Michael; Sripanidkulchai, Bungorn
Extracts of Kaempferia parviflora (KP) were formulated in solid lipid nanoparticles (SLNs) in order to enhance their transdermal permeability. The KP extracts were entrapped within SLNs by adding them to a melted mixture of oils, surfactants and PEGylating agents and subsequently forming an oil-in-water microemulsion at an elevated temperature. Cooling of this microemulsion resulted in the formation of SLNs. The formulation with the optimum properties was composed of stearyl alcohol as the nanoparticle matrix and Tocopheryl Polyethylene Glycol Succinate (TPGS) as the surfactant. Particle sizes of 82-108 nm were obtained with entrapment efficiencies as high as 87%. The release of the flavonoids from the SLN matrix was measured after suspending them in a Phosphate Buffered Saline (PBS)/Tween 80 solution and demonstrated biphasic patterns. Permeability studies using a skin model composed of human-derived epidermal keratinocytes were conducted in which a topically applied KP extract-loaded SLN was compared to a KP-hydroxypropyl methylcellulose/Tween 80 gel formulation containing KP extract. The amount of total KP flavonoids in the SLNs and gel that had permeated through the skin after 25 hours (95.57 +/- 9.08 and 81.04 +/- 5.82 g, respectively) were found to be significantly different (P < 0.05). In addition, the flux values of three of the flavonoids were greater when incorporated in SLNs.
Das, Surajit; Chaudhury, Anumita
Lipid nanoparticles based on solid matrix have emerged as potential drug carriers to improve gastrointestinal (GI) absorption and oral bioavailability of several drugs, especially lipophilic compounds. These formulations may also be used for sustained drug release. Solid lipid nanoparticle (SLN) and the newer generation lipid nanoparticle, nanostructured lipid carrier (NLC), have been studied for their capability as oral drug carriers. Biodegradable, biocompatible, and physiological lipids are generally used to prepare these nanoparticles. Hence, toxicity problems related with the polymeric nanoparticles can be minimized. Furthermore, stability of the formulations might increase than other liquid nano-carriers due to the solid matrix of these lipid nanoparticles. These nanoparticles can be produced by different formulation techniques. Scaling up of the production process from lab scale to industrial scale can be easily achieved. Reasonably high drug encapsulation efficiency of the nanoparticles was documented. Oral absorption and bioavailability of several drugs were improved after oral administration of the drug-loaded SLNs or NLCs. In this review, pros and cons, different formulation and characterization techniques, drug incorporation models, GI absorption and oral bioavailability enhancement mechanisms, stability and storage condition of the formulations, and recent advances in oral delivery of the lipid nanoparticles based on solid matrix will be discussed. © 2010 American Association of Pharmaceutical Scientists
Cai, Shuang; Zhang, Qiuhong; Bagby, Taryn; Forrest, M. Laird
The lymphatic system plays a crucial role in the immune system’s recognition and response to disease, and most solid cancers initially spread from the primary site via the tumor’s surrounding lymphatics before hematological dissemination. Hence, the lymphatic system is an important target for developing new vaccines, cancer treatments, and diagnostic agents. Targeting the lymphatic system by subcutaneous, intestinal, and pulmonary routes has been evaluated and subsequently utilized to improve lymphatic penetration and retention of drug molecules, reduce drug-related systemic toxicities, and enhance bioavailability of poorly soluble and unstable drugs. Lymphatic imaging is an essential tool for the detection and staging of cancer. New nano-based technologies offer improved detection and characterization of the nodal diseases, while new delivery devices can better target and confine treatments to tumors within the nodal space while sparing healthy tissues. This manuscript reviews recent advances in the field of lymphatic drug delivery and imaging and focuses specifically on the development ofliposomes and solid lipid nanoparticles for lymphatic introduction via the subcutaneous, intestinal, and pulmonary routes. PMID:21712055
Aji Alex, M R; Chacko, A J; Jose, S; Souto, E B
The poor orally available lopinavir was successfully encapsulated in glyceryl behenate based solid lipid nanoparticles (Lo-SLN) for its ultimate use to target intestinal lymphatic vessels in combined chemotherapy-the so-called Highly Active Anti-Retroviral Therapy (HAART). SLN with mean particle size of 230 nm (polydispersity index, PDI<0.27) and surface electrical charge of approx. -27mV, were produced by hot homogenization process followed by ultrasonication. Particles were characterized using differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) and atomic force microscopy (AFM) to confirm their solid character and the homogeneous distribution of drug within the lipid matrix. In vitro release studies at pH 6.8 phosphate buffer (PBS) and at pH 1.2 HCl 0.1N showed a slow release in both media. From the intestinal lymphatic transport study it became evident that SLN increased the cumulative percentage dose of lopinavir secreted into the lymph, which was 4.91-fold higher when compared with a conventional drug solution in methyl cellulose 0.5% (w/v) as suspending agent (Lo-MC). The percentage bioavailability was significantly enhanced. The AUC for the Lo-SLN was 2.13-fold higher than that obtained for the Lo-MC of similar concentration. The accelerated stability studies showed that there was no significant change in the mean particle size and PDI after storage at 25±2°C/60±5% RH. The shelf life of optimized formulation was assessed based on the remained drug content in the stabilized formulation and was shown to be 21.46 months. Copyright © 2010 Elsevier B.V. All rights reserved.
Jain, Sanyog; Mistry, Meghal A; Swarnakar, Nitin K
The present investigation was enthused by the possibility to develop solid lipid nanoparticles (SLNs) of hydrophilic drug acyclovir (ACV) and evaluate their potential as the carrier for dermal delivery. ACV-loaded SLNs (ACV-SLNs) were prepared by the optimized double emulsion process using Compritol 888 ATO as solid lipid. The prepared SLNs were smooth and spherical in shape with average diameter, polydispersity index, and entrapment efficiency of 262 ± 13 nm, 0.280 ± 0.01, and 40.08 ± 4.39% at 10% (w/w) theoretical drug loading with respect to Compritol 888 ATO content. Differential scanning calorimetry and powder X-ray diffraction pattern revealed that ACV was present in the amorphous state inside the SLNs. In vitro skin permeation studies on human cadaver and Sprague-Dawley rat skin revealed 17.65 and 15.17 times higher accumulation of ACV-SLNs in the dermal tissues in comparison to commercially available ACV cream after 24 h. Mechanism of topical permeation and dermal distribution was studied qualitatively using confocal laser scanning microscopy. While free dye (calcein) failed to penetrate skin barrier, the same encapsulated in SLNs penetrated deeply into the dermal tissue suggesting that pilosebaceous route was followed by SLNs for skin penetration. Histological examination and transdermal epidermal water loss measurement suggested that no major morphological changes occurred on rat skin surface due to the application of SLNs. Overall, it was concluded that ACV-loaded SLNs might be beneficial in improving dermal delivery of antiviral agent(s) for the treatment of topical herpes simplex infection.
Triplett, Michael D.; Rathman, James F.
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.
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
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.
Kharya, Parul; Jain, Ashish; Gulbake, Arvind; Shilpi, Satish; Jain, Ankit; Hurkat, Pooja; Majumdar, Subrata; Jain, Sanjay K.
The purpose of this study is to investigate the targeting potential of amino acid (phenylalanine)-coupled solid lipid nanoparticles (SLN) loaded with ionically complexed doxorubicin HCl (Dox). Ionic complexation was used to enhance the loading efficiency and release characteristics of water soluble form of Dox. l-Type amino acid transporters (LAT1) are highly expressed on blood brain barrier as well as on many brain cancer cells, thus targeting LAT1 using phenylalanine improved anticancer activity of prepared nanocarrier. The phenylalanine-coupled SLN were characterized by fourier transform infrared spectroscopy, scanning electron microscope, transmission electron microscopy, particle size, zeta potential, entrapment efficiency and in vitro release. The particle size of the resulting SLN was found to be in the range of 163.3 ± 5.2 to 113.0 ± 2.6 nm, with a slightly negative surface charge. In ex vivo study on C6 glioma cell lines, the cellular cytotoxicity of the SLN was highly increased when coupled with phenylalanine. In addition, stealthing sheath of PEG present on the surface of the SLN enhanced the cellular uptake of the SLN on C6 glioma cell line. Results of biodistribution and fluorescence studies clearly revealed that phenylalanine-coupled SLN could deliver high amount of drug into the brain tumor cells and showed the brain-targeting potential.
Shah, Kumar A; Date, Abhijit A; Joshi, Medha D; Patravale, Vandana B
The objective of this investigation was to develop solid lipid nanoparticles (SLN) of tretinoin (TRE) with the help of facile and simple emulsification-solvent diffusion (ESD) technique and to evaluate the viability of an SLN based gel in improving topical delivery of TRE. The feasibility of fabricating SLN of TRE by the ESD method was successfully demonstrated in this investigation. The developed SLN were characterized for particle size, polydispersity index, entrapment efficiency of TRE and morphology. Studies were carried out to evaluate the ability of SLN in improving the photostability of TRE as compared to TRE in methanol. Encapsulation of TRE in SLN resulted in a significant improvement in its photostability in comparison to methanolic TRE solution and also prevented its isomerization. Furthermore, the skin irritation studies carried out on rabbits showed that SLN based TRE gel is significantly less irritating to skin as compared to marketed TRE cream and clearly indicated its potential in improving the skin tolerability of TRE. In vitro permeation studies through rat skin indicated that an SLN based TRE gel has permeation profile comparable to that of the marketed TRE cream.
Jiang, Shan; Zhu, Rongrong; He, Xiaolie; Wang, Jiao; Wang, Mei; Qian, Yechang; Wang, Shilong
Curcumin (Cur) is a promising photosensitizer that could be used in photodynamic therapy. However, its poor solubility and hydrolytic instability limit its clinical use. The aim of the present study was to encapsulate Cur into solid lipid nanoparticles (SLNs) in order to improve its therapeutic activity. The Cur-loaded SLNs (Cur-SLNs) were prepared using an emulsification and low-temperature solidification method. The functions of Cur and Cur-SLNs were studied on the non-small cell lung cancer A549 cells for photodynamic therapy. The results revealed that Cur-SLNs induced ~2.27-fold toxicity higher than free Cur at a low concentration of 15 μM under light excitation, stocking more cell cycle at G2/M phase. Cur-SLNs could act as an efficient drug delivery system to increase the intracellular concentration of Cur and its accumulation in mitochondria; meanwhile, the hydrolytic stability of free Cur could be improved. Furthermore, Cur-SLNs exposed to 430 nm light could produce more reactive oxygen species to induce the disruption of mitochondrial membrane potential. Western blot analysis revealed that Cur-SLNs increased the expression of caspase-3, caspase-9 proteins and promoted the ratio of Bax/Bcl-2. Overall, the results from these studies demonstrated that the SLNs could enhance the phototoxic effects of Cur. PMID:28053531
Vandita, Kakkar; Shashi, Bhushan; Santosh, Kumar Guru; Pal, Kaur Indu
Curcumin is reported to show potent in vitro anticancer effects in a surfeit of human cancer cell lines and majorly in the carcinogenesis of GIT, in animals. Its poor pharmacokinetics and stability limit its vivo clinical efficacy for the other systemic cancers. We recently reported on a 32-155 times enhancement in bioavailability of curcumin when incorporated into solid lipid nanoparticles (C-SLNs). Presently we report on a 54-85% reduction in IC 50 values with developed C-SLNs in comparison to free curcumin against a panel of human cancer cell lines (HL-60, A549, and PC3). Results demonstrate mechanisms similar to those claimed for free curcumin, including induction of cellular apoptosis by activation of caspases, release of cyctochrome c, loss of membrane potential, blockade of nuclear factor kappa B (NF-κB) activation, and upregulation of TNF-R for C-SLNs. However, the extent of cell death provided by C-SLNs in all these tests was significantly higher (p < 0.001). This may be attributed to the presentation of curcumin in a dispersible/soluble form which enhanced permeability across the cell surface. The display of significantly better in vitro anticancer effect coupled with high in vivo bioavailability points toward a great potential of using C-SLNs for cancer therapeutics.
Jiang, Shan; Zhu, Rongrong; He, Xiaolie; Wang, Jiao; Wang, Mei; Qian, Yechang; Wang, Shilong
Curcumin (Cur) is a promising photosensitizer that could be used in photodynamic therapy. However, its poor solubility and hydrolytic instability limit its clinical use. The aim of the present study was to encapsulate Cur into solid lipid nanoparticles (SLNs) in order to improve its therapeutic activity. The Cur-loaded SLNs (Cur-SLNs) were prepared using an emulsification and low-temperature solidification method. The functions of Cur and Cur-SLNs were studied on the non-small cell lung cancer A549 cells for photodynamic therapy. The results revealed that Cur-SLNs induced ~2.27-fold toxicity higher than free Cur at a low concentration of 15 μM under light excitation, stocking more cell cycle at G2/M phase. Cur-SLNs could act as an efficient drug delivery system to increase the intracellular concentration of Cur and its accumulation in mitochondria; meanwhile, the hydrolytic stability of free Cur could be improved. Furthermore, Cur-SLNs exposed to 430 nm light could produce more reactive oxygen species to induce the disruption of mitochondrial membrane potential. Western blot analysis revealed that Cur-SLNs increased the expression of caspase-3, caspase-9 proteins and promoted the ratio of Bax/Bcl-2. Overall, the results from these studies demonstrated that the SLNs could enhance the phototoxic effects of Cur.
Zhang, Yong-Tai; Han, Meng-Qing; Shen, Li-Na; Zhao, Ji-Hui; Feng, Nian-Ping
In this study, solid lipid nanoparticles were formulated for transdermal delivery of aconitine to improve its safety and permeability. Aconitine-loaded solid lipid nanoparticles were formulated as an oil-in-water microemulsion. Drug encapsulation efficiencies for these formulations were higher than 85%, and correlated positively with levels of surfactant and oil matrix. The size of the solid lipid nanoparticles was increased with an increase of the oil matrix, and reduction of the surfactant levels. Compared with an ethanol tincture, all the tested solid lipid nanoparticle formulations achieved improved transdermal fluxes and drug deposition in skin in vitro. Real-time monitoring of drug distribution in rat dermis using in vivo microdialysis showed that aconitine concentration was markedly higher following application of solid lipid nanoparticles, compared to tincture, throughout the experimental period. A regional comparison of rat skin found that application of solid lipid nanoparticles to the scapular region resulted in higher AUC(0-t) and C(max), compared to those achieved with application to the abdomen or chest (p < 0.05). In contrast, the application to the chest resulted in the lowest AUC(0-t) and C(max). Together with findings of a structural study of the skin, these results indicated that the drug accumulated more readily in thicker skin regions, and to a lesser extent in well-perfused skin, because of drug transfer to capillaries. The superior transdermal permeability of aconitine-loaded solid lipid nanoparticles contributed to stronger anti-inflammatory and analgesic effects on mouse in vivo models of pain than the tincture (p < 0.05). In vitro and in vivo studies indicated that smaller particle sizes of solid lipid nanoparticles enhanced the transdermal permeability of aconitine, which can promote drug efficacy, reduce administration time, and improve medication safety.
Pizzol, Carine Dal; Filippin-Monteiro, Fabíola Branco; Restrepo, Jelver Alexander Sierra; Pittella, Frederico; Silva, Adny Henrique; Alves de Souza, Paula; Machado de Campos, Angela; Creczynski-Pasa, Tânia Beatriz
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.
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
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
Soni, Maheshkumar P.; Shelkar, Nilakash; Gaikwad, Rajiv V.; Vanage, Geeta R.; Samad, Abdul; Devarajan, Padma V.
Background: Buparvaquone (BPQ), a hydroxynaphthoquinone derivative, has been investigated for the treatment of many infections and is recommended as the gold standard for the treatment of theileriosis. Theileriosis, an intramacrophage infection is localized mainly in reticuloendotheileial system (RES) organs. The present study investigates development of solid lipid nanoparticles (SLN) of BPQ for targeted delivery to the RES. Materials and Methods: BPQ SLN was prepared using melt method by adding a molten mixture into aqueous Lutrol F68 solution (80°C). Larger batches were prepared up to 6 g of BPQ with GMS: BPQ, 2:1. SLN of designed size were obtained using ultraturrax and high pressure homogenizer. A freeze and thaw study was used to optimize type and concentration of cryoprotectant with Sf: Mean particle size, Si: Initial particle size <1.3. Differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and scanning electron microscope (SEM) study was performed on optimized formulation. Formulation was investigated for in vitro serum stability, hemolysis and cell uptake study. Pharmacokinetic and biodistribution study was performed in Holtzman rat. Results: Based on solubility in lipid; glyceryl monostearate (GMS) was selected for preparation of BPQ SLN. Batches of BPQ SLN were optimized for average particle size and entrapment efficiency at <100 mg solid content. A combination of Solutol HS-15 and Lutrol F68 at 2% w/v and greater enabled the desired Sf/Si < 1.3. Differential scanning calorimetry and powder X-ray diffraction revealed decrease in crystallinity of BPQ in BPQ SLN while, scanning electron microscope revealed spherical morphology. BPQ SLN revealed good stability at 4°C and 25°C. Low hemolytic potential (<8%) and in vitro serum stability up to 5 h was observed. Cytotoxicity of SLN to the U937 cell was low. The macrophage cell line revealed high (52%) uptake of BPQ SLN in 1 h suggesting the potential to RES uptake. SLN revealed longer
Jang, Dong-Jin; Moon, Cheol; Oh, Euichaul
This study aimed to enhance the in vivo antitumor effects of camptothecin (CPT), a strong antitumor agent whose delivery is limited by poor aqueous solubility and instability of the active lactone form. CPT was loaded into sterically stabilized, solid lipid nanoparticles (CPT-SLNs) formulated for intravenous administration. The influence of preinjected blank SLNs on the tumor targeting, pharmacokinetics and antitumor activity of CPT-SLNs was investigated. The CPT-SLNs composed of trilaurin-based lipid matrix containing poloxamer188 and pegylated phospholipid as stabilizers were prepared by hot homogenization method and evaluated for in vitro characteristics and in vivo performance. The CPT-SLNs showed an in vitro long-term sustained release pattern and effectively protected the CPT lactone form from hydrolysis under physiological conditions. Notable tumor targeting and tumor growth inhibition were observed after intravenous administration of CPT-SLNs to mice with subcutaneous transplants of CT26 carcinoma cells. In pharmacokinetic studies in rats, CPT-SLNs markedly elevated plasma CPT level and prolonged blood circulation compared to free CPT. Nonetheless, high uptake of CPT-SLNs by reticuloendothelial system (RES)-rich tissues resulted in limited tumor targeting of CPT-SLNs and plasma CPT levels. Preinjection of blank SLNs before administration of CPT-SLNs to tumor-bearing mice substantially reduced the accumulation of CPT-SLNs in RES organs. This led to significantly enhanced tumor targeting, improved pharmacokinetic parameters and increased antitumor efficacy of CPT-SLNs. These results suggested that the in vivo antitumor effects of CPT-SLNs could be further enhanced by preinjection of blank SLNs. Therefore, CPT-SLNs with preinjected blank SLNs could be a potential approach for stable and effective CPT-based cancer therapy.
He, Sai-Nan; Li, Yun-Long; Yan, Jing-Jing; Zhang, Wei; Du, Yong-Zhong; Yu, He-Yong; Hu, Fu-Qiang; Yuan, Hong
Background The objective of this research was to design an effective gene delivery system composed of cationic solid lipid nanoparticles (SLNs), protamine, and Deoxyribonucleic acid DNA. Methods Cationic SLNs were prepared using an aqueous solvent diffusion method with octadecylamine as the cationic lipid material. First, protamine was combined with DNA to form binary protamine/DNA nanoparticles, and the ternary nanoparticle gene delivery system was then obtained by combining binary protamine/DNA nanoparticles with cationic SLNs. The size, zeta potential, and ability of the binary and ternary nanoparticles to compact and protect DNA were characterized. The effect of octadecylamine content in SLNs and the SLNS/DNA ratios on transfection efficiency, cellular uptake and cytotoxicity of the ternary nanoparticles were also assessed using HEK293 cells. Results When the weight ratio of protamine to DNA reached 1.5:1, the plasmid DNA could be effectively compacted and protected. The average hydrodynamic diameter of the ternary nanoparticles when combined with protamine increased from 188.50 ± 0.26 nm to 259.33 ± 3.44 nm, and the zeta potential increased from 25.50 ± 3.30 mV to 33.40 ± 2.80 mV when the weight ratio of SLNs to DNA increased from 16/3 to 80/3. The ternary nanoparticles showed high gene transfection efficiency compared with Lipofectamine™ 2000/DNA nanoparticles. Several factors that might affect gene transfection efficiency, such as content and composition of SLNs, post-transfection time, and serum were examined. The ternary nanoparticles composed of SLNs with 15 wt% octadecylamine (50/3 weight ratio of SLNs to DNA) showed the best transfection efficiency (26.13% ± 5.22%) in the presence of serum. It was also found that cellular uptake of the ternary nanoparticles was better than that of the SLN/DNA and binary protamine/DNA nanoparticle systems, and DNA could be transported to the nucleus. Conclusion SLNs enhanced entry of binary protamine
Khatak, Sunil; Dureja, Harish
The various approaches have been utilized in the treatment of a variety of diseases by applying drug delivery system such as polymeric nanoparticles, self-emulsifying delivery systems, liposomes, microemulsions and micellar solutions. Recently, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) and lipid-drug conjugates (LDCs) have been exploited as a carrier of lipophilic and hydrophilic/amphiphilic substances for invasive and non-invasive routes of delivery. SLNs are colloidal drug carrier system and are like nanoemulsion, however, the lipid content in SLNs is solid in nature. These novel type of lipid nanoparticles with solid matrix offers to develop new prototype therapeutics in drug delivery, which could be used for controlled release, drug targeting, gene therapy, physical and chemical stability and site-specific drug delivery and thereby attracted the research groups worldwide. This manuscript overviews the recent patents, advantages, formulation techniques, stability aspects and applications of SLNs.
Barman, Ranjan Kumar; Iwao, Yasunori; Funakoshi, Yuka; Ranneh, Abdul-Hackam; Noguchi, Shuji; Wahed, Mir Imam Ibne; Itai, Shigeru
To improve the solubility of the drug nifedipine (NI), highly stabilized solid-lipid nanoparticles (SLNs) of nifedipine (NI-SLNs) were prepared by high pressure homogenization using two phospholipids, followed by lyophilization with individual sugar moieties (four monosaccharides and four disaccharides). The mean particle diameter, polydispersity index (PDI), zeta potential, drug loading, and the encapsulation efficiency of the NI-SLN suspension were determined to be 68.5 nm, 0.3, -62.1 mV, 2.7%, and 97.5%, respectively. In comparison with the NI-SLNs, the NI-SLNs lyophilized with trehalose (NI-SLN-Tre) showed a slight increase in the particle size from 68.5 to 107.7 nm, but the PDI decreased from 0.38 to 0.33, and no significant change in zeta potential was observed. Aqueous re-dispersibility study demonstrated that NI-SLNs lyophilized with trehalose had the maximum concentration (14.7 µg/mL) at 5 min, compared with lyophilized SLNs using other sugars; the use of other sugars also resulted in significant changes in the particle size, PDI, and zeta potential. A trehalose concentration of 2.5% w/v and a two-fold dilution of the SLN suspension were found to be the best conditions for lyophilization. Data from lyophilized SLNs using differential scanning calorimetry, powder X-ray diffraction, Fourier-transform infrared spectroscopy, and scanning electron microscopy indicated eventual transformation of NI-SLN-Tre from a crystalline to an amorphous state during the homogenization process. Finally, a stability study was performed with NI-SLN-Tre for up to 6 months at 30°C and 65% relative humidity, with no significant deterioration observed, suggesting that trehalose might be a useful cryoprotectant for NI-SLNs.
Ikeuchi-Takahashi, Yuri; Ishihara, Chizuko; Onishi, Hiraku
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.
Schoenitz, M; Joseph, S; Nitz, A; Bunjes, H; Scholl, S
The contribution describes the transfer from a batch to a micro-continuous process for the production of stable solid lipid nanoparticles as drug carrier systems. Solid lipid nanoparticles are commonly prepared batch-wise often resulting in poorly defined product qualities with regard to the polymorphic state of their lipid matrix. In order to obtain solid lipid nanoparticle dispersions that meet the requirements for an acceptable pharmaceutical product, the manufacture of reproducible product qualities preferably containing the stable crystal form of the respective matrix lipid is necessary. These requests are addressed by the continuous preparation process of solid lipid nanoparticles. A four step feasibility study for the standardized evaluation whether or not a colloidal lipid dispersion is suitable for continuous crystallization of the particles resulting in stable crystal forms is presented. The process is based on the continuous crystallization and subsequent thermal treatment of differently stabilized, tripalmitin-based nanoparticle formulations in microstructured devices. The successful production of the stable crystal form by means of a continuous process chain is shown for a dispersion stabilized with a blend of hydrogenated soybean lecithin and sodium glycocholate.
Uner, M; Wissing, S A; Yener, G; Müller, R H
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.
Investigations on the structure of solid lipid nanoparticles (SLN) and oil-loaded solid lipid nanoparticles by photon correlation spectroscopy, field-flow fractionation and transmission electron microscopy.
Jores, Katja; Mehnert, Wolfgang; Drechsler, Markus; Bunjes, Heike; Johann, Christoph; Mäder, Karsten
Recently, colloidal dispersions made from mixtures of solid and liquid lipids were described to combine controlled release characteristics with higher drug loading capacities than solid lipid nanoparticles (SLN). It has been proposed that these nanostructured lipid carriers (NLC) are composed of oily droplets which solubilize the drug and which are embedded in a solid lipid matrix. The structures of SLN and NLC based on glyceryl behenate and medium chain triglycerides were characterized by photon correlation spectroscopy (PCS) and laser diffraction (LD), field-flow fractionation (FFF) with multi-angle light scattering detection (MALS), and cryo transmission electron microscopy (cryo TEM). PCS indicates that SLN and NLC differ from a nanoemulsion with respect to Brownian motion due to asymmetric particle shapes. Non-spherical particles, in case of SLN and NLC, lead to higher polydispersity indices compared to the nanoemulsion. In FFF, the nanodroplets elute much earlier than SLN- and NLC-platelets although their PCS and LD data show similar particle sizes. In TEM platelet (for SLN), oil loaded platelet ("nanospoons"; for NLC) and droplet (for nanoemulsion) structures were observed. In contrast to literature reports, the investigated SLN appear as thin platelets. NLC are found to be lipid platelets with oil spots sticking on the surface. Very short diffusion pathways in platelets, increased water-lipid interfaces and low drug incorporation in crystalline lipids are the drawback of SLN and NLC compared to conventional nanoemulsions.
Fatouh, Ahmed M; Elshafeey, Ahmed H; Abdelbary, Ahmed
Agomelatine is a novel antidepressant drug suffering from an extensive first-pass metabolism leading to a diminished absolute bioavailability. The aim of the study is: first to enhance its absolute bioavailability, and second to increase its brain delivery. To achieve these aims, the nasal route was adopted to exploit first its avoidance of the hepatic first-pass metabolism to increase the absolute bioavailability, and second the direct nose-to-brain pathway to enhance the brain drug delivery. Solid lipid nanoparticles were selected as a drug delivery system to enhance agomelatine permeability across the blood-brain barrier and therefore its brain delivery. The optimum solid lipid nanoparticles have a particle size of 167.70 nm ±0.42, zeta potential of -17.90 mV ±2.70, polydispersity index of 0.12±0.10, entrapment efficiency % of 91.25%±1.70%, the percentage released after 1 h of 35.40%±1.13% and the percentage released after 8 h of 80.87%±5.16%. The pharmacokinetic study of the optimized solid lipid nanoparticles revealed a significant increase in each of the plasma peak concentration, the AUC(0-360 min) and the absolute bioavailability compared to that of the oral suspension of Valdoxan(®) with the values of 759.00 ng/mL, 7,805.69 ng⋅min/mL and 44.44%, respectively. The optimized solid lipid nanoparticles gave a drug-targeting efficiency of 190.02, which revealed more successful brain targeting by the intranasal route compared with the intravenous route. The optimized solid lipid nanoparticles had a direct transport percentage of 47.37, which indicates a significant contribution of the direct nose-to-brain pathway in the brain drug delivery. The intranasal administration of agomelatine solid lipid nanoparticles has effectively enhanced both the absolute bioavailability and the brain delivery of agomelatine.
Hsu, Ming-Huang; Su, Yu-Chuan
This paper presents the development of magnetic lipid nanoparticles that could serve as controlled delivery vehicles for releasing encapsulated drugs in a desired manner. The nanoparticles are composed of multiple drugs in lipid matrices, which are solid at body temperature and melt around 45 degrees C to 55 degrees C. In addition, super-paramagnetic gamma-Fe2O3 particles with sizes ranging from 5 to 25 nm are surface modified and dispersed uniformly in the lipid nanoparticles. In the prototype demonstration, lipid nanoparticles with average sizes between 100 and 180 nm were fabricated by high-pressure homogenization at elevated temperatures. When exposed to an alternating magnetic field of 60 kA/m at 25 kHz, a solution containing 2 g/L encapsulated gamma-Fe2O3 particles showed a temperature increase from 37 degrees C to 50 degrees C in 20 min. Meanwhile, the dissipated heat melted the surrounding lipid matrices and resulted in an accelerated release of the encapsulated drugs. Within 20 min, approximately 35% of the encapsulated drug molecules were released from the lipid nanoparticles through diffusion. As such, the presented lipid nanoparticles enable a new scheme that combines magnetic control of heating and drug delivery, which could greatly enhance the performance of encapsulated drugs.
Weber, S; Zimmer, A; Pardeike, J
Drug delivery by inhalation is a noninvasive means of administration that has following advantages for local treatment for airway diseases: reaching the epithelium directly, circumventing first pass metabolism and avoiding systemic toxicity. Moreover, from the physiological point of view, the lung provides advantages for systemic delivery of drugs including its large surface area, a thin alveolar epithelium and extensive vasculature which allow rapid and effective drug absorption. Therefore, pulmonary application is considered frequently for both, the local and the systemic delivery of drugs. Lipid nanoparticles - Solid Lipid Nanoparticles and Nanostructured Lipid Carriers - are nanosized carrier systems in which solid particles consisting of a lipid matrix are stabilized by surfactants in an aqueous phase. Advantages of lipid nanoparticles for the pulmonary application are the possibility of a deep lung deposition as they can be incorporated into respirables carriers due to their small size, prolonged release and low toxicity. This paper will give an overview of the existing literature about lipid nanoparticles for pulmonary application. Moreover, it will provide the reader with some background information for pulmonary drug delivery, i.e., anatomy and physiology of the respiratory system, formulation requirements, application forms, clearance from the lung, pharmacological benefits and nanotoxicity.
Qu, Jie; Zhang, Liangqiao; Chen, Zhihua; Mao, Guohua; Gao, Ziyun; Lai, Xianliang; Zhu, Xingen; Zhu, Jianming
Glioblastoma is a malignant brain tumor originating in the central nervous system. Successfully therapy of this disease required the efficient delivery of therapeutic agents to the tumor cells and tissues. Delivery of anticancer drugs using novel nanocarriers is promising in glioma treatment. Polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) were constructed for the delivery of temozolomide (TMZ). The anti-tumor effects of the three kinds of nanocarriers were compared to provide the optimum choice for gliomatosis cerebri treatment. TMZ-loaded PNPs (T-PNPs), SLNs (T-SLNs), and NLCs (T-NLCs) were formulated. Their particle size, zeta potential, drug encapsulation efficiency (EE), and drug loading (DL) capacity were evaluated. Anti-tumor efficacies of the three kinds of nanocarriers were evaluated on U87 malignant glioma cells (U87 MG cells) and mice-bearing malignant glioma model. T-NLCs displayed the best anti-tumor activity than other formulations in vivo and in vitro. The most significantly glioma inhibition was observed on NLCs formulations than PNPs and SLNs. This work demonstrates that NLCs can deliver TMZ into U87MG cells more efficiently, with higher inhibition efficacy than PNPs and SLNs. T-NLCs could be an excellent drug delivery system for glioblastoma chemotherapy.
Kumar, Sacheen; Kaur, Jaspreet
Solid lipid nanoparticles are new paradigm of drug delivery system of water insoluble active pharmaceutical ingredient. Paliperidone, an antipsychotic used in treatment of schizophrenia is a water insoluble molecule with low bioavailability was studied. Macrogol glyceride surfactant, bile salt based surfactant and sodium dodecyl sulphate were used to stabilize the solid lipid as dispersed nanoparticles form by adsorbing on the surface of the nanoparticles. Anionic surfactants bile salt and sodium dodecyl sulphate were found to stabilize forming a monomolecular layer of surfactants on the surface of nanoparticles; whereas macrogol glyceride based surfactant have intrusion in the matrix of lipid nanoparticles. So intrusion of macrogol glyceride in matrix was observed by studying the change in size of nanoparticles with respect to temperature with the help of dynamic light scattering. In case of macrogol glyceride size decrease start form 50°C, for bile salt and sodium dodecyl sulphate size deacrease start at 60°C. So that structural disturbance of nanoparticles by the macrogol glyceride on the surface was found maximum as compared to anionic surfactant.
Gönüllü, Ümit; Üner, Melike; Yener, Gülgün; Karaman, Ecem Fatma; Aydoğmuş, Zeynep
Solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsion (NE) of lornoxicam (LRX) were prepared for the treatment of painful and inflammatory conditions of the skin. Compritol® 888 ATO, Lanette® O and oleic acid were used as solid and liquid lipids. SLN, NLC and NE were found physically stable at various temperatures for 6 months. Case I diffusional drug release was detected as the dominant mechanism indicating Fickian drug diffusion from nanoparticles and nanoemulsion. The highest rate of drug penetration through rat skin was obtained with NE followed by NLC, SLN and a gel formulation. Nanoformulations significantly increased drug penetration through rat skin compared to the gel (p<0.05). Thus, SLN, NLC and NE of LRX can be suggested for relieving painful and inflammatory conditions of the skin.
Azhar Shekoufeh Bahari, Leila; Hamishehkar, Hamed
During the past decade, pharmaceutical science has seen rapid growth in interest for nanoscale materials. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are popular research topics recently introduced as nano-scale drug carriers; they have shown numerous merits in drug delivery. Size is the most important index in a nanocarrier affecting its drug delivery efficiency. The influence of preparation conditions and type of lipidic components on the size of SLN and NLC in comparable states seems to be interesting for researchers who investigate these types of carriers. This review highlights the results of SLN and NLC particle size and size distribution comparisons. PMID:27478775
Almeida, António J; Souto, Eliana
Solid lipid particulate systems such as solid lipid nanoparticles (SLN), lipid microparticles (LM) and lipospheres have been sought as alternative carriers for therapeutic peptides, proteins and antigens. The research work developed in the area confirms that under optimised conditions they can be produced to incorporate hydrophobic or hydrophilic proteins and seem to fulfil the requirements for an optimum particulate carrier system. Proteins and antigens intended for therapeutic purposes may be incorporated or adsorbed onto SLN, and further administered by parenteral routes or by alternative routes such as oral, nasal and pulmonary. Formulation in SLN confers improved protein stability, avoids proteolytic degradation, as well as sustained release of the incorporated molecules. Important peptides such as cyclosporine A, insulin, calcitonin and somatostatin have been incorporated into solid lipid particles and are currently under investigation. Several local or systemic therapeutic applications may be foreseen, such as immunisation with protein antigens, infectious disease treatment, chronic diseases and cancer therapy.
Natarajan, Jawahar; Baskaran, Mahendran; Humtsoe, Lireni C; Vadivelan, R; Justin, A
Olanzapine (OLZ) is a typical anti-psychotic drug, which is highly lipophilic in nature, belongs to Biopharmaceutical Classification System (BCS) class II category. Though OLZ is an effective agent in the treatment of Schizophrenia, but it exhibits poor bioavailability (57%) due to extensive first-pass metabolism resulted in high dose is required to achieve therapeutic concentration in brain. Emerging evidences are indicating that high dose administration of OLZ may cause Extrapyramidal symptoms (EPS) in the psychotic patients. Hence, the present study is designed to develop Olanzapine solid lipid (OLZ-SLNs) using minimal dose of OLZ thereby enhancing the brain efficacy as well as to reduce the side effects associated with OLZ. OLZ-SLNs have been prepared by "solvent diffusion method" using lipids, such as glyceryl monostearate (GMS), tripalmitin (TP), Tween 80, and Stearyl amine as positive charge inducer. The prepared OLZ-SLNs were subjected to particle size analysis, zeta potential, and poly dispersity index measurement by using Malvern Zetasizer. Pharmacokinetics assessments of OLZ-SLNs were carried in conscious male Wistar rats through intravenous administration. Results have shown that average particle size and zeta potential of SLNs of GMS and TP were ranged from 165.1 ± 2.2 to 110.5 ± 0.5 and 35.29 ± 1.2 and 66.50 ± 0.7 mV, respectively. Relative bioavailability of OLZ in the brain was increased up to 23-fold and clearance was decreased when OLZ-SLNs while administrated intravenously. The area under the curve (AUC) and mean residence time (MRT) of OLZ-SLNs in brain were higher than OLZ suspension. These results indicate that SLNs are a promising drug delivery for OLZ. It may be an effective tool to enhance the bioavailability of OLZ in the brain with less dose administration, which could reduce the EPS associated with OLZ.
Pooja, Deep; Kulhari, Hitesh; Kuncha, Madhusudana; Rachamalla, Shyam S; Adams, David J; Bansal, Vipul; Sistla, Ramakrishna
Oral delivery of anticancer drugs remains challenging despite the most convenient route of drug administration. Hydrophobicity and nonspecific toxicities of anticancer agents are major impediments in the development of oral formulation. In this study, we developed wheat germ agglutinin (WGA)-conjugated, solid lipid nanoparticles to improve the oral delivery of the hydrophobic anticancer drug, paclitaxel (PTX). This study was focused to improve the PTX loading in biocompatible lipid matrix with high bioconjugation efficiency. WGA-conjugated, PTX-loaded solid lipid nanoparticles (LPSN) exhibited enhanced anticancer activity against A549 lung cancer cells after internalization through lectin receptors than free PTX. Biodistribution studies in rats revealed that LPSN significantly improved the oral bioavailability and lung targetability of PTX, which could be due to cumulative bioadhesive property of the nanocarrier system and the targeting ligand WGA.
Silva, Elton Luiz; Carneiro, Guilherme; De Araújo, Lidiane Advíncula; Trindade, Mariana de Jesus Vaz; Yoshida, Maria Irene; Oréfice, Rodrigo Lambert; Farias, Luis de Macêdo; De Carvalho, Maria Auxiliadora Roque; Dos Santos, Simone Gonçalves; Goulart, Gisele Assis Castro; Alves, Ricardo José; Ferreira, Lucas Antônio Miranda
Topical therapy is the first choice for the treatment of mild to moderate acne and all-trans retinoic acid is one of the most used drugs. The combination of retinoids and antimicrobials is an innovative approach for acne therapy. Recently, lauric acid, a saturated fatty acid, has shown strong antimicrobial activity against Propionibacterium acnes. However, topical application of retinoic acid is followed by high incidence of side-effects, including erythema and irritation. Solid lipid nanoparticles represent an alternative to overcome these side-effects. This work aims to develop solid lipid nanoparticles loaded with retinoic acid and lauric acid and evaluate their antibacterial activity. The influence of lipophilic stearylamine on the characteristics of solid lipid nanoparticles was investigated. Solid lipid nanoparticles were characterized for size, zeta potential, encapsulation efficiency, differential scanning calorimetry and X-ray diffraction. The in vitro inhibitory activity of retinoic acid-lauric acid-loaded solid lipid nanoparticles was evaluated against Propionibacterium acnes, Staphylococcus aureus and Staphylococcus epidermidis. High encapsulation efficiency was obtained at initial time (94 ± 7% and 100 ± 4% for retinoic acid and lauric acid, respectively) and it was demonstrated that lauric acid-loaded-solid lipid nanoparticles provided the incorporation of retinoic acid. However, the presence of stearylamine is necessary to ensure stability of encapsulation. Moreover, retinoic acid-lauric acid-loaded solid lipid nanoparticles showed growth inhibitory activity against Staphylococcus epidermidis, Propionibacterium acnes and Staphylococcus aureus, representing an interesting alternative for the topical therapy of acne vulgaris.
Gastaldi, Lucia; Battaglia, Luigi; Peira, Elena; Chirio, Daniela; Muntoni, Elisabetta; Solazzi, Ilaria; Gallarate, Marina; Dosio, Franco
Central nervous system disorders are already prevalent and steadily increasing among populations worldwide. However, most of the pharmaceuticals present on world markets are ineffective in treating cerebral diseases, because they cannot effectively cross the blood brain barrier (BBB). Solid lipid nanoparticles (SLN) are nanospheres made from biocompatible solid lipids, with unique advantages among drug carriers: they can be used as vehicles to cross the BBB. This review examines the main aspects surrounding brain delivery with SLN, and illustrates the principal mechanisms used to enhance brain uptake of the delivered drug.
Souto, E B; Anselmi, C; Centini, M; Müller, R H
Solid lipid nanoparticles (SLN) containing a novel potential sunscreen n-dodecyl-ferulate (ester of ferulic acid) were developed. The preparation and stability parameters of n-dodecyl-ferulate-loaded SLN have been investigated concerning particle size, surface electrical charge (zeta potential) and matrix crystallinity. The chemical stability of n-dodecyl-ferulate at high temperatures was also assessed by thermal gravimetry analysis. For the selection of the appropriated lipid matrix, chemically different lipids were melted with 4% (m/m) of active and lipid nanoparticles were prepared by the so-called high pressure homogenization technique. n-Dodecyl-ferulate-loaded SLN prepared with cetyl palmitate showed the lowest mean particle size and polydispersity index, as well as the highest physical stability during storage time of 21 days at 4, 20 and 40 degrees C. These colloidal dispersions containing the sunscreen also exhibited the common melting behaviour of aqueous SLN dispersions.
Muchow, Marc; Maincent, Philippe; Muller, Rainer H
Solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and lipid-drug conjugates (LDC), commonly produced by high-pressure homogenization, are interesting vectors for oral delivery of lipophilic and, to a certain extent, hydrophilic substances. Their production can be done without the use of organic solvents. Techniques to make them a physically stable delivery system have been developed. Scaling up of the production process from lab-size to large-scale dimensions using high-pressure homogenization can be easily achieved by using a different type of homogenizer. The machines used for large-scale production often yield an even better product quality than the lab-scale types. This review article covers the methods of production, characterization, mechanisms of oral bioavailability enhancement, scale-up, final oral dosage forms, and regulatory aspects of lipid nanoparticles for oral drug delivery. It focuses mainly on high-pressure homogenization production methods.
Fatouh, Ahmed M; Elshafeey, Ahmed H; Abdelbary, Ahmed
Purpose Agomelatine is a novel antidepressant drug suffering from an extensive first-pass metabolism leading to a diminished absolute bioavailability. The aim of the study is: first to enhance its absolute bioavailability, and second to increase its brain delivery. Methods To achieve these aims, the nasal route was adopted to exploit first its avoidance of the hepatic first-pass metabolism to increase the absolute bioavailability, and second the direct nose-to-brain pathway to enhance the brain drug delivery. Solid lipid nanoparticles were selected as a drug delivery system to enhance agomelatine permeability across the blood–brain barrier and therefore its brain delivery. Results The optimum solid lipid nanoparticles have a particle size of 167.70 nm ±0.42, zeta potential of −17.90 mV ±2.70, polydispersity index of 0.12±0.10, entrapment efficiency % of 91.25%±1.70%, the percentage released after 1 h of 35.40%±1.13% and the percentage released after 8 h of 80.87%±5.16%. The pharmacokinetic study of the optimized solid lipid nanoparticles revealed a significant increase in each of the plasma peak concentration, the AUC(0–360 min) and the absolute bioavailability compared to that of the oral suspension of Valdoxan® with the values of 759.00 ng/mL, 7,805.69 ng⋅min/mL and 44.44%, respectively. The optimized solid lipid nanoparticles gave a drug-targeting efficiency of 190.02, which revealed more successful brain targeting by the intranasal route compared with the intravenous route. The optimized solid lipid nanoparticles had a direct transport percentage of 47.37, which indicates a significant contribution of the direct nose-to-brain pathway in the brain drug delivery. Conclusion The intranasal administration of agomelatine solid lipid nanoparticles has effectively enhanced both the absolute bioavailability and the brain delivery of agomelatine. PMID:28684900
Doktorovova, Slavomira; Souto, Eliana B; Silva, Amélia M
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were developed as alternative to other colloidal carriers. They were designed to overcome lipid nanoemulsions and liposomes in stability and ability to control the release of an encapsulated substance, and at the same time to be better tolerated than polymeric nanoparticles. Since the patenting of SLN discovery, large amount of data became available on the behaviour of these systems in vitro. SLN/NLC have many prerequisites to be a well tolerated carrier - the currently available data seem to confirm it, but there are also some contradictory results. In this review, we collected the available data from cytotoxicity, oxidative stress and hemocompatibility studies in vitro and analysed their outcomes. We also provide a summary of the available data in a form of reference table. Copyright © 2014 Elsevier B.V. All rights reserved.
Dong, Yuancai; Ng, Wai Kiong; Shen, Shoucang; Kim, Sanggu; Tan, Reginald B H
This work aimed at developing continuous and scalable nanoprecipitation synthesis of solid lipid nanoparticles (SLN) by mixing lipids acetonic solution with water using static mixers. The developed platform exhibited good control over the nanoprecipitation process and enabled the production of SLN below 200 nm at a throughput of 37.5-150 g/h (for 25 mg/ml lipid solution at a flow rate of 25-100 ml/min). Among the several process parameters investigated, the lipid concentration played primary role in influencing the size of the SLN and higher lipid concentration resulted in relatively larger particles. Fenofibrate, a model drug, has been successfully loaded into the SLN. Our work demonstrates the potential of applying static mixing-nanoprecipitation for continuous and large scale production of SLN. Copyright © 2012 Elsevier B.V. All rights reserved.
El-Salamouni, Noha S; Farid, Ragwa M; El-Kamel, Amal H; El-Gamal, Safaa S
Nanoparticulate delivery systems have recently been under consideration for topical ophthalmic drug delivery. Brimonidine base-loaded solid lipid nanoparticles and nanostructured lipid carrier formulations were prepared using glyceryl monostearate as solid lipid and were evaluated for their physical stability following sterilization by autoclaving at 121°C for 15min. The objective of this work was to evaluate the effect of autoclaving on the physical appearance, particle size, polydispersity index, zeta potential, entrapment efficiency and particle morphology of the prepared formulations, compared to non-autoclaved ones. Results showed that, autoclaving at 121°C for 15min allowed the production of physically stable formulations in nanometric range, below 500nm suitable for ophthalmic application. Moreover, the autoclaved samples appeared to be superior to non-autoclaved ones, due to their increased zeta potential values, indicating a better physical stability. As well as, increased amount of brimonidine base entrapped in the tested formulations.
Solid and liquid lipid-based binary solid lipid nanoparticles of diacerein: in vitro evaluation of sustained release, simultaneous loading of gold nanoparticles, and potential thermoresponsive behavior
Rehman, Mubashar; Madni, Asadullah; Ihsan, Ayesha; Khan, Waheed Samraiz; Khan, Muhammad Imran; Mahmood, Muhammad Ahmad; Ashfaq, Muhammad; Bajwa, Sadia Zafar; Shakir, Imran
Binary fatty acid mixture-based solid lipid nanoparticles (SLNs) were prepared for delivery of diacerein, a novel disease-modifying osteoarthritis drug, with and without simultaneously loaded gold nanoparticles (GNPs). In order to optimize SLNs for temperature-responsive release, lipid mixtures were prepared using different ratios of solid (stearic acid or lauric acid) and liquid (oleic acid) fatty acids. SLNs were prepared by microemulsification (53 nm), hot melt encapsulation (10.4 nm), and a solvent emulsification-evaporation technique (7.8 nm). The physicochemical characteristics of SLNs were studied by Zetasizer, Fourier transform infrared, and X-ray diffraction analysis. High encapsulation of diacerein was achieved with diacerein-loaded and simultaneously GNP-diacerein-loaded SLNs. In vitro dissolution studies revealed a sustained release pattern for diacerein over 72 hours for diacerein-loaded SLNs and 12 hours for GNP-diacerein-loaded SLNs. An increase in diacerein payload increased the release time of diacerein while GNPs decreased it. In addition, rapid release of diacerein over 4 hours was observed at 40°C (melting point of optimized fatty acid mixture), demonstrating that these binary SLNs could be used for thermoresponsive drug delivery. Kinetic modeling indicated that drug release followed zero order and Higuchi diffusion models (R10>0.9), while the Korsmeyer-Peppas model predicted a diffusion release mechanism (n<0.5). PMID:25897224
Solid and liquid lipid-based binary solid lipid nanoparticles of diacerein: in vitro evaluation of sustained release, simultaneous loading of gold nanoparticles, and potential thermoresponsive behavior.
Rehman, Mubashar; Madni, Asadullah; Ihsan, Ayesha; Khan, Waheed Samraiz; Khan, Muhammad Imran; Mahmood, Muhammad Ahmad; Ashfaq, Muhammad; Bajwa, Sadia Zafar; Shakir, Imran
Binary fatty acid mixture-based solid lipid nanoparticles (SLNs) were prepared for delivery of diacerein, a novel disease-modifying osteoarthritis drug, with and without simultaneously loaded gold nanoparticles (GNPs). In order to optimize SLNs for temperature-responsive release, lipid mixtures were prepared using different ratios of solid (stearic acid or lauric acid) and liquid (oleic acid) fatty acids. SLNs were prepared by microemulsification (53 nm), hot melt encapsulation (10.4 nm), and a solvent emulsification-evaporation technique (7.8 nm). The physicochemical characteristics of SLNs were studied by Zetasizer, Fourier transform infrared, and X-ray diffraction analysis. High encapsulation of diacerein was achieved with diacerein-loaded and simultaneously GNP-diacerein-loaded SLNs. In vitro dissolution studies revealed a sustained release pattern for diacerein over 72 hours for diacerein-loaded SLNs and 12 hours for GNP-diacerein-loaded SLNs. An increase in diacerein payload increased the release time of diacerein while GNPs decreased it. In addition, rapid release of diacerein over 4 hours was observed at 40°C (melting point of optimized fatty acid mixture), demonstrating that these binary SLNs could be used for thermoresponsive drug delivery. Kinetic modeling indicated that drug release followed zero order and Higuchi diffusion models (R(2)>0.9), while the Korsmeyer-Peppas model predicted a diffusion release mechanism (n<0.5).
Ngwuluka, Ndidi C; Kotak, Darsheen J; Devarajan, Padma V
Colorectal cancer is a global concern, and its treatment is fraught with non-selective effects including adverse side effects requiring hospital visits and palliative care. A relatively safe drug formulated in a bioavailability enhancing and targeting delivery platform will be of significance. Metformin-loaded solid lipid nanoparticles (SLN) were designed, optimized, and characterized for particle size, zeta potential, drug entrapment, structure, crystallinity, thermal behavior, morphology, and drug release. Optimized SLN were 195.01 ± 6.03 nm in size, -17.08 ± 0.95 mV with regard to surface charge, fibrous in shape, largely amorphous, and release of metformin was controlled. The optimized size, charge, and shape suggest the solid lipid nanoparticles will migrate and accumulate in the colon tumor preventing its proliferation and subsequently leading to tumor shrinkage and cell death.
Chabra, S; Ranjan, M; Bhandari, R; Kaur, T; Aggrawal, M; Puri, V; Mahajan, N; Kaur, IP; Puri, S; Sobti, RC
A rapid decline in self-renewability, viability and function, of isolated stem cells are major hurdles in developing cell based therapies. There has been an increasing interest towards identifying a support material for maintaining stem cell features of the isolated cells. Pioneering observations of the present paper, demonstrate functionally diverse potential of Solid Lipid Nanoparticles (SLNs) in deciding the fate & behavior of mouse mesenchymal stem cell. The evidences are provided to show the dual nature of the SLNs for being a scaffold for the stem cell attachment, to retain stemness, and as reagent for inducing stem cell differentiation. Scanning electron microscopic examinations together with expression analysis were used to conform to such observations. Results of the study thus suggest that Solid lipid nanoparticles can be used as a good support material when functionalized to achieve adhesive properties and as a molecular paradigm for studying the adipocytic differentiation. We envisage a new role of SLNs towards regulating stem cell character by orchestrating the structural alignment during preparation of Solid lipid nanoparticles PMID:24693174
Gohla, S H; Dingler, A
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.
Chauhan, Harsh; Mohapatra, Sarat; Munt, Daniel J; Chandratre, Shantanu; Dash, Alekha
Pure glyceryl mono-oleate (GMO) (lipid) and different batches of GMO commonly used for the preparation of GMO-chitosan nanoparticles were characterized by modulated differential scanning calorimetry (MDSC), cryo-microscopy, and cryo-X-ray powder diffraction techniques. GMO-chitosan nanoparticles containing poloxamer 407 as a stabilizer in the absence and presence of polymers as crystallization inhibitors were prepared by ultrasonication. The effect of polymers (polyvinyl pyrrolidone (PVP), Eudragits, hydroxyl propyl methyl cellulose (HPMC), polyethylene glycol (PEG)), surfactants (poloxamer), and oils (mineral oil and olive oil) on the crystallization of GMO was investigated. GMO showed an exothermic peak at around -10°C while cooling and another exothermic peak at around -12°C while heating. It was followed by two endothermic peaks between 15 and 30 C, indicative of GMO melting. The results are corroborated by cryo-microscopy and cryo-X-ray. Significant differences in exothermic and endothermic transition were observed between different grades of GMO and pure GMO. GMO-chitosan nanoparticles resulted in a significant increase in particle size after lyophilization. MDSC confirmed that nanoparticles showed similar exothermic crystallization behavior of lipid GMO. MDSC experiments showed that PVP inhibits GMO crystallization and addition of PVP showed no significant increase in particle size of solid lipid nanoparticle (SLN) during lyophilization. The research highlights the importance of extensive physical-chemical characterization for successful formulation of SLN.
Weyhers, H; Ehlers, S; Hahn, H; Souto, E B; Müller, R H
Solid lipid nanoparticles (SLN) composed of two different lipid matrices were produced to assess their in vivo toxicity in mice. Matrix substances were (i) Compritol (glycerol behenate), a physiological lipid with GRAS status (generally recognized as safe [FDA]), and (ii) cetyl palmitate, a less physiological compound. Physicochemical data proved the suitability of SLN batches for intravenous administration. To assess the in vivo toxicity of produced batches, 400 microl SLN dispersion (lipid content 10% [m/m]) were administered to mice via a bolus injection for six times within a period of 20 days (high dose administration). Additionally, a multiple low dose administration was performed with Compritol-SLN as well (200 microl SLN dispersion, lipid content 2.5% [m/m]). Hepatic and splenic tissues were analysed histologically. In vivo results were dependent on the lipid matrix, as well as on the dose administered. For cetyl palmitate containing SLN no pathological results were obtained, while high dosed Compritol containing formulations led to accumulation of the lipid in liver and spleen and subsequently to pathological alterations. These alterations were found to be partially reversible within six weeks after completing intravenous administration. Liver architecture was nearly recovered. In contrast, low dosed Compritol SLN were well tolerated. Lipid accumulation and pathological alterations of high dosed Compritol SLN were attributed to the slow degradation of the Compritol matrix which could be shown by performing in vitro studies in human plasma.
Dikmen, Gokhan; Guney, Gamze; Genc, Lutfi
Many anticancer drugs that are currently used in cancer treatment are natural products or their analogues by structural modification. Caffeic acid (3, 4-dihydroxycinnamic acid; CA) is classified as hydroxycinnamic acid and has a variety of potential pharmacological effects, including antioxidant, immunomodulatory and anti-inflammatory activities. As a drug carrier, solid lipid nanoparticles (SLNs) introduced to improve stability, provide controlled drug release, avoid organic solvents and are obtained in small sizes. In this study, we developed solid lipid nanoparticles incorporating with caffeic acid using hot homogenization method. Caffeic acid loaded solid lipid nanoparticles were characterized regarding particle size, zeta potential, drug entrapment efficiency, drug release, scanning electron microscopy (SEM) and FT-IR. The effects of caffeic acid loaded solid lipid nanoparticles on MCF-7 cells were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-dimethyl tetrazolium bromide (MTT) test and Annexin V-PI analysis. As a result, solid lipid nanoparticles could potentially be used for the delivery of caffeic acid and solid lipid nanoparticles formulation enhanced the effects of caffeic acid on MCF-7 cells. Some relevant patents are also referred in this article.
Kushwaha, Anand Kumar; Vuddanda, Parameswara Rao; Karunanidhi, Priyanka; Singh, Sanjay Kumar; Singh, Sanjay
Raloxifene hydrochloride (RL-HCL) is an orally selective estrogen receptor modulator (SERM) with poor bioavailability of nearly 2% due to its poor aqueous solubility and extensive first pass metabolism. In order to improve the oral bioavailability of raloxifene, raloxifene loaded solid lipid nanoparticles (SLN) have been developed using Compritol 888 ATO as lipid carrier and Pluronic F68 as surfactant. Raloxifene loaded SLN were prepared by solvent emulsification/evaporation method, and different concentrations of surfactant, and homogenization speed were taken as process variables for optimization. SLN were characterized for particle size, zeta potential, entrapment efficiency, surface morphology, and crystallinity of lipid and drug. In vitro drug release studies were performed in phosphate buffer of pH 6.8 using dialysis bag diffusion technique. Particle sizes of all the formulations were in the range of 250 to 1406 nm, and the entrapment efficiency ranges from 55 to 66%. FTIR and DSC studies indicated no interaction between drug and lipid, and the XRD spectrum showed that RL-HCL is in amorphous form in the formulation. In vitro release profiles were biphasic in nature and followed Higuchi model of release kinetics. Pharmacokinetics of raloxifene loaded solid lipid nanoparticles after oral administration to Wistar rats was studied. Bioavailability of RL-HCL loaded SLN was nearly five times than that of pure RL-HCL.
Spada, Gianpiera; Gavini, Elisabetta; Cossu, Massimo; Rassu, Giovanna; Giunchedi, Paolo
New solid lipid nanoparticles (SLN), composed of Compritol ATO888 (C) and hydroxypropyl-β-cyclodextrin (HP), were developed in order to study a new colon-specific formulation for diclofenac sodium (D) delivery. The prepared batches differ from each other by the molecular ratio between HP and D and by the composition of the matrix. Nanoparticles composed of an exclusively lipid matrix and nanoparticles with an oligomeric and lipid matrix were compared in order to establish the effect of both components on the drug delivery tests performed. The SLN preparation method was based on the oil/water hot homogenization process. Emulsions produced were cooled at room temperature and lyophilized in order to obtain dried nanoparticles; possible damage to nanoparticle shape and size was avoided by the addition of cryoprotectants to the aqueous dispersion of nanoparticles before exsiccation. An in vitro toxicity study was performed using CaCo2 cells to establish the safety of the prepared SLN. Data obtained showed that production method studied guarantees emulsions composed of nanosized drops which can be dried by lyophilization into SLN with a size range of 300-600 nm. In vitro and ex vivo tests demonstrated that dried SLN can be considered as colon delivery systems; however, the matrix composition as well as the presence of cryoprotectant on their surface influences the release and permeation rate of D. The in vitro toxicity studies indicated that the SLN are well tolerated.
Elnaggar, Yosra SR; El-Massik, Magda A; Abdallah, Ossama Y
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
Elnaggar, Yosra S R; El-Massik, Magda A; Abdallah, Ossama Y
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.
Müller, R H; Runge, S A; Ravelli, V; Thünemann, A F; Mehnert, W; Souto, E B
Solid lipid nanoparticles (SLN) were produced loaded with cyclosporine A in order to develop an improved oral formulation. In this study, the particles were characterized with regard to the structure of the lipid particle matrix, being a determining factor for mode of drug incorporation and drug release. Differential scanning calorimetry (DSC) and wide-angle X-ray scattering (WAXS) measurements were employed for the analysis of the polymorphic modifications and mode of drug incorporation. Particles were produced using Imwitor 900 as lipid matrix (the suspension consisted of 10% particles, 8% Imwitor 900, 2% cyclosporine A), 2.5% Tagat S, 0.5% sodium cholate and 87% water. DSC and WAXS were used to analyse bulk lipid, bulk drug, drug incorporated in the bulk and unloaded and drug-loaded SLN dispersions. The processing of the bulk lipid into nanoparticles was accompanied by a polymorphic transformation from the beta to the alpha-modification. After production, the drug-free SLN dispersions converted back to beta-modification, while the drug-loaded SLN stayed primarily in alpha-modification. After incorporation of cyclosporine A into SLN, the peptide lost its crystalline character. Based on WAXS data, it could be concluded that cyclosporine is molecularly dispersed in between the fatty acid chains of the liquid-crystalline alpha-modification fraction of the loaded SLN.
Reddy, L Harivardhan; Vivek, K; Bakshi, Nishant; Murthy, R S R
Solid lipid nanoparticles (SLN) were prepared by emulsification and high pressure homogenization technique and characterized by size analysis and differential scanning calorimetry. The influence of experimental factors such as homogenization pressure, time, and surfactant concentration on the nanoparticle size and distribution were investigated to optimize the formulation. Homogenization at 15,000 psi for 3 cycles was found to be optimum and resulted in smaller sized nanoparticles. In case of tristearin SLN (TSSLN), tripalmitin SLN (TPSLN), and glycerol behenate SLN (GBSLN), the relatively smaller sized nanoparticles were obtained with 3% sodium tauroglycocholate. The SLN were loaded with an anticancer agent, tamoxifen citrate (TC). The TC-loaded TSSLN shown lower entrapment efficiency (78.78%) compared to the TPSLN (86.75%) and GBSLN (98.64%). Short term stability studies indicated a significant increase in size of nanoparticles when stored at 500C, compared to those stored at 30 degrees C and 4 degrees C. The particle destabilization upon storage in case of all the types of nanoparticles studied was in the order of day light > artificial light > dark. An ultraviolet (UV) spectrophotometric method of estimation of tamoxifen in rat plasma was developed and validated. The TC-loaded TSSLN was administered to the rats intravenously and the pharmacokinetic parameters in the plasma were determined. The t(1/2) and mean residence time of TC-loaded TSSLN in plasma was about 3.5-fold (p < 0.001) and 3-fold (p < 0.001) higher, respectively, than the free tamoxifen, indicating the potential of TC-loaded TSSLN as a long circulating system in blood. Thus the above mentioned solid lipid nanoparticles can be a beneficial system to deliver tamoxifen to cancer tissues through enhanced permeability and retention (EPR) effect.
Pople, Pallavi V; Singh, Kamalinder K
The purpose of this research was to investigate novel particulate carrier system such as solid lipid nanoparticles (SLN) for topical application of vitamin A palmitate and to study its beneficial effects on skin. Topical gels enriched with SLN of vitamin A were prepared. The solid lipid nanoparticulate dispersion was prepared using high-pressure homogenization technique and was incorporated into polymeric gels of Carbopol, Pemulen, Lutrol, and Xanthan gum for convenient application. The nanoparticulate dispersion and its gels were evaluated for various parameters such as particle size, in vitro drug release, in vitro penetration, in vivo skin hydration, and skin irritation. The solid lipid nanoparticulate dispersion showed mean particle size of 350 nm. Differential scanning calorimetry studies revealed no drug-excipient incompatibility. In vitro release profile of vitamin A palmitate from nanoparticulate dispersion and its gel showed prolonged drug release up to 24 hours, which could be owing to embedment of drug in the solid lipid core. In vitro penetration studies showed almost 2 times higher drug concentration in the skin with lipid nanoparticle-enriched gel as compared with conventional gel, thus indicating better localization of the drug in the skin. In vivo skin hydration studies in albino rats revealed increase in the thickness of the stratum corneum with improved skin hydration. The developed formulation was nonirritant to the skin with no erythema or edema and had primary irritation index of 0.00. Thus it can be concluded that SLN represents a promising particulate carrier having controlled drug release, improved skin hydration, and potential to localize the drug in the skin with no skin irritation.
Becker Peres, Luana; Becker Peres, Laize; de Araújo, Pedro Henrique Hermes; Sayer, Claudia
Encapsulation of hydrophilic compounds for drug delivery systems with high loading efficiency is not easily feasible and remains a challenge, mainly due to the leaking of the drug to the outer aqueous phase during nanoparticle production. Usually, encapsulation of hydrophilic drugs is achieved by using double emulsion or inverse miniemulsion systems that often require the use of organic solvents, which may generate toxicological issues arising from solvent residues. Herein, we present the preparation of solid lipid nanoparticles loaded with a hydrophilic compound by a novel organic solvent free double emulsion/melt dispersion technique. The main objective of this study was to investigate the influence of important process and formulation variables, such as lipid composition, surfactant type, sonication parameters and lipid solidification conditions over physicochemical characteristics of SLN dispersion. Particle size and dispersity, as well as dispersion stability were used as responses. SLN dispersions with average size ranging from 277 to 550 nm were obtained, showing stability for over 60 days at 4 °C depending on the chosen emulsifying system. Entrapment efficiency of fluorescent dyes used as model markers was assessed by fluorescence microscopy and UV-vis spectrophotometry and results suggest that the obtained lipid based nanoparticles could be potentially applied as a delivery system of water soluble drugs.
Esmaeili, Maryam; Aghajani, Mahdi; Abbasalipourkabir, Roghayeh; Amani, Amir
Advantages of lipid nanoparticles for pulmonary applications are possibility of deep lung deposition with prolonged release and low toxicity. This study aimed to evaluate the effects of formulation and processing parameters on particle size of prepared SLNs. Budesonide-loaded solid lipid nanoparticles (BUD-SLNs) were prepared with different values of drug content, ultrasonication amplitude, and homogenization time and the data were modeled using artificial neural networks (ANNs). Optimal conditions for fabrication of small-sized particles of 170-200 nm were found to be low drug content with high-amplitude and high-homogenization time. In vitro aerosolization performance of BUD-SLNs was then compared to that of commercial budesonide which indicated enhancement in fine particle fraction value.
Hosny, Khaled Mohamed; Banjar, Zainy Mohammed; Hariri, Amani H; Hassan, Ali Habiballah
According to the World Health Organization, 46% of the world’s children suffer from anemia, which is usually treated with iron supplements such as ferrous sulfate. The aim of this study was to prepare iron as solid lipid nanoparticles, in order to find an innovative way for alleviating the disadvantages associated with commercially available tablets. These limitations include adverse effects on the digestive system resulting in constipation and blood in the stool. The second drawback is the high variability in the absorption of iron and thus in its bioavailability. Iron solid lipid nanoparticles (Fe-SLNs) were prepared by hot homogenization/ultrasonication. Solubility of ferrous sulfate in different solid lipids was measured, and effects of process variables such as the surfactant type and concentration, homogenization and ultrasonication times, and charge-inducing agent on the particle size, zeta potential, and encapsulation efficiency were determined. Furthermore, in vitro drug release and in vivo pharmacokinetics were studied in rabbits. Results indicated that Fe-SLNs consisted of 3% Compritol 888 ATO, 1% Lecithin, 3% Poloxamer 188, and 0.2% dicetylphosphate, with an average particle size of 25 nm with 92.3% entrapment efficiency. In vivo pharmacokinetic study revealed more than fourfold enhanced bioavailability. In conclusion, Fe-SLNs could be a promising carrier for iron with enhanced oral bioavailability. PMID:25609917
Hosny, Khaled Mohamed; Banjar, Zainy Mohammed; Hariri, Amani H; Hassan, Ali Habiballah
According to the World Health Organization, 46% of the world's children suffer from anemia, which is usually treated with iron supplements such as ferrous sulfate. The aim of this study was to prepare iron as solid lipid nanoparticles, in order to find an innovative way for alleviating the disadvantages associated with commercially available tablets. These limitations include adverse effects on the digestive system resulting in constipation and blood in the stool. The second drawback is the high variability in the absorption of iron and thus in its bioavailability. Iron solid lipid nanoparticles (Fe-SLNs) were prepared by hot homogenization/ultrasonication. Solubility of ferrous sulfate in different solid lipids was measured, and effects of process variables such as the surfactant type and concentration, homogenization and ultrasonication times, and charge-inducing agent on the particle size, zeta potential, and encapsulation efficiency were determined. Furthermore, in vitro drug release and in vivo pharmacokinetics were studied in rabbits. Results indicated that Fe-SLNs consisted of 3% Compritol 888 ATO, 1% Lecithin, 3% Poloxamer 188, and 0.2% dicetylphosphate, with an average particle size of 25 nm with 92.3% entrapment efficiency. In vivo pharmacokinetic study revealed more than fourfold enhanced bioavailability. In conclusion, Fe-SLNs could be a promising carrier for iron with enhanced oral bioavailability.
Salminen, Hanna; Gömmel, Christina; Leuenberger, Bruno H; Weiss, Jochen
We investigated the influence of physicochemical properties of encapsulated functional lipids--vitamin A, β-carotene and ω-3 fish oil--on the structural arrangement of solid lipid nanoparticles (SLN). The relationship between the crystal structure and chemical stability of the incorporated bioactive lipids was evaluated with different emulsifier compositions of a saponin-rich, food-grade Quillaja extract alone or combined with high-melting or low-melting lecithins. The major factors influencing the structural arrangement and chemical stability of functional lipids in solid lipid dispersions were their solubility in the aqueous phase and their crystallization temperature in relation to that of the carrier lipid. The results showed that the stabilization of the α-subcell crystals in the lattice of the carrier lipid is a key parameter for forming stable solid lipid dispersions. This study contributes to a better understanding of SLN as a function of the bioactive lipid. Copyright © 2015 Elsevier Ltd. All rights reserved.
Lages, Eduardo Burgarelli; de Freitas, Maria Betânia; Gonçalves, Isadora Marques Brum; Alves, Ricardo José; Vianna-Soares, Cristina Duarte; Ferreira, Lucas Antônio Miranda; de Oliveira, Mônica Cristina; de Oliveira, Renata Barbosa
Nitroheterocyclic compounds have received considerable interest as hypoxia-selective cytotoxins (HSC) for cancer treatment. In the present study, we investigated antitumor activity of an iodide analogue of metronidazole, 1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I), using Swiss mice bearing solid Ehrlich tumor. MTZ-I showed potent anti-cancer activity at a dose of 40 mg/kg. MTZ-I loaded solid lipid nanoparticles (SLN) were developed as an alternative colloidal carrier system to enhance tumor drug uptake. SLN were characterized for particle size, polydispersity index, zeta potential and entrapment efficiency. In addition, the influence of presence of the cationic lipid stearylamine (STE) on stability of formulation was assessed. The results of DSC study showed that MTZ-I exhibited interaction with STE.
Bhushan, Shashi; Kakkar, Vandita; Pal, Harish Chandra; Guru, Santosh Kumar; Kumar, Ajay; Mondhe, D M; Sharma, P R; Taneja, Subhash Chandra; Kaur, Indu Pal; Singh, Jaswant; Saxena, A K
A pentacyclic triterpenediol (TPD) from Boswellia serrata has significant cytotoxic and apoptotic potential in a large number of human cancer cell lines. To enhance its anticancer potential, it was successfully formulated into solid lipid nanoparticles (SLNs) by the microemulsion method with 75% drug entrapment efficiency. SEM and TEM studies indicated that TPD-SLNs were regular, solid, and spherical particles in the range of 100-200 nm, and the system indicated that they were more or less stable upon storing up to six months. TPD loaded SLNs showed significantly higher cytotoxic/antitumor potential than the parent drug. TPD-SLNs have 40-60% higher cytotoxic and apoptotic potential than the parent drug in terms of IC(50), extent of apoptosis, DNA damage, and expression of pro-apoptotic proteins like TNF-R1, cytochrome-c, and PARP cleavage in HL-60 cells. Moreover, blank SLNs did not have any cytotoxic effect on the cancer as well as in normal mouse peritoneal macrophages. The in vivo antitumor potential of TPD-SLNs was significantly higher than that of TPD alone in Sarcoma-180 solid tumor bearing mice. Therefore, SLNs of TPD successfully increased the apoptotic and anticancer potential of TPD at comparable doses (both in vitro and in vivo). This work provides new insight into improvising the therapeutic efficacy of TPD by adopting novel delivery strategies such as solid lipid nanoparticles.
Kashanian, Soheila; Rostami, Elham
In this study, poly ethylene glycol 100 stearate (PEG 100-S) was used to prepare coated solid lipid nanoparticles with loading levothyroxine sodium (levo-loaded PEG 100-S-coated SLNs) by microemulsification technique. Evaluation of the release kinetic of prepared colloidal carriers was conducted. The particle size and zeta potential of levo-loaded PEG 100-S-coated SLNs have been measured to be 187.5 nm and -23.0 mV, respectively, using photon correlation spectroscopy (PCS). Drug entrapment efficiency (EE) was calculated to be 99 %. Differential scanning calorimetry indicated that the majority of drug loaded in PEG 100-S-coated SLNs were in amorphous state which could be considered desirable for drug delivery. The purpose of this study was to develop a new nanoparticle system, consisting lipid nanoparticles coated with PEG 100-S. The modification procedure led to a reduction in the zeta potential values, varying from -40.0 to -23.0 mV for the uncoated and PEG-coated SLNs, respectively. Stability results of the nanoparticles in gastric and intestinal media show that the low pH of the gastric medium is responsible for the critical aggregation and degradation of the uncoated lipid nanoparticles. PEG 100-S-coated SLNs were more stable due to their polymer coating layer which prevented aggregation of SLNs. Consequently, it is possible that the PEG surrounds the particles reducing the attachment of enzymes and further degradation of the triglyceride cores. Shape and surface morphology of particles were determined by transition electron microscopy and scanning electron microscopy that revealed spherical shape of nanoparticles. In vitro drug release of PEG 100-S-coated SLNs was characterized using diffusion cell which showed a controlled release for drug.
Hazzah, Heba A; Farid, Ragwa M; Nasra, Maha M A; El-Massik, Magda A; Abdallah, Ossama Y
This study aimed to prepare and evaluate mucoadhesive sponges as dosage forms for delivering solid lipid nanoparticles. For this purpose curcumin (Cur) was formulated as solid nanoparticles (SLN) using Gelucire 50/13, and polaxomer 407. The prepared CurSLN dispersion was thickened with different mucoadhesive polymers. Different concentrations of glycerol, and mannitol of range (0.25-20%), and (0-1%), respectively were also examined. The formed gel was poured into oblong molds and freeze dried to form mucoadhesive sponge to be applied to the buccal mucosa. The prepared sponges were evaluated for their, in-vivo residence time, in-vitro and in-vivo drug release, and hydration capacity. Surface morphology for the different sponges were examined using SEM. TEM was also carried out for sponge fragments previously dispersed into water. Infrared spectroscopy was conducted to investigate interaction between used ingredients. The results showed that the CurSLN loaded HPMC, and Polycarbophil sponges showed 4, and 15 h in-vivo residence time, respectively, providing a considerable amount of curcumin into saliva. The incorporation of glycerol and mannitol at concentration of 1% provided elegant and flexible sponges. The SEM showed that the deposition of CurSLN differed according to the type of polymer used. TEM confirmed the integrity of liberated CurSLN from sponges. IR spectra showed an interaction between HPMC and poloxamer 407, which affected its behavior as a gelling agent. The obtained results provide an efficient approach for delivering solid lipid nanoparticles in a solid dosage form keeping the nanoparticle characters and integrity.
Dasgupta, Sandipan; Ghosh, Surajit K; Ray, Subhabrata; Mazumder, Bhaskar
Solid lipid nanoparticles (SLN) are very potential formulations for topical delivery of anti-inflammatory and anti-arthritic drugs. The solid state of the lipid particles enable efficient drug encapsulation and controlled drug release. In the present study, the evaluation of different formulation parameters based on variation of concentration of lipid and cosurfactant was studied. The SLN gel formulations of the dispersions were compared to the SLN dispersions and with the marketed gel of aceclofenac. The SLNs were prepared by high speed homogenization and ultra-sonication method with fixed amount of aceclofenac (10%) and pluronic F68 (1.5%). The particle size, zeta potential and span of developed formulations was found to be within the range of 123 nm to 323 nm, -12.4 to -18.5 and 0.42 to 0.86 respectively as the lipid concentration was increased from 7.5% to 40%. The highest entrapment efficiency was found to be 75% with the formulation having lipid concentration of 30% and 0.85% of phospholipon 90G. Permeation rate and controlled release property of xanthan gum loaded SLN gel formulations and SLN dispersion was studied through excised pig skin for 24hr. The drug release of SLN gel formulations was better controlled as compare to SLN dispersions. In vivo anti-inflammatory study showed that action of aceclofenac was enhanced for SLN dispersion and gel formulations. The results indicated the superiority of SLN based formulations for topical delivery of aceclofenac.
Demirbilek, Murat; Laçin Türkoglu, Nelisa; Aktürk, Selçuk; Akça, Cem
Vitamin D3 (VitD3) has several beneficial effects on many metabolic pathways such as immunity system, bone development. The aim of the study, encapsulation of VitD3 with solid lipids, determine encapsulation efficiency and biocompatibility of nanoparticles. Therefore, VitD3-loaded solid lipid nanoparticles (SLNPs) were developed by optimising ratios of VitD3, stearic acid, beeswax and sodium dodecyl sulphate (SDS). Thermal stability, degradation profile, crystallinity rate, encapsulation efficiency and release profile of SLNPs were determined. Cytotoxicity of SLNPs on HaCaT, L929 and HUVEC cells were investigated. Negatively charged and VitD3-loaded nanoparticles with diameters between 30 and 60 nm were obtained. SLNPs containing up to 5.1 mg VitD3 per 10 mg powder samples were obtained. Cell proliferations were stimulated after exposure with VitD3-loaded SLNPs. Besides, inflammatory response after exposure to VitD3-loaded SLNPs was evaluated via determining IL10 and TNF-alpha levels on THP-1 cells. According to the results, no inflammatory response was observed.
Neves, Ana Rute; Queiroz, Joana Fontes; Reis, Salette
The present study takes advantage of the beneficial effects of resveratrol as a neuroprotective compound. Resveratrol-loaded solid lipid nanoparticles were functionalized with apolipoprotein E which can be recognized by the LDL receptors overexpressed on the blood-brain barrier. Transmission electron microscopy images revealed spherical nanoparticles, dynamic light scattering gave a Z-average lower than 200 nm, and a zeta potential of around -13 mV and very high resveratrol entrapment efficiency (ca. 90 %). In vitro cytotoxic effects were assessed by MTT and LDH assays in hCMEC/D3 cell line and revealed no toxicity up to 50 μM over 4 h of incubation. The permeability through hCMEC/D3 monolayers showed a significant increase (1.8-fold higher) for resveratrol-loaded solid lipid nanoparticles functionalized with apolipoprotein E when compared to non-functionalized ones. In conclusion, these nanosystems might be a promising strategy for resveratrol delivery into the brain, while protecting it from degradation in the blood stream. Graphical abstract .
The objective of this research was to formulate ciprofloxacin (CIP) in solid lipid nanoparticles (SLNs) in an attempt to develop a controlled drug delivery system. An ultrasonic melt-emulsification method was used for preparing CIP-loaded SLNs. Key findings included that SLNs were successfully produced with average particle sizes ranging from 165 to 320 nm and polydispersity index in the range of 0.18–0.33. High entrapment efficiency values were reported in all formulations. The atomic force scanning microscopic images showed spherical shape with the size range closer to those found by the particle size analyzer. CIP release exhibited controlled-release behavior with various lipids. Ciprofloxacin solid lipid nanoparticles formula containing stearic acid (CIPSTE) displayed the strongest burst effect and the most rapid release rate. The release data revealed a better fit to the Higuchi diffusion model. After storing the CIPSTE formula at room temperature for 120 days, no significant difference in particle size and zeta potential was found. CIP-loaded SLNs exhibited superior antibacterial activity. Incorporation of CIP into SLNs leads to controlled release and a superior antibacterial effect of CIP. PMID:28194408
Urbán-Morlán, Zaida; Ganem-Rondero, Adriana; Melgoza-Contreras, Luz María; Escobar-Chávez, José Juan; Nava-Arzaluz, María Guadalupe; Quintanar-Guerrero, David
Solid lipid nanoparticles (SLNs) have been used for carrying different therapeutic agents because they improve absorption and bioavailability. The aim of the study was to prepare lipidic nanoparticles containing cyclosporine (CyA) by the emulsification-diffusion method and to study their physicochemical stability. Glyceryl behenate (Compritol® ATO 888) and lauroyl macrogolglycerides (Gelucire® 44/14) were used as carrier materials. Nanoparticles with good stability were obtained with Gelucire®, while it was difficult to obtain stable systems with Compritol®. Systems with Gelucire® were characterized by particle size, Z-potential, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), entrapment efficiency and in vitro release. Particle size and Z-potential were evaluated for at least three months. With a high CyA content (≥60 mg) in Gelucire® SLNs, variations in size were greater and particle size also increased over time in all batches; this effect may have been caused by a probable expulsion of the drug due to the lipid’s partial rearrangement. While the Z-potential decreased 10 mV after three months, this effect may be explained by the superficial properties of the drug that make the molecules to be preferably oriented at the solid-liquid interface, causing a change in the net charge of the particle. SEM confirmed size and shape of the nanoparticles. DSC studies evidenced that CyA affects the lipid structure by a mechanism still unknown. The entrapment efficiency was higher than 92%, and CyA release from SLNs was relatively fast (99.60% in 45 min). PMID:20856836
Singh, Indu; Swami, Rajan; Pooja, Deep; Jeengar, Manish Kumar; Khan, Wahid; Sistla, Ramakrishna
Delivery of drugs to brain is a subtle task in the therapy of many severe neurological disorders. Solid lipid nanoparticles (SLN) easily diffuse the blood-brain barrier (BBB) due to their lipophilic nature. Furthermore, ligand conjugation on SLN surface enhances the targeting efficiency. Lactoferin (Lf) conjugated SLN system is first time attempted for effective brain targeting in this study. Preparation of Lf-modified docetaxel (DTX)-loaded SLN for proficient delivery of DTX to brain. DTX-loaded SLN were prepared using emulsification and solvent evaporation method and conjugation of Lf on SLN surface (C-SLN) was attained through carbodiimide chemistry. These lipidic nanoparticles were evaluated by DLS, AFM, FTIR, XRD techniques and in vitro release studies. Colloidal stability study was performed in biologically simulated environment (normal saline and serum). These lipidic nanoparticles were further evaluated for its targeting mechanism for uptake in brain tumour cells and brain via receptor saturation studies and distribution studies in brain, respectively. Particle size of lipidic nanoparticles was found to be optimum. Surface morphology (zeta potential, AFM) and surface chemistry (FTIR) confirmed conjugation of Lf on SLN surface. Cytotoxicity studies revealed augmented apoptotic activity of C-SLN than SLN and DTX. Enhanced cytotoxicity was demonstrated by receptor saturation and uptake studies. Brain concentration of DTX was elevated significantly with C-SLN than marketed formulation. It is evident from the cytotoxicity, uptake that SLN has potential to deliver drug to brain than marketed formulation but conjugating Lf on SLN surface (C-SLN) further increased the targeting potential for brain tumour. Moreover, brain distribution studies corroborated the use of C-SLN as a viable vehicle to target drug to brain. Hence, C-SLN was demonstrated to be a promising DTX delivery system to brain as it possessed remarkable biocompatibility, stability and efficacy than
Ahmad, Javed; Amin, Saima; Rahman, Mahfoozur; Rub, Rehan Abdur; Singhal, Madhur; Ahmad, Mohammad Zaki; Rahman, Ziyaur; Addo, Richard T; Ahmad, Farhan Jalees; Mushtaq, Gohar; Kamal, Mohammad Amjad; Akhter, Sohail
Chemotherapeutic delivery by oral route in cancer patients has the potential to create "hospitalization free chemotherapy" which is a vision of oncologists, formulation scientists and patients. Such a therapeutic approach will improve patients' compliance, ease the burden of the patients' caregivers and significantly reduce the cost of treatment. In current clinical practice, chemotherapy carried out by intravenous injection or infusion leads to undesired side-effects such as plasma concentrations crossing the maximum safe concentration, rapid body clearance and lower bioavailability. Despite the presence of challenges such as poor aqueous solubility and stability of drugs and the presence of biological barriers like multidrug efflux transporter in the GI tract, oral cancer chemotherapy has the potential to surmount those obstacles. Lipid nanoparticles (LNPs) such as solid lipid nanoparticle, nanostructured lipid carriers, nano lipid-drug conjugates, mixed micelles, liposomes and nanoemulsions have shown some promising results for use in oral anticancer drug delivery through nanotechnological approach. LNPs demonstrate enhanced oral bioavailability owing to their ability to inhibit first pass metabolism via lymphatic absorption by chylomicron-linked and/or M-cell uptake. LNPs reduce the inter- and intrasubject pharmacokinetics variability of administrated drugs. Moreover, certain classes of phospholipids and surfactants used in the formulations of LNPs can suppress the P-glycoprotein efflux system. Here, we shall be discussing the biopharmaceutical challenges in oral cancer chemotherapy and how the LNPs may provide solutions to such challenges. The effect of GI tract environment on LNPs and pharmacokinetics shall also be discussed.
Botto, Chiara; Mauro, Nicolò; Amore, Erika; Martorana, Elisabetta; Giammona, Gaetano; Bondì, Maria Luisa
Solid lipid nanoparticles (SLNs) may be considered as a new approach for therapeutics for many diseases. In addition to drug delivery, their use as non-viral vectors for gene delivery can be obtained by including cationic lipids, which provide a positive surface potential that favors binding to the nucleic acids as DNA, siRNA, miRNA, etc. In fact, the addition of cationic surfactants is indispensable for obtaining nanoparticles with surface positive charge. In this study, three different cationic lipids (dioctadecyl dimethyl ammonium bromide, cetyltrimethyl ammonium bromide, cetylpyridinium chloride) and Brij 76 as nonionic surfactant were employed to formulate Precirol ATO 5 based cSLN using pEGFP-LUC as model plasmid. The physicochemical properties of cSLN were influenced by both type and amount of surfactants. Thermal analyses of bulk cSLN showed endothermic peaks significantly different from the ones of the single pure components, hinting a complete entanglement of the lipid matrix with the surfactants and justifying the different behavior of the cSLN in the ability to interact with the plasmid DNA. Finally, the biocompatibility of cSLN was demonstrated by hemolytic assays. These results may give an insight into the choice of surfactants in order to obtain non-toxic and highly effective delivery systems for gene therapy. Copyright © 2016 Elsevier B.V. All rights reserved.
Ansari, Mohammad Javed; Anwer, Md Khalid; Jamil, Shahid; Al-Shdefat, Ramadan; Ali, Bahaa E; Ahmad, Mohammad Muqtader; Ansari, Mohammad Nazam
Insulin is a hormone used in the treatment of diabetes mellitus. Multiple injections of insulin every day may causes pain, allergic reactions at injection site, which lead to low patient compliance. The aim of this work was to develop and evaluate an efficient solid lipid nanoparticle (SLN) carrier for oral delivery of insulin. SLNs were prepared by double emulsion solvent evaporation (w/o/w) technique, employing glyceryltrimyristate (Dynasan 114) as lipid phase and soy lecithin and polyvinyl alcohol as primary and secondary emulsifier, respectively, and evaluated in vitro for particle size, polydispersity index (PDI) and drug entrapment. Among the eight different developed formulae (F1-F8), F7 showed an average particle size (99 nm), PDI (0.021), high entrapment of drug (56.5%). The optimized formulation (F7) was further evaluated by FT-IR, DSC, XRD, in vitro release, permeation, stability, bioavailability and pharmacological studies. Insulin-loaded SLNs showed better protection from gastrointestinal environment as evident from the relative bioavailability, which was enhanced five times as compared to the insulin solution. A significant enhancement of relative bioavailability of insulin was observed, i.e. approximately five times of pure insulin solution when loaded in SLN (8.26% versus 1.7% only).
Song, Aihua; Zhang, Xiaoshu; Li, Yanting; Mao, Xinjuan; Han, Fei
The aim of this study is to evaluate the effect of liquid-to-solid lipid ratio on properties of flurbiprofen-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), and to clarify the superiority of NLCs over SLNs for transdermal administration. Particle size, zeta potential, drug encapsulation efficiency, in vitro occlusion factor, differential scanning calorimetry, X-ray diffractometry, in vitro percutaneous permeation profile, and stability of SLNs and NLCs were compared. Particle size, zeta potential, drug encapsulation efficiency, in vitro occlusion factor, and in vitro percutaneous permeation amount of the developed NLCs were all <200 nm, < -20 mV, >78%, >35, and >240 μg/cm(2), respectively, however, for SLNs were 280 nm, -29.11 mV, 63.2%, 32.54, and 225.9 μg/cm(2), respectively. After 3 months storage at 4 °C and 25 °C, almost no significant differences between the evaluated parameters of NLCs were observed. However, for SLNs, particle size was increased to higher than 300 nm (4 °C and 25 °C), drug encapsulation efficiency was decreased to 51.2 (25 °C), in vitro occlusion factor was also decreased to lower than 25 (4 °C and 25 °C), and the cumulative amount was decreased to 148.9 μg/cm(2) (25 °C) and 184.4 μg/cm(2) (4 °C), respectively. And DSC and XRD studies indicated that not only the crystalline peaks of the encapsulated flurbiprofen disappeared but also obvious difference between samples and bulk Compritol® ATO 888 was seen. It could be concluded that liquid-to-solid lipid ratio has significant impact on the properties of SLNs and NLCs, and NLCs showed better stability than SLNs. Therefore, NLCs might be a better option than SLNs for transdermal administration.
Mohamed, Radwa A; Abass, Haidy A; Attia, Mohamed A; Heikal, Ola A
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.
Ezzati Nazhad Dolatabadi, Jafar; Valizadeh, Hadi; Hamishehkar, Hamed
In recent years, nanomaterials have been widely applied as advanced drug and gene delivery nanosystems. Among them, solid lipid nanoparticles (SLNs) have attracted great attention as colloidal drug delivery systems for incorporating hydrophilic or lipophilic drugs and various macromolecules as well as proteins and nucleic acids. Therefore, SLNs offer great promise for controlled and site specific drug and gene delivery. This article includes general information about SLN structures and properties, production procedures, characterization. In addition, recent progress on development of drug and gene delivery systems using SLNs was reviewed. PMID:26236652
Guo, Dawei; Dou, Dandan; Li, Xinyu; Zhang, Qian; Bhutto, Zohaib Ahmed; Wang, Liping
To avoid potential systematical toxicity, solid lipid nanoparticles (SLNs) were prepared as a vehicle for transdermal delivery of ivermectin (IVM) using hot homogenisation followed by ultrasonic method. The as-prepared SLNs were approximately spherical shape with good stability. IVM was encapsulated in amorphous form within SLNs and displayed prolonged release from SLNs without burst release due to high encapsulation efficiency (EE). The cumulative permeation of IVM across excised rat skin from SLNs was significantly increased compared to the ivermection suspension. These results indicated that the proposed SLNs can be considered as an efficient carrier for dermal delivery of IVM to effectively treat scabies.
Helgason, T; Awad, T S; Kristbergsson, K; McClements, D J; Weiss, J
The effect of surfactant surface coverage on formation and stability of Tween 20 stabilized tripalmitin solid lipid nanoparticles (SLN) was investigated. A lipid phase (10% w/w tripalmitin) and an aqueous phase (2% w/w Tween 20, 10 mM phosphate buffer, pH 7) were heated to 75 degrees C and then homogenized using a microfluidizer. The resulting oil-in-water emulsion was kept at a temperature (37 degrees C) above the crystallization temperature of the tripalmitin to prevent solidification of emulsion droplets, and additional surfactant at various concentrations (0-5% w/w Tween 20) was added. Droplets were then cooled to 5 degrees C to initiate crystallization and stored at 20 degrees C for 24 h. Particle size and/or aggregation were examined visually and by light scattering, and crystallization behavior was examined by differential scanning calorimetry (DSC). Excess Tween 20 concentration remaining in the aqueous phase was measured by surface tensiometry. Emulsion droplets after homogenization had a mean particle diameter of 134.1+/-2.0 nm and a polydispersity index of 0.08+/-0.01. After cooling to 5 degrees C at low Tween 20 concentrations, SLN dispersions rapidly gelled due to aggregation of particles driven by hydrophobic attraction between insufficiently covered lipid crystal surfaces. Upon addition of 1-5% w/w Tween 20, SLN dispersions became increasingly stable. At low added Tween 20 concentration (<1% w/w) the SLN formed gels but only increased slightly at higher surfactant concentrations (>1% w/w). The Tween 20 concentration in the aqueous phase decreased after tripalmitin crystallization suggesting additional surfactant adsorption onto solid surfaces. At higher Tween 20 concentrations, SLN had increasingly complex crystal structures as evidenced by the appearance of additional thermal transition peaks in the DSC. The results suggest that surfactant coverage at the interface may influence crystal structure and stability of solid lipid nanoparticles via
Barbosa, R. M.; da Silva, C. M. G.; Bella, T. S.; de Araújo, D. R.; Marcato, P. D.; Durán, N.; de Paula, E.
Dibucaine (DBC) is powerful long-lasting local anesthetic, but it is also considered fairly toxic to the CNS. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have attracted attention as carriers for drug delivery. The aim of this study was to develop and to evaluate the cytotoxic activity of DBC-loaded SLN and NLC against 3T3 fibroblast and HaCat keratinocyte cells. The SLN and NLC had myristyl myristate and Liponate®GC as their lipid matrices, respectively, plus a surfactant. SLN and NLC were characterized in terms in their diameter, size distribution, surface charge and DBC encapsulation efficiency. The particle size of SLN and NLC were around 234.33 and 166.62 nm, respectively. The polydispersity index was kept below 0.2 for both nanomaterials. Negative surface charges were observed for both nanoparticles, which decreased in the presence of the anesthetic. Encapsulation efficiency reached 76% and 90%, respectively, in SLN and NLC. DBC alone was found to be toxic to 3T3 and HaCat cells in culture. However, NLC and SLN loaded DBC decreased its intrinsic cytotoxic effect against 3T3 and HaCat cells. In conclusion, encapsulation of DBC in SLN and NLC decreased the in vitro toxicity of the local anesthetic, indicating the potential of these nanocarriers for clinical applications.
Van de Ven, H; Vermeersch, M; Shunmugaperumal, T; Vandervoort, J; Maes, L; Ludwig, A
The present pilot study explored the potential of solid lipid nanoparticles (SLN) to entrap saponins and reduce the membrane toxicity of these compounds. SLN composed of different types of solid lipid were prepared by the cold homogenisation technique. Combinations of anionic, cationic and non-ionic stabilisers were selected in order to obtain negatively, positively and neutrally charged SLN. Mean particle size and zeta potential of blank and saponin-loaded formulations were measured by Dynamic Light Scattering (DLS), Electrophoretic Light Scattering (ELS) and in vitro cytotoxicity on MRC-5 SV2 and J774 cells was assessed using a resazurin-based assay. The type of solid lipid used for the formulation influenced the mean particle size, while the zeta potential mainly depended on the kind of surfactant utilised. Blank SLN composed of hard fat and anionic or non-ionic surfactants did not result in cytotoxicity. After loading with saponin, the anionic hard fat SLN was found to be the optimal formulation.
Wang, Ting; Chen, Xiaojin; Lu, Mengmeng; Li, Xihe; Zhou, WenZhong
A florfenicol-loaded solid lipid nanoparticle (FFC-SLN) suspension was prepared by hot homogenisation and ultrasonic technique. The suspension was characterised for its release profile, stability, toxicity, and the physicochemical properties of the nanoparticles. Antibacterial activity of the suspension was evaluated in vitro and in vivo. The results showed that the mean diameter, polydispersity index and zeta potential of the nanoparticles were 253 ± 3 nm, 0.409 ± 0.022 and 47.5 ± 0.21 mV, respectively. In vitro release profile showed the FFC-SLN suspension had sustained release effect. The minimum inhibition concentration values of the FFC-SLN suspension were 6 and 3 µg/mL against Staphylococcus aureus and Escherichia coli respectively, compared with 3.5 and 2 µg/mL of native florfenicol. The suspension was relatively stable at 4°C and less stable at room temperature during 9 months storage. Although the nanoparticle carriers exhibited cytotoxicity in cell cultures, the LD50 of the lyophilised dry power of the suspension was higher than 5 g/kg body weight. Mortality protection against E. coli lethal infection in mice showed that the nanoparticle suspension had much better efficacy (6/10) than native drug (1/10). These results indicate that FFC-SLN suspension could be a promising formulation in veterinary medicine.
Campos, Estefânia Vangelie Ramos; de Oliveira, Jhones Luiz; da Silva, Camila Morais Gonçalves; Pascoli, Mônica; Pasquoto, Tatiane; Lima, Renata; Abhilash, P C; Fraceto, Leonardo Fernandes
Carbendazim (MBC) (methyl-2-benzimidazole carbamate) and tebuconazole (TBZ) ((RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol) are widely used in agriculture for the prevention and control of fungal diseases. Solid lipid nanoparticles and polymeric nanocapsules are carrier systems that offer advantages including changes in the release profiles of bioactive compounds and their transfer to the site of action, reduced losses due to leaching or degradation, and decreased toxicity in the environment and humans. The objective of this study was to prepare these two types of nanoparticle as carrier systems for a combination of TBZ and MBC, and then investigate the release profiles of the fungicides as well as the stabilities and cytotoxicities of the formulations. Both nanoparticle systems presented high association efficiency (>99%), indicating good interaction between the fungicides and the nanoparticles. The release profiles of MBC and TBZ were modified when the compounds were loaded in the nanoparticles, and cytotoxicity assays showed that encapsulation of the fungicides decreased their toxicity. These fungicide systems offer new options for the treatment and prevention of fungal diseases in plants.
Campos, Estefânia Vangelie Ramos; Oliveira, Jhones Luiz De; da Silva, Camila Morais Gonçalves; Pascoli, Mônica; Pasquoto, Tatiane; Lima, Renata; Abhilash, P. C.; Fernandes Fraceto, Leonardo
Carbendazim (MBC) (methyl-2-benzimidazole carbamate) and tebuconazole (TBZ) ((RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol) are widely used in agriculture for the prevention and control of fungal diseases. Solid lipid nanoparticles and polymeric nanocapsules are carrier systems that offer advantages including changes in the release profiles of bioactive compounds and their transfer to the site of action, reduced losses due to leaching or degradation, and decreased toxicity in the environment and humans. The objective of this study was to prepare these two types of nanoparticle as carrier systems for a combination of TBZ and MBC, and then investigate the release profiles of the fungicides as well as the stabilities and cytotoxicities of the formulations. Both nanoparticle systems presented high association efficiency (>99%), indicating good interaction between the fungicides and the nanoparticles. The release profiles of MBC and TBZ were modified when the compounds were loaded in the nanoparticles, and cytotoxicity assays showed that encapsulation of the fungicides decreased their toxicity. These fungicide systems offer new options for the treatment and prevention of fungal diseases in plants.
Campos, Estefânia Vangelie Ramos; Oliveira, Jhones Luiz de; da Silva, Camila Morais Gonçalves; Pascoli, Mônica; Pasquoto, Tatiane; Lima, Renata; Abhilash, P. C.; Fernandes Fraceto, Leonardo
Carbendazim (MBC) (methyl-2-benzimidazole carbamate) and tebuconazole (TBZ) ((RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol) are widely used in agriculture for the prevention and control of fungal diseases. Solid lipid nanoparticles and polymeric nanocapsules are carrier systems that offer advantages including changes in the release profiles of bioactive compounds and their transfer to the site of action, reduced losses due to leaching or degradation, and decreased toxicity in the environment and humans. The objective of this study was to prepare these two types of nanoparticle as carrier systems for a combination of TBZ and MBC, and then investigate the release profiles of the fungicides as well as the stabilities and cytotoxicities of the formulations. Both nanoparticle systems presented high association efficiency (>99%), indicating good interaction between the fungicides and the nanoparticles. The release profiles of MBC and TBZ were modified when the compounds were loaded in the nanoparticles, and cytotoxicity assays showed that encapsulation of the fungicides decreased their toxicity. These fungicide systems offer new options for the treatment and prevention of fungal diseases in plants. PMID:26346969
Kim, Byung-Do; Na, Kun; Choi, Hoo-Kyun
Solid lipid nanoparticles (SLN) were prepared using cacao butter, as the lipid core, and curdlan, as the shell material. Tween 80 was used as a co-surfactant in order to prevent aggregation and gelling of the curdlan. Mannitol was used as a cryoprotectant in order to prevent aggregation during redispersion. No significant change in the size of the SLN was observed up to a lipid concentration of 1.0%, and the particle size ranged from 140 to 200 nm with a unimodal distribution. When an alternating pH between 7 and 11 was used to test the physical stability of an SLN solution, the change in the particle size remained within a narrow range up to a lipid concentration of 0.5%. Above 0.5%, the particles began to aggregate due to the insufficient amount of the coating material, curdlan and Tween 80. The critical aggregation concentration at pH 7.4 was found to be 6.95 x 10(-4) mg/ml. Pyrene was used as a fluorescence probe. As the temperature increased, pyrene was gradually released from the SLN. The loading efficiency was >75% when the verapamil to lipid ratios were 1:10 and 1:5 and decreased significantly as the ratio became 1:1. The release rate was significantly delayed when verapamil was loaded into the SLN.
Singh, Bhupender; Vuddanda, Parameswara Rao; M R, Vijayakumar; Kumar, Vinod; Saxena, Preeti S; Singh, Sanjay
The present research work is focused on the development of solid lipid nanoparticles of cefuroxime axetil (CA-SLN) for its enhanced inhibitory activity against Staphylococcus aureus produced biofilm. CA-SLN was prepared by solvent emulsification/evaporation method using single lipid (stearic acid (SA)) and binary lipids (SA and tristearin (TS)). Process variables such as volume of dispersion medium, concentration of surfactant, homogenization speed and time were optimized. The prepared SLN were characterized for encapsulation efficiency, drug polymer interaction studies (DSC and FT-IR), shape and surface morphology (SEM and AFM), in vitro drug release, stability studies and in vitro anti biofilm activity against S. aureus biofilm. Among the process variables, increased volume of dispersion medium, homogenization speed and time led to increase in particle size whereas increase in surfactant concentration decreased the particle size. SLN prepared using binary lipids exhibited higher entrapment efficiency than the single lipid. DSC and FT-IR studies showed no incompatible interaction between drug and excipients. CA-SLN showed two folds higher anti-biofilm activity in vitro than pristine CA against S. aureus biofilm.
Oehlke, Kathleen; Behsnilian, Diana; Mayer-Miebach, Esther; Weidler, Peter G; Greiner, Ralf
Ferulic acid (FA) and tocopherol (Toc) loaded solid lipid nanoparticles (SLN) were prepared by a hot homogenisation method. The particle size distribution, zeta potential and melting behaviour of the SLN as well as the stability, encapsulation efficiency and radical scavenging activity of FA and Toc in the SLN were analysed. The different formulations containing up to 2.8 mg g-1 of FA or Toc were stable during at least 15 weeks of storage at room temperature. Despite partial degradation and / or release of FA and Toc during storage, significant radical scavenging activity was maintained. DSC measurements and radical scavenging tests after different time periods revealed that the re-structuring of the lipid matrix was connected to the enhanced antioxidant activity of Toc but did not affect the activity of FA.
Raj, Rakesh; Mongia, Pooja; Ram, Alpana; Jain, N K
The aim of the present study was to develop solid lipid nanoparticles (SLN) and formulate a hydrogel for enhanced topical delivery of aceclofenac (ACF). The SLN were prepared by the ultrasonic emulsification method and optimized on the basis of stirring speed and lipid content. The optimized formulation was characterized for particle size (189 ± 9.2 nm), polydispersity index (PDI) (0.162 ± 0.02), zeta potential (-32.51 ± 0.12 mV), entrapment efficiency (86.51 ± 2.46%), surface morphology, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In vivo performance of ACF-loaded SLN hydrogel showed prolonged inhibition of edema, as compared to that observed using plain ACF hydrogel, after 24 h. The results demonstrated that the ACF-SLN formulation for skin targeting could be a promising carrier for topical delivery of ACF.
Ridolfi, D. M.; Marcato, P. D.; Machado, D.; Silva, R. A.; Justo, G. Z.; Durán, N.
In recent years, the interest in nanostructured systems to drug delivery has increased because they offer several advantages over conventional dosage forms. Solid Lipid Nanoparticles (SLN) have been highlighted among these systems because they have advantages such as high physical stability, protection against drug degradation and ease of scale-up and manufacturing, without using organic solvent. The aim of this work was to evaluate the potential of SLN, by in vitro cytotoxicity assays, for dermal drug delivery. SLN of three different lipids were prepared by hot high pressure homogenization and the cytotoxicity was assessed by 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test in mouse 3T3 fibroblasts and human HaCaT keratinocytes. SLN showed no cytotoxic potential suggesting a great potential for dermal application.
Oehlke, Kathleen; Behsnilian, Diana; Mayer-Miebach, Esther; Weidler, Peter G.; Greiner, Ralf
Ferulic acid (FA) and tocopherol (Toc) loaded solid lipid nanoparticles (SLN) were prepared by a hot homogenisation method. The particle size distribution, zeta potential and melting behaviour of the SLN as well as the stability, encapsulation efficiency and radical scavenging activity of FA and Toc in the SLN were analysed. The different formulations containing up to 2.8 mg g−1 of FA or Toc were stable during at least 15 weeks of storage at room temperature. Despite partial degradation and / or release of FA and Toc during storage, significant radical scavenging activity was maintained. DSC measurements and radical scavenging tests after different time periods revealed that the re-structuring of the lipid matrix was connected to the enhanced antioxidant activity of Toc but did not affect the activity of FA. PMID:28192494
Gaspar, Diana P; Faria, Vasco; Gonçalves, Lídia M D; Taboada, Pablo; Remuñán-López, Carmen; Almeida, António J
Systemic administration of antitubercular drugs can be complicated by off-target toxicity to cells and tissues that are not infected by Mycobacterium tuberculosis . Delivery of antitubercular drugs via nanoparticles directly to the infected cells has the potential to maximize efficacy and minimize toxicity. The present work demonstrates the potential of solid lipid nanoparticles (SLN) as a delivery platform for rifabutin (RFB). Two different RFB-containing SLN formulations were produced using glyceryl dibehenate or glyceryl tristearate as lipid components. Full characterization was performed in terms of particle size, encapsulation and loading efficiency, morphology by transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) studies. Physical stability was evaluated when formulations were stored at 5 ± 3°C and in the freeze-dried form. Formulations were stable throughout lyophilization without significant variations on physicochemical properties and RFB losses. The SLN showed to be able to endure harsh temperature conditions as demonstrated by dynamic light scattering (DLS). Release studies revealed that RFB was almost completely released from SLN. In vitro studies with THP1 cells differentiated in macrophages showing a nanoparticle uptake of 46 ± 3% and 26 ± 9% for glyceryl dibehenate and glyceryl tristearate SLN, respectively. Cell viability studies using relevant lung cell lines (A549 and Calu-3) revealed low cytotoxicity for the SLN, suggesting these could be new potential vehicles for pulmonary delivery of antitubercular drugs.
Xie, Shuyu; Zhu, Luyan; Dong, Zhao; Wang, Yan; Wang, Xiaofang; Zhou, WenZhong
The purpose of this study was to use solid lipid nanoparticles (SLN) to improve the pharmacological activity of ofloxacin. Ofloxacin-loaded SLN were prepared using palmitic acid as lipid matrix and poly vinyl alcohol (PVA) as emulsifier by a hot homogenization and ultrasonication method. The physicochemical characteristics of SLN were investigated by optical microscope, scanning electron microscopy, and photon correlation spectroscopy. Pharmacokinetics was studied after oral administration in mice. In vitro antibacterial activity and in vivo antibacterial efficacy of the SLN were investigated using minimal inhibitory concentrations (MIC) and a mouse protection model. The results demonstrated that the encapsulation efficiency, loading capacity, diameter, polydispersivity index, and zeta potential of the nanoparticles were 41.36% ± 1.50%, 4.40% ± 0.16%, 156.33 ± 7.51 nm, 0.26 ± 0.04, and −22.70 ± 1.40 mv, respectively. The SLN showed sustained release and enhanced antibacterial activity in vitro. Pharmacokinetic results demonstrated that SLN increased the bioavailability of ofloxacin by 2.27-fold, and extended the mean residence time of the drug from 10.50 to 43.44 hours. Single oral administrations of ofloxacin-loaded nanoparticles at 3 drug doses, 5 mg/kg, 10 mg/kg, and 20 mg/kg, all produced higher survival rates of lethal infected mice compared with native ofloxacin. These results indicate that SLN might be a promising delivery system to enhance the pharmacological activity of ofloxacin. PMID:21468357
Chirio, Daniela; Gallarate, Marina; Peira, Elena; Battaglia, Luigi; Serpe, Loredana; Trotta, Michele
Curcumin (CU) loaded solid lipid nanoparticles (SLNs) of fatty acids (FA) were prepared with a coacervation technique based on FA precipitation from their sodium salt micelles in the presence of polymeric non-ionic surfactants. Myristic, palmitic, stearic, and behenic acids, and different polymers with various molecular weights and hydrolysis grades were employed as lipid matrixes and stabilisers, respectively. Generally, spherical-shaped nanoparticles with mean diameters below 500 nm were obtained, and using only middle-high hydrolysis, grade-polymer SLNs with diameters lower than 300 nm were produced. CU encapsulation efficiency was in the range 28-81% and highly influenced by both FA and polymer type. Chitosan hydrochloride was added to FA SLN formulations to produce bioadhesive, positively charged nanoparticles. A CU-chitosan complex formation could be hypothesised by DSC analysis, UV-vis spectra and chitosan surface tension determination. A preliminary study on HCT-116 colon cancer cells was developed to evaluate the influence of CU-loaded FA SLNs on cell viability.
Battani, Somashekhar; Pawar, Harish; Suresh, Sarasija
The objective of the present investigation was formulation of raloxifene loaded solid lipid nanoparticles (R-SLN) for oral administration and evaluation of its anticancer potential in 7,12- dimethylbenzanthracene (DMBA)-induced breast cancer in Sprague-Dawley rats. Optimized R-SLN formulation prepared by modified micro-emulsion method resulted in R-SLN of 288.0±28.5 nm size and 95.56% entrapment efficiency. R-SLN exhibited in vitro prolonged release of raloxifene for 72 h in phosphate buffered saline. R-SLN was stable in simulated gastro-intestinal (GIT) fluids consisting of pH 1.2, pH 7.4, simulated gastric fluid and simulated intestinal fluid. A two-fold increase was observed in raloxifene oral bioavailability from R-SLN. R-SLN exhibited enhanced efficacy and chemopreventive activity over pure raloxifene as indicated by evaluation of tumor burden (P < 0.001) and tumor incidence (P < 0.001). The results indicate the potential of raloxifene solid lipid nanoparticles in optimizing chemoprevention of breast cancer by R-SLN.
Carneiro, Zumira A.; da S. Maia, Pedro I.; Sesti-Costa, Renata; Lopes, Carla D.; Pereira, Tatiana A.; Milanezi, Cristiane M.; da Silva, Marcelo A. Pereira.; Lopez, Renata F. V.; Silva, João S.; Deflon, Victor M.
The parasite Trypanosoma cruzi causes Chagas disease, which remains a serious public health concern and continues to victimize thousands of people, primarily in the poorest regions of Latin America. In the search for new therapeutic drugs against T. cruzi, here we have evaluated both the in vitro and the in vivo activity of 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-benzyl dithiocarbazate) (H2bdtc) as a free compound or encapsulated into solid lipid nanoparticles (SLN); we compared the results with those achieved by using the currently employed drug, benznidazole. H2bdtc encapsulated into solid lipid nanoparticles (a) effectively reduced parasitemia in mice at concentrations 100 times lower than that normally employed for benznidazole (clinically applied at a concentration of 400 µmol kg−1 day−1); (b) diminished inflammation and lesions of the liver and heart; and (c) resulted in 100% survival of mice infected with T. cruzi. Therefore, H2bdtc is a potent trypanocidal agent. PMID:24810753
Majrad, Mohamed Saleh
The primary goal of this research work was to develop solid lipid nanoparticles (SLNs) containing 5-Flourouracil and to evaluate its effect on various cell lines. The solid lipid nanoparticles were prepared through a new temperature modulated solidification technique developed in our laboratory. Particle size analysis by dynamic light scattering (DLS) and morphology evaluation by transmission electron microscopy (TEM) demonstrated that the SLNs are nanoparticulates. Cytotoxic activity of SLN loaded 5-Fluorouracil showed a decrease in viability when compared to pure solution of 5-FU on PC-3 and Caco-2 cell line. Blank SLN showed no decrease in cell viability when the concentration increased. Biocompatibility studies of SLNs in human RBCs indicated that 5-FU SLN formulations are compatible. Bovine permeability study shows that apparent permeability for 5-FU SLN was 0.000348 cm/s and 1.339 cm/s for 5-FU solution. The preliminary results from various in vitro evaluations suggest that 5-FU loaded SLNs have the potential to be used as an anti-cancer drug delivery system.
Omwoyo, Wesley N; Melariri, Paula; Gathirwa, Jeremiah W; Oloo, Florence; Mahanga, Geoffrey M; Kalombo, Lonji; Ogutu, Bernhards; Swai, Hulda
Effective use of dihydroartemisinin (DHA) is limited by poor water-solubility, poor pharmacokinetic profile and unsatisfactory clinical outcome especially in monotherapy. To reduce such limitations, we reformulated DHA into solid lipid nanoparticles (SLNs) as a nanomedicine drug delivery system. DHA-SLNs were characterized for physical parameters and evaluated for in vitro and in vivo antimalarial efficacy. DHA-SLNs showed desirable particle characteristics including particle size (240.7 nm), particle surface charge (+17.0 mV), drug loadings (13.9 wt %), encapsulation efficacy (62.3%), polydispersity index (0.16) and a spherical appearance. Storage stability up to 90 days and sustained release of drug over 20 h was achieved. Enhanced in vitro (IC50 0.25 ng/ml) and in vivo (97.24% chemosuppression at 2mg/kg/day) antimalarial activity was observed. Enhancement in efficacy was 24% when compared to free DHA. These encouraging results show potential of using the described formulation for DHA drug delivery for clinical application. Malaria still poses a significant problem worldwide. One of the current drugs, artemisinin has been shown to be effective, but has poor water-solubility. The authors here described their formulation of making dihydroartemisinin (DHA) into solid lipid nanoparticles, with subsequent enhancement in efficacy. These results would have massive potential in the clinical setting. Copyright © 2015 Elsevier Inc. All rights reserved.
Liu, X-h; Liang, X-z; Fang, X; Zhang, W-P
Octylmethoxycinnamate (OMC)-loaded solid lipid nanoparticles (SLNs) were prepared by ultrasonic emulsification method. Effects of process variables and formulation composition were investigated on particle size and polydispersity index (PI), and the UV absorbance. Effect of OMC concentration on entrapment efficiency (EE) was also studied. The optimal formulation was characterized and evaluated by environment emission scanning electron microscopy (ESEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). In addition, the degradations of OMC from SLNs and OMC conventional emulsion were compared. The composition of optimal formulation was determined as 5% (w/w) of solid lipid, 7% (w/w) of emulsifier and 9% of loaded OMC, resulting in a particle size of 392.8 nm, and EE of 88.73%, LD of 38.05% under the preparation condition of 6 min of sonication, 400 W of sonication power. ESEM study showed spherical particles with smooth surface. DSC studies indicated OMC encapsulation within the nanoparticle matrix. The characteristic peaks for OMC-SLNs stood at 1710, 1604, 1513, 1465 and 830.3 cm(-1) . The degradation rate of OMC was decreased when using SLNs formulations compared to conventional emulsion. Hence, the developed SLNs can be used as sunscreen carrier for improve the stability. © 2015 Society of Cosmetic Scientists and the Société Française de Cosmétologie.
Deshpande, Ameya Abhay
The aim of this research was to formulate, characterize, and evaluate the paclitaxel loaded solid lipid nanoparticles (SLNs) prepared by a temperature modulated solidification technique developed and optimized in our laboratory. The particle size analysis through dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed and confirmed the spherical shape and nanometer size range of the formulated nanoparticles. Zeta potential measurements confirmed the physical stability of the SLNs with a negative surface charge. Atomic force microscopy (AFM) studies were done to study the surface topography and particle size and shape. AFM data showed minimal aggregation and more or less spherical SLNs. Differential scanning calorimetry (DSC), powder X-ray diffraction (P-XRD) and Fourier transform infrared spectroscopy (ATR-FTIR) confirmed the conversion of bulk lipid into SLNs and high entrapment of paclitaxel into the lipid matrix. The optimized formulation had an entrapment efficiency of approximately 62%. The in-vitro drug release depicted a sustained release of paclitaxel from the SLNs over duration of one week. The drug release data was found to best fit and hence followed the Higuchi drug-release model.
Dal Pizzol, Carine; O'Reilly, Andre; Winter, Evelyn; Sonaglio, Diva; de Campos, Angela Machado; Creczynski-Pasa, Tânia Beatriz
Solid lipid nanoparticles (SLN) are colloidal particles consisting of a matrix composed of solid (at room and body temperatures) lipids dispersed in aqueous emulsifier solution. During manufacture, their physicochemical properties may be affected by several formulation parameters, such as type and concentration of lipid, proportion of emulsifiers and amount of solvent. Thus, the aim of this work was to study the influence of these variables on the preparation of SLN. A D-optimal Response Surface Methodology design was used to establish a mathematical model for the optimization of SLN. A total of 30 SLN formulations were prepared using the ultrasound method, and then characterized on the basis of their physicochemical properties, including particle size, polydispersity index (PI) and Zeta Potential (s). Particle sizes ranged between 107 and 240 nm. All SLN formulations showed negative sigma and PI values below 0.28. Prediction of the optimal conditions was performed using the desirability function targeting the reduction of all responses. The optimized SLN formulation showed similar theoretical and experimental values, confirming the sturdiness and predictive ability of the mathematical model for SLN optimization.
Doktorovová, Slavomira; Santos, Dario L; Costa, Inês; Andreani, Tatiana; Souto, Eliana B; Silva, Amélia M
Solid lipid nanoparticles (SLN) are colloidal drug and/or gene carriers developed from solid lipids and surfactants that are considered safe. Cationic SLN, usually used for formulating poorly water-soluble drugs and for gene delivery purposes, as positively charged particles may attach to cellular surfaces and be internalized more easily than negatively charged SLN, but they can also cause damage. The main aim of this work was to test a set of cationic SLN and investigate its influence on the amount of reactive oxygen species (ROS), on antioxidant enzymes activities and on possible oxidative damage to membrane lipids in HepG2 cells. The Dichlorofluorescein assay revealed great increase in ROS presence after cell exposure to SLN. While the exposure to SLN increased the activities of superoxide dismutase and glutathione peroxidase it decreased glutathione reductase activity. Although no significant increase in thiobarbituric reactive species was found, a decrease in sulfhydryl groups was detected. These results indicate that cationic SLN caused oxidative stress in HepG2 cells, but under reported exposure conditions HepG2 cells could attenuate the stress and thus the damage to cellular components was minimal.
Solid lipid nanoparticles (SLNs) consist of spherical solid lipid particles in the nanometer size range, which are dispersed in water or in an aqueous surfactant solution. SLN technology represents a promising new approach to deliver hydrophilic as well as lipophilic drugs. The commercialization of SLN technology remains limited despite numerous efforts from researchers. The purpose of this research was to advance SLN preparation methodology by investigating the feasibility of preparing glyceryl monostearate (GMS) nanoparticles by using three preparation methods namely microemulsion technique, magnetic stirring technique and temperature modulated solidification technique of which the latter two were developed in our laboratory. An anticancer drug 5-fluorouracil was incorporated in the SLNs prepared via the temperature modulated solidification process. Optimization of the magnetic stirring process was performed to evaluate how the physicochemical properties of the SLN was influenced by systematically varying process parameters including concentration of the lipid, concentration of the surfactant, type of surfactant, time of stirring and temperature of storage. The results demonstrated 1:2 GMS to tween 80 ratio, 150 ml dispersion medium and 45 min stirring at 4000 RPM speed provided an optimum formulation via the temperature modulated solidification process. SLN dispersions were lyophilized to stabilize the solid lipid nanoparticles and the lyophilizates exhibited good redispersibility. The SLNs were characterized by particle size analysis via dynamic light scattering (DLS), zeta potential, transmission electron microscopy (TEM), differential scanning calorimetry (DSC), drug encapsulation efficiency and in vitro drug release studies. Particle size of SLN dispersion prepared via the three preparation techniques was approximately 66 nm and that of redispersed lyophilizates was below 500 nm. TEM images showed spherical to oval particles that were less dense in the core
Karmakar, Gourab; Nahak, Prasant; Guha, Pritam; Roy, Biplab; Chettri, Priyam; Sapkota, Manish; Koirala, Suraj; Misono, Takeshi; Torigoe, Kanjiro; Ghosh, Shilpi; Panda, Amiya Kumar
Mutual miscibility of soylecithin, tristearin, fatty acids (FAs), and curcumin was assessed by means of surface pressure-area isotherms at the air-solution interface in order to formulate modified solid lipid nanoparticles (SLN). Appearance of minima in the excess area (Aex) and changes in free energy of mixing (∆G(0)ex) were recorded for systems with 20 mole% FAs. Modified SLNs, promising as topical drug delivery systems, were formulated using the lipids in combination with curcumin, stabilized by an aqueous Tween 60 solution. Optimal formulations were assessed by judiciously varying the FA chain length and composition. Physicochemical properties of SLNs were studied such as the size, zeta potential (by dynamic light scattering), morphology (by freeze fracture transmission electron microscopy), and thermal behavior (by differential scanning calorimetry). The size and zeta potential of the formulations were in the range 300-500 nm and -10 to -20 mV, respectively. Absorption and emission spectroscopic analyses supported the dynamic light scattering and differential scanning calorimetry data and confirmed localization of curcumin to the palisade layer of SLNs. These nanoparticles showed a sustained release of incorporated curcumin. Curcumin-loaded SLNs were effective against a gram-positive bacterial species, Bacillus amyloliquefaciens. Our results on the physicochemical properties of curcumin-loaded SLNs, the sustained release, and on antibacterial activity suggest that SLNs are promising delivery agents for topical drugs.
Gaur, Praveen Kumar; Mishra, Shikha; Bajpai, Meenakshi; Mishra, Anushika
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 (Cmax) and 10.98-fold increase in AUC in comparison to Efavirenz suspension (ES). PMID:24967360
Joshi, Ashwini S; Patel, Hitesh S; Belgamwar, Veena S; Agrawal, Anshuman; Tekade, Avinash R
The present investigation deals with the development and statistical optimization of solid lipid nanoparticles (SLNs) of ondansetron HCl (OND) for intranasal (i.n.) delivery. SLNs were prepared using the solvent diffusion technique and a 2(3) factorial design. The concentrations of lipid, surfactant and cosurfactant were independent variables in this design, whereas, particle size and entrapment efficiency (EE) were dependent variables. The particle size of the SLNs was found to be 320-498 nm, and the EE was between 32.89 and 56.56 %. The influence of the lipid, surfactant and cosurfactant on the particle size and EE was studied. A histological study revealed no adverse response of SLNs on sheep nasal mucosa. Transmission electron microscopic analysis showed spherical shape particles. Differential scanning calorimetry and X-ray diffraction studies indicated that the drug was completely encapsulated in a lipid matrix. In vitro drug release studies carried out in phosphate buffer (pH 6.6) indicated that the drug transport was of Fickian type. Gamma scintigraphic imaging in rabbits after i.n. administration showed rapid localization of the drug in the brain. Hence, OND SLNs is a promising nasal delivery system for rapid and direct nose-to-brain delivery.
Dawoud, Mohamed Z.; Nasr, Mohamed
Colloidal lipid particles such as solid lipid nanoparticles and liquid crystalline nanoparticles have great opportunities as drug carriers especially for lipophilic drugs intended for intravenous administration. In order to evaluate drug release from these nanoparticles and determine their behavior after administration, emulsion droplets were used as a lipophilic compartment to which the transfer of a model drug was measured. The detection of the model drug transferred from monoolein cubic particles and trimyristin solid lipid nanoparticles into emulsion droplets was performed using a flow cytometric technique. A higher rate and amount of porphyrin transfer from the solid lipid nanoparticles compared to the monoolein cubic particles was observed. This difference might be attributed to the formation of a highly ordered particle which leads to the expulsion of drug to the surface of the crystalline particle. Furthermore, the sponge-like structure of the monoolein cubic particles decreases the rate and amount of drug transferred. In conclusion, the flow cytometric technique is a suitable technique to study drug transfer from these carriers to large lipophilic acceptors. Monoolein cubic particles with their unique structure can be used successfully as a drug carrier with slow drug release compared with trimyristin nanoparticles. PMID:27006901
Xu, Qiang; Zhu, Tao; Yi, Chaoli; Shen, Qi
Considered a popular drug for diabetes in recent years, metformin was determined to have a moderate anti-tumor effect, particularly in breast cancer. In this study, the anticancer mechanism of metformin was verified by preparing solid lipid nanoparticles (SLNs) and chitosan-modified solid lipid nanoparticles (CSLNs) containing metformin and then estimating the potential of these SLNs for uptake in cells and mitochondria. Metformin-SLNs were prepared using an emulsification and low-temperature solidification method. The mean particle size, zeta potential, entrapment efficiency, and loading efficiency of metformin-SLNs and metformin chitosan-modified SLNs were 102.3 ± 4.16 and 200.1 ± 17.69 nm, -21.25 ± 4.89 and 50.6 ± 4.09 mv, 26.25 ± 2.59% and 33.6 ± 2.21%, and 1.74 ± 0.16% and 1.46 ± 0.10%, respectively. TEM images showed that both the nanoparticles had spherical morphologies with no aggregation. Results of cellular and mitochondrial uptake showed that the metformin-SLNs were easier to uptake in cells and mitochondria than the pure drug group (that was the control group without SLN structure modification). The findings of this research provide a basis for conducting further studies on the anticancer mechanism of metformin.
Chai, Gui-Hong; Hu, Fu-Qiang; Sun, Jihong; Du, Yong-Zhong; You, Jian; Yuan, Hong
An understanding of drug delivery system transport across epithelial cell monolayer is very important for improving the absorption and bioavailability of the drug payload. The mechanisms of epithelial cell monolayer transport for various nanocarriers may differ significantly due to their variable components, surface properties, or diameter. Solid lipid nanoparticles (SLNs), conventionally formed by lipid materials, have gained increasing attention in recent years due to their excellent biocompatibility and high oral bioavailability. However, there have been few reports about the mechanisms of SLNs transport across epithelial cell monolayer. In this study, the molecular mechanisms utilized by SLNs of approximately 100 nm in diameter crossing intestinal epithelial monolayer were carefully studied using a simulative intestinal epithelial monolayer formed by Madin-Darby canine kidney (MDCK) epithelial cells. The results demonstrated that SLNs transportation did not induce a significant change on tight junction structure. We found that the endocytosis of SLNs into the epithelial cells was energy-dependent and was significantly greater than nanoparticle exocytosis. The endocytosis of SLNs was found to be rarely mediated via macropinocytosis, as confirmed by the addition of 5-(N-ethyl-N-isopropyl)amiloride (EIPA) as an inhibitory agent, and mainly depended on lipid raft/caveolae- and clathrin-mediated pathways. After SLNs was internalized into MDCK cells, lysosome was one of the main destinations for these nanoparticles. The exocytosis study indicated that the endoplasmic reticulum, Golgi complex, and microtubules played important roles in the transport of SLNs out of MDCK cells. The transcytosis study indicated that only approximately 2.5% of the total SLNs was transported from the apical side to the basolateral side. For SLNs transportation in MDCK cell monolayer, greater transport (approximately 4-fold) was observed to the apical side than to the basolateral side. Our
Nasseri, Mahboobeh; Golmohammadzadeh, Shiva; Arouiee, Hossein; Jaafari, Mahmoud Reza; Neamati, Hossein
Objective(s): The aim of the present study was to prepare, characterize, and evaluate solid lipid nanoparticles (SLNs) containing Zataria multiflora essential oil (ZEO). Materials and Methods: In this study, Z. multiflora essential oil-loaded solid lipid nanoparticles (ZE-SLNs) were prepared to improve its efficiency in controlling some fungal pathogens. SLNs containing Z. multiflora essential oil were prepared by high shear homogenization and ultra sound technique. ZEO-SLNs contained 0.03% ZEO in 5% of lipid phase (Glyceryl monostearate-GMS and Precirol® ATO 5). Tween 80 and Poloxamer 188 (2.5% w/v) were used as surfactant in the aqueous phase. The antifungal efficacy of ZE-SLNs and ZEO was compared under in vitro conditions. Results: The particle size of ZE-SLNs was around 255.5±3 nm with PDI of 0.369±0.05 and zeta potential was about -37.8±0.8 mV. Encapsulation efficacy of ZE-SLNs in crystalline form was 84±0.92%. The results showed that the ZEO and ZE-SLNs had 54 and 79% inhibition on the growth of fungal pathogens, respectively. The minimum inhibitory concentration (MIC) under in vitro conditions for the ZEO on the fungal pathogens of Aspergillus ochraceus, Aspergillus niger, Aspergillus flavus, Alternaria solani, Rhizoctonia solani, and Rhizopus stolonifer was 300, 200, 300, 200, 200 and 200 ppm, respectively, for ZE-SLNs, it was 200, 200, 200, 100, 50 and 50 ppm. The antifungal efficacy of ZE-SLNs was significantly more than ZEO. Conclusion: Our results showed that the SLNs were suitable carriers for Z. multiflora essential oil in controlling the fungal pathogens and merits further investigation. PMID:27917280
Tiwari, Radheshyam; Pathak, Kamla
Nanostructured lipid carrier (NLC) system of simvastatin was investigated for improvement in release, pharmacokinetics and biodistribution over its solid lipid nanoparticles (SLN). The NLC formulations prepared by solvent injection technique were optimized by 2(3) full factorial design. Optimized NLC was deduced on the basis of dependent variables that were analyzed using Design expert 8.0.2 software (Stat Ease, Inc., USA). Pareto charts and response surface plots were utilized to study the effect of variables on the response parameters. The optimized NLC was a suspension of nanosized homogeneous particles with significantly higher entrapment efficiency (>90%) and lower recrystallization properties (p<0.01) than SLNs. The pharmacokinetic parameters of Tc(99) labeled optimized NLC in mice, obtained using Quickcal software (Plexus, India) revealed 4.8 folds increase in bioavailability as compared to simvastatin suspension and 2.29 folds as compared to SLNs. Biodistribution study revealed preferential accumulation of NLC in the liver and this is advantageous because liver is the target organ for simvastatin. IVIVC studies demonstrated level A correlation between in vitro release and percent drug absorbed. This investigation demonstrated the superiority of NLC over SLN for improved oral delivery and it was deduced that the liquid lipid, oleic acid was the principal formulation factor responsible for the improvement in characteristics, pharmacokinetics and biodistribution of NLCs. Copyright © 2011 Elsevier B.V. All rights reserved.
Shegokar, R; Singh, K K; Müller, R H
The production of stavudine-loaded solid lipid nanoparticles (SLN) for intravenous injection was scaled up from lab scale (40 g) to medium scale (10 kg) and large scale (20/60 kg). The SLN were produced by high pressure homogenization of stavudine lipid melt dispersed in hot surfactant solution (pre-emulsion) applying 800 bar pressure. Employed were piston-gap homogenizers with increasing capacity (APV Gaulin products LAB 40, LAB 60 and Gaulin 5.5, and Avestin C50), using them in the continuous (circulation) and discontinuous mode. Size analysis was performed by photon correlation spectroscopy (PCS), laser diffractometry and light microscopy. At lab scale a PCS size of 53 nm was obtained. At the same pressure, all homogenizers on larger scale yielded a size in the range of the lab scale product (35-70 nm). Differences were found in the size as a function of circulation time (size increase or size reduction with time) and the number of cycles required (1 or 5) for the optimal product. The stavudine SLN formulation (2% lipid content, high surfactant to lipid ratio) showed a different behavior to conventional higher concentrated SLN suspensions or nanoemulsions (10% or 20% lipid/oil, low surfactant to lipid ratio). In general, smallest sizes were obtained in the discontinuous mode after just one homogenization cycle. The continuous production mode was only efficient with a 10 kg batch size using the LAB 60. In addition, the long-term stability over 1 year was monitored at refrigeration, room temperature and at 40°C to assess a potential effect of the homogenizer type on stability. All batches at room temperature and below were stable, only a negligible increase in size was observed.
Leonardi, Antonio; Crasci', Lucia; Panico, Annamaria; Pignatello, Rosario
Idebenone (IDE) is a lipophilic benzoquinone electron carrier synthetic analogue of coenzyme Q10, which behaves as an antioxidant and free radical scavenging molecule. Recently, the therapeutic application of IDE in Leber's hereditary optic neuropathy has been discussed. This work was aimed at evaluating the encapsulation of IDE in solid-lipid nanoparticles (SLN). In particular, we tested the possibility of adapting the quasi-emulsion solvent diffusion technique, already proposed to produce polymeric nanoparticles, to prepare positively charged SLN with different compositions. Such a charge, due to the addition of a cationic lipid, would facilitate the interaction with the negatively charged eye surface epithelium, with a consequent longer pre-corneal residence time of the colloidal systems. In a preliminary evaluation of the produced IDE-loaded SLN, the antioxidant activity of the drug was demonstrated using an oxygen radical absorbance capacity assay. Encapsulation of the drug in the nanocarrier systems seems able to protect IDE from degradation and prolong its antioxidant potential.
Schubert, M A; Müller-Goymann, C C
Solid lipid nanoparticles (SLN), an alternative colloidal drug delivery system to polymer nanoparticles, emulsions and liposomes, are generally produced by high pressure melt-emulsification. However, the harsh production process is not applicable for formulations containing shear and temperature sensitive compounds. For that reason, subsequent adsorptive SLN loading might be a promising alternative. The aim of the present study was the development and characterisation of surface-modified SLN for adsorptive protein loading by variation of both the lipid matrix and the emulsifier concentration in the continuous phase. Variations in SLN composition resulted in particle sizes between 674 and 61 nm corresponding to specific surfaces of 4.5 m(2)/g and 48.9 m(2)/g and zeta potentials between -23.4 mV and -0.9 mV. In dependence of SLN surface properties, albumin payload ranged from 2.5 to 15%. Thermoanalysis, X-ray diffraction and electron microscopy revealed anisometrical and crystalline particles. In vitro cytotoxicity was low in terms of both haemolysis, which was between 1 and 2%, and neutral red test (NRT) showing a half lethal dose between 1.1 and 4.6%.
Gonçalves, L M D; Maestrelli, F; Di Cesare Mannelli, L; Ghelardini, C; Almeida, A J; Mura, P
A solid lipid nanoparticle (SLN) formulation was developed with the aim of improving the oral bioavailability and the therapeutic effectiveness of glibenclamide (GLI), a poorly water-soluble drug used in the treatment of type 2 diabetes. The SLN was prepared using different lipid components (Precirol® and Compritol®) and preparation procedures. Precirol-based SLN, obtained with the emulsion of solvent evaporation technique gave the best results and was selected for drug loading. Addition of lecithin to the SLN core or PEG coating was effective in increasing the nanoparticles stability in simulated gastric solution. Both such formulations were stable after one month storage at 5±3°C, exhibited the absence of in vitro cytotoxicity, and presented a similar in vitro prolonged-release, reaching 100% release after 24h. The lecithin-containing GLI-loaded SLN formulation, selected for in vivo studies in virtue of its higher EE% than the PEG-coated formulation (70.3% vs 19.6%), showed a significantly stronger hypoglycemic effect with respect to the drug alone, in terms of both shorter onset time and longer duration of the effect. These positive results indicated that the proposed SLN approach was successful in improving GLI oral bioavailability, confirming its potential as an effective delivery system for a suitable therapy of diabetes.
Akanda, Mushfiq H; Rai, Rajeev; Slipper, Ian J; Chowdhry, Babur Z; Lamprou, Dimitrios; Getti, Giulia; Douroumis, Dennis
In this study retinoic acid (RTA) loaded solid lipid nanoparticles (SLNs) were optimized by tuning the process parameters (pressure/temperature) and using different lipids to develop nanodispersions with enhanced anticancer activity. The RTA-SLN dispersions were produced by high-pressure homogenization and characterized in terms of particle size, zeta potential, drug entrapment efficiency, stability, transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and in vitro drug release. Thermal and X-ray analysis showed the RTA to be in the amorphous state, whilst microscopic images revealed a spherical shape and uniform particle size distribution of the nanoparticles. Anticancer efficiency was evaluated by incubating RTA-SLNs with human prostate cancer (LNCap) cells, which demonstrated reduced cell viability with increased drug concentrations (9.53% at 200 ug/ml) while blank SLNs displayed negligible cytotoxicity. The cellular uptake of SLN showed localization within the cytoplasm of cells and flow cytometry analysis indicated an increase in the fraction of cells expressing early apoptotic markers, suggesting that the RTA loaded SLNs are able to induce apoptosis in LNCap cells. The RTA-SLN dispersions have the potential to be used for prostate anticancer treatment.
Keck, Cornelia M; Kovačević, Andjelka; Müller, Rainer H; Savić, Snežana; Vuleta, Gordana; Milić, Jela
Alkyl polyglycosides (APGs) represent a group of nonionic tensides with excellent skin compatibility. Thus they seem to be excellent stabilizers for lipid nanoparticles for dermal application. To investigate this, different APGs were selected to evaluate their influence on the formation and characteristics of solid lipid nanoparticles (SLN). Contact angle analysis of the aqueous solutions/dispersions of the APGs on cetyl palmitate films revealed good wettability for all APG surfactants. Cetyl palmitate based SLN were prepared by hot high pressure homogenization and subjected to particle size, charge and inner structure analysis. 1% of each APG was sufficient to obtain SLN with a mean size between 150 nm and 175 nm and a narrow size distribution. The zeta potential in water was ∼ -50 mV; the values in the original medium were distinctly lower, but still sufficient high to provide good physical stability. Physical stability at different temperatures (5°C, 25°C and 40°C) was confirmed by a constant particle size over an observation period of 90 days in all dispersions. In comparison to SLN stabilized with classical surfactants, e.g., Polysorbate, APG stabilized SLN possess a smaller size, improved physical stability and contain less surfactant. Therefore, the use of APGs for the stabilization of lipid nanoparticles is superior in comparison to classical stabilizers. Further, the results indicate that the length of the alkyl chain of the APG influences the diminution efficacy, the final particle size and the crystallinity of the particles. APGs with short alkyl chain led to a faster reduction in size during high pressure homogenization, to a smaller particle size of the SLN and to a lower recrystallization index, i.e., to a lower crystallinity of the SLN. The crystallinity of the SLN increased with an increase in the alkyl chain length of APGs. Therefore, by using the tested APGs differing in the alkyl chain length, not only small sized and physically stable but
Gokce, Evren H; Korkmaz, Emrah; Dellera, Eleonora; Sandri, Giuseppina; Bonferoni, M Cristina; Ozer, Ozgen
Background Excessive generation of radical oxygen species (ROS) is a contributor to skin pathologies. Resveratrol (RSV) is a potent antioxidant. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can ensure close contact and increase the amount of drug absorbed into the skin. In this study, RSV was loaded into SLN and NLC for dermal applications. Methods Nanoparticles were prepared by high shear homogenization using Compritol 888ATO, Myglyol, Poloxamer188, and Tween80. Particle size (PS), polydispersity index (PI), zeta potential (ZP), drug entrapment efficiency (EE), and production yield were determined. Differential scanning calorimetry (DSC) analysis and morphological transmission electron microscopy (TEM) examination were conducted. RSV concentration was optimized with cytotoxicity studies, and net intracellular accumulation of ROS was monitored with cytofluorimetry. The amount of RSV was determined from different layers of rat abdominal skin. Results PS of uniform RSV-SLN and RSV-NLC were determined as 287.2 nm ± 5.1 and 110.5 nm ± 1.3, respectively. ZP was −15.3 mV ± 0.4 and −13.8 mV ± 0.1 in the same order. The drug EE was 18% higher in NLC systems. TEM studies showed that the drug in the shell model was relevant for SLN, and that the melting point of the lipid in NLC was slightly lower. Concentrations below 50 μM were determined as suitable RSV concentrations for both SLN and NLC in cell culture studies. RSV-NLC showed less fluorescence, indicating less ROS production in cytofluorometric studies. Ex vivo skin studies revealed that NLC are more efficient in carrying RSV to the epidermis. Conclusion This study suggests that both of the lipid nanoparticles had antioxidant properties at a concentration of 50 μM. When the two systems were compared, NLC penetrated deeper into the skin. RSV-loaded NLC with smaller PS and higher drug loading appears to be superior to SLN for dermal applications. PMID:22605933
Calderón-Colón, Xiomara; Patchan, Marcia W.; Theodore, Mellisa L.; Le, Huong T.; Sample, Jennifer L.; Benkoski, Jason J.; Patrone, Julia B.
Solid lipid nanoparticles (SLNs) are a promising platform for sensing in vivo biomarkers due to their biocompatibility, stability, and their ability to carry a wide range of active ingredients. The skin is a prominent target organ for numerous inflammatory and stress-related biomarkers, making it an excellent site for early detection of physiological imbalance and application of sensory nanoparticles. Though smaller particle size has generally been correlated with increased penetration of skin models, there has been little attention paid to the significance of other nanoparticle synthesis parameters with respect to their physical properties. In this study, we demonstrate the synthesis of sub-10 nm SLNs by the phase inversion temperature (PIT) method. These particles were specifically designed for topical delivery of hydrogen peroxide-detecting chemiluminescent dyes. A systematic design of experiments approach was used to investigate the role of the processing variables on SLN form and properties. The processing variables were correlated with the SLN properties (e.g., dye solubility, phase inversion temperature, particle size, polydispersity, melting point, and latent heat of melting). Statistical analysis revealed that the PIT method, while allowing total control over the thermal properties, resulted in well-controlled synthesis of ultra-small particles, while allowing great flexibility in the processing conditions and incorporated compounds.
Cavaco, Marco C; Pereira, Carolina; Kreutzer, Bruna; Gouveia, Luis F; Silva-Lima, Beatriz; Brito, Alexandra M; Videira, Mafalda
Multidrug resistance (MDR), whereby cancer cells become resistant to the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents, is a major problem in the clinical treatment of cancer. P-glycoprotein (P-gp) is a transmembrane protein responsible for drug efflux, which decreases drug intracellular bioavailability, consequently decreasing their efficacy against cancer. Solid Lipid Nanoparticles (SLNs) have not only the ability to protect the entrapped drug against proteolytic degradation, but also allow a selective intracellular targeting. Hypothetically, the entrapped drug enter the target cells by different uptake mechanisms, "nanocitose", as compared to the free drug and may evade efflux-transporters, like P-gp. The functional role of P-gp in limiting the permeability of the anticancer drug paclitaxel (Ptx) was assessed in MDA-MB-436 cells. The observed increase in the pharmacologic efficacy of drug entrapped in SLN relatively to the free drug indicates that this system is shielding the drug. Therefore, "blinding" the nanoparticle from the efflux transporters. The effect was confirmed by the decrease expression of P-gp with loaded-SLNs and through the impact on cellular MDR1 expression. Besides the ability to prevent MDR events, functionalization of SLN with a specific antibody against membrane receptors (anti-CD44v6) improves the nanoparticle capability to target selectively malignant cells. This results allow to anticipate that poor clinical outcomes related to tumour P-gp overexpression might be overcome in a near future.
Nunes, Sara; Madureira, Ana Raquel; Campos, Débora; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Manuela; Reis, Flávio
Drug delivery systems, accompanied by nanoparticle technology, have recently emerged as prominent solutions to improve the pharmacokinetic properties, namely bioavailability, of therapeutic and nutraceutical agents. Solid lipid nanoparticles (SLNs) have received much attention from researchers due to their potential to protect or improve drug properties. SLNs have been reported to be an alternative system to traditional carriers, such as emulsions, liposomes, and polymeric nanoparticles. Phenolic compounds are widespread in plant-derived foodstuffs and therefore abundant in our diet. Over the last decades, phenolic compounds have received considerable attention due to several health promoting properties, mostly related to their antioxidant activity, which can have important implications for health. However, most of these compounds have been associated with poor bioavailability being poorly absorbed, rapidly metabolized and eliminated, which compromises its biological and pharmacological benefits. This paper provides a systematic review of the use of SLNs as oral delivery systems of phenolic compounds, in order to overcome pharmacokinetic limitations of these compounds and improved nutraceutical potential. In vitro studies, as well as works describing topical and oral treatments will be revisited and discussed. The classification, synthesis, and clinical application of these nanomaterials will be also considered in this review article.
Ghaffari, Solmaz; Varshosaz, Jaleh; Saadat, Afrooz; Atyabi, Fatemeh
Solid lipid nanoparticles (SLNs) of amikacin were designed in this study for pulmonary delivery to reduce the dose or its administration intervals leading to reduction of its toxicities especially in long term treatment. Nanoparticles of amikacin were prepared from cholesterol by solvent diffusion technique and homogenization. The size, zeta potential, loading efficiency, and release profile of the nanoparticles were studied. The conventional broth macrodilution tube method was used to determine the minimum inhibitory concentration (MIC) and minimum bacteriostatic concentration (MBC) of amikacin SLNs with respect to Pseudomonas aeruginosa in vitro. To guarantee the stability of desired SLNs, they were lyophilized using cryoprotectants. Results showed that considering the release profile of amikacin from the studied nanocarrier, MIC and MBC of amikacin could be about two times less in SLNs of amikacin compared to the free drug. Therefore, fewer doses of amikacin in SLNs can clear the infection with less adverse effects and more safety. Particle size enlargement after lyophilization of desired SLNs after two months storage was limited in comparison with non-lyophilized particles, 996 and 194 nm, respectively. Zeta potential of lyophilized particles was increased to +17 mV from +4 mV before lyophilization. Storage of particles in higher temperature caused accelerated drug release. PMID:21289980
Qi, Ce; Chen, Yan; Jing, Qing-Zhe; Wang, Xing-Guo
Catalase-loaded solid lipid nanoparticles (SLNs) were prepared by the double emulsion method (w/o/w) and solvent evaporation techniques, using acetone/methylene chloride (1:1) as an organic solvent, lecithin and triglyceride as oil phase and Poloxmer 188 as a surfactant. The optimized SLN was prepared by lecithin: triglyceride ratio (5%), 20-second + 30-second sonication, and 2% Poloxmer 188. The mean particle size of SLN was 296.0 ± 7.0 nm, polydispersity index range and zeta potential were 0.322–0.354 and −36.4 ± 0.6, respectively, and the encapsulation efficiency reached its maximum of 77.9 ± 1.56. Catalase distributed between the solid lipid and inner aqueous phase and gradually released from Poloxmer coated SLNs up to 20% within 20 h. Catalase-loaded SLN remained at 30% of H2O2-degrading activity after being incubated with Proteinase K for 24 h, while free catalase lost activity within 1 h. PMID:21845078
Yang, Junsi; Ciftci, Ozan Nazim
Fish oil was encapsulated in hollow solid lipid micro- and nanoparticles formed from fully hydrogenated soybean oil (FHSO) using a novel green method based on atomization of supercritical carbon dioxide (SC-CO2)-expanded lipid. The highest fish oil loading efficiency (97.5%, w/w) was achieved at 50%, w/w, initial fish oil concentration. All particles were spherical and in the dry free-flowing form; however, less smooth surface with wrinkles was observed when the initial fish oil concentration was increased up to 50%. With increasing initial fish oil concentration, melting point of the fish oil-loaded particles shifted to lower onset melting temperatures, and major polymorphic form transformed from α to β and/or β'. Oxidative stability of the loaded fish oil was significantly increased compared to the free fish oil (p<0.05). This innovative method forms free-flowing powder products that are easy-to-use solid fish oil formulation, which makes the handling and storage feasible and convenient. Copyright © 2017 Elsevier Ltd. All rights reserved.
Shi, Feng; Zhao, Ji-Hui; Liu, Ying; Wang, Zhi; Zhang, Yong-Tai; Feng, Nian-Ping
The aim of the present study was to prepare solid lipid nanoparticles (SLNs) for the oral delivery of frankincense and myrrh essential oils (FMO). Aqueous dispersions of SLNs were successfully prepared by a high-pressure homogenization method using Compritol 888 ATO as the solid lipid and soybean lecithin and Tween 80 as the surfactants. The properties of the SLNs such as particle size, zeta potential (ZP), and drug encapsulation efficiency (EE) were investigated. The morphology of SLNs was observed by transmission electron microscopy (TEM). The crystallinity of the formulation was analyzed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In addition, drug evaporation release and antitumor activity were also studied. Round SLNs with a mean size of 113.3 ± 3.6 nm, a ZP of -16.8 ± 0.4 mV, and an EE of 80.60% ± 1.11% were obtained. DSC and XRD measurements revealed that less ordered structures were formed in the inner cores of the SLN particles. Evaporation loss of the active components in FMO could be reduced in the SLNs. Furthermore, the SLN formulation increased the antitumor efficacy of FMO in H22-bearing Kunming mice. Hence, the presented SLNs can be used as drug carriers for hydrophobic oil drugs extracted from traditional Chinese medicines.
Shi, Feng; Zhao, Ji-Hui; Liu, Ying; Wang, Zhi; Zhang, Yong-Tai; Feng, Nian-Ping
The aim of the present study was to prepare solid lipid nanoparticles (SLNs) for the oral delivery of frankincense and myrrh essential oils (FMO). Aqueous dispersions of SLNs were successfully prepared by a high-pressure homogenization method using Compritol 888 ATO as the solid lipid and soybean lecithin and Tween 80 as the surfactants. The properties of the SLNs such as particle size, zeta potential (ZP), and drug encapsulation efficiency (EE) were investigated. The morphology of SLNs was observed by transmission electron microscopy (TEM). The crystallinity of the formulation was analyzed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In addition, drug evaporation release and antitumor activity were also studied. Round SLNs with a mean size of 113.3 ± 3.6 nm, a ZP of −16.8 ± 0.4 mV, and an EE of 80.60% ± 1.11% were obtained. DSC and XRD measurements revealed that less ordered structures were formed in the inner cores of the SLN particles. Evaporation loss of the active components in FMO could be reduced in the SLNs. Furthermore, the SLN formulation increased the antitumor efficacy of FMO in H22-bearing Kunming mice. Hence, the presented SLNs can be used as drug carriers for hydrophobic oil drugs extracted from traditional Chinese medicines. PMID:22619540
Khurana, S; Bedi, P M S; Jain, N K
The aim of the current investigation was to prepare and investigate the potential of solid lipid nanoparticles based gel (SLN-gel) for the dermal delivery of meloxicam (MLX). The meloxicam loaded SLN (MLX-SLN) gel was developed and characterized by means of photon correlation spectroscopy, rheometry, and differential scanning calorimetry to determine the physicochemical properties. The behavior of SLN gel on rat skin was evaluated in vitro using Franz diffusion cells to determine the skin permeation and penetration characteristics, in vivo on mice to determine the skin tolerance by histopathological examinations. The anti-inflammatory potential of SLN gel was assessed by carrageenan induced rat paw edema test. Biophysical studies including differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were undertaken to study the interaction between the SLN gel and skin. MLX-SLN gel with nanometric particle size exhibited the controlled release abilities and simultaneously the potential to transport the drug to various skin layers. SLN gel displayed viscoelastic properties with predominantly elastic behavior and exhibited plastic flow. Biophysical studies elucidated the interaction between the SLN gel and stratum corneum (SC) lipids, and proposed the lipid bilayer fluidization as the possible mechanism for the increased penetration of meloxicam into skin. The nano-gel system showed marked anti-inflammatory activity and excellent skin tolerability. It can be concluded that SLN gel may be a promising delivery system for MLX in the treatment of inflammatory disorders.
Silva, A C; Kumar, A; Wild, W; Ferreira, D; Santos, D; Forbes, B
A solid lipid nanoparticles (SLN) formulation to improve the oral delivery of risperidone (RISP), a poorly water-soluble drug, was designed and tested. Initially, lipid-RISP solubility was screened to select the best lipid for SLN preparation. Compritol(®)-based formulations were chosen and their long-term stability was assessed over two years of storage (at 25 °C and 4 °C) by means of particle size, polydispersity index (PI), zeta potential (ZP) and encapsulation efficiency (EE) measurements. SLN shape was observed by transmission electron microscopy (TEM) at the beginning and end of the study. The oxidative potential (OP) of the SLN was measured and their biocompatibility with Caco-2 cells was evaluated using the (4,5-dimethylthiazol-2-yl)2,5-dyphenyl-tetrazolium bromide (MTT) assay. In vitro drug release and transport studies were performed to predict the in vivo release profile and to evaluate the drug delivery potential of the SLN formulations, respectively. The RISP-loaded SLN systems were stable and had high EE and similar shape to the placebo formulations before and after storage. Classical Fickian diffusion was identified as the release mechanism for RISP from the SLN formulation. Biocompatibility and dose-dependent RISP transport across Caco-2 cells were observed for the prepared SLN formulations. The viability of SLN as formulations for oral delivery of poorly water-soluble drugs such as RISP was illustrated.
Tupal, Ailar; Sabzichi, Mehdi; Ramezani, Fatemeh; Kouhsoltani, Maryam; Hamishehkar, Hamed
Dermal delivery of Doxorubicin (Dox) would be an ideal way in maximising drug efficiency against skin cancer accompanying with minimising side effects. We investigated the potential of Dox-loaded Solid lipid nanoparticles (SLNs) for topical delivery against skin cancer. In vitro and in vivo cytotoxicity of optimised formulation were evaluated on murine melanoma (B16F10) cells by MTT assay and melanoma induced Balb/C mice, respectively. Animal study followed by histological analysis. Optimised formulation showed mean particle size and encapsulation efficiency (EE) of 92 nm and 86% w/w (0.86% w/w value of encapsulated Dox in the lipid matrix), respectively. FTIR experiment confirmed drug-lipid interaction interpreting the observed high EE value for Dox. In vitro and in vivo results indicated the superiority of cytotoxic performance of Dox-loaded SLN compared to Dox solution. Our findings may open the possibilities for the topical delivery of Dox to the skin cancerous tissues.
Wang, Yanzhi; Deng, Yihui; Mao, Shirui; Jin, Shengxuan; Wang, Jian; Bi, Dianzhou
Solid lipid nanoparticles (SLN) containing beta-elemene, a volatile oil used for the treatment of cancer, were prepared by the method combining probe sonication and membrane extrusion. Effects of the formulations and procedures on the characteristics of SLN were investigated. Body distribution of beta-elemene SLN in rats after intravenous administration was compared with that of the commercial emulsion. The results showed that dispersing the surfactant in the melted lipid matrix could obtain smaller particles than that dispersing in the water phase. Increasing the ratio of monostearin in the lipid matrix or the concentration of surfactant reduced the mean volume size of the SLN. Optimized formulation was composed of monostearin and precirol ATO 5 at a mass ratio of 3:7, which was quite stable for 8 months at room temperature. In vitro release of beta-elemene from the SLN was slow and stable without obvious burst release and was found to follow the Higuich equation. After intravenous administration, the beta-elemene levels after 5 min injection of SLN formulation were 1.5, 2.9, and 1.4 times higher than those of beta-elemene emulsion in liver, spleen, and kidney, respectively, while the concentrations of beta-elemene were decreased 30% in heart and lung. Therefore, the SLN containing beta-elemene might be an attractive candidate for the treatment of liver cancer.
Hippalgaonkar, Ketan; Adelli, Goutham R.; Hippalgaonkar, Kanchan; Repka, Michael A.
Abstract Purpose The goal of this study was to develop and characterize indomethacin-loaded solid lipid nanoparticles (IN-SLNs; 0.1% w/v) for ocular delivery. Methods Various lipids, homogenization pressures/cycles, Tween 80 fraction in the mixture of surfactants (Poloxamer 188 and Tween 80; total surfactant concentration at 1% w/v), and pH were investigated in the preparation of the IN-SLNs. Compritol® 888 ATO was selected as the lipid phase for the IN-SLNs, as indomethacin exhibited a highest distribution coefficient and solubility in this phase. Results Homogenization at 15,000 psi for 6 cycles resulted in the smallest particle size. Increase in the Poloxamer 188 fraction resulted in decrease in the entrapment efficiency (EE). The mean particle size, polydispersity index, zeta-potential, and EE of the optimized formulation were 140 nm, 0.16, −21 mV, and 72.0%, respectively. IN-SLNs were physically stable post-sterilization and on storage for a period of 1 month (last timepoint tested). A dramatic increase in the chemical stability and in vitro corneal permeability of indomethacin was observed with the IN-SLN formulation in comparison to the indomethacin solution- (0.1% w/v) and indomethacin hydroxypropyl-beta-cyclodextrin-based formulations (0.1% w/v). Conclusion Results from this study suggest that topical IN-SLNs could significantly improve ocular bioavailability of indomethacin. PMID:23421502
Zhu, Liu; Luo, Cheng-Feng; Yuan, Mu; Chen, Min-Sheng; Ji, Hong
To investigate the effects of puerarin solid lipid nanoparticle on fore brain ischemic-reperfusion injury in gerbils and it's mechanisms. Gerbils were randomly divided into 4 groups: sham group, cerebral ischemia-reperfusion injury group, puerarin solid lipid nanoparticle group and puerarin injection control group. The gerbils' cerebral ischemia-reperfusion injury model was constructed with ligating bilater carotids method. The histomorphology and Bcl-2, Caspase-3 and HSP70 expressions were detected by HE dyeing and immunohistochemical method. After 24 h ischemia and reperfusion in gerbils, the level of Bcl-2 and HSP70 expressions in puerarin solid lipid nanoparticle group increased (P < 0.01) compared with the ischemic-reperfusion model group, and the level of Caspase-3 expression decreased (P < 0.01). The same results was consistent in puerarin injection control group. Puerarin solid lipid nanoparticle group can protect the cerebral ischemia-reperfusion injury in gerbils, which may be related to the upregulation of Bcl-2 and HSP70 expression and downregulation of Caspase-3 expression.
Fontana, Giacomo; Maniscalco, Laura; Schillaci, Domenico; Cavallaro, Gennara; Giammona, Gaetano
Solid lipid nanoparticles (SLNs) containing tamoxifen, a nonsteroidal antiestrogen used in breast cancer therapy, were prepared by microemulsion and precipitation techniques. Tamoxifen loaded SLNs seem to have dimensional properties useful for parenteral administration, and in vitro plasmatic drug release studies demonstrated that these systems are able to give a prolonged release of the drug in the intact form. Preliminary study of antiproliferative activity in vitro, carried out on MCF-7 cell line (human breast cancer cells), demonstrated that SLNs, containing tamoxifen showed an antitumoral activity comparable to free drug. The results of characterization studies and of in vitro antiproliferative activity strongly support the potential application of tamoxifen-loaded SLNs as a carrier system at prolonged release useful for intravenous administration in breast cancer therapy.
Tran, Tuan Hiep; Ramasamy, Thiruganesh; Cho, Hyuk Jun; Kim, Yong Il; Poudel, Bijay Kumar; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh
The main aim of this study was to improve the oral bioavailability of raloxifene (RXF), a selective estrogen receptor modulator, by incorporation into solid lipid nanoparticles (SLN). RXF-loaded SLN was prepared by homogenization-sonication technique and characterized through physicochemical, pharmacokinetic, and cytotoxicity studies. The optimized SLN formulation exhibited a spherical shape with average size around 140 nm, easing its transport across the lymphatic system. Augmentation in the profiles of C(max) (308%) and AUC (270%) indicated a significant enhancement in the rate and extent of bioavailability by SLN formulations compared to free drug. In vitro cytotoxicity study performed in NIH-3T3 cells revealed that RXF-SLN was cytocompatible, and SLN remained unchanged during the freeze-drying process. Furthermore, the optimized formulation was quite stable at room temperature for more than two months, exemplifying its superior performance. In conclusion, SLN provides a promising platform for the pronounced enhancement of RXF bioavailability.
Uner, Melike; Yener, Gülgün
Solid lipid nanoparticles (SLN) have been reported to be an alternative system to emulsions, liposomes, microparticles and their polymeric counterparts for various application routes since the early 1990s due to their advantages. Various research groups have also increasingly focused on improving their stability in body fluids after administration by coating of particles with hydrophilic molecules such as poly(ethylene)glycol (PEG) derivatives. Altering surface characteristics by coating SLN with hydrophilic molecules improves plasma stability and biodistribution, and subsequent bioavailability of drugs entrapped. Their storage stability is also increased. This paper basicly reviews types of SLN, principles of drug loading and models of drug incorporation. The influence of PEG coating on particle size and surface characteristics is discussed followed by alteration in pharmacokinetics and bioavailability of drugs in order to target the site of action via SLN. The future direction of research and clinical implications of SLN is also considered.
Chen, Zhao-Jie; Zhang, Zhen; Xie, Bei-Bei; Zhang, Hai-Yan
The study aims at statistical development of solid lipid nanoparticles (SLNs) loaded with topotecan hydrochloride for avoiding the drawbacks of conventional drug therapies used in cervical cancer. Twenty SLN batches were prepared using organic solvent evaporation method to provide response surface curves. Thereafter, optimized SLNs were obtained using numeric method based on desirability functions providing maximum drug loading and appropriate particle size. Physical characterization of optimized TPH loaded SLNs was performed in terms of particle size, zeta potential, transmission and scanning electron microscopic evaluation. Cytotoxicity studies were performed against cervical cancer cell lines, including cervical squamous cell carcinoma cell line (HeLa) and human squamous cell carcinoma cell line (SiHa). Also, Swiss mouse embryo fibroblast cells (3T3-L1) and African green monkey kidney epithelial (Vero) cells were used to evaluate biocompatibility in normal cells. As pronounced from the results, optimized SLNs may provide an attractive alternative to conventional cervical cancer drug products.
Geszke-Moritz, Małgorzata; Moritz, Michał
This work briefly reviews up-to-date developments in solid lipid nanoparticles (SLNs) as effective nanocolloidal system for drug delivery. It summarizes SLNs in terms of their preparation, surface modification and properties. The application of SLNs as a carrier system enables to improve the therapeutic efficacy of drugs from various therapeutic groups. Present uses of SLNs include cancer therapy, dermatology, bacterial infections, brain targeting and eye disorders among others. The usage of SLNs provides enhanced pharmacokinetic properties and modulated release of drugs. SLN ubiquitous application results from their specific features such as possibility of surface modification, increased permeation through biological barriers, resistance to chemical degradation, possibility of co-delivery of various therapeutic agents or stimuli-responsiveness. This paper will be useful to the scientists working in the domain of SLN-based drug delivery systems. Copyright © 2016 Elsevier B.V. All rights reserved.
Fàbregas, Anna; Prieto-Sánchez, Silvia; Suñé-Pou, Marc; Boyero-Corral, Sofía; Ticó, Josep Ramón; García-Montoya, Encarna; Pérez-Lozano, Pilar; Miñarro, Montserrat; Suñé-Negre, Josep Mª; Hernández-Munain, Cristina; Suñé, Carlos
Non-viral delivery using cationic solid lipid nanoparticles (SLNs) represents a useful strategy to introduce large DNA and RNA molecules to target cells. A careful selection of components and their amounts is critical to improve transfection efficiency. In this work, a selected and optimized formulation of SLNs was used to efficiently transfect circular DNA and linear RNA molecules into cells. We characterized the main physicochemical characteristics and binding capabilities of these SLNs and show that they deliver DNA and RNA molecules into cells where they display full bioactivity at nontoxic concentrations using fluorescence- and luminescence-based methodologies. Hence, we established a novel and simple SLN formulation as a powerful tool for future therapeutic use. Copyright © 2016 Elsevier B.V. All rights reserved.
Üner, Melike; Yener, Gülgün
Solid lipid nanoparticles (SLN) have been reported to be an alternative system to emulsions, liposomes, microparticles and their polymeric counterparts for various application routes since the early 1990s due to their advantages. Various research groups have also increasingly focused on improving their stability in body fluids after administration by coating of particles with hydrophilic molecules such as poly(ethylene)glycol (PEG) derivatives. Altering surface characteristics by coating SLN with hydrophilic molecules improves plasma stability and biodistribution, and subsequent bioavailability of drugs entrapped. Their storage stability is also increased. This paper basicly reviews types of SLN, principles of drug loading and models of drug incorporation. The influence of PEG coating on particle size and surface characteristics is discussed followed by alteration in pharmacokinetics and bioavailability of drugs in order to target the site of action via SLN. The future direction of research and clinical implications of SLN is also considered. PMID:18019829
Wang, Taoran; Hu, Qiaobin; Zhou, Mingyong; Xue, Jingyi; Luo, Yangchao
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.
Chai, Gui-Hong; Xu, Yingke; Chen, Shao-Qing; Cheng, Bolin; Hu, Fu-Qiang; You, Jian; Du, Yong-Zhong; Yuan, Hong
Solid lipid nanoparticles (SLNs) have been extensively investigated and demonstrated to be a potential nanocarriers for improving oral bioavailability of many drugs. However, the molecular mechanisms related to this discovery are not yet understood. Here, the molecular transport mechanisms of the SLNs crossing simulative intestinal epithelial cell monolayers (Caco-2 cell monolayers) were studied. The cytotoxicology results of the SLNs in Caco-2 cells demonstrated that the nanoparticles had low cytotoxicity, had no effect on the integrity of the cell membrane, did not induce oxidative stress, and could significantly reduce cell membrane fluidity. The endocytosis of the SLNs was time-dependent, and their delivery was energy-dependent. For the first time, the transport of the SLNs was directly verified to be a vesicle-mediated process. The internalization of the SLNs was mediated by macropinocytosis pathway and clathrin- and caveolae (or lipid raft)-related routes. Transferrin-related endosomes, lysosomes, endoplasmic reticulum (ER), and Golgi apparatus were confirmed to be the main destinations of the SLNs in Caco-2 cells. As for the transport of the SLNs in Caco-2 cell monolayers, the results demonstrated that the SLNs transported to the basolateral side were intact, and the transport of the nanoparticles did not destroy the structure of tight junctions. The transcytosis of the SLNs across the Caco-2 cell monolayer was demonstrated to be mediated by the same routes as that in the endocytosis study. The ER, Golgi apparatus, and microtubules were confirmed to be important for the transport of the SLNs to both the basolateral and apical membrane sides. This study provides a more thoroughly understand of SLNs transportation crossing intestinal epithelial cell monolayers and could be beneficial for the fabrication of SLNs.
Jahanfar, Farhad; Hasani, Akbar; Shanebandi, Dariush; Rahmati, Mohammad; Hamishehkar, Hamed
Purpose: In this study the effectiveness of encapsulating of 5-azacytidine into the lipid nanoparticles was investigated and in vitro effect of encapsulated 5-azacytidine studied on MCF-7 cell lines Methods: 5-azacytidine -loaded solid lipid nanoparticles were produced by double emulsification (w/o/w) method by using stearic acid as lipid matrix, soy lecithin and poloxamer 407 as surfactant and co-surfactant respectively. Particle size, zeta potential, surface morphology, entrapment efficiency and kinetic of drug release were studied. In vitro effect of 5-azacytidine on MCF-7 cell line studied by MTT assay, DAPI staining, Rhodamine B relative uptake, and also Real time RT-PCR was performed for studying difference effect of free and encapsulated drug on expression of RARß2 gene. Results: The formulation F5 with 55.84±0.46 % of entrapment efficiency shows zero order kinetic of drug release and selected for in vitro studies; the cytotoxicity of free drug and encapsulated drug in 48 h of incubation have significant difference. DAPI staining shows morphology of apoptotic nucleus in both free and encapsulated drug, Rhodamine B labeled SLNs show time dependency and accumulation of SLNs in cytoplasm. Real time qRT-PCR doesn’t show any significant difference (p>0.05) in expression of RARß2 gene in both cells treated with free or encapsulated drug. Conclusion: The results of the present study indicated that the entrapment of 5-azacytidine into SLNs enhanced its cytotoxicity performance and may pave a way for the future design of a desired dosage form for 5-azacytidine. PMID:27766220
Wang, Shengpeng; Chen, Tongkai; Chen, Ruie; Hu, Yangyang; Chen, Meiwan; Wang, Yitao
The objective of the present study was to prepare and characterize emodin (EMO)-loaded solid lipid nanoparticles (E-SLNs) and evaluate their antitumor activity in vitro. EMO and pharmaceutical lipid material were used to prepare E-SLNs by high pressure homogenization (HPH). Poloxamer 188 and Tween 80 were used as surfactants. The physicochemical properties of the E-SLNs were investigated by particle size analysis, zeta potential measurement, drug entrapment efficiency (EE), stability and in vitro drug release behavior. The E-SLNs showed stable particle size at 28.6 ± 3.1 nm, ideal drug EE and relative long-term physical stability after being stored for 4 months. The drug release of E-SLNs could last 72 h and exhibited a sustained profile, which made it a promising vehicle for oral drug delivery. MTT assay showed that E-SLNs could significantly enhance the in vitro cytotoxicity against human breast cancer cell line MCF-7 and MDA-MB-231 cells compared to the EMO solution, while free EMO, blank SLNs (B-SLNs) and E-SLNs all showed no significant toxicity to human mammary epithelial line MCF-10A cells. Flow cytometric analysis demonstrated that E-SLNs also showed more significant cell cycle arrest effect in MCF-7 cells compared to bulk EMO solution. Hoechst 33342 staining and Annexin V-FITC/PI double staining further confirmed that E-SLNs induced higher apoptotic rates in MCF-7 cells, indicating that cell cycle arrest and apoptosis maybe the underlying mechanism of the enhanced cytotoxicity. Taken together, it seems that HPH was a simple, available and effective method for preparing high quality E-SLNs to enhance its aqueous solubility. Moreover, these results suggest that the delivery of EMO as lipid nanoparticles maybe a promising approach for cancer therapy. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.
K S, Joshy; Sharma, Chandra P; Kalarikkal, Nandakumar; Sandeep, K; Thomas, Sabu; Pothen, Laly A
Zidovudine loaded solid lipid nanoparticles of stearic acid modified with Aloe Vera (AV) have been prepared via simple emulsion solvent evaporation method which showed excellent stability at room temperature and refrigerated condition. The nanoparticles were examined by Fourier transform infrared spectroscopy (FT-IR), which revealed the overlap of the AV absorption peak with the absorption peak of modified stearic acid nanoparticles. The inclusion of AV to stearic acid decreased the crystallinity and improved the hydrophilicity of lipid nanoparticles and thereby improved the drug loading efficacy of lipid nanoparticles. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) imaging revealed that, the average particle size of unmodified (bare) nanoparticles was 45.66±12.22nm and modified solid lipid nanoparticles showed an average size of 265.61±80.44nm. Solid lipid nanoparticles with well-defined morphology were tested in vitro for their possible application in drug delivery. Cell culture studies using C6 glioma cells on the nanoparticles showed enhanced growth and proliferation of cells without exhibiting any toxicity. In addition, normal cell morphology and improved uptake were observed by fluorescence microscopy images of rhodamine labeled modified solid lipid nanoparticles compared with unmodified nanoparticles. The cellular uptake study suggested that these nanoparticles could be a promising drug delivery system to enhance the uptake of antiviral drug by brain cells and it could be a suitable drug carrier system for the treatment of HIV.
Hu, Xiongwei; Fan, Wufa; Yu, Zhou; Lu, Yi; Qi, Jianping; Zhang, Jian; Dong, Xiaochun; Zhao, Weili; Wu, Wei
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
Doktorovová, Slavomira; Kovačević, Andjelka B; Garcia, Maria L; Souto, Eliana B
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were designed as exceptionally safe colloidal carriers for the delivery of poorly soluble drugs. SLN/NLC have the particularity of being composed of excipientsalready approved for use in medicines for human use, which offers a great advantage over any other nanoparticulate system developed from novel materials. Despite this fact, any use of excipients in new route of administration or in new dosage form requires evidence of safety. After 25 years of research on SLN and NLC, enough evidence on their preclinical safety has been published. In the present work, published data on in vitro and in vivo compatibility of SLN/NLC have been surveyed, in order to provide evidence of high biocompatibility distinguished by intended administration route. We also identified critical factors and possible weak points in SLN/NLC formulations, such as the effect of surfactants on the cell viability in vitro, which should be considered for further development. Copyright © 2016 Elsevier B.V. All rights reserved.
Berkman, M S; Yazan, Y
An efficient sunscreen formulation shows good absorption in the relevant UV range. Efficacy also means that the UV absorber must be easily incorporated in any kind of formulation. In this study, a chemical absorber, octocrylene, and one of the most important physical blockers, zinc oxide, could be successfully incorporated into Solid Lipid Nanoparticle (SLN) systems which themselves have UV blocking potential similar to physical sunscreens, and remained stable for a period of 360 days while providing UVA and UVB protection. Crystalline structure related to the chemical nature of the solid lipid is a key factor to decide whether a sunscreening agent will be expelled or incorporated in the long-term and for a controlled optimization of active ingredient incorporation and loading, intensive characterization of the physical state of the lipid particles was highly essential. Thus, FT-IR, NMR, XRD and DSC analyses were performed and the results did not indicate stability problems. pH values of the SLN systems were found to be between 5.4-5.9 in all formulations which may be buffered by the skin. Transpore test results proved the UV blocking potential of the SLNs with not any active ingredient and the synergistic effects by the incorporation of molecular sunscreens. Therefore, concentration of molecular sunscreens in the formulations was decreased to 0.6%. UVA and UVB screening potentials of octocrylene and zinc oxide formulations were compared in the 290-400 nm wavelength region. Zinc oxide loaded SLN suspensions were found to be more effective in the UVA region while octocrylene loaded ones performed better in the UVB region.
Chen, Ying-Chen; Liu, Der-Zen; Liu, Jun-Jen; Chang, Tsung-Wei; Ho, Hsiu-O; Sheu, Ming-Thau
To resolve problems of long treatment durations and frequent administration of the antifungal agent terbinafine (TB), solid lipid nanoparticles (SLNs) with the ability to load lipophilic drugs and nanosize were developed. The SLNs were manufactured by a microemulsion technique in which glyceryl monostearate (GMS), glyceryl behenate (Compritol® 888; Gattefossé), and glyceryl palmitostearate (Precirol® ATO 5; Gattefossé) were used as the solid lipid phases, Tween® and Cremophor® series as the surfactants, and propylene glycol as the cosurfactant to construct ternary phase diagrams. The skin of nude mice was used as a barrier membrane, and penetration levels of TB of the designed formulations and a commercial product, Lamisil® Once™ (Novartis Pharmaceuticals), in the stratum corneum (SC), viable epidermis, and dermis were measured; particle sizes were determined as an indicator of stability. The optimal SLN system contained a <5% lipid phase and >50% water phase. The addition of ethanol or etchants had no significant effect on enhancing the amount of TB that penetrated the skin layers, but it was enhanced by increasing the percentage of the lipid phase. Furthermore, the combination of GMS and Compritol® 888 was able to increase the stable amount of TB that penetrated all skin layers. For the ACP1-GM1 (4% lipid phase; Compritol® 888: GMS of 1:1) formulation, the amount of TB that penetrated the SC was similar to that of Lamisil® Once™, whereas the amount of TB of the dermis was higher than that of Lamisil® Once™ at 12 hours, and it was almost the same as that of Lamisil® Once™ at 24 hours. It was concluded that the application of ACP1-GM1 for 12 hours might have an efficacy comparable to that of Lamisil® Once™ for 24 hours, which would resolve the practical problem of the longer administration period that is necessary for Lamisil® Once™. PMID:22923986
Abrishami, Majid; Vakili Ahrari Roodi, Mohammad
Purpose. In order to improve the drug availability after intravitreal administration, solid lipid nanoparticles (SLNs) containing diclofenac were prepared. Methods. In this experimental study, 18 albino rabbits were included. In right and left eyes of all rabbits, SLNs containing diclofenac and commercial form of diclofenac (0.3 mg drug) were intravitreally injected, respectively. One, four, twelve, twenty-four, and forty-eight hours after injection, vitreous and aqueous humor samples were obtained in all cases. Then, the concentration of diclofenac sodium was evaluated in all samples. Results. Size of nanoparticles was around 170 nm after preparation. Drug concentration in eyes injected with SLNs was significantly higher than left eyes injected with commercial formulation up to 4 hours after intravitreal injection (p < 0.05). Diclofenac was quantified in samples up to 48 hours after intraocular injection. Four hours after intravitreal injection, the concentration of diclofenac in vitreous and aqueous humor of eyes receiving SLNs was, respectively, 2.5 and 6.5 times higher than eyes injected with commercial form of drug. Conclusions. Here, we demonstrate the potential of SLNs as a carrier of diclofenac for intraocular injection in order to prevent the systemic effects of the drug, increase the injection intervals, and improve the patient compliance. PMID:27803815
Patel, Sonal; Chavhan, Sandip; Soni, Heena; Babbar, A K; Mathur, Rashi; Mishra, A K; Sawant, Krutika
Intranasal drug delivery is known to overcome the blood-brain barrier (BBB) for delivery of drugs to brain. The objective of this study was to prepare risperidone (RSP)-loaded solid lipid nanoparticles (RSLNs) and explore the possibility of brain targeting by nose-to-brain delivery. RSLNs were prepared by solvent emulsification-solvent evaporation method and characterized for drug content, particle size and size distribution, zeta potential, and in vitro drug-release study. The pharmacodynamic study of RSLNs, which was performed by paw test using Perspex platform, showed higher hindlimb retraction time (HRT) values as compared with RSP solution (RS) indicating the superiority of RSLNs over the RS for brain targeting. The pharmacokinetics and biodistribution studies in mice showed that brain/blood ratio 1 h post-administration of RSLNs (i.n.) was found to be 1.36 ± 0.06 (nearly 10- and 5-fold higher) as compared with 0.17 ± 0.05 for RS (i.v.) and 0.78 ± 0.07 for RSLNs (i.v.), respectively. Gamma scintigraphy imaging of mice brain following intravenous and intranasal administration confirmed the localization of drug in brain. This finding substantiates the existence of direct nose-to-brain delivery route for nanoparticles administered to the nasal cavity.
Kim, Jin-Ho; Kim, Youngwook; Bae, Ki Hyun; Park, Tae Gwan; Lee, Jung Hee; Park, Keunchil
Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous administration, we developed biocompatible anticancer therapeutic solid lipid nanoparticles (SLNs), mimicking the structure and composition of natural particles, low-density lipoproteins (LDLs), for tumor-targeted delivery of paclitaxel. These therapeutic nanoparticles contained water-insoluble paclitaxel in the core with tumor-targeting ligand covalently conjugated on the polyethylene glycol (PEG)-modified surface (targeted PtSLNs). In preclinical human cancer xenograft mouse model studies, the paclitaxel-containing tumor-targeting SLNs exhibited pronounced in vivo stability and enhanced biocompatibility. Furthermore, these SLNs had superior antitumor activity to in-class nanoparticular therapeutics in clinical use (Taxol and Genexol-PM) and yielded long-term complete responses. The in vivo targeted antitumor activities of the SLN formulations in a mouse tumor model suggest that LDL-mimetic SLN formulations can be utilized as a biocompatible, tumor-targeting platform for the delivery of various anticancer therapeutics.
Albuquerque, João; Moura, Catarina Costa; Sarmento, Bruno; Reis, Salette
Rheumatoid arthritis (RA) is the most common joint-related autoimmune disease and one of the most severe. Despite intensive investigation, the RA inflammatory process remains largely unknown and finding effective and long lasting therapies that specifically target RA is a challenging task. This study proposes a different approach for RA therapy, taking advantage of the new emerging field of nanomedicine to develop a targeted theranostic system for intravenous administration, using solid lipid nanoparticles (SLN), a biocompatible and biodegradable colloidal delivery system, surface-functionalized with an anti-CD64 antibody that specifically targets macrophages in RA. Methotrexate (MTX) and superparamagnetic iron oxide nanoparticles (SPIONs) were co-encapsulated inside the SLNs to be used as therapeutic and imaging agents, respectively. All the formulations presented sizes under 250 nm and zeta potential values lower than -16 mV, suitable characteristics for intravenous administration. Transmission electron microscopy (TEM) photographs indicated that the SPIONs were encapsulated inside the SLN matrix and MTX association efficiency values were higher than 98%. In vitro studies, using THP-1 cells, demonstrated that all formulations presented low cytotoxicity at concentrations lower than 500 μg/mL. It was proven that the proposed NPs were not cytotoxic, that both a therapeutic and imaging agent could be co-encapsulated and that the SLN could be functionalized for a potential future application such as anti-body specific targeting. The proposed formulations are, therefore, promising candidates for future theranostic applications.
Hansraj, Girotra Priti; Singh, Shailendra Kumar; Kumar, Pawan
The objective of the present investigation was to prepare chitosan solid lipid nanoparticles (SLN), containing sumatriptan succinate using solvent injection method and to optimize the formulations for brain targeting potential. The formulation optimization was performed using three factor two level full factorial design so as to minimize the particle size and zeta potential, maximize the entrapment efficiency as well as maximize the concentration of drug in brain with maximized brain/plasma ratio of the drug. The particle size, zeta potential and entrapment efficiency for all the batches were in the range of 192-301.4nm, 30.2-51.4mV and 76.3-91.1% respectively. The optimized formulation showed a 4.54-fold increase in brain/blood ratio of drug after 2h of drug administration in male Wistar rats. The optimized nanoparticles were characterized by FT-IR spectroscopy, DSC, TGA, powder X-ray diffraction study and TEM analysis. It could be elucidated from the experimental in vivo and behavioral studies that the formulations successfully crossed the blood brain barrier and significantly exhibited its anti-migraine activity. Present investigation indicated that the hydrophilic drug sumatriptan succinate, loaded in chitosan SLN, can be successfully targeted to brain via oral delivery and thus present an effective approach for the therapeutic management of migraine.
Paranjpe, M; Finke, J H; Richter, C; Gothsch, T; Kwade, A; Büttgenbach, S; Müller-Goymann, C C
For the development of any colloidal system, thorough characterization is extremely essential. This article discusses the physicochemical characterization of sildenafil-loaded solid lipid nanoparticle dispersions (SLN) including stability analysis over 6 months time period for possible pulmonary administration for the treatment of pulmonary arterial hypertension (PAH). SLN consisting of phospholipid and triglycerides were manufactured using a novel microchannel homogenization method. These sildenafil-loaded SLN were then subjected to physicochemical characterization namely, particle size and distribution over shelf life, differential scanning calorimetry (DSC), wide angle X-ray diffraction (WAXD) and analysis of nebulization performance of these SLN by the means of next generation impactor (NGI). Additionally, the morphology of nebulized particles was assessed by transmission electron microscopy using negative staining technique. The solubility of sildenafil citrate and base in the lipid matrix was determined and was 0.1% w/w and 1% w/w, respectively. From the particle size measurements, it was observed that SLN without sildenafil demonstrated consistent particle sizes over 6 months. For the sildenafil-loaded SLN, increased particle sizes were found after manufacturing and further increased within weeks. From WAXD studies, after 6 months high intensity reflections corresponding to the stable β modification were observed. From DSC results, the peak minimum temperatures increased upon storage, hinting at a transformation to the stable β modification of triglycerides in the case of sildenafil-loaded SLN. Hence, it can be concluded that even small drug concentration influences particle size and stability.
Hashem, Fahima M; Nasr, Mohamed; Khairy, Ahmed
The objective of this study was to evaluate the influence of solid lipid nanoparticles (SLN) loaded with the poorly water-soluble drug tamoxifen citrate (TC) on the in vitro antitumor activity and bioavailability of the drug. TC-loaded SLN were prepared by solvent injection method using glycerol monostearate (GMS) or stearic acid (SA) as lipid matrix. Poloxamer 188 or tween 80 were used as stabilizers. TC-loaded SLN (F3 and F4) prepared using GMS and stabilized by poloxamer 188 showed highest entrapment efficiency % (86.07 ± 1.74 and 90.40 ± 1.22%) and reasonable mean particle sizes (130.40 ± 9.45 and 243.80 ± 12.33 nm), respectively. The in vitro release of TC from F3 and F4 exhibited an initial burst effect followed by a sustained drug release. In vitro cytotoxicity of F3 against human breast cancer cell line MCF-7 showed comparable antitumor activity to free drug. Moreover, the results of bioavailability evaluation of TC-loaded SLN in rats compared to free TC indicated that 160.61% increase in the oral bioavailability of TC. The obtained results suggest that incorporation of the poorly water-soluble drug TC in SLN preserves the in vitro antitumor activity and significantly enhance oral bioavailability of TC in rats.
Geetha, T; Kapila, Meenakshi; Prakash, Om; Deol, Parneet Kaur; Kakkar, Vandita; Kaur, Indu Pal
Abstract Role of reactive oxygen species (ROS) in skin carcinogenesis is well documented. Natural molecules, like sesamol, with marked antioxidant potential can be useful in combating skin cancers. In vitro antiproliferative (using MTT assay) and DNA fragmentation studies in HL 60 cell lines, confirmed the apoptotic nature of sesamol. However, it showed a significant flux across the mice skin upon topical application, such that its local availability in skin is limited. Former is attributed mainly to its properties like small size, low molecular weight (138.28), and a sufficient lipid and water solubility (log P 1.29; solubility 38.8 mg/ml). To achieve its maximum epicutaneous delivery, packaging it into a suitable carrier system is thus indicated. Sesamol-loaded solid lipid nanoparticles (S-SLN) were thus prepared with particle size of 127.9 nm (PI: 0.256) and entrapment efficiency of 88.21%. Topical application of S-SLN in a cream base indicated significant retention in the skin with minimal flux across skin as confirmed by the in-vivo skin retention and ex-vivo skin permeation studies. In vivo anticancer studies performed on TPA-induced and benzo(a)pyrene initiated tumour production (ROS mediated) in mouse epidermis showed the normalization (in histology studies) of skin cancers post their induction, upon treatment with S-SLN.
Li, Su; Ji, Zhaoshuai; Zou, Meijuan; Nie, Xin; Shi, Yijie; Cheng, Gang
Tetrandrine (TET) is a poorly water-soluble bisbenzylisoquinoline alkaloid. In this study, TET solid lipid nanoparticles (SLNs) were prepared by a melt-emulsification and ultrasonication technique. Precirol(®) ATO 5, glyceryl monostearate, and stearic acid were used as the lipid matrix for the SLNs, while Lipoid E80, Pluronic F68, and sodium deoxycholate were used as emulsifying and stabilizing agents. The physicochemical characteristics of the TET-SLNs were investigated when it was found that the mean particle size and zeta potential of the TET-SLNs were 134 ± 1.3 nm and -53.8 ± 1.7 mV, respectively, and the entrapment efficiency (EE) was 89.57% ± 0.39%. Differential scanning calorimetry indicated that TET was in an amorphous state in SLNs. TET-SLNs exhibited a higher release rate at a lower pH and a lower release rate at a higher pH. The release pattern of the TET-SLNs followed the Weibull model. The pharmacokinetics of TET-SLNs after intravenous administration to male rats was studied. TET-SLN resulted in a higher plasma concentration and lower clearance. The biodistribution study indicated that TET-SLN showed a high uptake in reticuloendothelial system organs. In conclusion, TET-SLNs with a small particle size, and high EE, can be produced by the method described in this study. The SLN system is a promising approach for the intravenous delivery of tetrandrine.
Talluri, Siddhartha Venkata; Kuppusamy, Gowthamarajan; Karri, Veera Venkata Satyanarayana Reddy; Yamjala, Karthik; Wadhwani, Ashish; Madhunapantula, SubbaRao V; Pindiprolu, Saikiran S S
The current work was carried out by the principles of quality-by-design approach to develop an optimized solid lipid nanoparticles (SLNs) formulation of diallyl disulfide (DADS) through systematic statistical study. And its antitumor activity of DADS was also evaluated on breast cancer cell lines. To understand the effect of formulation variables (critical parameters) on the responses (critical quality attributes) of SLN, a 3-factor, 3-level Box-Behnken design, was explored to predict the responses such as particle size (Y1) and % entrapment efficiency (EE) (Y2) when concentration of surfactant (X1), amount of lipid (X2), and volume of solvent (X3) were selected as independent variables. Particle size analysis revealed that all the batches were within the nanometer range. DADS was released from the SLN much more rapidly at pH 4.5 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. The cytotoxicity, reactive oxygen species (ROS), determination revealed that the antitumor activity of DADS is enhanced with SLN compared to DADS-free drug, and apoptosis is the mechanism underlying the cytotoxicity. The present study indicated the remarkable potential of DADS-SLN in enhancing the anticancer effect of DADS in breast cancer cells in vitro.
Kakkar, Vandita; Muppu, Sravan Kumar; Chopra, Kanwaljit; Kaur, Indu Pal
To evaluate curcumin loaded solid lipid nanoparticles (C-SLNs) in the experimental paradigm of cerebral ischemia (BCCAO model) in rats. Oral administration of free curcumin and C-SLNs (25 and 50 mg/kg) was started 5 days prior and continued for 3 days after BCCAO. Alleviation in behavioral, oxidative and nitrosative stress, acetylcholinesterase, mitochondrial enzyme complexes, and physiological parameters were assessed. Confirmation of effective brain delivery of C-SLNs (p.o) was done using biodistribution studies in mice and confocal microscopy of rat brain section. There was an improvement of 90% in cognition and 52% inhibition of acetylcholinesterase versus cerebral ischemic group (I/R). Neurological scoring improved by 79%. Levels of superoxide dismutase, catalase, glutathione, and mitochondrial complex enzyme activities were significantly increased, while lipid peroxidation, nitrite, and acetylcholinesterase levels decreased (p<0.05) after C-SLNs administration. It is noteworthy to report the restoration of SOD, GSH, catalase, and mitochondrial complex enzyme levels equivalent to sham control values. Gamma-scintigraphic studies show 16.4 and 30 times improvement in brain bioavailability (AUC) upon oral and i.v administration of C-SLNs versus solubilized curcumin (C-S). Study indicates protective role of curcumin against cerebral ischemic insult; provided it is packaged suitably for improved brain delivery. Copyright © 2013 Elsevier B.V. All rights reserved.
Aboud, Heba M; El Komy, Mohammed H; Ali, Adel A; El Menshawe, Shahira F; Abd Elbary, Ahmed
Carvedilol, a beta-adrenergic blocker, suffers from poor systemic availability (25%) due to first-pass metabolism. The aim of this work was to improve carvedilol bioavailability through developing carvedilol-loaded solid lipid nanoparticles (SLNs) for nasal administration. SLNs were prepared by emulsion/solvent evaporation method. A 2(3) factorial design was employed with lipid type (Compritol or Precirol), surfactant (1 or 2% w/v poloxamer 188), and co-surfactant (0.25 or 0.5% w/v lecithin) concentrations as independent variables, while entrapment efficiency (EE%), particle size, and amount of carvedilol permeated/unit area in 24 h (Q 24) were the dependent variables. Regression analysis was performed to identify the optimum formulation conditions. The in vivo behavior was evaluated in rabbits comparing the bioavailability of carvedilol after intravenous, nasal, and oral administration. The results revealed high drug EE% ranging from 68 to 87.62%. Carvedilol-loaded SLNs showed a spherical shape with an enriched core drug loading pattern having a particle size in the range of 66 to 352 nm. The developed SLNs exhibited significant high amounts of carvedilol permeated through the nasal mucosa as confirmed by confocal laser scanning microscopy. The in vivo pharmacokinetic study revealed that the absolute bioavailability of the optimized intranasal SLNs (50.63%) was significantly higher than oral carvedilol formulation (24.11%). Hence, we conclude that our developed SLNs represent a promising carrier for the nasal delivery of carvedilol.
Vaghasiya, Harshad; Kumar, Abhinesh; Sawant, Krutika
The study describes the development and evaluation of solid lipid nanoparticles (SLNs) of terbinafine hydrochloride (TH) for sustained release and skin targeting. TH-loaded SLNs were prepared by solvent-injection technique and optimized using 3(3) full-factorial design. Effect of drug:lipid ratio, surfactant concentration and volume of organic solvent were studied on % entrapment efficiency (%EE) and particle size (PS). The optimum formulation based on desirability (0.945) exhibited %EE of 73.74% and PS of 300 nm. Optimized SLNs were incorporated into Carbopol gel and evaluated for drug content, pH, in vitro release, ex vivo retention, in vivo pharmacodynamic and stability studies. Drug release from SLNs dispersion followed Korsmeyer-Peppas model, indicating Fickian drug release, while that from the gel followed Higuchi model. The ex vivo studies through rat abdominal skin indicated skin retention ability of SLNs as compared to commercial product. In vivo pharmacodynamic studies showed that the SLNs based gel reduced fungal burden of Candida albicans in rats as compared to commercial product in shorter duration of time. The SLNs dispersion and gel exhibited physicochemical stability under refrigeration upto 3 months. It was concluded that SLNs incorporated Carbopol gel had skin targeting ability and may serve as a promising carrier in treatment of fungal skin infections. Copyright © 2013 Elsevier B.V. All rights reserved.
de Jesus, Marcelo B; Zuhorn, Inge S
Solid lipid nanoparticles (SLNs) have been proposed in the 1990s as appropriate drug delivery systems, and ever since they have been applied in a wide variety of cosmetic and pharmaceutical applications. In addition, SLNs are considered suitable alternatives as carriers in gene delivery. Although important advances have been made in this particular field, fundamental knowledge of the underlying mechanisms of SLN-mediated gene delivery is conspicuously lacking, an imperative requirement in efforts aimed at further improving their efficiency. Here, we address recent advances in the use of SLNs as platform for delivery of nucleic acids as therapeutic agents. In addition, we will discuss available technology for conveniently producing SLNs. In particular, we will focus on underlying molecular mechanisms by which SLNs and nucleic acids assemble into complexes and how the nucleic acid cargo may be released intracellularly. In discussing underlying mechanisms, we will, when appropriate, refer to analogous studies carried out with systems based on cationic lipids and polymers, that have proven useful in the assessment of structure-function relationships. Finally, we will give suggestions for improving SLN-based gene delivery systems, by pointing to alternative methods for SLNplex assembly, focusing on the realization of a sustained nucleic acid release.
Yang, Yihui; Corona, Alessandro; Henson, Michael A
Solid lipid nanoparticles (SLNs) have applications in drug delivery and the encapsulation of bioactive, lipophilic compounds. However, SLNs tend to aggregate when stored due to the lipid crystals undergoing a polymorphic transformation from the unstable α form to the stable β form. We developed a population balance equation (PBE) model for prediction of average polymorph content and aggregate size distribution to better understand this undesirable behavior. Experiments with SLNs stored at room temperature showed that polymorphic transformation was the rate determining step for our system, SLNs with smaller initial size distributions aggregated more rapidly, and aggregates contained particles with both α and β crystals. Using parameter values estimated from our data, the PBE model was able to capture the bimodal nature of aggregate size distributions, the α-to-β polymorph ratio, and the faster aggregation dynamics of SLNs with smaller initial size distributions. However, the model was unable to adequately capture the fast disappearance rate of primary particles, the broad size distributions of formed aggregates, and the significant α content of aggregating particles. These discrepancies suggest that a PBE model which accounts for polymorph content as an internal variable along with aggregate size may be required to better reproduce experimental observations. Published by Elsevier Inc.
Ibrahim, Waheed M; AlOmrani, Abdullah H; B Yassin, Alaa Eldeen
Background Solid lipid nanoparticles (SLN), novel drug delivery carriers, can be utilized in enhancing both intestinal permeability and dissolution of poorly absorbed drugs. The aim of this work was to enhance the intestinal permeability of sulpiride by loading into SLN. Methods A unique ultrasonic melt-emulsification method with minimum stress conditions was used for the preparation of SLN. The mixture of the drug and the melted lipids was simply dispersed in an aqueous solution of a surfactant at a temperature that was 10°C higher than the melting points of the lipids using probe sonication, and was then simultaneously dispersed in cold water. Several formulation parameters were optimized, including the drug-to-lipid ratio, and the types of lipids and surfactants used. The produced SLN were evaluated for their particle size and shape, surface charge, entrapment efficiency, crystallinity of the drug and lipids, and the drug release profile. The rat everted sac intestine model was utilized to evaluate the change in intestinal permeability of sulpiride by loading into SLN. Results The method adopted allowed successful preparation of SLN with a monodispersed particle size of 147.8–298.8 nm. Both scanning electron microscopic and atomic force microscopic images showed uniform spherical particles and confirmed the sizes determined by the light scattering technique. Combination of triglycerides with stearic acid resulted in a marked increase in zeta potential, entrapment efficiency, and drug loading; however, the particle size was increased. The type of surfactant used was critical for particle size, charge, drug loading, and entrapment efficiency. Generally, the in vitro release profile demonstrated by all formulations showed the common biphasic mode with a varying degree of burst release. The everted sac model showed markedly enhanced sulpiride permeability in the case of the SLN-loaded formulation. The in situ results showed a very good correlation with the in
Chantaburanan, Thitirat; Teeranachaideekul, Veerawat; Chantasart, Doungdaw; Jintapattanakit, Anchalee; Junyaprasert, Varaporn Buraphacheep
The physicochemical properties of solid lipid nanoparticles (SLN) depend on lipid compositions. An addition of secondary solid complex triglycerides (Softisan 378; S378) into solid wax (cetyl palmitate; CP) is expected to influence the properties of obtained SLN compared to SLN prepared from sole CP. Ibuprofen-loaded SLN (IBSLN-TG) composed of different ratios of CP and S378 were prepared and evaluated in term of size, zeta potential (ZP), entrapment efficiency (E.E.), crystallinity, lipid-drug interaction and in vitro drug release. After production, all developed IBSLN-TG prepared from different ratios of CP and S378 had the particle size in the nanometer range (180-200nm) with the ZP values of higher than |-40mV| and possessed approximately 100% E.E. The release of IBSLN-TG demonstrated the biphasic pattern with a fast release followed by sustained release, which was fitted to Higuchi's kinetics. The addition of S378 into CP-matrix led to a slight decrease in particle size and surface charge, and distortion of CP crystallization. The results from (1)H-NMR indicated the formation of tiny liquid S378 nanocompartments within CP-matrix. The localization of ibuprofen in the S378 nanocompartments and the interaction between ibuprofen and S378 had an impact on the release profiles of IBSLN-TG depending on the ratios of CP and S378. Copyright © 2017 Elsevier Inc. All rights reserved.
Gupta, Renuka; Rousseau, Dérick
Oil-in-water (O/W) emulsions solely stabilized by surface-active solid lipid nanoparticles (SLNs) were developed. The SLNs were generated by quench-cooling hot O/W nanoemulsions consisting of 7.5% glyceryl stearyl citrate (GSC) dispersed in water. Their initial volume-weighted mean particle diameter (∼152 nm) and zeta potential (ca.-49 mV) remained unchanged for 24 weeks. O/W emulsions (oil phase volume fraction: 0.2) containing 7.5% (w/w) GSC SLNs in the aqueous phase were kinetically-stable for 12 weeks and did not visually phase-separate over 24 weeks. The O/W emulsions generated with solid-state GSC SLNs had a volume-weighted mean oil droplet diameter of ∼459 nm and a zeta potential of ca.-43 mV. Emulsion microstructure evaluated with TEM revealed dispersed oil droplets sparsely covered with adsorbed Pickering-type SLNs as well aggregated SLNs present in the continuous phase. Gradual emulsion destabilization resulted from GSC SLN dissolution during the experimental timeframe. Overall, surface-active SLNs developed via nanoemulsions effectively kinetically stabilized O/W emulsions.
Negi, Jeetendra Singh; Chattopadhyay, Pronobesh; Sharma, Ashok Kumar; Ram, Veerma
Solid lipid nanoparticles (SLNs) of poor orally bioavailable drug lopinavir were prepared using hot self nano-emulsification (SNE) technique. Hot isotropic mixture of stearic acid, poloxamer and polyethylene glycol was spontaneously self nano-emulsify in hot water and SLNs were formed with subsequent rapid cooling. Self nano-emulsification ability of stearic acid, poloxamer and polyethylene glycol mixture was assessed by ternary phase diagram study. Optimized SLNs were having particle size of 180.6 ± 2.32 nm (PDI=0.133 ± 0.001), 91.5 ± 1.3% entrapment efficiency and zeta potential of -13.4 ± 0.56 mV. SLNs were evaluated by transmission electron microscopy (TEM) and atomic force microscopy (AFM) for morphological study. Further, Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) of SLNs were also performed for checking solid state characterization. Higher oral bioavailability was found for lopinavir loaded SLNs in comparison to bulk lopinavir due to higher lymphatic drug transport (p<0.05). Results indicate that SLNs of higher fatty acids can be successfully prepared by hot SNE technique.
Patel, Ravi R; Chaurasia, Sundeep; Khan, Gayasuddin; Chaubey, Pramila; Kumar, Nagendra; Mishra, Brahmeshwar
Cromolyn sodium (CS), a mast cell stabiliser, is widely employed for the prevention and treatment of allergic conditions. However, high hydrophilicity and poor oral permeability hinder its oral clinical translation. Here, solid lipid nanoparticles (SLNs) have been developed for the purpose of oral bioavailability enhancement. The CS-SLNs were engineered by double emulsification method (W1/O/W2) and optimised by using Box-Behnken experimental design. The surface and solid-state characterisations revealed the presence of CS in an amorphous form without any interactions inside the spherical-shaped SLNs. The in-vitro release study showed an extended release up to 24 hr by diffusion controlled process. Ex-vivo and in-vivo intestinal permeation study showed ∼2.96-fold increase in permeability of CS by presentation as SLNs (p < 0.05). Further, in-vivo pharmacokinetic study exhibited ∼2.86-fold enhancements in oral bioavailability of CS by encapsulating inside SLNs, which clearly indicate that SLNs can serve as the potential therapeutic carrier system for oral delivery of CS.
Omwoyo, Wesley Nyaigoti; Ogutu, Bernhards; Oloo, Florence; Swai, Hulda; Kalombo, Lonji; Melariri, Paula; Mahanga, Geoffrey Maroa; Gathirwa, Jeremiah Waweru
Primaquine (PQ) is one of the most widely used antimalarial drugs and is the only available drug that combats the relapsing form of malaria. PQ use in higher doses is limited by severe tissue toxicity including hematological- and gastrointestinal-related side effects. Nanoformulation of drugs in an appropriate drug carrier system has been extensively studied and shown to have the potential to improve bioavailability, thereby enhancing activity, reducing dose frequency, and subsequently reducing toxicity. The aim of this work was to design, synthesize, and characterize PQ-loaded solid lipid nanoparticles (SLNs) (PQ-SLNs) as a potential drug-delivery system. SLNs were prepared by a modified solvent emulsification evaporation method based on a water-in-oil-in-water (w/o/w) double emulsion. The mean particle size, zeta potential, drug loading, and encapsulation efficiency of the PQ-SLNs were 236 nm, +23 mV, 14%, and 75%, respectively. The zeta potential of the SLNs changed dramatically, from −6.54 mV to +23.0 mV, by binding positively charged chitosan as surface modifier. A spherical morphology of PQ-SLNs was seen by scanning electron microscope. In vitro, release profile depicted a steady drug release over 72 hours. Differential scanning calorimeter thermograms demonstrated presence of drug in drug-loaded nanoparticles along with disappearance of decomposition exotherms, suggesting increased physical stability of drug in prepared formulations. Negligible changes in characteristic peaks of drug in Fourier transform infrared spectra indicated absence of any interaction among the various components entrapped in the nanoparticle formulation. The nanoformulated PQ was 20% more effective as compared with conventional oral dose when tested in Plasmodium berghei-infected Swiss albino mice. This study demonstrated an efficient method of forming a nanomedicine delivery system for antimalarial drugs. PMID:25143734
Mulik, Rohit S; Mönkkönen, Jukka; Juvonen, Risto O; Mahadik, Kakasaheb R; Paradkar, Anant R
Broad spectrum therapeutic potential of curcumin is usually hampered by its photodegradation and low bioavailability. Present investigation was designed with an objective to develop transferrin-mediated solid lipid nanoparticles (Tf-C-SLN) resistant to the photostability and capable of enhancing the bioavailability by targeted drug delivery to elicit anticancer activity against SH-SY5Y neuroblastoma cells in vitro. Hot homogenization method was used for the formulation of Tf-C-SLN and evaluated physicochemically using parameters such as, size, zeta potential, entrapment efficiency and photostability, transmission electron microscopy (TEM), nuclear magnetic resonance (NMR), differential scanning colorimetry (DSC), and in vitro release study. In vitro cytotoxicity and apoptosis investigations were performed using microplate analysis and flow cytometry techniques. The physicochemical characterization confirmed the suitability of formulation method and various parameters therein. TEM investigation revealed the spherical morphology while NMR and DSC study confirmed the entrapment of curcumin inside the nanoparticles. The cytotoxicity, reactive oxygen species, and cell uptake were found to be increased considerably with Tf-C-SLN compared with curcumin-solubilized surfactant solution, and curcumin-loaded SLN (C-SLN) suggesting the targeting effect. AnnexinV-FITC/PI double staining, DNA analysis, caspase detection, and reduced mitochondrial potential confirmed the induction of apoptosis with nanoparticle treatment. Enhanced anticancer activity with Tf-C-SLN compared with curcumin-solubilized surfactant solution and C-SLN was observed from flow cytometry investigations with apoptosis being the major underlying mechanism. The in vitro observations of our investigation are very compelling and concrete to advocate the potential of Tf-C-SLN in enhancing the anticancer effect of curcumin against neuroblastoma in vivo and possible clinical applications.
Nazemiyeh, Elham; Eskandani, Morteza; Sheikhloie, Hossein; Nazemiyeh, Hossein
Purpose: Lycopene belongs to the carotenoids that shows good pharmacological properties including antioxidant, anti-inflammatory and anticancer. However, as a result of very low aqueous solubility, it has a limited systemic absorption, following oral administration. Methods: Here, we prepared a stable lycopene-loaded solid lipid nanoparticles using Precirol® ATO5, Compritol 888 ATO and myristic acid by hot homogenization method with some modification. The size and morphological characteristics of nanoparticles were evaluated using Scanning Electron Microscopy (SEM). Moreover, zeta potential and dispersity index (DI) were measured using zeta sizer. In addition, encapsulation efficiency (EE%), drug loading (DL) and cumulative drug release were quantified. Results: The results showed that the size and DI of particles was generally smaller in the case of SLNs prepared with precirol when compared to SLNs prepared with compritol. Scanning electron microscopy (SEM) and particle size analyses showed spherical SLNs (125 ± 3.89 nm), monodispersed distribution, and zeta potential of −10.06 ± 0.08 mV. High EE (98.4 ± 0.5 %) and DL (44.8 ± 0.46 mg/g) were achieved in the case of nanoparticles prepared by precirol. The stability study of the lycopene-SLNs in aqueous medium (4 °C) was showed that after 2 months there is no significant differences seen in size and DI compared with the fresh formulation. Conclusion: Conclusively, in this investigation we prepared a stable lycopene-SLNs with good physicochemical characteristic which candidate it for the future in vivo trials in nutraceutical industries. PMID:27478786
Ghanbarzadeh, Saeed; Hariri, Reza; Kouhsoltani, Maryam; Shokri, Javad; Javadzadeh, Yousef; Hamishehkar, Hamed
Hydroquinone (HQ), a well-known anti-hyperpigmentation agent suffers from (a) instability due to rapid oxidation, (b) insufficient skin penetration because of hydrophilic structure, and (c) severe side effects as a results of systemic absorption. This study aimed to load HQ into solid lipid nanoparticles (SLNs) to overcome the mentioned drawbacks for the efficient treatment of hyperpigmentation. The optimized SLN formulation was prepared by hot melt homogenization method and fully characterized by various techniques. The ability of SLNs in dermal delivery of HQ was assessed through the excised rat skin. The optimized HQ-loaded SLNs (particle size of 86 nm, encapsulation efficiency% of 89.5% and loading capacity% of 11.2%) exhibited a good physicochemical stability during a period of five months. XRD and DSC results showed that HQ was dispersed in an amorphous state, confirming uniform drug dispersion in the SLNs structure and embedment of drug in the solid lipid matrix. In vitro penetration studies showed almost 3 times higher drug accumulation in the skin and 6.5 times lower drug entrance to receiving compartment of Franz diffusion cell from HQ-loaded SLN hydrogel compared with HQ Carbopol made hydrogel. These results indicated the better HQ localization in the skin and its lower systemic absorption. It was concluded that SLN is a promising colloidal drug carrier for topical administration of HQ in the treatment of hyperpigmentation due to suitable HQ loading value in spite of its hydrophilic structure, high stability against oxidation and appropriate skin penetration along with the low systemic absorption.
Jo, Yeon-Ji; Choi, Mi-Jung
This study was performed to investigate the effect of palm or coconut solid lipid nanoparticles (PO-SLNs or CO-SLNs) on growth of Lactobacillus plantarum (L. plantarum) in milk during storage period. The PO or CO (0.1% or 1.0%) was dispersed both in distilled water (DW) and ultra high temperature milk (UHTM), and subsequently emulsified with Tween® 80 by ultrasonication (30% power, 2 min). Increase in particle size and encapsulation efficiency (EE%) in DW was observed with an increase in oil concentration, whereas a decrease in ζ-potential of SLNs was noted with an increment in oil concentration. Moreover, the CO-SLNs exhibited relatively smaller particle size and higher EE% than PO-SLNs. The CO-SLNs were found to be more stable than PO-SLNs. Higher lipid oxidation of PO or CO-SLNs in UHTM was observed during the storage test, when compared to PO or CO-SLNs in DW. However, there was no remarkable difference in lipid oxidation during storage period (p>0.05). In the growth test, the viability of L. plantarum in control (without PO or CO-SLNs in DW) exhibited a dramatic decrease with increasing storage period. In addition, viability of L. plantarum of PO or CO-SLNs in UHTM was higher than that of SLNs in DW. Based on the present study, production of SLNs containing PO or CO in UHTM is proposed, which can be used in lactobacilli fortified beverages in food industry. PMID:26761828
Vijayakumar, Ajay; Baskaran, Rengarajan; Jang, Young Soo; Oh, Seung Hyun; Yoo, Bong Kyu
The objective of this study was to formulate and characterize properties of solid lipid nanoparticle (SLN) dispersion containing quercetin. SLN was prepared by ultrasonication method using tripalmitin and lecithin as lipid core and then the surface was coated with chitosan. Entrapment efficiency was greater than 99%, and mean particle size of SLN was 110.7 ± 1.97 nm with significant increase in the coated SLN (c-SLN). Zeta potential was proportionally increased and reached plateau at 5% of chitosan coating with respect to tripalmitin. Differential scanning calorimetry showed disappearance of endothermic peak of quercetin in SLNs, indicating conversion of crystalline state to amorphous state. FTIR study of SLNs showed no change in the spectrum of quercetin, which indicates that the lipid and chitosan were not incompatible with quercetin. When coating amount was greater than 2.5% of tripalmitin, particle size and zeta potential were very stable even at 40°C up to 90 days. All SLN dispersions showed significantly faster release profile compared to pure quercetin powder. At pH 7.0, the release rate was increased in proportion to the coating amount. Interestingly, at pH 3.0, chitosan coating of 5.0% or greater decreased the rate. Cellular uptake of quercetin was performed using Caco-2 cells and showed that all SLN dispersions were significantly better than quercetin dispersed in distilled water. However, cellular uptake of quercetin from c-SLN was significantly lower than that from uncoated SLN.
Jo, Yeon-Ji; Choi, Mi-Jung; Kwon, Yun-Joong
This study was performed to investigate the effect of palm or coconut solid lipid nanoparticles (PO-SLNs or CO-SLNs) on growth of Lactobacillus plantarum (L. plantarum) in milk during storage period. The PO or CO (0.1% or 1.0%) was dispersed both in distilled water (DW) and ultra high temperature milk (UHTM), and subsequently emulsified with Tween(®) 80 by ultrasonication (30% power, 2 min). Increase in particle size and encapsulation efficiency (EE%) in DW was observed with an increase in oil concentration, whereas a decrease in ζ-potential of SLNs was noted with an increment in oil concentration. Moreover, the CO-SLNs exhibited relatively smaller particle size and higher EE% than PO-SLNs. The CO-SLNs were found to be more stable than PO-SLNs. Higher lipid oxidation of PO or CO-SLNs in UHTM was observed during the storage test, when compared to PO or CO-SLNs in DW. However, there was no remarkable difference in lipid oxidation during storage period (p>0.05). In the growth test, the viability of L. plantarum in control (without PO or CO-SLNs in DW) exhibited a dramatic decrease with increasing storage period. In addition, viability of L. plantarum of PO or CO-SLNs in UHTM was higher than that of SLNs in DW. Based on the present study, production of SLNs containing PO or CO in UHTM is proposed, which can be used in lactobacilli fortified beverages in food industry.
Clares, Beatriz; Calpena, Ana C; Parra, Alexander; Abrego, Guadalupe; Alvarado, Helen; Fangueiro, Joana F; Souto, Eliana B
The aim of this study was to develop biocompatible lipid-based nanocarriers for retinyl palmitate (RP) to improve its skin delivery, photostability and biocompatibility, and to avoid undesirable topical side effects. RP loaded nanoemulsions (NEs), liposomes (LPs) and solid lipid nanoparticles (SLNs) were characterized in terms of size, surface electrical charge, pH, drug encapsulation efficiency and morphology. Spherical-shaped nanocarriers with a negatively charged surface (>|40|mV) and mean size lower than 275 nm were produced with adequate skin compatibility. The rheological properties showed that aqueous dispersions of SLNs followed a non-Newtonian behavior, pseudoplastic fluid adjusted to Herschel-Bulkley equation, whereas LPs and NEs exhibited a Newtonian behavior. SLNs offered significantly better photoprotection than LPs and NEs for RP. The cumulative amount of drug permeated through human skin at the end of 38 h was 6.67 ± 1.58 μg, 4.36 ± 0.21 μg and 3.64 ± 0.28 μg for NEs, LPs and SLNs, respectively. NEs flux was significantly higher than SLNs and LPs: NEs (0.37 ± 0.12 μg/h) > LPs (0.15 ± 0.09 μg/h) > SLNs (0.10 ± 0.05 μg/h). LPs offered significant higher skin retention than NEs and SLNs. Finally, even though all developed nanocarriers were found to be biocompatible, according to histological studies, NE was the system that most disrupted the skin. These encouraging findings can guide in proper selection of topical carriers among the diversity of available lipid-based nanocarriers, especially when a dermatologic or cosmetic purpose is desired.
Girotra, Priti; Singh, Shailendra Kumar
The present investigation aimed at development of brain-targeted rizatriptan benzoate-loaded solid lipid nanoparticles (RB-SLNs) by design of experiment, for improvement of its anti-migraine potential. Several formulation variables affecting the fabrication of RB-SLNs were screened using the Plackett-Burman design (PBD). The PBD results demonstrated lipid (Precirol® ATO 5) concentration, co-surfactant (Phospholipon® 90 H) concentration and temperature of lipid melt to be the critical variables, having a significant effect on the achievement of minimum particle size, maximum entrapment efficiency coupled with sustained drug release. The interactions between these formulation parameters and the variability between the batches were further explored employing the Box-Behnken design (BBD). The BBD results were validated by fabricating the suggested optimized solution, which yielded 220.4 ± 2.3 nm particle size with a sufficiently high entrapment efficiency of 71.8 ± 1.9% and 45.9 ± 2.7% cumulative drug release in 8 h. The optimized formulation was, thereafter, characterized by FTIR spectroscopy, wide angle XRD, thermal analysis and TEM imaging technique. The in vivo studies revealed the brain uptake potential of optimized RB-SLNs to be 18.43-folds higher with respect to the pure drug in its free form, post 2 h of oral drug administration. The significant anti-migraine efficacy of RB-SLNs was corroborated through the pharmacodynamic studies on adult male Swiss albino mice. The results hence explicate that RB-SLNs have distinctly improved brain target ability and offer an apt approach for the efficient therapeutic management of migraine.
Hosny, Khaled Mohamed
Treatment of osteoporosis with alendronate sodium has several challenges. The first challenge is the low bioavailability. The second main challenge is side effects, which include oesophageal ulceration. The aim of this research was to reformulate alendronate sodium as enteric coated solid lipid nanoparticles in order to enhance its bioavailability, and preventing the free alendronate sodium from coming into direct contact with the gastrointestinal mucosa, and thereby reducing the possibility of side effects. Enteric coated solid lipid nanoparticles were prepared according to the Box-Behnken design employing Design expert® software, and characterized for size, morphology, and entrapment efficiency. The optimized formula was coated with an Eudragit S100 and evaluated for drug release in acidic and basic media, stability studies and pharmacokinetic evaluations on rabbits. The results indicated that, using Derringer's desirability functional tool for optimization, the highest entrapment efficiency value of 74.3% and the smallest size value of 98 nm were predicted under optimum conditions with a desirability value of 0.917. The optimized nanoparticles released alendronate sodium only at an alkaline pH. The pharmacokinetic evaluation revealed that alendronate sodium bioavailability was enhanced by more than 7.4-fold in rabbits. In conclusion, enteric coated solid lipid nanoparticles is a promising formula for the delivery of alendronate sodium, eliminating its oesophageal side effects and enhancing its bioavailability. PMID:27148747
Hosny, Khaled Mohamed
Treatment of osteoporosis with alendronate sodium has several challenges. The first challenge is the low bioavailability. The second main challenge is side effects, which include oesophageal ulceration. The aim of this research was to reformulate alendronate sodium as enteric coated solid lipid nanoparticles in order to enhance its bioavailability, and preventing the free alendronate sodium from coming into direct contact with the gastrointestinal mucosa, and thereby reducing the possibility of side effects. Enteric coated solid lipid nanoparticles were prepared according to the Box-Behnken design employing Design expert® software, and characterized for size, morphology, and entrapment efficiency. The optimized formula was coated with an Eudragit S100 and evaluated for drug release in acidic and basic media, stability studies and pharmacokinetic evaluations on rabbits. The results indicated that, using Derringer's desirability functional tool for optimization, the highest entrapment efficiency value of 74.3% and the smallest size value of 98 nm were predicted under optimum conditions with a desirability value of 0.917. The optimized nanoparticles released alendronate sodium only at an alkaline pH. The pharmacokinetic evaluation revealed that alendronate sodium bioavailability was enhanced by more than 7.4-fold in rabbits. In conclusion, enteric coated solid lipid nanoparticles is a promising formula for the delivery of alendronate sodium, eliminating its oesophageal side effects and enhancing its bioavailability.
Rangsimawong, Worranan; Opanasopit, Praneet; Rojanarata, Theerasak; Duangjit, Sureewan; Ngawhirunpat, Tanasait
The effect of surface grafting with N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG2000-DSPE) onto three types of lipid nanocarriers, liposomes, niosomes and solid lipid nanoparticles (SLNs) on the skin penetration of sodium fluorescein (NaFI) was investigated. Confocal laser scanning microscopy (CLSM) was used to visualize the penetration pathways. Fourier transform infrared spectroscopy (FT-IR) was used to determine the skin hydration. The results showed that the physicochemical properties of each nanocarrier were modified after PEG grafting. In the skin penetration study, PEG grafting increased the flux of NaFI-loaded PEGylated liposomes and significantly decreased the flux of NaFI-loaded PEGylated niosomes and NaFI-loaded PEGylated SLNs. The skin deposition study and CLSM images showed that the intact liposome vesicles permeated into the skin. The niosomes and SLNs had little or no vesicles in the skin, suggesting that NaFI may have been released from these nanocarriers before permeation. Additionally, the fluorescent CLSM images of the SLNs showed that NaFI deposited along the length of hair follicles inside the skin, indicating that the skin penetration route may be through the transfollicular pathway. For the PEGylated nanocarriers, the PEGylated liposomes had higher fluorescence intensities than the non-PEGylated liposomes, indicating higher NaFI concentrations. The PEGylated niosomes and PEGylated SLNs had lower fluorescence intensities than those of the non-PEG modified niosomes and SLNs. For FT-IR results, PEGylated liposomes increased the skin hydration, while the grafting PEG onto niosomes and SLN surfaces decreased the skin hydration. This study showed that the surface grafting of PEG onto various nanocarriers affected the skin transport of NaFI.
Ayan, Arif Kursad; Yenilmez, Ayse; Eroglu, Hayrettin
Curcumin-loaded solid lipid nanoparticles (C-SLNs) were prepared using micro emulsion and ultrasonication methods in the first stage of this study to determine the role of C-SLN on liver-spleen scintigraphy. It was concluded that the curcumin that was encapsulated in solid lipid nanoparticles had a β' polymorph structure according to the X-ray diffraction (XRD) analysis. İt was concluded that these particles were at nano scale according to the laser diffraction (LD) analysis. Fourier transform infrared spectroscopy (FT-IR) analysis suggested an interaction between the curcumin and the solid lipid matrix, and the curcumin was loaded on the solid lipid nanoparticles. Moreover, the particles were concluded to be spherical and at nanoscale according to the scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images. On the other hand, thermogravimetric analysis (TGA) suggested that the curcumin loaded solid nanoparticles were stable against the temperature. C-SLNs were labeled with Technetium-99m ((99m)Tc) radioisotope in the second stage of the study, then using scintigraphic methods in-vivo studies were performed on New Zealand rabbit and made a comparison with Phytate colloid, routinely used in liver-spleen scintigraphy. After analyzing the images and the biological distributions obtained from the experiments, uptake was observed in the liver and the spleen. Following from the experiment results, (99m)Tc-labeled C-SLNs was concluded to be a possible imaging agent. In particular, it could be a new radiopharmaceutical alternative to (99m)Tc-labeled compounds that are used in liver and spleen imaging in colloid scintigraphy. Copyright © 2017 Elsevier B.V. All rights reserved.
Chen, Chunhui; Fan, Tingting; Jin, Yun; Zhou, Zhou; Yang, Yang; Zhu, Xi; Zhang, Zhi-Rong; Zhang, Qiang; Huang, Yuan
The purpose of this study was to develop a new orally delivered nanoparticulate system to improve the bioavailability of salmon calcitonin (sCT). Four sCT-loaded solid lipid nanoparticles (SLNs) were prepared successfully by micelle-double emulsion technique via either the sole use of stearic acid (SA) or the combined use of SA and triglycerides (including tripalmitin [TP], trimyristin or trilaurin). Compared with other SLNs, the combination of SA and TP could not only significantly improve the colloidal stability of SLNs and enhance the drug stability in the simulated intestinal fluids, but also intensively increase the intracellular uptake of drugs compared with the other SLNs (p < 0.05). The mechanism of internalization was an active transport involved in clathrin- and caveolae-dependent endocytosis. In vivo, the sCT SLNs prepared with SA and TP exhibited the highest reduction of plasma Ca(2+) level (17.44 ± 3.68%) with a bioavailability of 13.01 ± 3.24%. The SLNs formed by SA and TP as the solid lipids may be a promising carrier for oral delivery of peptide drugs.
Akbari, Jafar; Saeedi, Majid; Morteza-Semnani, Katayoun; Rostamkalaei, Seyyed Sohrab; Asadi, Masoumeh; Asare-Addo, Kofi; Nokhodchi, Ali
The aim of the current investigation was to produce naproxen solid lipid nanoparticles (Nap-SLNs) by the ultrasonication method to improve its skin permeation and also to investigate the influence of Hydrophilic-lipophilic balance (HLB) changes on nanoparticles properties. The properties of obtained SLNs loaded with naproxen were characterized by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM) and differential scanning calorimetry (DSC). FT-IR was also used to investigate any interaction between naproxen and the excipients used at the molecular level during the preparation of the SLNs. The performance of the formulations was investigated in terms of skin permeation and also the retention of the drug by the skin. It was found that generally, with increasing the lipid concentration, the average particle size and polydispersity index (PDI) of SLNs increased from 94.257±4.852nm to 143.90±2.685nm and from 0.293±0.037 to 0.525±0.038 respectively. The results also showed that a reduction in the HLB resulted in an increase in the PDI, particle size, zeta potential and entrapment efficiency (EE%). DSC showed that the naproxen encapsulated in the SLNs was in its amorphous form. The peaks of prominent functional groups of naproxen were found in the FT-IR spectra of naproxen-SLN, which confirmed the entrapment of naproxen in the lipid matrix. FT-IR results also ruled out any chemical interaction between drug and the chemicals used in the preparation of SLNs. The amount of naproxen detected in the receptor chamber at all the sampling times for the reference formulation (naproxen solution containing all surfactants at pH 7.4) was higher than that of the Nap-SLN8 formulation. Nap-SLN8 showed an increase in the concentration of naproxen in the skin layer with less systemic absorption. This indicates that most of the drug in Nap-SLN8 remains in the skin which can reduce the side effect of systemic absorption of the drug and increases the
Puglia, Carmelo; Bonina, Francesco; Castelli, Francesco; Micieli, Dorotea; Sarpietro, Maria Grazia
Diethyltoluamide and ethylhexyl p-methoxycinnamate (OMC) are two active ingredients in insect repellent and sunscreen products, respectively. The concurrent application of these two substances often increases their systemic absorption, compromising the safety and efficiency of the cosmetic product. In this study, diethyltoluamide and OMC were incorporated into solid lipid nanoparticles, a colloidal drug delivery system, to reduce percutaneous absorption and avoid toxic effects and also maintain the efficacy of the two active compounds on the skin surface for a long duration. Solid lipid nanoparticles were prepared based on an ultrasonication technique and characterized by differential scanning calorimetry (DSC) analyses. In-vitro studies determined the percutaneous absorption of diethyltoluamide and OMC. DSC data carried out on unloaded and diethyltoluamide- and/or OMC-loaded solid lipid nanoparticles highlighted that diethyltoluamide and OMC modified the temperature and the enthalpy change associated to the calorimetric peak of solid lipid nanoparticles. The concurrent presence of the two compounds in the solid lipid nanoparticles caused a synergic effect, indicating that the lipid matrix of nanoparticles guaranteed a high encapsulation of both diethyltoluamide and OMC. Results from the in-vitro study demonstrated that the particles were able to reduce the skin permeation of the two cosmetic ingredients in comparison with an oil-in-water emulsion. This study has provided supplementary evidence as to the potential of lipid nanoparticles as carriers for topical administration of cosmetic active compounds.
Ying, Bo; Campbell, Robert B.
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 carrier 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
Hathout, Rania M; Metwally, Abdelkader A
This study represents one of the series applying computer-oriented processes and tools in digging for information, analysing data and finally extracting correlations and meaningful outcomes. In this context, binding energies could be used to model and predict the mass of loaded drugs in solid lipid nanoparticles after molecular docking of literature-gathered drugs using MOE® software package on molecularly simulated tripalmitin matrices using GROMACS®. Consequently, Gaussian processes as a supervised machine learning artificial intelligence technique were used to correlate the drugs' descriptors (e.g. M.W., xLogP, TPSA and fragment complexity) with their molecular docking binding energies. Lower percentage bias was obtained compared to previous studies which allows the accurate estimation of the loaded mass of any drug in the investigated solid lipid nanoparticles by just projecting its chemical structure to its main features (descriptors).
Jose, S; Anju, S S; Cinu, T A; Aleykutty, N A; Thomas, S; Souto, E B
Resveratrol is a potent anticancer. However, because of its low half-life (<0.25 h) the molecule is difficult to achieve the therapeutic concentration at the site of action. The aim of this work was to check the brain targeting ability of glyceryl behenate-based solid lipid nanoparticles (SLN) for resveratrol. SLN were prepared by solvent evaporation technique employing high speed homogenization followed by ultrasonication. SLN were designed at varying drug-lipid ratios (1:5, 1:9, 1:10, 1:11, 1:12 and 1:15) using Tween 80 or a combination of Tween 80 and polyvinyl alcohol (PVA) as surfactants. The mean particle size and zeta potential of the optimized formulation (drug-lipid ratio of 1:10) were 248.30 ± 3.80nm and -25.49 ± 0.49mV, respectively. The particle size and the encapsulation efficiency (EE) increased when varying the drug-lipid ratio from 1:5 to 1:15. Scanning electron microscopic (SEM) analysis showed that SLN were spherical in shape and had a smooth surface. The X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses revealed that the matrix of drug-loaded SLN was in disordered crystalline phase. The in vitro release study in phosphate buffer pH 7.4 followed a sustained release pattern. The drug release data was found to fit best into Higuchi kinetic model suggesting the diffusion controlled mechanism of drug release. The cytotoxicity assay (MAT) showed that SLN were equally effective (P<0.5) as free resveratrol, as an anti-tumor agent. The in vivo biodistribution study using Wistar rats demonstrated that SLN could significantly (P<0.001) increase the brain concentration of resveratrol (17.28 ± 0.6344 μg/g) as compared to free resveratrol (3.45 ± 0.3961 μg/g). The results showed that our resveratrol-loaded SLN serve as promising therapeutic systems to treat neoplastic diseases located in the brain tissue. Copyright © 2014 Elsevier B.V. All rights reserved.
Wang, Yan; Zhu, Luyan; Dong, Zhao; Xie, Shuyu; Chen, Xiaojin; Lu, Mengmeng; Wang, Xiaofang; Li, Xihe; Zhou, WenZhong
This work aims to develop norfloxacin-loaded solid lipid nanoparticle (NFX-SLN) suspensions as a novel formulation. NFX-SLN suspensions were prepared by hot homogenization and ultrasonic technique. The stability of the suspensions was studied after stored at 4°C and room temperature from 3 to 9 months. The physicochemical characteristics of the NFX-SLN, in vitro release patterns, in vitro antibacterial activity and in vivo therapeutic efficacy in mice after infection with Escherichia coli were conducted and used to evaluate the stability of the suspension. The results showed that the mean diameter (MD), polydispersity index (PDI), zeta potential (ZP) and loading capacity (LC) of nanoparticles were 250±5 nm, 0.256±0.065, -31.1±1.85 mV and 9.63±0.16%, respectively. After 9 months of storage at 4°C, the NFX-SLN showed no significant changes in MD, PDI and LC except a miner change in ZP. Moreover, the stored suspension displayed same sustained release patterns and in vitro sustained bactericidal activities as that of the fresh preparation. In vivo therapeutic results revealed that the stored suspension had similar enhanced therapeutic efficacy as the fresh preparation compared with native drug. At room temperature the formulation was stable for 3 months, but the LC, ZP and PDI changed and the suspension displayed accelerated release and weakened in vitro antibacterial activity after 6 months. These results demonstrate that NFX-SLN suspensions could be a promising formulation for enhanced pharmacological activity of norfloxacin and were stable at 4°C and less stable at room temperature. Copyright © 2012 Elsevier B.V. All rights reserved.
Dudhipala, Narendar; Veerabrahma, Kishan
Candesartan cilexetil (CC) is used in the treatment of hypertension and heart failure. It has poor aqueous solubility and low oral bioavailability. In this work, CC loaded solid lipid nanoparticles (CC-SLNs) were developed to improve the oral bioavailability. Components of the SLNs include either of trimyristin/tripalmitin/tristearin, and surfactants (Poloxamer 188 and egg lecithin E80). The CC loaded nanoparticles were prepared by hot homogenization followed by ultrasonication method. The physicochemical properties, morphology of CC-SLNs were characterized, the pharmacokinetic and pharmacodynamic behaviour of CC-SLNs were evaluated in rats. Stable CC-SLNs having a mean particle size of 180-220 nm with entrapment efficiency varying in between 91-96% were developed. The physical stability of optimized formulation was studied at refrigerated and room temperature for 3 months. Further, freeze drying was tried for improving the physical stability. DSC and XRD analyses indicated that the drug incorporated into SLN was in amorphous form but not in crystalline state. The SLN-morphology was found to be nearly spherical by electron microscopic studies. Pharmacokinetic results indicated that the oral bioavailability of CC was improved over 2.75-fold after incorporation into SLNs. Pharmacodynamic study of SLNs in hypertensive rats showed a decrease in systolic blood pressure for 48 h, while suspension showed a decrease in systolic blood pressure for only 2 h. Taken together, these effects are due to enhanced bioavailability coupled with sustained action of CC in SLN formulation. Thus, the results conclusively demonstrated the role of CC-SLNs for a significant enhancement in oral bioavailability along with improved pharmacodynamic effect.
Rute Neves, Ana; Fontes Queiroz, Joana; Weksler, Babette; Romero, Ignacio A.; Couraud, Pierre-Olivier; Reis, Salette
Nanotechnology can be an important tool to improve the permeability of some drugs for the blood-brain barrier. In this work we created a new system to enter the brain by functionalizing solid lipid nanoparticles with apolipoprotein E, aiming to enhance their binding to low-density lipoprotein receptors on the blood-brain barrier endothelial cells. Solid lipid nanoparticles were successfully functionalized with apolipoprotein E using two distinct strategies that took advantage of the strong interaction between biotin and avidin. Transmission electron microscopy images revealed spherical nanoparticles, and dynamic light scattering gave a Z-average under 200 nm, a polydispersity index below 0.2, and a zeta potential between -10 mV and -15 mV. The functionalization of solid lipid nanoparticles with apolipoprotein E was demonstrated by infrared spectroscopy and fluorimetric assays. In vitro cytotoxic effects were evaluated by MTT and LDH assays in the human cerebral microvascular endothelial cells (hCMEC/D3) cell line, a human blood-brain barrier model, and revealed no toxicity up to 1.5 mg ml-1 over 4 h of incubation. The brain permeability was evaluated in transwell devices with hCMEC/D3 monolayers, and a 1.5-fold increment in barrier transit was verified for functionalized nanoparticles when compared with non-functionalized ones. The results suggested that these novel apolipoprotein E-functionalized nanoparticles resulted in dynamic stable systems capable of being used for an improved and specialized brain delivery of drugs through the blood-brain barrier.
Zariwala, M Gulrez; Elsaid, Naba; Jackson, Timothy L; Corral López, Francisco; Farnaud, Sebastien; Somavarapu, Satyanarayana; Renshaw, Derek
Iron (Fe) loaded solid lipid nanoparticles (SLN's) were formulated using stearic acid and iron absorption was evaluated in vitro using the cell line Caco-2 with intracellular ferritin formation as a marker of iron absorption. Iron loading was optimised at 1% Fe (w/w) lipid since an inverse relation was observed between initial iron concentration and SLN iron incorporation efficiency. Chitosan (Chi) was included to prepare chitosan coated SLN's. Particle size analysis revealed a sub-micron size range (300.3±31.75 nm to 495.1±80.42 nm), with chitosan containing particles having the largest dimensions. As expected, chitosan (0.1%, 0.2% and 0.4% w/v) conferred a net positive charge on the particle surface in a concentration dependent manner. For iron absorption experiments equal doses of Fe (20 μM) from selected formulations (SLN-FeA and SLN-Fe-ChiB) were added to Caco-2 cells and intracellular ferritin protein concentrations determined. Caco-2 iron absorption from SLN-FeA (583.98±40.83 ng/mg cell protein) and chitosan containing SLN-Fe-ChiB (642.77±29.37 ng/mg cell protein) were 13.42% and 24.9% greater than that from ferrous sulphate (FeSO4) reference (514.66±20.43 ng/mg cell protein) (p≤0.05). We demonstrate for the first time preparation, characterisation and superior iron absorption in vitro from SLN's, suggesting the potential of these formulations as a novel system for oral iron delivery.
Patro, Nagaraju M.; Devi, Kshama; Pai, Roopa S.; Suresh, Sarasija
We investigated the bioavailability, efficacy, and toxicity of doxorubicin-loaded solid lipid nanoparticles (DOX-SLNs) prepared by a simple modified double-emulsification method. A 3-factor, 3-level Box-Behnken statistical design was adopted in the optimization of DOX-SLN formulation considering dependent factors particle size and entrapment efficiency. Optimized SLN formulation composed of lipid (2 %) consisting of soya lecithin and Precirol ATO 5 (1:3) with Pluronic F68 (0.3 %) resulted in 217.36 ± 3.31 nm particle size and 59.45 ± 1.75 % entrapment efficiency. DOX-SLN exhibited significant enhancement ( p < 0.05) in bioavailability as compared with free DOX in Sprague-Dawley (SD) rats. DOX-SLN exhibited higher peak plasma concentration (6.761 ± 0.08 vs. 2.412 ± 0.04 μg/ml), increased AUC (61.368 ± 3.54 vs. 5.812 ± 0.49 μg/ml h), decreased clearance (36 ± 0.01 vs. 619 ± 0.005 mL/h kg), and volume of distribution (733 ± 0.092 vs. 2,064 ± 0.061 mL/kg) when compared to free DOX. The collective results of cardiac and kidney enzyme assay, antioxidant enzyme levels, hematological parameters, effect on body weight and tumor volume, tumor necrosis factor-α level, histopathological examination, and survival analysis confirmed the improved efficacy and safety profile of DOX-SLN in 7,12-dimethyl benzanthracene-induced breast cancer in SD rats.
Khare, Anubha; Singh, Inderbir; Pawar, Pravin; Grover, Kanchan
Voriconazole is a second-generation antifungal agent with excellent broad spectrum of antifungal activity commercially available for oral and intravenous administration. Systemic administration of voriconazole is associated with side effects including visual and hepatic abnormalities. This study assessed the feasibility of using solid lipid nanoparticles for ocular delivery of voriconazole adopting stearic acid as lipidic material, tween 80 as a stabilizer, and Carbopol 934 as controlled release agent and for increasing the precorneal residence time in eye. The systems were prepared using two different methods, that is, ultrasonication method and microemulsion technique. The results indicated that the larger particle size of SLNs was found with microemulsion technique (308 ± 3.52 nm to 343 ± 3.51) compared to SLN prepared with ultrasonication method (234 ± 3.52 nm to 288 ± 4.58 nm). The polydispersity index values were less than 0.3 for all formulations and zeta potential of the prepared formulations by these two methods varied from −22.71 ± 0.63 mV to −28.86 ± 0.58 mV. Powder X-ray diffraction and differential scanning calorimetry indicated decrease in crystallinity of drug. The in vitro release study and the SLN formulations prepared with ultrasonication method demonstrated sustained release up to 12 hours. This study demonstrated that SLN prepared by ultrasonication method is more suitable than microemulsion technique without causing any significant effect on corneal hydration level. PMID:27293896
Goindi, Shishu; Guleria, Ankita; Aggarwal, Nidhi
N-6-furfuryl adenine (N6FA) also known as "kinetin" is a biologically active natural phytochemical. It belongs to the category of cytokinins, the natural plant growth hormones that promote cell division and play role in cell differentiation. Overall, N6FA aids in increasing the plant's life span. Human cells also contain.small quantities of N6FA. Scientists are trying to understand its function in humans. N6FA is being investigated for its properties such as antiplatelet, antioxidant, antiproliferative and anti-aging effects on human cells. The aim of the present investigation was to prepare solid lipid nanoparticle (SLN) based topical formulations of N6FA and to evaluate its efficacy against ultraviolet (UV) radiation induced skin photodamage. SLNs were prepared by hot microemulsion technique and optimized for the type and concentration of lipid and surfactant(s). The optimized SLN formulation was characterized in terms of particle size, drug entrapment efficiency, zeta potential and pH; evaluated for stability, spreadability, ex-vivo skin permeation and photoprotective effects against UV induced skin damage. The cumulative amount of drug permeated through mice skin using SLNs was 3 folds higher than from conventional cream base. The results of biochemical and histopathological investigations of skin treated with N6FA loaded SLNs clearly demonstrated the efficacy of optimized formulation in preventing photodamage (lesions, ulcers and changes in skin integrity) due to chronic UV exposure. The effects were comparable with widely used marketed formulation, Garnier wrinkle lift anti-aging cream. Results suggested that N6FA incorporated into SLNs may provide therapeutic as well as cosmeceutical benefits.
Goto, Patrícia L; Siqueira-Moura, Marigilson P; Tedesco, Antonio C
Cutaneous melanoma is the most aggressive skin cancer and is particularly resistant to current therapeutic approaches. Photodynamic therapy (PDT) is a well-established photoprocess that is employed to treat some cancers, including non-melanoma skin cancer. Aluminum chloride phthalocyanine (ClAlPc) is used as a photosensitizer in PDT; however, its high hydrophobicity hampers its photodynamic activity under physiological conditions. The aim of this study was to produce solid lipid nanoparticles (SLN) containing ClAlPc using the direct emulsification method. ClAlPc-loaded SLNs (ClAlPc/SLNs) were characterized according to their particle size and distribution, zeta potential, morphology, encapsulation efficiency, stability, and phototoxic action in vitro in B16-F10 melanoma cells. ClAlPc/SLN had a mean diameter between 100 and 200nm, homogeneous size distribution (polydispersity index <0.3), negative zeta potential, and spherical morphology. The encapsulation efficiency was approximately 100%. The lipid crystallinity was investigated using X-ray diffraction and differential scanning calorimetry and indicated that ClAlPc was integrated into the SLN matrix. The ClAlPc/SLN formulations maintained their physicochemical stability without expelling the drug over a 24-month period. Compared to free ClAlPc, ClAlPc/SLN exerted outstanding phototoxicity effects in vitro against melanoma cells. Therefore, our results demonstrated that the ClAlPc/SLN described in the current study has the potential for use in further preclinical and clinical trials in PDT for melanoma treatment.
Xue, Mei; Yang, Ming-xing; Zhang, Wei; Li, Xiu-min; Gao, De-hong; Ou, Zhi-min; Li, Zhi-peng; Liu, Su-huan; Li, Xue-jun; Yang, Shu-yu
The high aqueous solubility, poor permeability, and absorption of berberine (BBR) result in its low plasma level after oral administration, which greatly limits its clinical application. BBR solid lipid nanoparticles (SLNs) were prepared to achieve improved bioavailability and prolonged effect. Developed SLNs showed homogeneous spherical shapes, small size (76.8 nm), zeta potential (7.87 mV), encapsulation efficiency (58%), and drug loading (4.2%). The power of X-ray diffraction combined with (1)H nuclear magnetic resonance spectroscopy was employed to analyze chemical functional groups and the microstructure of BBR-SLNs, and indicated that the drug was wrapped in a lipid carrier. Single dose (50 mg/kg) oral pharmacokinetic studies in rats showed significant improvement (P<0.05) in the peak plasma concentration, area under the curve, and variance of mean residence time of BBR-SLNs when compared to BBR alone (P<0.05), suggesting improved bioavailability. Furthermore, oral administration of both BBR and BBR-SLNs significantly suppressed body weight gain, fasting blood glucose levels, and homeostasis assessment of insulin resistance, and ameliorated impaired glucose tolerance and insulin tolerance in db/db diabetic mice. BBR-SLNs at high dose (100 mg/kg) showed more potent effects when compared to an equivalent dose of BBR. Morphologic analysis demonstrated that BBR-SLNs potentially promoted islet function and protected the islet from regeneration. In conclusion, our study demonstrates that by entrapping BBR into SLNs the absorption of BBR and its anti-diabetic action were effectively enhanced.
Liu, Donghua; Liu, Chunxi; Zou, Weiwei; Zhang, Na
This study was aimed to prepare N3- O-toluyl-fluorouracil (TFu) loaded cationic solid lipid nanoparticles (TFu-SLNs) and evaluate the potential of a novel lipid-based drug delivery system to enhance the oral absorption of TFu. TFu-SLNs were prepared by the film dispersion-ultrasonication method, using hexadecyltrimethylammonium bromide as cationic tenside. The formulation and manufacture parameters were optimized concerning the drug encapsulation efficiency and the particle size. The in vitro release characteristics, in vivo pharmacokinetic properties and bioavailability, and in situ intestinal absorption features were investigated. The morphology of TFu-SLNs was approximately spherical and the mean particle size was 178.8 ± 9.99 nm; the zeta potential was +19.54 ± 0.32 mV. The mean entrapment efficiency and drug loading were 71.03 ± 1.19% and 3.57 ± 0.08%, respectively. The release behaviors of TFu from TFu-SLNs in PBS were fitted to the bioexponential model, while in artificial gastric juice, artificial intestinal juice and artificial gastric juice (2 h) followed by artificial intestinal juice (2-48 h) were fitted to the Weibull equation. The results of the pharmacokinetic studies in mice showed that the bioavailability of TFu-SLNs was significantly increased compared with that of the TFu suspensions after oral administration. The absorption of TFu-SLNs in intestine of rat was fitted to first-order kinetics with passive diffusion mechanism and the main segments of TFu-SLNs absorbed in intestine were duodenum and jejunum for the bioadhesion mediated by electrostatic interaction between the positively charged colloidal particles and the negatively charged mucosal surface. These results indicated that cationic SLNs would offer a promising delivery system for the facilitation of the bioavailability of poorly oral absorption drugs by enhancing the bioadhesion between the absorption mucosal surface and the drug carriers.
Hamishehkar, Hamed; Shokri, Javad; Fallahi, Shahoo; Jahangiri, Azin; Ghanbarzadeh, Saeed; Kouhsoltani, Maryam
Cellulite refers to dimpled appearance of the skin, usually located in the thighs and buttocks regions of most adult women. The aim of this study was to formulate topically used caffeine-loaded solid lipid nanoparticle (SLN) for the treatment of cellulite. SLNs were prepared by hot homogenization technique using Precirol® as lipid phase. The physical characterization and stability studies of SLNs as well as in vitro skin permeation and histological studies in rat skin were conducted. The mean particle size, encapsulation efficiency and loading efficiency percentages for optimized SLN formulation were 94 nm, 86 and 28%, respectively. In vitro drug release demonstrated that caffeine-loaded SLN incorporated into carbopol made hydrogel (caffeine-SLN-hydrogel) exhibited a sustained drug release compared to the caffeine hydrogel over 24 h. Caffeine-loaded SLNs showed a good stability during 12 months of storage at room temperature. The DSC and XRD results showed that caffeine was dispersed in SLN in an amorphous state. In vitro permeation studies illustrated higher drug accumulation in the skin with caffeine-SLN-hydrogel compared to caffeine hydrogel. The flux value of caffeine through rat skin in caffeine-SLN-hydrogel was 3.3 times less than caffeine hydrogel, representing lower systemic absorption. In contrast with caffeine hydrogel, the histological studies showed the complete lysis of adipocytes by administration of caffeine-SLN-hydrogel in the deeper skin layers. Results of this study indicated that SLNs are promising carrier for improvement of caffeine efficiency in the treatment of cellulite following topical application on the skin.
Wissing, S A; Müller, R H
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.
Oliveira, Mariana S; Mussi, Samuel V; Gomes, Dawidson A; Yoshida, Maria Irene; Frezard, Frederic; Carregal, Virgínia M; Ferreira, Lucas A M
This work aimed to develop solid lipid nanoparticles (SLN) co-loaded with doxorubicin and α-tocopheryl succinate (TS), a succinic acid ester of α-tocopherol that exhibits anticancer actions, evaluating the influence of TS on drug encapsulation efficiency. The SLN were characterized for size, zeta potential, entrapment efficiency (EE), and drug release. Studies of in vitro anticancer activity were also conducted. The EE was significantly improved from 30 ± 1% to 96 ± 2% for SLN without and with TS at 0.4%, respectively. In contrast, a reduction in particle size from 298 ± 1 to 79 ± 1 nm was observed for SLN without and with TS respectively. The doxorubicin release data show that SLN provide a controlled drug release. The in vitro studies showed higher cytotoxicity for doxorubicin-TS-loaded SLN than for free doxorubicin in breast cancer cells. These findings suggest that TS-doxorubicin-loaded SLN is a promising alternative for the treatment of cancer. Copyright © 2015 Elsevier B.V. All rights reserved.
Chen, Guohua; Zeng, Shuang; Jia, Huaijie; He, Xiaobing; Fang, Yongxiang; Jing, Zhizhong; Cai, Xuepeng
In this paper, we investigated the enhancement of adjuvant effects of porcine IL-2 (pIL-2) by packaging it into a solid lipid nanoparticle (SLN) delivery system. SLN-pIL-2 was prepared using hydrogenated castor oil and Polylactide-co-glycolide by double emulsion solvent evaporation methods (w/o/w). In animal trials, BALB/c mice were immunized with inactivated foot and mouth disease virus (FMDV) antigen combined with the SLN-pIL-2 adjuvant on days 0 and 14. Antibody titer, splenocyte proliferation, and secretion of IFN-γ and IL-4 cytokines were determined. Our results showed that SLN-pIL-2 could significantly enhance FMDV-specific antibody level compared with recombinant pIL-2 alone (p<0.05). In addition, SLN-pIL-2 significantly increased the proliferative responses of antigen-specific spleen cells. Furthermore, SLN-pIL-2 induced the secretion of IFN-γ at a level higher than that induced by recombinant pIL-2 alone. Our results indicate that packaging recombinant pIL-2 in SLNs can be an effective way of boosting the effectiveness of pIL-2 as an adjuvant to enhance immune responses of vaccines.
Radaic, Allan; de Paula, Eneida; de Jesus, Marcelo Bispo
Several scientific hurdles still have to be overcome before gene therapy becomes a reality. One of them is the development of safe and efficient gene delivery system. Here, we have employed factorial design to optimize the production of solid lipid nanoparticles (SLN) for gene delivery. A 2 x 3 full-factorial experimental design was used for the optimization of SLNs formulations. The variables were defined by the components of the formulation: concentration of stearic acid, DOTAP, and Pluronic F68 at two levels (-1, 1) and 3 central points (0). Different SNL formulations were prepared by varying the amount of components and several properties were tested, including their capacity to accommodate DNA and protection against DNase degradation, colloidal stability, in vitro cytotoxicity, and transfection efficiency in prostate cancer cells. Finally, response Surface Methodology was used to select the most effective formulation for gene delivery to prostate cancer cells in vitro. In conclusion, this study revealed that stearic acid and Pluronic F68 were determinant to SLN size and stability, respectively, while small amounts of DOTAP are essential for a successful transfection.
Mosallaei, Navid; Jaafari, Mahmoud Reza; Hanafi-Bojd, Mohammad Yahya; Golmohammadzadeh, Shiva; Malaekeh-Nikouei, Bizhan
The aim of the present study was to prepare, characterize, and evaluate solid lipid nanoparticles (SLNs) containing docetaxel (DTX) to improve the efficacy of this chemotherapeutic agent. SLNs containing DTX (SLN-DTX) were prepared by microemulsion and probe sonication techniques. In vitro cytotoxicity of SLN-DTX compared with Taxotere® (TXT) was evaluated on colorectal (C-26) and malignant melanoma (A-375) cell lines. Cellular uptake experiment was also carried out on C-26 cells. In in vivo tests, tumor inhibitory efficacy and survival were compared with TXT on C-26-implanted BALB/c mice. SLN-DTX particle size was 180 nm and PDI of 0.2 with spherical shape. Encapsulation efficacy was more than 98%. SLN-DTX at concentration of 100 μM caused 100% and 99.9% viability reduction in C-26 and A-375 after 48 and 72 h, respectively. The half maximal inhibitory concentration (IC50 ) of SLN-DTX on C-26 and A-375 was respectively 0.769 and 28.132 μM after 24 h. DTX cell uptake from SLN-DTX was remarkably higher than TXT. SLN-DTX showed better tumor inhibitory efficacy and survival at a dose of 10 mg/kg versus 10 and 20 mg/kg TXT. In conclusion, the results of the present study showed that the efficacy of SLN-DTX was better than TXT in cell-uptake and in vivo experiments.
Martins, Susana M; Sarmento, Bruno; Nunes, Cláudia; Lúcio, Marlene; Reis, Salette; Ferreira, Domingos C
This study intended to investigate the ability of solid lipid nanoparticles (SLN) to deliver camptothecin into the brain parenchyma after crossing the blood-brain barrier. For that purpose, camptothecin-loaded SLN with mean size below 200 nm, low polydispersity index (<0.25), negative surface charge (-20 mV), and high camptothecin association efficiency (>94%) were produced. Synchrotron small and wide angle X-ray scattering (SAXS/WAXS) analysis indicates that SLN maintain their physical stability in contact with DMPC membrane, whereas SLN change the lamellar structure of DMPC into a cubic phase, which is associated with efficient release of the incorporated drugs. Cytotoxicity studies against glioma and macrophage human cell lines revealed that camptothecin-loaded SLN induced cell death with the lowest maximal inhibitory concentration (IC50) values, revealing higher antitumour activity of camptothecin-loaded SLN against gliomas. Furthermore, in vivo biodistribution studies of intravenous camptothecin-loaded SLN performed in rats proved the positive role of SLN on the brain targeting since significant higher brain accumulation of camptothecin was observed, compared to non-encapsulated drug. Pharmacokinetic studies further demonstrated lower deposition of camptothecin in peripheral organs, when encapsulated into SLN, with consequent decrease in potential side toxicological effects. These results confirmed the potential of camptothecin-loaded SLN for antitumour brain treatments.
Bhalekar, Mangesh R; Madgulkar, Ashwini R; Desale, Puja S; Marium, Gyce
The purpose of this work was to formulate piperine solid lipid nanoparticle (SLN) dispersion to exploit its efficacy orally and topically. Piperine SLN were prepared by melt emulsification method and formula was optimized by the application of 3(2) factorial design. The nanoparticulate dispersion was evaluated for particle size, entrapment efficiency and zeta potential (ZP). Optimized batch (128.80 nm average size, 78.71% entrapment efficiency and -23.34 mV zeta potential) was characterized for differential scanning calorimetry (DSC), X-ray diffraction which revealed amorphous nature of piperine in SLN. The prepared SLN were administered orally and topically to CFA-induced arthritic rats. Ex vivo study using Franz diffusion cell indicate that piperine from SLN gel formulation accumulates in the skin. Pharmacodynamic study result indicates both the topical and oral piperine evoked a significant response compared to orally administered chloroquine suspension. The results of ELISA show significant reduction in TNFα in treated rat which might be the reason behind the DMARD action of piperine SLN.
Bikkad, Mahesh L; Nathani, Ajaz H; Mandlik, Satish K; Shrotriya, Shilpa N; Ranpise, Nisharani S
The clinical use of halobetasol propionate (HP) is related to some adverse effects like irritation, pruritus and stinging. The purpose of this work was to construct HP-loaded solid lipid nanoparticles (HP-SLN) formulation with skin targeting to minimizing the adverse side effects and providing a controlled release. HP-SLN were prepared by solvent injection method and formula was optimized by the application of 3(2) factorial design. The nanoparticulate dispersion was evaluated for particle size and entrapment efficiency (EE). Optimized batch was characterized for differential scanning calorimetry (DSC), scanning electron microscopy, X-ray diffraction study and finally incorporated into polymeric gels of carbopol for convenient application. The nanoparticulate gels were evaluated comparatively with the commercial product with respect to ex-vivo skin permeation and deposition study on human cadaver skins and finally skin irritation study. HP-SLN showed average size between 200 nm and 84-94% EE. DSC studies revealed no drug-excipient incompatibility and amorphous dispersed of HP in SLN. Ex vivo study of HP-SLN loaded gel exhibited prolonged drug release up to 12 h where as in vitro drug deposition and skin irritation studies showed that HP-SLN formulation can avoid the systemic uptake, better accumulative uptake of the drug and nonirritant to the skin compared to marketed formulation. These results indicate that the studied HP-SLN formulation represent a promising carrier for topical delivery of HP, having controlled drug release, and potential of skin targeting with no skin irritation.
Chirio, Daniela; Gallarate, Marina; Peira, Elena; Battaglia, Luigi; Muntoni, Elisabetta; Riganti, Chiara; Biasibetti, Elena; Capucchio, Maria Teresa; Valazza, Alberto; Panciani, Pierpaolo; Lanotte, Michele; Annovazzi, Laura; Caldera, Valentina; Mellai, Marta; Filice, Gaetano; Corona, Silvia; Schiffer, Davide
Paclitaxel loaded solid lipid nanoparticles (SLN) of behenic acid were prepared with the coacervation technique. Generally, spherical shaped SLN with mean diameters in the range 300–600 nm were obtained. The introduction of charged molecules, such as stearylamine and glycol chitosan into the formulation allowed to obtain positive SLN with Zeta potential in the 8-20 mV range and encapsulation efficiency in the 25–90% range.Blood–brain barrier (BBB) permeability, tested in vitro through hCMEC/D3 cells monolayer, showed a significantly increase in the permeation of Coumarin-6, used as model drug, when vehicled in SLN. Positive-charged SLN do not seem to enhance permeation although stearylamine-positive SLN resulted the best permeable formulation after 24 h.Cytotoxicity studies on NO3 glioblastoma cell line demonstrated the maintenance of cytotoxic activity of all paclitaxel-loaded SLN that was always unmodified or greater compared with free drug. No difference in cytotoxicity was noted between neutral and charged SLN.Co-culture experiments with hCMEC/D3 and different glioblastoma cells evidenced that, when delivered in SLN, paclitaxel increased its cytotoxicity towards glioblastoma cells.
Nguyen, Hiep Minh; Hwang, In-Cheon; Park, Jae-Won; Park, Hyun-Jin
In the natural environment, photodegradation is one of the most common degradative processes of pesticides. In order to reduce the photodegradation of pesticides, and so increase their killing activity against target pests, chitosan-coated beeswax solid lipid nanoparticles (CH-BSLNs) were prepared by a combination of hot homogenization and sonication, with deltamethrin as an active ingredient. Under optimal conditions, the highest encapsulation efficiency (95%) and a high payload of deltamethrin (approximately 12.5%) were achieved. In direct photolysis, in the case of CH-BSLNs after UV irradiation for 24 h, 37.3% of deltamethrin remained, as opposed to only 14.6% of the free-form deltamethrin. In addition, in indirect photolysis, in the case of CH-BSLNs after UV irradiation for 2 h in 2% acetone solution, approximately 74.5% of deltamethrin remained, as opposed to only 37.6% of the free-form deltamethrin. CH-BSLNs showed good protection for deltamethrin against photodegradation. This novel nanocarrier may be useful in crop protection as an economical strategy to enhance the effect of pesticides in the field and protect the environment as well. Copyright © 2012 Society of Chemical Industry.
Loureiro, Joana A; Andrade, Stephanie; Duarte, Ana; Neves, Ana Rute; Queiroz, Joana Fontes; Nunes, Cláudia; Sevin, Emmanuel; Fenart, Laurence; Gosselet, Fabien; Coelho, Manuel A N; Pereira, Maria Carmo
The aggregation of amyloid-β peptide (Aβ) has been linked to the formation of neuritic plaques, which are pathological hallmarks of Alzheimer's disease (AD). Various natural compounds have been suggested as therapeutics for AD. Among these compounds, resveratrol has aroused great interest due to its neuroprotective characteristics. Here, we provide evidence that grape skin and grape seed extracts increase the inhibition effect on Aβ aggregation. However, after intravenous injection, resveratrol is rapidly metabolized into both glucuronic acid and sulfate conjugations of the phenolic groups in the liver and intestinal epithelial cells (within less than 2 h), which are then eliminated. In the present study, we show that solid lipid nanoparticles (SLNs) functionalized with an antibody, the anti-transferrin receptor monoclonal antibody (OX26 mAb), can work as a possible carrier to transport the extract to target the brain. Experiments on human brain-like endothelial cells show that the cellular uptake of the OX26 SLNs is substantially more efficient than that of normal SLNs and SLNs functionalized with an unspecific antibody. As a consequence, the transcytosis ability of these different SLNs is higher when functionalized with OX-26.
Sun, Xue-hui; Guo, Tao; He, Jin; Zhao, Ming-hong; Nie, Shu-fang
To investigate the tissue distribution of the diallyl disulfide (DADS) and diallyl trisulfide (DATS) in solid lipid nanoparticles loaded garlic oil (GO-SLN) in rats. The gas chromatography-electron capture detection (GC-ECD) method was established to determined the DADS and DATS simultaneously in the biological samples of rats after administration of 0.5 mL garlic oil injection or GO-SLN (containing about 10 mg garlic oil) via jugular vein cannula. The conditions for gas chromatographic separation were as follows. The oven temperature was set at 110 degrees C and maintained for 15 min. Temperatures at the injection port and detector were 180 degrees C and 300 degrees C, respectively. Ultra-pure nitrogen (purity > 99.999%, Shenyang Kerui Special Gases Co. Ltd., China) was used as a carrier gas and made-up gas at flow-rates of 1 mL x min(-1) and 60 mL x min(-1), respectively. All injections were carried out in the split injection mode with a split ratio of 1:10. The GC-ECD method was fit for determing the concentration of DADS and DATS in garlic oil. The distribution character of GO-SLN in rats had changed to some extent and the concentration of GO-SLN in tissues was higher than that of GO-Injection. The SLN can elevate the passive targeting of drugs and lengthen their action time in tissues.
Battaglia, Luigi; Gallarate, Marina; Peira, Elena; Chirio, Daniela; Solazzi, Ilaria; Giordano, Susanna Marzia Adele; Gigliotti, Casimiro Luca; Riganti, Chiara; Dianzani, Chiara
Glioblastoma, the most common primary brain tumor in adults, has an inauspicious prognosis, given that overcoming the blood-brain barrier is the major obstacle to the pharmacological treatment of brain tumors. As neoangiogenesis plays a key role in glioblastoma growth, the US Food and Drug Administration approved bevacizumab (BVZ), an antivascular endothelial growth factor antibody for the treatment of recurrent glioblastoma in patients whose the initial therapy has failed. In this experimental work, BVZ was entrapped in solid lipid nanoparticles (SLNs) prepared by the fatty-acid coacervation technique, thanks to the formation of a hydrophobic ion pair. BVZ activity, which was evaluated by means of four different in vitro tests on HUVEC cells, increased by 100- to 200-fold when delivered in SLNs. Moreover, SLNs can enhance the permeation of fluorescently labelled BVZ through an hCMEC/D3 cell monolayer—an in vitro model of the blood brain barrier. These results are promising, even if further in vivo studies are required to evaluate the effective potential of BVZ-loaded SLNs in glioblastoma treatment.
Das, Shrabanti; Maity, Arnab; Purkayastha, Pradipta
Photophysical modulation of fisetin has been extensively studied in bulk aqueous as well as solid lipid nanoparticles (SLN) by varying the pH of the medium. The solution pH was varied from 5 to 9 to mimic biological environments. Neutral and anionic forms of fisetin coexist in ground state in both acidic and alkaline conditions. However, in the excited state and at low pH, the anionic form of fisetin predominates over the proton transferred form, whereas in SLNs, the proton transferred form is the major emitting species. Higher pH showed enhancement in anionic emission to different extent in the two types of environments. Limited percolation of H(+) and OH(-) ions inside the SLNs that host fisetin molecules controls their photophysics. The experimental results encourage usage of fisetin as a drug depending on the ratio of the neutral and anionic as well as the proton transferred forms under various pH conditions. Copyright © 2015 Elsevier B.V. All rights reserved.
Genç, Lütfi; Kutlu, H Mehtap; Güney, Gamze
Nanostructure-mediated drug delivery, a key technology for the realization of nanomedicine, has the potential to improve drug bioavailability, ameliorate release deviation of drug molecules and enable precision drug targeting. Due to their multifunctional properties, solid lipid nanoparticles (SLNs) have received great attention of scientists to find a solution to cancer. Vitamin supplements may contribute to a reduction in the risk of cancer. Vitamin B12 has several characteristics that make it an attractive entity for cancer treatment and possible therapeutic applications. The aim of this study was to produce B12-loaded SLNs (B12-SLNs) and determine the cytotoxic effects of B12-SLNs on H-Ras 5RP7 and NIH/3T3 control cell line. Results obtained by MTT assay, transmission electron and confocal microscopy showed that B12-loaded SLNs are more effective than free vitamin B12 on cancer cells. In addition, characterization studies indicate that while the average diameter of the B12 was about 650 nm, B12-SLNs were about 200 nm and the drug release efficiency of vit. B12 by means of SLNs increased up to 3 h. These observations point to the fact that B12-SLNs could be used as carrier systems due to the therapeutic effects on cancer.
Khameneh, Bahman; Halimi, Vahid; Jaafari, Mahmoud Reza; Golmohammadzadeh, Shiva
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
Sandri, Giuseppina; Bonferoni, Maria Cristina; D'Autilia, Francesca; Rossi, Silvia; Ferrari, Franca; Grisoli, Pietro; Sorrenti, Milena; Catenacci, Laura; Del Fante, Claudia; Perotti, Cesare; Caramella, Carla
The management of difficult to heal wounds can considerably reduce the time required for tissue repairing and promote the healing process, minimizing the risk of infection. Silver compounds, especially silver sulfadiazine (AgSD), are often used to prevent or to treat wound colonization, also in presence of antibiotic-resistant bacteria. However, AgSD has been shown to be cytotoxic in vitro toward fibroblasts and keratinocytes and consequently to retard wound healing in vivo. Recently, platelet lysate (PL) has been proposed in clinical practice for the healing of persistent lesions. The aim of the present work was the development of wound dressings based on AgSD loaded in solid lipid nanoparticles (SLNs), to be used in association with PL for the treatment for skin lesions. SLN were based on chondroitin sulfate and sodium hyaluronate, bioactive polymers characterized by well-known tissue repairing properties. The encapsulation of AgSD in SLN aimed at preventing the cytotoxic effect of the drug on normal human dermal fibroblasts (NHDFs) and at enabling the association of the drug with PL. SLN were loaded in wound dressings based on hydroxypropylmethyl cellulose (HPMC) or chitosan glutamate (CS glu). These polymers were chosen to obtain a sponge matrix with suitable elasticity and softness and, moreover, with good bioadhesive behavior on skin lesions. Dressings based on chitosan glutamate showed antimicrobial activity with and without PL. Even though further in vivo evaluation could be envisaged, chitosan based dressings demonstrated to be a suitable prototype for the treatment for skin lesions.
Pandurangan, Dinesh Kumar; Bodagala, Prathima; Palanirajan, Vijayaraj Kumar; Govindaraj, Saravanan
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.
Mulik, Rohit S; Mönkkönen, Jukka; Juvonen, Risto O; Mahadik, Kakasaheb R; Paradkar, Anant R
Photodegradation and low bioavailability are major hurdles for the therapeutic use of curcumin. Aim of the present study was to formulate transferrin-mediated solid lipid nanoparticles (Tf-C-SLN) to increase photostability, and enhance its anticancer activity against MCF-7 breast cancer cells. Tf-C-SLN were prepared by homogenization method and characterized by size, zeta potential, entrapment efficiency and stability, transmission electron microscopy (TEM), X-ray diffraction (XRD) and in vitro release study. Microplate analysis and flow cytometry techniques were used for cytotoxicity and apoptosis study. The physical characterization showed the suitability of method of preparation. TEM and XRD study revealed the spherical nature and entrapment of curcumin in amorphous form, respectively. The cytotoxicity, ROS and cell uptake was found to be increased considerably with Tf-C-SLN compared to curcumin solubilized surfactant solution (CSSS) and curcumin-loaded SLN (C-SLN) suggesting the targeting effect. AnnexinV-FITC/PI double staining, DNA analysis and reduced mitochondrial potential confirmed the apoptosis. The flow cytometric studies revealed that the anticancer activity of curcumin is enhanced with Tf-C-SLN compared to CSSS and C-SLN, and apoptosis is the mechanism underlying the cytotoxicity. The present study indicated the potential of Tf-C-SLN in enhancing the anticancer effect of curcumin in breast cancer cells in vitro.
Zhu, R. R.; Qin, L. L.; Wang, M.; Wu, S. M.; Wang, S. L.; Zhang, R.; Liu, Z. X.; Sun, X. Y.; Yao, S. D.
In an effort to develop an alternative formulation of podophyllotoxin suitable for drug release and delivery, podophyllotoxin-loaded solid lipid nanoparticles (PPT-SLNs) were constructed, characterized and examined for in vitro cytotoxicity and tumor inhibition. The SLNs were prepared by using a solvent emulsification-evaporation method, and their size was around 50 nm. TEM detection showed that the SLNs were homogeneous and spherical in shape, and differential scanning calorimetry (DSC) measurement revealed a new conformation of PPT-SLNs. An in vitro drug release study showed that PPT was released from the SLNs in a slow but time-dependent manner. Furthermore, the treatment of 293T and HeLa cells with PPT-SLNs demonstrated that PPT-SLNs were less toxic to normal cells and more effective in anti-tumor potency compared with unconjugated PPT. A colony forming efficiency assay showed an effective long-term cancer growth suppression of PPT-SLNs; in addition, they can also enhance the apoptotic and cellular uptake processes on tumor cells compared with PPT. These results collectively demonstrated that this SLN formulation has a potential application as an alternative delivery system for anti-tumor drugs.
Shah, Rohan M; Rajasekaran, Dhivya; Ludford-Menting, Mandy; Eldridge, Daniel S; Palombo, Enzo A; Harding, Ian H
Development of drug delivery systems, as much as the drug molecule itself, is an important consideration for improving drug absorption and bioavailability. The mechanisms by which drug carriers enter target cells can differ depending on their size, surface properties and components. Solid lipid nanoparticles (SLNs) have gained an increased attention in recent years and are the drug carriers of interest in this paper. They are known to breach the cell-membrane barrier and have been actively sought to transport biomolecules. Previous studies by our group, and also other groups, provided an extensive characterization of SLNs. However, few studies have investigated the uptake of SLNs and these have had limited mechanistic focus. The aim of this work was to investigate the pathway of uptake of SLNs by human epithelial cells i.e., lung A549 and cervical HeLa cells. To the best of our knowledge, this is first study that investigates the cellular uptake of SLNs by human epithelial cells. The mechanism of cellular uptake was deciphered using pharmacologic inhibitors (sucrose, potassium-free buffer, filipin and cytochalasin B). Imaging techniques and flow assisted cell sorting (FACS) were used to assess the cellular uptake of SLNs loaded with rhodamine 123 as a fluorescent probe. This study provided evidence that the cellular uptake of SLNs was energy-dependent, and the endocytosis of SLNs was mainly dependent on clathrin-mediated mechanisms. The establishment of entry mechanism of SLNs is of fundamental importance for future facilitation of SLNs as biological or drug carriers.
Penumarthi, Alekhya; Parashar, Deepti; Abraham, Amanda N.; Dekiwadia, Chaitali; Macreadie, Ian; Shukla, Ravi; Smooker, Peter M.
There is an increasing demand for novel DNA vaccine delivery systems, mainly for the non-viral type as they are considered relatively safe. Therefore, solid lipid nanoparticles (SLNs) were investigated for their suitability as a non-viral DNA vaccine delivery system. SLNs were synthesised by a modified solvent-emulsification method in order to study their potential to conjugate with plasmid DNA and deliver them in vitro to dendritic cells using eGFP as the reporter plasmid. The DNA-SLN complexes were characterised by electron microscopy, gel retardation assays and dynamic light scattering. The cytotoxicity assay data supported their biocompatibility and was used to estimate safe threshold concentration resulting in high transfection rate. The transfection efficiency of these complexes in a dendritic cell line was shown to increase significantly compared to plasmid alone, and was comparable to that mediated by lipofectamine. Transmission electron microscopy studies delineated the pathway of cellular uptake. Endosomal escape was observed supporting the mechanism of transfection.
Zhao, Yongxue; Wang, Chunling; Wang, Long; Yang, Qiang; Tang, Wenya; She, Zhennan; Deng, Yihui
Colloidal particles have preferential access to the lymphatic system following subcutaneous administration, achieving lymphatic targeting by drug accumulation in the regional lymph nodes. Moreover, the surface PEGylated colloidal particles have shown enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes after subcutaneous injection. Nevertheless, it is reported that upon repeated intravenous injection, the PEG-specific IgM produced by the administration of the PEGylated colloidal particles markedly accelerates the clearance of subsequent doses of PEGylated particles. In this article, we report that the first subcutaneous injection of PEGylated solid lipid nanoparticles also induces the intravenously administered PEGylated particles to be cleared very rapidly from the circulation, and the "ABC index," a parameter for the intensity of accelerated blood clearance, for subcutaneous injection was equivalent to or even lower than that following the first intravenous injection. Moreover, the small quantities of distributed particles in the spleen after the first s.c. dose but the significantly higher elimination rate of the second i.v. dose, strongly suggest that, in addition to the spleen, the regional lymph nodes also play a promotive role in this phenomenon, although the exact lymphocytes causing this phenomenon remain unclear. Our observations may thus have important implications for considering combination therapy with PEGylated productions requiring different administration routes such as intravenous and subcutaneous injection, and great care is needed. Copyright © 2012 Elsevier B.V. All rights reserved.
Montenegro, Lucia; Modica, Maria N; Salerno, Loredana; Panico, Anna Maria; Crascì, Lucia; Puglisi, Giovanni; Romeo, Giuseppe
Idebenone (IDE) has been proposed for the treatment of neurodegenerative diseases involving mitochondria dysfunctions. Unfortunately, to date, IDE therapeutic treatments have not been as successful as expected. To improve IDE efficacy, in this work we describe a two-step approach: (1) synthesis of IDE ester derivatives by covalent linking IDE to other two antioxidants, trolox (IDETRL) and lipoic acid (IDELIP), to obtain a synergic effect; (2) loading of IDE, IDETRL, or IDELIP into solid lipid nanoparticles (SLN) to improve IDE and its esters' water solubility while increasing and prolonging their antioxidant activity. IDE and its derivatives loaded SLN showed good physico-chemical and technological properties (spherical shape, mean particle sizes 23-25 nm, single peak in the size distribution, ζ potential values -1.76/-2.89 mV, and good stability at room temperature). In vitro antioxidant activity of these SLN was evaluated in comparison with free drugs by means of oxygen radical absorbance capacity (ORAC) test. IDETRL and IDELIP showed a greater antioxidant activity than IDE and encapsulation of IDE and its derivatives into SLN was able to prolong their antioxidant activity. These results suggest that loading IDETRL and IDELIP into SLN could be a useful strategy to improve IDE efficacy.
Jain, Amit K; Jain, Ashay; Garg, Neeraj K; Agarwal, Abhinav; Jain, Atul; Jain, Som Akshay; Tyagi, Rajeev K; Jain, Rakesh K; Agrawal, Himanshu; Agrawal, Govind P
Salient features such as controlled release, target ability, potential of penetration, improved physical stability, low cost compared to phospholipids, and ease of scaling-up makes solid lipid nanoparticles (SLNs) a viable alternative to liposomes for effective drug delivery. Adapalene (ADA) is a second generation retinoid effective in treating various dermatologic disorders such as Acne vulgaris with a few noticeable dose-mediated side effects. The present study was aimed at developing and characterizing ADA loaded SLNs for effective topical delivery. The formulated SLN system was characterized for particle size, poly dispersity index, entrapment efficiency and drug release properties. The resultant formulation (ADA loaded SLNs incorporated into carbopol hydrogel) was evaluated for in vitro drug release, skin permeation and bio-distribution, rheological behaviour, and texture profile analysis. The SLNs based ADA gel has shown its potential in targeting skin epidermal layer, and reducing systemic penetration. The developed system can avoid systemic uptake of ADA in skin layers, and can localize drug in skin epidermis as confirmed by rat skin model. Our results advocate potential of SLNs as a novel carrier for topical delivery of ADA in topical therapeutic approaches. This study open new avenues for drug delivery which better meets the need of anti-acne research. Copyright © 2014 Elsevier B.V. All rights reserved.
Berkman, M S; Yazan, Y
UV filters are traditionally classified as chemical absorbers and physical blockers depending on their mechanism of action. In this study, one of the most important chemical UVB absorber, octocrylene, was incorporated into Solid Lipid Nanoparticle (SLN) systems which themselves have UV blocking potential similar to physical blockers. Determination of octocrylene in the formulations was performed by HPLC (High Performance Liquid Chromatography) using a new validated method based on ICH harmonised tripartite guideline "validation of analytical procedures Q2(R1)". Determination and validation studies were carried out on a 4.6 x 250 mm, 5 microm C18 ACE column using an optimized mobile phase of acetonitrile:water (75:25, v/v) at a flow rate of 1.5 mL x min(-1). UV detection was performed at 210 nm and the column temperature was adjusted to 50 degrees C. Cyclosporine A was used as an internal standard (IS). The specified working range was derived from linearity studies and kept in the concentration range of 2.5 x -5.5 x 10(-5) M. Good correlation and accuracy were obtained. Limit of detection (LOD) and limit of quantitation (LOQ) values were determined to be 1.64 x 10(-6) M and 4.97 x 10-6 M, respectively. Octocrylene recovery % results of the SLN formulations stored at 25 degrees C, 4 degrees C and 40 degrees C for 360 days were investigated and compared to the freshly prepared samples.
Li, Shaoyong; Zhao, Baokai; Wang, Fenghua; Wang, Ming; Xie, Shuyu; Wang, Siliang; Han, Chao; Zhu, Luyan; Zhou, Wenzhong
To explore the potential of a novel animal interferon formulation for controlled release, the yak interferon-alpha (IFN-alpha) glutathione S-transferase (GST) fusion protein was expressed in Escherichia coli (E. coli) and the purified recombinant IFN-alpha was encapsulated into solid lipid nanoparticles (SLN) by double emulsion solvent evaporation (w/o/w) method. The particle size and zeta potential of IFN-alpha-loaded SLN were 124.2+/-10.2 nm and -11.2+/-0.6 mV. The encapsulation efficiency of IFN-alpha and loading capacity of the SLN were 83.7+/-4.5% and 1.73+/-0.15%, respectively. In vitro release study and antiviral assay demonstrated that the IFN-alpha released from the SLN in a 16-day period exhibited antiviral activity in Madin-Darby bovine kidney (MDBK) cells against vesicular stomatitis virus (VSV), and showed a release pattern of an initial burst release followed by a sustained and slow release. Cytotoxicity assay in cell culture demonstrated that the SLN were not toxic. The results of this exploratory study suggest that the IFN-alpha-loaded SLN could be a useful formulation for controlled release in veterinary therapeutics. Copyright 2009 Elsevier Ltd. All rights reserved.
Fazly Bazzaz, Bibi Sedigheh; Khameneh, Bahman; Zarei, Hamed; Golmohammadzadeh, Shiva
The aim of the present study was to assess the in vitro anti-biofilm activities of solid lipid nanoparticles (SLN) loaded with rifampin against biofilm-producing Staphylococcus epidermidis. SLN were prepared and characterized for size, zeta potentials and encapsulation efficacy. The morphological and thermal properties of formulation were evaluated by TEM imagining and DSC analysis. The anti-biofilm activity of different formulations was assessed at different incubation times and concentrations by crystal violet (CV) and viable biofilm count methods. The zeta potentials, particle sizes and encapsulation efficiencies of final formulations were 17 ± 0.7 mV, 101 ± 4.7 nm and approximately 70%; respectively. Rifampin-SLN was able to reduce the biomass of biofilm at time- and concentration-dependent manner. According to biofilm count results, the Rifampin-SLN was more effective for removal of the bacteria with respect to free rifampin. The results of this study highlight the advantages and efficiency of Rifampin-SLN in biofilm eradication. Copyright © 2016 Elsevier Ltd. All rights reserved.
Pandurangan, Dinesh Kumar; Bodagala, Prathima; Palanirajan, Vijayaraj Kumar; Govindaraj, Saravanan
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. PMID:27014620
Liu, Dongfei; Jiang, Sunmin; Shen, Hong; Qin, Shan; Liu, Juanjuan; Zhang, Qing; Li, Rui; Xu, Qunwei
The preparation of solid lipid nanoparticles (SLNs) suffers from the drawback of poor incorporation of water-soluble drugs. The aim of this study was therefore to assess various formulation and process parameters to enhance the incorporation of a water-soluble drug (diclofenac sodium, DS) into SLNs prepared by the emulsion/solvent evaporation method. Results showed that the entrapment efficiency (EE) of DS was increased to approximately 100% by lowering the pH of dispersed phase. The EE of DS-loaded SLNs (DS-SLNs) had been improved by the existence of cosurfactants and increment of PVA concentration. Stabilizers and their combination with PEG 400 in the dispersed phase also resulted in higher EE and drug loading (DL). EE increased and DL decreased as the phospholipid/DS ratio became greater, while the amount of DS had an opposite effect. Ethanol turned out to be the ideal solvent making DS-SLNs. EE and DL of DS-SLNs were not affected by either the stirring speed or the viscosity of aqueous and dispersed phase. According to the investigations, drug solubility in dispersion medium played the most important role in improving EE.
Ren, Jungang; Zou, Meijuan; Gao, Ping; Wang, Yue; Cheng, Gang
The main purpose of this research was to prepare borneol-modified and non-borneol ganciclovir-loaded solid lipid nanoparticles (SLNs) to study whether borneol could enhance the transport of ganciclovir (GCV) incorporated in SLN to the brain in mice after their intravenous administration. Ganciclovir injection (GCV-inj) was selected as a control. The SLNs were prepared using a modified microemulsion method. Pharmacokinetic and biodistribution studies were conducted in kunming mice after intravenous administration of GCV-inj, GCV solid lipid nanoparticles without borneol (GCV-SLN), and three types of GCV solid lipid nanoparticles containing different ratios of borneol (GCVb-SLN). It was found that, in plasma, the area under the concentration-time curve (AUC 0 ∼ t) for GCVb-SLN and GCV-SLN was greater than that for the GCV-inj. In the brain, the AUC 0 ∼ t of GCVb-SLN was significantly increased compared with that of a GCV-inj and GCV-SLN. In the other mouse tissues, the peak concentration of GCV achieved was always lower after the injection of any of the four types of SLN than after the commercial injection. These results indicate that GCV-SLN modified with borneol enhances the transport of ganciclovir to the brain. Therefore, SLN modified with borneol is a potential delivery system for transporting drugs to the central nervous system (CNS).
Misra, Shubham; Chopra, Kanwaljit; Sinha, V R; Medhi, Bikash
Galantamine hydrobromide, a promising acetylcholinesterase inhibitor is reported to be associated with cholinergic side effects. Its poor brain penetration results in lower bioavailability to the target site. With an aim to overcome these limitations, solid-lipid nanoparticulate formulation of galantamine hydrobromide was developed employing biodegradable and biocompatible components. The selected galantamine hydrobromide-loaded solid-lipid nanoparticles offered nanocolloidal with size lower than 100 nm and maximum drug entrapment 83.42 ± 0.63%. In vitro drug release from these spherical drug-loaded nanoparticles was observed to be greater than 90% for a period of 24 h in controlled manner. In vivo evaluations demonstrated significant memory restoration capability in cognitive deficit rats in comparison with naive drug. The developed carriers offered approximately twice bioavailability to that of plain drug. Hence, the galantamine hydrobromide-loaded solid-lipid nanoparticles can be a promising vehicle for safe and effective delivery especially in disease like Alzheimer's.
Pradhan, Madhulika; Singh, Deependra; Singh, Manju Rawat
Aim of the study was to develop solid lipid nanoparticles (SLN) of triamcinolone acetonide (TA) and to study the effect of various process variables in order to optimize the formulation for effective delivery. Drug loaded SLNs were successfully prepared and characterized by TEM, XRD and DSC study. Process variables like surfactant concentration, drug concentration, lipid concentration etc. showed significant effect on the particle size and entrapment efficiency. SLNs exhibited prolonged drug release following Higuchi release kinetics (R(2) = 0.9909). In vitro skin distribution study demonstrated systemic escape of drug from TA loaded SLNs which might eliminate side effects associated with systemic exposure.
Yuan, Qing; Han, Jing; Cong, Wenshu; Ge, Ying; Ma, Dandan; Dai, Zhaoxia; Li, Yaping; Bi, Xiaolin
Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors; however, its toxicity and side effects limit its clinical efficacy. Herein, docetaxel-loaded solid lipid nanoparticles (DSNs) were developed to reduce systemic toxicity of docetaxel while still keeping its anticancer activity. To evaluate its anticancer activity and toxicity, and to understand the molecular mechanisms of DSNs, different cellular, molecular, and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel (Taxotere®) and induced more apoptosis at 24 hours after treatment in vitro. DSNs can cause the treated cancer cells to arrest in the G2/M phase in a dose-dependent manner similar to Taxotere. They can also suppress tumor growth very effectively in a mice model with human xenograft breast cancer. Systemic analysis of gene expression profiles by microarray and subsequent verification experiments suggested that both DSNs and Taxotere regulate gene expression and gene function, including DNA replication, DNA damage response, cell proliferation, apoptosis, and cell cycle regulation. Some of these genes expressed differentially at the protein level although their messenger RNA expression level was similar under Taxotere and DSN treatment. Moreover, DSNs improved the main side effect of Taxotere by greatly lowering myelosuppression toxicity to bone marrow cells from mice. Taken together, these results expound the antitumor efficacy and the potential working mechanisms of DSNs in its anticancer activity and toxicity, which provide a theoretical foundation to develop and apply a more efficient docetaxel formulation to treat cancer patients. PMID:25378924
Xie, Shuyu; Pan, Baoliang; Shi, Baoxin; Zhang, Zhuangzhi; Zhang, Xu; Wang, Ming; Zhou, Wenzhong
Hydatid disease caused by tapeworm is an increasing public health and socioeconomic concern. In order to enhance the therapeutic efficacy of praziquantel (PZQ) against tapeworm, PZQ-loaded hydrogenated castor oil solid lipid nanoparticle (PZQ-HCO-SLN) suspension was prepared by a hot homogenization and ultrasonication method. The stability of the suspension at 4°C and room temperature was evaluated by the physicochemical characteristics of the nanoparticles and in-vitro release pattern of the suspension. Pharmacokinetics was studied after subcutaneous administration of the suspension in dogs. The therapeutic effect of the novel formulation was evaluated in dogs naturally infected with Echinococcus granulosus. The results showed that the drug recovery of the suspension was 97.59% ± 7.56%. Nanoparticle diameter, polydispersivity index, and zeta potential were 263.00 ± 11.15 nm, 0.34 ± 0.06, and -11.57 ± 1.12 mV, respectively and showed no significant changes after 4 months of storage at both 4°C and room temperature. The stored suspensions displayed similar in-vitro release patterns as that of the newly prepared one. SLNs increased the bioavailability of PZQ 5.67-fold and extended the mean residence time of the drug from 56.71 to 280.38 hours. Single subcutaneous administration of PZQ-HCO-SLN suspension obtained enhanced therapeutic efficacy against tapeworm in infected dogs. At the dose of 5 mg/kg, the stool-ova reduction and negative conversion rates and tapeworm removal rate of the suspension were 100%, while the native PZQ were 91.55%, 87.5%, and 66.7%. When the dose reduced to 0.5 mg/kg, the native drug showed no effect, but the suspension still got the same therapeutic efficacy as that of the 5 mg/kg native PZQ. These results demonstrate that the PZQ-HCO-SLN suspension is a promising formulation to enhance the therapeutic efficacy of PZQ.
Suter, Franz; Schmid, Daniel; Wandrey, Franziska; Zülli, Fred
The cosmetic industry requires more and more expensive actives and ingredients such as retinol, coenzyme Q10, proteins, peptides and biotechnologically produced molecules. In this study, we demonstrate the development of a cost effective formulation of a nanostructured lipid carrier (NLC) or solid lipid nanoparticles (SLN) improving peptide delivery into skin. NLC or SLN are very suitable vehicles for the delivery of active ingredients into skin. The SLN, produced by using hot high pressure homogenization method combine advantages such as physical stability, protection of incorporated labile actives and controlled release. By the used method we dispersed the amorphous heptapeptide DEETGEF in shea butter and homogenized this pre-dispersion at 60°C together with the water phase using a Microfluidizer at 1000bar. The analysis of the obtained SLN-P7 showed a particle size of 173nm, incorporated peptide of 0.014%, entrapment efficiency of 90.8%, melting peak (DSC) of the core lipid of 27°C and a zeta potential of -54mV. By an ex vivo study with skin explants we could stimulate NQO1 (NAD(P)H quinone oxidoreductase), HMOX1 (Heme oxygenase-1) and PRDX1 (Peroxiredoxin-1) genes all of which are cell protecting enzymes. In a multicellular protection against UV induced stress study with skin explants we detected the formation of sun burn cells and the number and morphology of Langerhans cells. The application of our SLN-P7 formulation on skin explants led to a significant and dose dependent protection against UV irradiation. In the clinical suction blister study, irradiation with UVA light for two hours after final product application led to a statistically significant increase of the 8-OhdG (8-hydroxy-2'-deoxyguanosine) concentration in the human epidermis. The skin treated with our verum formulation showed a statistically significant 20% decrease in DNA damage compared to placebo. In conclusion, it was demonstrated that SLN technology enabled peptide delivery into skin
Zhang, Yongtai; Li, Zhe; Zhang, Kai; Yang, Gang; Wang, Zhi; Zhao, Jihui; Hu, Rongfeng; Feng, Nianping
trans-Ferulic acid (TFA) has antioxidative, anti-inflammatory, and cardioprotective effects, but its poor solubility in water results in unsatisfactory oral bioavailability when administered conventionally at a standard dosage. However, the limited bioavailability of TFA can be overcome by delivering it in nanostructured lipid carriers (NLCs). In this study, a microemulsion (ME)-based method was used to prepare NLCs with ethyl oleate as the liquid lipid component and glyceryl behenate as the solid lipid component. These NLCs and solid lipid nanoparticles (SLNs) were then used as vehicles for TFA. Their entrapment efficiencies (EE), stability during storage, in vitro release profiles, and in vivo pharmacokinetics were compared. The NLC formulation afforded a drug entrapment efficiency that was significantly greater than that of the SLN formulation, which was made using a single solid lipid. Furthermore, the TFA that was dispersed in the disordered binary lipid matrix of the NLC formulation was more stable than that in the SLN formulation, and thus showed less expulsion from the vehicle during storage. In in vivo pharmacokinetic studies, the NLC TFA formulation yielded a greater Cmax and AUC than that produced by the SLN formulation and an aqueous TFA suspension. This showed that the oral bioavailability of TFA was markedly improved by packaging in NLCs. NLCs are thus a promising vehicle for oral TFA administration, with significant advantages over SLNs. Copyright © 2016 Elsevier B.V. All rights reserved.
Svetlichny, G; Külkamp-Guerreiro, I C; Cunha, S L; Silva, F E K; Bueno, K; Pohlmann, A R; Fuentefria, A M; Guterres, S S
The aim of this work was to develop solid lipid nanoparticles (SLN) containing copaiba oil with and without allantoin (NCOA, NCO, respectively) and to evaluate their antifungal activity. Nanoparticle suspensions were prepared using a high homogenisation technique and characterised by dynamic light scattering, laser diffraction, nanoparticle tracking analysis, multiple light scattering analysis, high-pressure liquid chromatography, pH and rheology. The antifungal activities of the formulations were tested in vitro against the emergent yeasts Candida krusei and Candida parapsilosis, and the fungal pathogens of human skin Trichophyton rubrum and Microsporum canis. The dynamic light scattering analysis showed z-average diameters (intensity) between 118.63 ± 8.89 nm for the nanoparticles with both copaiba oil and allantoin and 126.06 ± 9.84nm for the nanoparticles with just copaiba oil. The D[4,3] determined by laser diffraction showed similar results of 123 ± 1.73 nm for the nanoparticles with copaiba oil and allantoin and 130 ± 3.6 nm for the nanoparticles with copaiba oil alone. Nanoparticle tracking analysis demonstrated that both suspensions had monomodal profiles and consequently, the nanoparticle populations were homogeneous. This analysis also corroborated the results of dynamic light scattering and laser diffraction, exhibiting a smaller mean diameter for the nanoparticles with copaiba oil and allantoin (143 nm) than for the nanoparticles with copaiba oil (204 nm). The physicochemical properties indicated that the dispersions were stable overtime. Rheology evidenced Newtonian behaviour for both suspensions. Antifungal susceptibility showed a MIC90 of 125 μg/mL (nanoparticles with copaiba oil) and 7.8 μg/mL (nanoparticles with copaiba oil and allantoin) against C. parapsilosis. The nanoparticles with copaiba oil and the nanoparticles with copaiba oil and allantoin presented a MIC90 of 500 μg/mL and 250 μg/mL, respectively, against C. krusei. The MIC90
Chen, J; Dai, W T; He, Z M; Gao, L; Huang, X; Gong, J M; Xing, H Y; Chen, W D
Curcumin has very broad spectrum of biological activities; however, photodegradation, short half-life and low bioavailability have limited its clinical application. Curcumin-loaded solid lipid nanoparticles were studied to overcome these problems. The aim of this study was to optimize the best formulation on curcumin-loaded solid lipid nanoparticles. Emulsion-evaporation and low temperature-solidification technique was applied with monostearin as lipid carriers. The single factor analysis and orthogonal design were used to optimize formulation and various parameters were investigate. By the optimisation of a single factor analysis and orthogonal test, the particles size, polydispersity index, zeta potential, encapsulation efficiency and drug loading capacity of the optimised formulation were 99.99 nm, 0.158, -19.9 mV, 97.86%, and 4.35%, respectively. The differential scanning calorimetry and X-ray diffraction analysis results demonstrated new structure was formed in nanoparticles. The release kinetics in vitro demonstrated curcumin-loaded solid lipid nanoparticles can control drug release. These studies confirmed that curcumin-loaded solid lipid nanoparticles could be prepared successfully with high drug entrapment efficiency and loading capacity. Curcumin-loaded solid lipid nanoparticles may be a promising drug delivery system to control drug release and improve bioavailability.
Sucrose ester stabilized solid lipid nanoparticles and nanostructured lipid carriers: I. Effect of formulation variables on the physicochemical properties, drug release and stability of clotrimazole-loaded nanoparticles
Das, Surajit; Kiong Ng, Wai; Tan, Reginald B. H.
The objective of this study was to develop and evaluate solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) utilizing sucrose ester as a stabilizer/emulsifier for the controlled release of drug/active. Both SLNs and NLCs were prepared using different sugar esters to screen out the most suitable stabilizer. Clotrimazole was used as a model active/drug. The effect of different formulation variables on the particle size, polydispersity index and drug encapsulation efficiency of SLNs and NLCs was evaluated and compared. SLNs and NLCs were physicochemically characterized and compared using Cryo-SEM, DSC and XRD. Furthermore, a drug release study of SLNs and NLCs was conducted. Finally, physicochemical stability (size, PI, ZP, EE) of the SLNs and NLCs was checked at 25 ± 2 °C and at 2-8 °C. Among the sucrose esters, D-1216 was found to be most suitable for both SLNs and NLCs. Formulation variables exhibited a significant impact on size, PI and EE of the nanoparticles. SLNs with ˜120 nm size, ˜0.23 PI, ˜I26I mV ZP, ˜87% EE and NLCs with ˜160 nm size, 0.15 PI, ˜I26I mV ZP, ˜88% EE were produced. Cryo-SEM revealed spherical particles with a smooth surface but did not exhibit any difference in surface morphology between SLNs and NLCs. DSC and XRD results demonstrated the disappearance of clotrimazole peak(s) in drug-loaded SLNs and NLCs. Faster drug release was observed from SLNs than NLCs. NLCs were found to be more stable than SLNs in terms of size, PI, EE and drug release. The results indicated that both SLNs and NLCs stabilized with sucrose ester D-1216 can be used as controlled release carriers although NLCs have an edge over SLNs.
Lin, Chih-Hung; Chen, Chun-Han; Lin, Zih-Chan; Fang, Jia-You
Chemical and enzymatic barriers in the gastrointestinal (GI) tract hamper the oral delivery of many labile drugs. The GI epithelium also contributes to poor permeability for numerous drugs. Drugs with poor aqueous solubility have difficulty dissolving in the GI tract, resulting in low bioavailability. Nanomedicine provides an opportunity to improve the delivery efficiency of orally administered drugs. Solid lipid nanoparticles (SLNs) are categorized as a new generation of lipid nanoparticles consisting of a complete solid lipid matrix. SLNs used for oral administration offer several benefits over conventional formulations, including increased solubility, enhanced stability, improved epithelium permeability and bioavailability, prolonged half-life, tissue targeting, and minimal side effects. The nontoxic excipients and sophisticated material engineering of SLNs tailor the controllable physicochemical properties of the nanoparticles for GI penetration via mucosal or lymphatic transport. In this review, we highlight the recent progress in the development of SLNs for disease treatment. Recent application of oral SLNs includes therapies for cancers, central nervous system-related disorders, cardiovascular-related diseases, infection, diabetes, and osteoporosis. In addition to drugs that may be active cargos in SLNs, some natural compounds with pharmacological activity are also suitable for SLN encapsulation to enhance oral bioavailability. In this article, we systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for drug- and natural compound-loaded SLNs. Copyright © 2017. Published by Elsevier B.V.
Hamishehkar, Hamed; Same, Saeideh; Adibkia, Khosro; Zarza, Kamyar; Shokri, Javad; Taghaee, Mehran; Kouhsoltani, Maryam
The water content of the epidermis is a main factor in maintaining skin smoothness and elasticity and preventing skin dryness. Occlusive products can greatly affect skin hydration by forming a barrier on the skin following the topical administration of oil-based formulations. These products repair the skin barrier by restoring the skin lipids as well. Solid lipid nanoparticles (SLNs) have recently been introduced as a novel carrier with several benefits in pharmaceutics and cosmeceutics. It has been suggested that SLNs may have an occlusive effect following topical application. In this study, the occlusion effects of lipidic particles in different size ranges were investigated in vitro, ex vivo, and in vivo, and the results were compared with the positive (vaseline) and negative (blank) controls. Although larger lipidic particles showed better occlusion properties than nanoparticles in vitro, but ex vivo experiments confirmed the benefits of nanoparticles (almost 30% higher occlusion factor for particles in the range of 170 nm than ones in the range of 600 and 1800 nm). The superiority of SLN formulation to Vaseline as a positive reference was confirmed by the in vivo study. SLN formulation resulted in much thicker stratum corneum than Vaseline. It was indicated that in vitro and ex vivo study methods may not be a good reflective of the in vivo method for determining the occlusive properties of nanoparticulate systems. It was concluded that formulations containing SLNs can be used as efficient skin moisturizer products. PMID:26752986
Hamishehkar, Hamed; Same, Saeideh; Adibkia, Khosro; Zarza, Kamyar; Shokri, Javad; Taghaee, Mehran; Kouhsoltani, Maryam
The water content of the epidermis is a main factor in maintaining skin smoothness and elasticity and preventing skin dryness. Occlusive products can greatly affect skin hydration by forming a barrier on the skin following the topical administration of oil-based formulations. These products repair the skin barrier by restoring the skin lipids as well. Solid lipid nanoparticles (SLNs) have recently been introduced as a novel carrier with several benefits in pharmaceutics and cosmeceutics. It has been suggested that SLNs may have an occlusive effect following topical application. In this study, the occlusion effects of lipidic particles in different size ranges were investigated in vitro, ex vivo, and in vivo, and the results were compared with the positive (vaseline) and negative (blank) controls. Although larger lipidic particles showed better occlusion properties than nanoparticles in vitro, but ex vivo experiments confirmed the benefits of nanoparticles (almost 30% higher occlusion factor for particles in the range of 170 nm than ones in the range of 600 and 1800 nm). The superiority of SLN formulation to Vaseline as a positive reference was confirmed by the in vivo study. SLN formulation resulted in much thicker stratum corneum than Vaseline. It was indicated that in vitro and ex vivo study methods may not be a good reflective of the in vivo method for determining the occlusive properties of nanoparticulate systems. It was concluded that formulations containing SLNs can be used as efficient skin moisturizer products.
Gao, Gang; Liu, Ya; Zhou, Chang-Hua; Jiang, Ping; Sun, Jian-Jun
Background: Antioxidants and the duration of treatment after noise exposure on hearing recovery are important. We investigated the protective effects of an antioxidant substance, edaravone, and its slow-release dosage form, edaravone solid lipid nanoparticles (SLNs), in steady noise-exposed guinea pigs. Methods: SLNs loaded with edaravone were produced by an ultrasound technique. Edaravone solution or edaravone SLNs were administered by intratympanic or intravenous injection after the 1st day of noise exposure. Guinea pigs were exposed to 110 dB sound pressure level (SPL) noise, centered at 0.25–4.0 kHz, for 4 days at 2 h/d. After noise exposure, the guinea pigs underwent auditory brainstem response (ABR) threshold measurements, reactive oxygen species (ROS) were detected in their cochleas with electron spin resonance (ESR), and outer hair cells (OHCs) were counted with silvernitrate (AgNO3) staining at 1, 4, and 6 days. Results: The ultrasound technique was able to prepare adequate edaravone SLNs with a mean particle size of 93.6 nm and entrapment efficiency of 76.7%. Acoustic stress-induced ROS formation and edaravone exerted a protective effect on the cochlea. Comparisons of hearing thresholds and ROS changes in different animal groups showed that the threshold shift and ROS generation were significantly lower in treated animals than in those without treatment, especially in the edaravone SLN intratympanic injection group. Conclusions: Edaravone SLNs show noticeable slow-release effects and have certain protective effects against noise-induced hearing loss (NIHL). PMID:25591563
Abuasal, Bilal S; Lucas, Courtney; Peyton, Breanne; Alayoubi, Alaadin; Nazzal, Sami; Sylvester, Paul W; Kaddoumi, Amal
γ-Tocotrienol (γ-T3), a member of the vitamin E family, has been reported to possess an anticancer activity. γ-T3 is a lipophilic compound with low oral bioavailability. Previous studies showed that γ-T3 has low intestinal permeability. Thus, we have hypothesized that enhancing γ-T3 intestinal permeability will increase its oral bioavailability. Solid lipid nanoparticles (SLN) were tested as a model formulation to enhance γ-T3 permeability and bioavailability. γ-T3 intestinal permeability was compared using in situ rat intestinal perfusion, followed by in vivo relative oral bioavailability studies. In addition, in vitro cellular uptake of γ-T3 from SLN was compared to mixed micelles (MM) in a time and concentration-dependent studies. To elucidate the uptake mechanism(s) of γ-T3 from SLN and MM the contribution of NPC1L1 carrier-mediated uptake, endocytosis and passive permeability were investigated. In situ studies demonstrated SLN has tenfold higher permeability than MM. Subsequent in vivo studies showed γ-T3 relative oral bioavailability from SLN is threefold higher. Consistent with in situ results, in vitro concentration dependent studies revealed γ-T3 uptake from SLN was twofold higher than MM. In vitro mechanistic characterization showed that while endocytosis contributes to γ-T3 uptake from both formulations, the reduced contribution of NPC1L1 to the transport of γ-T3, and passive diffusion enhancement of γ-T3 are primary explanations for its enhanced uptake from SLN. In conclusion, SLN successfully enhanced γ-T3 oral bioavailability subsequent to enhanced passive permeability.
Dwivedi, Pankaj; Khatik, Renuka; Khandelwal, Kiran; Taneja, Isha; Raju, Kanumuri Siva Rama; Wahajuddin; Paliwal, Sarvesh Kumar; Dwivedi, Anil Kumar; Mishra, Prabhat Ranjan
Arteether (ART), an artemisinin derivative, is a life saving drug for multiple drug resistant malaria. It has a deliverance effect in Falciparum malaria and cerebral malaria. We have prepared solid lipid nanoparticles (SLN) by high pressure homogenization (HPH) technique. ART-loaded SLN (ART-SLN) has been produced reproducibly with homogeneous particle size. ART-SLN was characterized for their size measured by Zetasizer Nano-ZS, Malvern, UK and by high resolution transmission electron microscopy (HR-TEM) and which was found to be 100 ± 11.2 nm. The maximum percentage entrapment efficiency (%EE) determined with the high-performance liquid chromatography (HPLC) has been found to be 69 ± 4.2% in ART-SLN-3. The release pattern from ART-SLN revealed that the release of ART is slow but time-dependent manner, which is desirable as it will help to protect the acid degradation of ART in stomach. The percentage cytotoxicity of blank SLN has been found within the acceptable range. The pharmacokinetics results indicated that ART-SLN-3 absorption has been significantly enhanced in comparison to ART in aqueous suspension and ART in ground nut oil (GNO) in rats. The % relative bioavailability (RB%) of ART-SLN to the ART in GNO and ART in aqueous suspension in rats was 169.99% and 7461%, respectively which was found to be significantly high in both the cases. From the results, it can be concluded that ART-SLN offers a new approach to improve the oral bioavailability of ART.
Chen, Ruie; Wang, Shengpeng; Zhang, Jinming; Chen, Meiwan; Wang, Yitao
Aloe-emodin (AE) is a promising anti-tumor candidate for its significant activity against various tumors such as lung cancer, hepatic cancer, breast cancer and so on. Nevertheless, AE is clinically limited due to its poor water solubility and low bioavailability. This study was designed to prepare AE-loaded solid lipid nanoparticles (AE-SLNs) in an attempt to improve the anti-cancer efficacy of AE. The AE-SLNs were prepared with optimized prescription using high pressure homogenization (HPH) technique. Ultimately, the AE-SLNs showed stable particle size at 88.9 ± 5.2 nm, ideal drug entrapment efficiency (EE) of 97.71 ± 0.5% and good stability with regard to zeta-potential as high as -42.8 mV. The in vitro release profiles revealed that AE achieved sustained release by loading into SLNs. Moreover, AE-SLNs showed significantly higher in vitro cytotoxicity against human breast cancer MCF-7 cells and human hepatoma HepG2 cells as compared to the AE solution, while they showed no significant toxicity on human mammary epithelial MCF-10A cells. Hoechst 33342 staining and Annexin V/PI double staining indicated that AE-SLNs induced higher apoptotic rates in MCF-7 cells. Further study elucidated that the improved anti-cancer efficacy may be attributed to the increased cellular uptake of AE. Based on these findings, we believe that the development of AE-SLNs is an effective way for improving the anti-cancer efficacy of AE.
Kalhapure, Rahul S; Sonawane, Sandeep J; Sikwal, Dhiraj R; Jadhav, Mahantesh; Rambharose, Sanjeev; Mocktar, Chunderika; Govender, Thirumala
New and effective strategies to transform current antimicrobials are required to address the increasing issue of microbial resistance and declining introduction of new antibiotic drugs. In this context, metal complexes of known drugs and nano delivery systems for antibiotics are proving to be promising strategies. The aim of the study was therefore to synthesize a silver complex of clotrimazole and formulate it into a nano delivery system for enhanced and sustained antibacterial activity against susceptible and resistant Staphylococcus aureus. A silver complex of clotrimazole was synthesized, characterized and further encapsulated into solid lipid nanoparticles to evaluate its antibacterial activity against S. aureus and methicillin-resistant S. aureus (MRSA). An in vitro cytotoxicity study was performed on HepG2 cell lines to assess the overall biosafety of the synthesized clotrimazole silver complex to mammalian cells, and was found to be non-toxic to mammalian cells (cell viability >80%). The minimum inhibitory concentrations (MIC) of clotrimazole and clotrimazole-silver were 31.25 and 9.76 μg/mL against S. aureus, and 31.25 and 15.62 against MRSA, respectively. Clotrimazole SLNs exhibited MIC values of 104 and 208 μg/mL against both MSSA and MRSA at the end of 18 and 36 h, respectively, but thereafter completely lost its antibacterial activity. Clotrimazole-silver SLNs had an MIC value of 52 μg/mL up to 54 h, after which the MIC value was 104 μg/mL against both strains at the end of 72 h. Thus, clotrimazole-silver SLNs was found to be an efficient nanoantibiotic. Copyright © 2015 Elsevier B.V. All rights reserved.
Gaber, Dina M; Nafee, Noha; Abdallah, Osama Y
Myricetin - a natural flavonoid - has attracted a great interest due to its antioxidant and free-radical scavenging potential. However, its physicochemical instability critically impairs its dosage form design, evaluation and administration. In an attempt to protect from degradation, MYR was encapsulated into Gelucire-based solid lipid nanoparticles (SLNs). The impact of medium pH, processing temperature and different additives on the drug degradation either in free or nanoencapsulated form was assessed. MYR stability was further monitored in essential biorelevant fluids. Investigations have led to the recommendation that the presence of fat-soluble antioxidant is necessary during SLN preparation to protect the drug at high temperature. Meanwhile, physiological buffers as well as simulated fluids should be supplemented with stabilizers as tween 80 and Poloxamer 407, in addition to water-soluble antioxidant such as sodium sulfite. Interestingly, mucin-containing fluids are suggested to provide better protection to MYR, in contrast, cell culture media do not guarantee MYR stability. The degradation kinetics changed from 1st to 2nd order mechanism after MYR nanoencapsulation. In presence of the aforementioned additives, MYR-SLNs significantly reduced the drug degradation rate constant up to 300-folds and prolonged the half-life time up to 4500-folds compared to free MYR in physiological buffers (One-way ANOVA, p<0.05). As a proof of concept, in vitro release experiment in presence of phosphate buffer (pH7.4) supplemented with these additives ensured sustained release of MYR over >8h with no signs of degradation. The study emphasizes virtuous guidance regarding appropriate nanoencapsulation conditions and evaluation attributes ensuing MYR physicochemical stability. Copyright © 2017. Published by Elsevier B.V.
Fang, Yi-Ping; Chuang, Chih-Hung; Wu, Pao-Chu; Huang, Yaw-Bin; Tzeng, Cherng-Chyi; Chen, Yeh-Long; Liu, Ya-Ting; Tsai, Yi-Hung; Tsai, Ming-Jun
Amsacrine analog is a novel chemotherapeutic agent that provides potentially broad antitumor activity when compared to traditional amsacrine. However, the major limitation of amsacrine analog is that it is highly lipophilic, making it nonconductive to intravenous administration. The aim of this study was to utilize solid lipid nanoparticles (SLN) to resolve the delivery problem and to investigate the biodistribution of amsacrine analog-loaded SLN. Physicochemical characterizations of SLN, including particle size, zeta potential, entrapment efficiency, and stability, were evaluated. In vitro release behavior was also measured by the dialysis method. In vivo pharmacokinetics and biodistribution behavior of amsacrine analog were investigated and incorporated with a non invasion in vivo imaging system to confirm the localization of SLN. The results showed that amsacrine analog-loaded SLN was 36.7 nm in particle size, 0.37 in polydispersity index, and 34.5±0.047 mV in zeta potential. More than 99% of amsacrine analog was successfully entrapped in the SLN. There were no significant differences in the physicochemical properties after storage at room temperature (25°C) for 1 month. Amsacrine analog-loaded SLN maintained good stability. An in vitro release study showed that amsacrine analog-loaded SLN sustained a release pattern and followed the zero equation. An in vivo pharmacokinetics study showed that amsacrine analog was rapidly distributed from the central compartment to the tissue compartments after intravenous delivery of amsacrine analog-loaded SLN. The biodistribution behavior demonstrated that amsacrine analog mainly accumulated in the lungs. Noninvasion in vivo imaging system images also confirmed that the drug distribution was predominantly localized in the lungs when IR-780-loaded SLN was used. PMID:27019595
Müller, R H; Runge, S; Ravelli, V; Mehnert, W; Thünemann, A F; Souto, E B
For the development of an optimized oral formulation for cyclosporine A, 2% of this drug has been formulated in solid lipid nanoparticles (SLN, mean size 157 nm) and as nanocrystals (mean size 962 nm). The encapsulation rate of SLN was found to be 96.1%. Nanocrystals are composed of 100% of drug. For the assessment of the pharmacokinetic parameters the developed formulations have been administered via oral route to three young pigs. Comparison studies with a commercial Sandimmun Neoral/Optoral used as reference have been performed. The blood profiles observed after oral administration of the commercial microemulsion Sandimmun revealed a fast absorption of drug leading to the observation of a plasma peak above 1,000 ng/ml within the first 2 h. For drug nanocrystals most of the blood concentrations were in the range between 30 and 70 ng/ml over a period of 14 h. These values were very low, showing huge differences between the measuring time points and between the tested animals. On the contrary, administration of cyclosporine-loaded SLN led to a mean plasma profile with almost similarly low variations in comparison to the reference microemulsion, however with no initial blood peak as observed with the Sandimmun Neoral/Optoral. Comparing the area under the curves (AUC) obtained with the tested animals it could be stated that the SLN formulation avoids side effects by lacking blood concentrations higher than 1,000 ng/ml. In this study it has been proved that using SLN as a drug carrier for oral administration of cyclosporine A a low variation in bioavailability of the drug and simultaneously avoiding the plasma peak typical of the first Sandimmun formulation can be achieved.
Wang, Taoran; Ma, Xiaoyu; Lei, Yu; Luo, Yangchao
Solid lipid nanoparticles (SLNs) are regarded as promising carriers to improve the safety and effectiveness of delivery for drugs and nutrients, however, the clinic applications for oral administration are limited by their poor stability in gastrointestinal conditions. In this study, surface modification was explored to confer new physicochemical properties to SLNs and thus achieve enhanced functionalities. Novel SLNs with biopolymeric double layer (DL) coating using two natural biopolymers, i.e. caseinate (NaCas) and pectin, were prepared to encapsulate and deliver curcumin, a lipophilic bioactive compound studied as a model drug/nutrient. The DL coating was chemically cross-linked by creating covalent bonds between NaCas and pectin, using two different cross-linkers, i.e. glutaraldehyde (GA) and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-Hydroxysuccinimide (EDC/NHS). Prior to cross-linking, the mean particle size, polydispersity index and zeta potential of DL-SLNs were 300-330nm, 0.25-0.30, -45-40mV, respectively. It was found that cross-linking with GA had a more prominent effect on particle size and polydispersity index than EDC/NHS. The cross-linking process significantly improved physicochemical properties of DL-SLNs, resulting in higher encapsulation efficiency and loading capacity, better stability and slower release profile in simulated gastrointestinal conditions. Particularly, an optimal zero-order release kinetic was observed for EDC/NHS crosslinked DL-SLNs. The electron microscopy revealed that both cross-linked DL-SLNs exhibited spherical shape with homogeneous size and smooth surface. Encapsulation of curcumin in SLNs dramatically enhanced its antioxidant activity in aqueous condition. The cross-linking process further helped spray drying of SLNs by forming homogenous powder particles. These results indicated that coating with cross-linked polymers could significantly improve the physicochemical properties of SLNs and expand their potentials as
Varshosaz, Jaleh; Jafarian, Abbas; Salehi, Golnaz; Zolfaghari, Behzad
Quercetin (QT) is a potential chemotherapeutic drug with low solubility that seriously limits its clinical use. The aim of this study was enhancing cellular penetration of QT by sterol containing solid lipid nanoparticles (SLNs) which make bilayers fluent for targeting hepatocellular carcinoma cells. Three variables including sterol type (cholesterol, stigmasterol and stigmastanol), drug and sterol content were studied in a surface response D-optimal design for preparation of QT-SLNs by emulsification solvent evaporation method. The studied responses included particle size, zeta potential, drug loading capacity and 24 h release efficiency (RE24%). Scanning electron and atomic force microscopy were used to study the morphology of QT-SLNs and their thermal behavior was studied by DSC analysis. Cytotoxicity of QT-SLNs was determined by MTT assay on HepG-2 cells and cellular uptake by fluorescence microscopy method. Optimized QT-SLNs obtained from cholesterol and QT with the ratio of 2:1 that showed particle size of 78.0 ± 7.0 nm, zeta potential of -22.7 ± 1.3 mV, drug loading efficiency of 99.9 ± 0.5% and RE24 of 56.3 ± 3.4%. IC50 of QT in cholesterol SLNs was about six and two times less than free QT and phytosterol SLNs, respectively, and caused more accumulation of QT in HepG2 cells. Blank phytosterol SLNs were toxic on cells.
Minelli, R; Serpe, L; Pettazzoni, P; Minero, V; Barrera, G; Gigliotti, CL; Mesturini, R; Rosa, AC; Gasco, P; Vivenza, N; Muntoni, E; Fantozzi, R; Dianzani, U; Zara, GP; Dianzani, C
BACKGROUND AND PURPOSE Cholesteryl butyrate solid lipid nanoparticles (cholbut SLN) provide a delivery system for the anti-cancer drug butyrate. These SLN inhibit the adhesion of polymorphonuclear cells to the endothelium and may act as anti-inflammatory agents. As cancer cell adhesion to endothelium is crucial for metastasis dissemination, here we have evaluated the effect of cholbut SLN on adhesion and migration of cancer cells. EXPERIMENTAL APPROACH Cholbut SLN was incubated with a number of cancer cell lines or human umbilical vein endothelial cells (HUVEC) and adhesion was quantified by a computerized micro-imaging system. Migration was detected by the scratch ‘wound-healing’ assay and the Boyden chamber invasion assay. Expression of ERK and p38 MAPK was analysed by Western blot. Expression of the mRNA for E-cadherin and claudin-1 was measured by RT-PCR. KEY RESULTS Cholbut SLN inhibited HUVEC adhesiveness to cancer cell lines derived from human colon–rectum, breast, prostate cancers and melanoma. The effect was concentration and time-dependent and exerted on both cancer cells and HUVEC. Moreover, these SLN inhibited migration of cancer cells and substantially down-modulated ERK and p38 phosphorylation. The anti-adhesive effect was additive to that induced by the triggering of B7h, which is another stimulus inhibiting both ERK and p38 phosphorylation, and cell adhesiveness. Furthermore, cholbut SLN induced E-cadherin and inhibited claudin-1 expression in HUVEC. CONCLUSION AND IMPLICATIONS These results suggest that cholbut SLN could act as an anti-metastastic agent and they add a new mechanism to the anti-tumour activity of this multifaceted preparation of butyrate. PMID:22049973
Chetoni, Patrizia; Burgalassi, Susi; Monti, Daniela; Tampucci, Silvia; Tullio, Vivian; Cuffini, Anna Maria; Muntoni, Elisabetta; Spagnolo, Rita; Zara, Gian Paolo; Cavalli, Roberta
Eye drops are widely accepted as formulations for targeting the anterior segment notwithstanding their limitations in terms of bioavailability. The unique structure of the eye requires specially-designed formulations able to favor the pharmacokinetic profile of administered drugs, mainly minimizing the influence of ocular barriers. Nanotechnology-based delivery systems lead to significant technological and therapeutical advantages in ophthalmic therapy. The aim of the present study was to determine whether tobramycin as ion-pair incorporated in mucoadhesive Solid Lipid Nanoparticles (SLN) reaches the inner parts of the eye favoring drug activity. After technological characterization of the tobramycin entrapped SLN formulation (Tobra-SLN), a pharmacokinetic study in rabbits after topical instillation and intravenous administration of the formulation has been carried out. In addition, the intracellular activity of Tobra-SLN formulation against phagocytosed Pseudomonas aeruginosa was investigated. The SLN were spherical in shape, and showed a hydrodynamic diameter of about 80nm, a negative zeta potential (-25.7mV) with a polydispersity index of 0.15, representative of a colloidal dispersion with high quality, characterized by an unimodal relatively narrow size distribution. As demonstrated by FTIR and DSC, tobramycin ion-pair could be concentrated into lipid inner core of SLN, without interaction with the stearic acid, thus promoting a slow and constant drug release profile in the dissolution medium. Surprisingly, the drug concentration was significantly higher in all ocular tissues after ocular and intravenous administration of Tobra-SLN formulation with respect to reference formulations and only Tobra-SLN allowed the penetration of drug into retina. Furthermore, the use of Tobra-SLN resulted in both higher intraphagocytic antibiotic concentrations in polymorphonuclear granulocytes and greater bactericidal activity against intracellular Pseudomonas aeruginosa
Ruktanonchai, Uracha; Limpakdee, Surachai; Meejoo, Siwaporn; Sakulkhu, Usawadee; Bunyapraphatsara, Nuntavan; Junyaprasert, Varaporn; Puttipipatkhachorn, Satit
This present study was aimed at investigating the effect of the crystallinity of cetyl palmitate based solid lipid nanoparticles (SLNs) on the physical properties of γ-oryzanol-loaded SLNs. SLNs consisting of varying ratios of cetyl palmitate and γ-oryzanol were prepared. Their hydrodynamic diameters were in the range 210-280 nm and the zeta potentials were in the range -27 to -35 mV. The size of SLNs increased as the amount of cetyl palmitate decreased whereas no significant change of zeta potentials was found. Atomic force microscopy pictures indicated the presence of disc-like particles. The crystallinity of SLNs, determined by differential scanning calorimetry and powder x-ray diffraction, was directly dependent on the ratio of cetyl palmitate to γ-oryzanol and decreased with decreasing cetyl palmitate content in the lipid matrix. Varying this ratio in the lipid mix resulted in a shift in the melting temperature and enthalpy, although the SLN structure remained unchanged as an orthorhombic lamellar lattice. This has been attributed to a potential inhibition by γ-oryzanol during lipid crystal growth as well as a less ordered structure of the SLNs. The results revealed that the crystallinity of the SLNs was mainly dependent on the solid lipid, and that the crystallinity has an important impact on the physical characteristics of active-loaded SLNs.
Tran, Tuan Hiep; Choi, Ju Yeon; Ramasamy, Thiruganesh; Truong, Duy Hieu; Nguyen, Chien Ngoc; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh
Hyaluronic acid (HA)-decorated solid lipid nanoparticles (SLNs) were developed for tumor-targeted delivery of vorinostat (VRS), a histone deacetylase inhibitor. HA, a naturally occurring polysaccharide, which specifically binds to the CD44 receptor, was coated on a cationic lipid core through electrostatic interaction. After the optimization process, HA-coated VRS-loaded SLNs (HA-VRS-SLNs) were spherical, core-shell nanoparticles, with small size (∼100 nm), negative charge (∼-9 mV), and narrow size distribution. In vitro release profile of HA-VRS-SLNs showed a typical bi-phasic pattern. In addition, the intracellular uptake of HA-VRS-SLNs was significantly enhanced in CD44 overexpressing cells, A549 and SCC-7 cells, but reduced when HA-VRS-SLNs were incubated with SCC-7 cells pretreated with HA or MCF-7 cells with low over-expressed CD44. Of particular importance, HA-VRS-SLNs were more cytotoxic than the free drug and VRS-SLNs in A549 and SCC-7 cells. In addition, HA shell provided longer blood circulation and reduced VRS clearance rate in rats, resulting in enhanced higher plasma concentration and bioavailability. These results clearly indicated the potential of the HA-functionalized lipid nanoparticle as a nano-sized drug formulation for chemotherapy.
Ji, Peng; Yu, Tong; Liu, Ying; Jiang, Jie; Xu, Jie; Zhao, Ying; Hao, Yanna; Qiu, Yang; Zhao, Wenming; Wu, Chao
Naringenin (NRG), a flavonoid compound, had been reported to exhibit extensive pharmacological effects, but its water solubility and oral bioavailability are only~46±6 µg/mL and 5.8%, respectively. The purpose of this study is to design and develop NRG-loaded solid lipid nanoparticles (NRG-SLNs) to provide prolonged and sustained drug release, with improved stability, involving nontoxic nanocarriers, and increase the bioavailability by means of pulmonary administration. Initially, a group contribution method was used to screen the best solid lipid matrix for the preparation of SLNs. NRG-SLNs were prepared by an emulsification and low-temperature solidification method and optimized using an orthogonal experiment approach. The morphology was examined by transmission electron microscopy, and the particle size and zeta potential were determined by photon correlation spectroscopy. The total drug content of NRG-SLNs was measured by high-performance liquid chromatography, and the encapsulation efficiency (EE) was determined by Sephadex gel-50 chromatography and high-performance liquid chromatography. The in vitro NRG release studies were carried out using a dialysis bag. The best cryoprotectant to prepare NRG-SLN lyophilized powder for future structural characterization was selected using differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy. The short-term stability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, cellular uptake, and pharmacokinetics in rats were studied after pulmonary administration of NRG-SLN lyophilized powder. Glycerol monostearate was selected to prepare SLNs, and the optimal formulation of NRG-SLNs was spherical in shape, with a particle size of 98 nm, a polydispersity index of 0.258, a zeta potential of −31.4 mV, a total drug content of 9.76 mg, an EE of 79.11%, and a cumulative drug release of 80% in 48 hours with a sustained profile. In addition, 5% mannitol (w
Ji, Peng; Yu, Tong; Liu, Ying; Jiang, Jie; Xu, Jie; Zhao, Ying; Hao, Yanna; Qiu, Yang; Zhao, Wenming; Wu, Chao
Naringenin (NRG), a flavonoid compound, had been reported to exhibit extensive pharmacological effects, but its water solubility and oral bioavailability are only~46±6 µg/mL and 5.8%, respectively. The purpose of this study is to design and develop NRG-loaded solid lipid nanoparticles (NRG-SLNs) to provide prolonged and sustained drug release, with improved stability, involving nontoxic nanocarriers, and increase the bioavailability by means of pulmonary administration. Initially, a group contribution method was used to screen the best solid lipid matrix for the preparation of SLNs. NRG-SLNs were prepared by an emulsification and low-temperature solidification method and optimized using an orthogonal experiment approach. The morphology was examined by transmission electron microscopy, and the particle size and zeta potential were determined by photon correlation spectroscopy. The total drug content of NRG-SLNs was measured by high-performance liquid chromatography, and the encapsulation efficiency (EE) was determined by Sephadex gel-50 chromatography and high-performance liquid chromatography. The in vitro NRG release studies were carried out using a dialysis bag. The best cryoprotectant to prepare NRG-SLN lyophilized powder for future structural characterization was selected using differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy. The short-term stability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, cellular uptake, and pharmacokinetics in rats were studied after pulmonary administration of NRG-SLN lyophilized powder. Glycerol monostearate was selected to prepare SLNs, and the optimal formulation of NRG-SLNs was spherical in shape, with a particle size of 98 nm, a polydispersity index of 0.258, a zeta potential of -31.4 mV, a total drug content of 9.76 mg, an EE of 79.11%, and a cumulative drug release of 80% in 48 hours with a sustained profile. In addition, 5% mannitol (w
Sakaguchi, Naotoshi; Kimura, Yasuo; Hirano-Iwata, Ayumi; Ogino, Toshio
We fabricated gold nanoparticle (Au-NP)-embedded supported lipid bilayers (SLBs) by two methods. In the vesicle-vesicle fusion method, vesicles with hydrophobized Au-NPs are ruptured and fused on SiO2/Si substrates. In the vesicle-membrane fusion method, SLBs without Au-NPs were preformed on the substrate and then vesicles with Au-NPs were fused into the preformed membranes. In the former method, Au-NP incorporation into the SLBs was observed as an increase in the membrane thickness in atomic force microscopy (AFM) images and directly observed by transmission electron microscopy. In the latter method, fusion of vesicles into the preformed membranes was confirmed by the fluorescent color change in the preformed membranes, and Au-NP incorporation was also confirmed by an increase in the membrane thickness in the AFM images. Key techniques for the successful vesicle-membrane fusion are hydrophobization of Au-NPs, approach control of vesicles by mixing the charged lipids, and destabilization of the lipid bilayers by adding lipids with a small polar headgroup.
Nabi-Meibodi, Mohsen; Vatanara, Alireza; Najafabadi, Abdolhossein Rouholamini; Rouini, Mohammad Reza; Ramezani, Vahid; Gilani, Kambiz; Etemadzadeh, Seyed Mohammad Hossein; Azadmanesh, Kayhan
Raloxifene HCl (RH), a selective estrogen receptor modulator (SERM), is indicated for the prophylaxis or treatment of postmenopausal osteoporosis. RH shows extremely poor bioavailability due to limited solubility and an extensive intestinal/hepatic first-pass metabolism. Solid lipid nanoparticles (SLNs) are valuable carriers that can enhance drug bioavailability. However, in the case of RH, the encapsulation of the drug in SLNs remains a challenge because of its poor solubility in both water and lipids. In this study, a series of RH-containing SLNs (RH-SLNs) were generated using a modified double emulsion solvent evaporation (DESE) method. Briefly, RH with various drug/lipid ratios was solubilized in the inner core of a double emulsion using different water/organic solvent mixtures. Our best formulation was achieved with the formation of negatively charged nanoparticles, 180nm in diameter, with an encapsulation and loading efficiency of 85% and 4.5%, respectively. It also showed a Fickian mechanism of the drug release in the basic dissolution media. Thermal analysis revealed a distinct decrease in the crystallinity of lipids and RH in comparison with the unprocessed materials. The results of a cell viability assay also showed a better antiproliferative effect of the drug-loaded SLNs versus the free drug solution. Thus, these results indicated that the modified DESE method could be proposed for the effective encapsulation of RH in SLNs with appropriate physicochemical and biological properties. Copyright © 2013 Elsevier B.V. All rights reserved.
Madureira, Ana Raquel; Nunes, Sara; Campos, Débora A; Fernandes, João C; Marques, Cláudia; Zuzarte, Monica; Gullón, Beatriz; Rodríguez-Alcalá, Luís M; Calhau, Conceição; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Maria Manuela; Reis, Flávio
Rosmarinic acid (RA) possesses several protective bioactivities that have attracted increasing interest by nutraceutical/pharmaceutical industries. Considering the reduced bioavailability after oral use, effective (and safe) delivery systems are crucial to protect RA from gastrointestinal degradation. This study aims to characterize the safety profile of solid lipid nanoparticles produced with Witepsol and Carnauba waxes and loaded with RA, using in vitro and in vivo approaches, focused on genotoxicity and cytotoxicity assays, redox status markers, hematological and biochemical profile, liver and kidney function, gut bacterial microbiota, and fecal fatty acids composition. Free RA and sage extract, empty nanoparticles, or nanoparticles loaded with RA or sage extract (0.15 and 1.5 mg/mL) were evaluated for cell (lymphocytes) viability, necrosis and apoptosis, and antioxidant/prooxidant effects upon DNA. Wistar rats were orally treated for 14 days with vehicle (control) and with Witepsol or Carnauba nanoparticles loaded with RA at 1 and 10 mg/kg body weight/d. Blood, urine, feces, and several tissues were collected for analysis. Free and loaded RA, at 0.15 mg/mL, presented a safe profile, while genotoxic potential was found for the higher dose (1.5 mg/mL), mainly by necrosis. Our data suggest that both types of nanoparticles are safe when loaded with moderate concentrations of RA, without in vitro genotoxicity and cytotoxicity and with an in vivo safety profile in rats orally treated, thus opening new avenues for use in nutraceutical applications.
Madureira, Ana Raquel; Nunes, Sara; Campos, Débora A; Fernandes, João C; Marques, Cláudia; Zuzarte, Monica; Gullón, Beatriz; Rodríguez-Alcalá, Luís M; Calhau, Conceição; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Maria Manuela; Reis, Flávio
Rosmarinic acid (RA) possesses several protective bioactivities that have attracted increasing interest by nutraceutical/pharmaceutical industries. Considering the reduced bioavailability after oral use, effective (and safe) delivery systems are crucial to protect RA from gastrointestinal degradation. This study aims to characterize the safety profile of solid lipid nanoparticles produced with Witepsol and Carnauba waxes and loaded with RA, using in vitro and in vivo approaches, focused on genotoxicity and cytotoxicity assays, redox status markers, hematological and biochemical profile, liver and kidney function, gut bacterial microbiota, and fecal fatty acids composition. Free RA and sage extract, empty nanoparticles, or nanoparticles loaded with RA or sage extract (0.15 and 1.5 mg/mL) were evaluated for cell (lymphocytes) viability, necrosis and apoptosis, and antioxidant/prooxidant effects upon DNA. Wistar rats were orally treated for 14 days with vehicle (control) and with Witepsol or Carnauba nanoparticles loaded with RA at 1 and 10 mg/kg body weight/d. Blood, urine, feces, and several tissues were collected for analysis. Free and loaded RA, at 0.15 mg/mL, presented a safe profile, while genotoxic potential was found for the higher dose (1.5 mg/mL), mainly by necrosis. Our data suggest that both types of nanoparticles are safe when loaded with moderate concentrations of RA, without in vitro genotoxicity and cytotoxicity and with an in vivo safety profile in rats orally treated, thus opening new avenues for use in nutraceutical applications. PMID:27536103
Siddiqui, Akhtar; Alayoubi, Alaadin; Nazzal, Sami
The objective of this study was to investigate the effect of cetyl alcohol (CA) and Tween® 60 (polysorbate), the primary components of emulsifying wax, on the size, zeta potential and stability of cetyltrimethyl ammonium bromide (CTAB)-based solid lipid nanoparticles (SLN) by D-optimal mixture design. A binary CTAB/polysorbate surfactant blend did not offer an advantage over a simple CTAB-stabilized SLN. This led to the conclusion that emulsifying wax could be readily substituted with CA in simple SLNs based on binary CTAB/CA blends. Polysorbate, however, may be added as a co-emulsifier to adjust the physical properties of the nanoparticles, as dictated by the formulator.
Kurakula, Mallesh; Ahmed, Osama A A; Fahmy, Usama A; Ahmed, Tarek A
Avanafil (AVA) is used in the treatment of erectile dysfunction, but is reported for its poor aqueous solubility. Solid lipid nanoparticles (SLNs) are lipid carriers that can greatly enhance drug solubility and bioavailability. This work was aimed to formulate and optimize AVA SLNs with subsequent loading into hydrogel films for AVA transdermal delivery. AVA SLNs were prepared utilizing homogenization followed by ultra-sonication technique. The prepared SLNs were characterized for particle size, charge, surface morphology and drug content. The optimized SLNs formulation was incorporated into transdermal films prepared using HPMC and chitosan. Hydrogel films were evaluated for ex-vivo rat skin permeation using automated Franz diffusion cells. The permeation parameters and the release mechanism were evaluated. The transdermal permeation of the prepared AVA SLNs through the skin layers was studied using confocal laser scanning microscope. Lipid concentration and % of oil in lipid had a pronounced effect on particle size while, entrapment efficiency was significantly affected by lipid concentration and % of cholesterol. The optimized AVA SLNs showed particle size and entrapment efficiency of 86 nm and 85.01%, respectively. TEM images revealed spherecity of the particles. High permeation parameters were observed from HPMC films loaded with AVA SLNs. The release data were in favor of Higuchi diffusion model. The prepared AVA SLNs were able to penetrate deeper in skin layers. HPMC transdermal film-loaded AVA SLNs is an effective and alternative to per-oral drug administration.
Rahman, Mohamed Habibur; Ramanathan, Muthiah; Sankar, Veintramuthu
Curcumin (diferuloylmethane) possesses low bioavailability due to its poor solubility, permeability and rapid metabolism. Solid Lipid Nanoparticle of curcumin was prepared by high-speed homogenization technique. Stearic acid was used as a lipid, tween 80 as surfactant and various co surfactants were used for the preparation of SLN. The prepared SLN was characterized using zeta sizer, TEM analysis and the average particle size was found to be in the range of 80 nm - 200nm. The entrapment efficiency of the SLN was ~58 to 85%. The characteristic FTIR peaks suggest that the stearic acid is compatible with curcumin. MTT assay was performed on the optimized formulation and the results are indicative that curcumin SLN showed better cytotoxicity in low dose while compared to plain curcumin. The developed Cu-SLN can find its better place in the anticancer therapy.
Durán-Lobato, Matilde; Enguix-González, Alicia; Fernández-Arévalo, Mercedes; Martín-Banderas, Lucía
Lipid nanoparticles (LNPs) are a promising carrier for all administration routes due to their safety, small size, and high loading of lipophilic compounds. Among the LNP production techniques, the easy scale-up, lack of organic solvents, and short production times of the high-pressure homogenization technique (HPH) make this method stand out. In this study, a statistical analysis was applied to the production of LNP by HPH. Spherical LNPs with mean size ranging from 65 nm to 11.623 μm, negative zeta potential under -30 mV, and smooth surface were produced. Manageable equations based on commonly used parameters in the pharmaceutical field were obtained. The lipid to emulsifier ratio ( R L/S) was proved to statistically explain the influence of oil phase and surfactant concentration on final nanoparticles size. Besides, the homogenization pressure was found to ultimately determine LNP size for a given R L/S, while the number of passes applied mainly determined polydispersion. α-Tocopherol was used as a model drug to illustrate release properties of LNP as a function of particle size, which was optimized by the regression models. This study is intended as a first step to optimize production conditions prior to LNP production at both laboratory and industrial scale from an eminently practical approach, based on parameters extensively used in formulation.
Wang, Yuhong; Rajala, Ammaji; Rajala, Raju V. S.
Lipids contain hydrocarbons and are the building blocks of cells. Lipids can naturally form themselves into nano-films and nano-structures, micelles, reverse micelles, and liposomes. Micelles or reverse micelles are monolayer structures, whereas liposomes are bilayer structures. Liposomes have been recognized as carriers for drug delivery. Solid lipid nanoparticles and lipoplex (liposome-polycation-DNA complex), also called lipid nanoparticles, are currently used to deliver drugs and genes to ocular tissues. A solid lipid nanoparticle (SLN) is typically spherical, and possesses a solid lipid core matrix that can solubilize lipophilic molecules. The lipid nanoparticle, called the liposome protamine/DNA lipoplex (LPD), is electrostatically assembled from cationic liposomes and an anionic protamine-DNA complex. The LPD nanoparticles contain a highly condensed DNA core surrounded by lipid bilayers. SLNs are extensively used to deliver drugs to the cornea. LPD nanoparticles are used to target the retina. Age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy are the most common retinal diseases in humans. There have also been promising results achieved recently with LPD nanoparticles to deliver functional genes and micro RNA to treat retinal diseases. Here, we review recent advances in ocular drug and gene delivery employing lipid nanoparticles. PMID:26062170
Cho, Hyun-Jong; Park, Jin Woo; Yoon, In-Soo; Kim, Dae-Duk
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
Grillone, Agostina; Riva, Eugenio Redolfi; Mondini, Alessio; Forte, Claudia; Calucci, Lucia; Innocenti, Claudia; de Julian Fernandez, Cesar; Cappello, Valentina; Gemmi, Mauro; Moscato, Stefania; Ronca, Francesca; Sacco, Rodolfo; Mattoli, Virgilio; Ciofani, Gianni
Sorafenib is an anticancer drug approved by the Food and Drug Administration for the treatment of hepatocellular and advanced renal carcinoma. The clinical application of sorafenib is promising, yet limited by its severe toxic side effects. The aim of this study is to develop sorafenib-loaded magnetic nanovectors able to enhance the drug delivery to the disease site with the help of a remote magnetic field, thus enabling cancer treatment while limiting negative effects on healthy tissues. Sorafenib and superparamagnetic iron oxide nanoparticles are encapsulated in solid lipid nanoparticles by a hot homogenization technique using cetyl palmitate as lipid matrix. The obtained nanoparticles (Sor-Mag-SLNs) have a sorafenib loading efficiency of about 90% and are found to be very stable in an aqueous environment. Plain Mag-SLNs exhibit good cytocompatibility, whereas an antiproliferative effect against tumor cells (human hepatocarcinoma HepG2) is observed for drug-loaded Sor-Mag-SLNs. The obtained results show that it is possible to prepare stable Sor-Mag-SLNs able to inhibit cancer cell proliferation through the sorafenib cytotoxic action, and to enhance/localize this effect in a desired area thanks to a magnetically driven accumulation of the drug. Moreover, the relaxivity properties observed in water suspensions hold promise for Sor-Mag-SLN tracking through clinical magnetic resonance imaging. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Cho, Hyun-Jong; Park, Jin Woo; Yoon, In-Soo; Kim, Dae-Duk
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.
Zhou, Yan; Zhang, Guoqiang; Rao, Zhi; Yang, Yang; Zhou, Qian; Qin, Hongyan; Wei, Yuhui; Wu, Xin'an
Venlafaxine (VLX) could be pumped out of the brain by P-glycoprotein (P-gp). Moreover, the expression of P-gp distributed in blood-brain barrier could be significantly induced by VLX. Thus, P-gp could be considered as the nature barrier for delivering of VLX to the brain. The aim of this study was to investigate whether the efflux function and increased expression of P-gp could be reversed by utilizing solid lipid nanoparticles (SLN). VLX solid lipid nanoparticles (VLX - SLN) were prepared and evaluated. Pharmacokinetics and brain distribution of VLX in different formulations were conducted after oral or intravenous administration. P-gp efflux function to VLX was evaluated by the brain uptake amount of VLX, while P-gp expression was investigated by Western blotting. Results indicated that the entrapment, mean size and zata potential of VLX - SLN was 74.9 ± 3.0 %, 186.3 ± 69.26 nm and -22.8 ± 7.78 mv, respectively. After vein injection of VLX formulations, the brain uptake amount of VLX from VLX - SLN was significantly higher than that of VLX solution, VLX solution with empty SLN (VLX+ empty SLN) and VLX solution with Verapamil (VLX + Ver), respectively. Furthermore, the protein mass of P-gp in VLX - SLN treated group was the lowest among all the investigated groups. These results indicated that SLN could overcome P-gp and achieve brain target by intravenous administration.
Taylor, Erik N.; Kummer, Kim M.; Dyondi, Deepti; Webster, Thomas J.; Banerjee, Rinti
Infections are both frequent and costly in hospitals around the world, leading to longer hospital stays, overuse of antibiotics, and excessive costs to the healthcare system. Moreover, antibiotic resistant organisms, such as Pseudomonas aeruginosa are increasing in frequency, leading to 1.7 million infections per year in USA hospitals, and 99 000 deaths, both due to the evolution of antibiotic resistance and the formation of biofilms on medical devices. In particular, respiratory infections are costly, deadly to 4.5 million persons per year worldwide, and can spread to the lungs through the placement of endotracheal tubing. In this study, towards a reduction in infections, solid lipid nanoparticles were formulated from free fatty acids, or natural lipophilic constituents found in tissues of the body. A strategy was developed to target infections by producing coatings made of non-toxic chemistries lauric acid and oleic acid delivered by core-shell solid lipid nanoparticles that act against bacteria by multiple mechanisms at the nanoscale, including disruption of bacteria leading to DNA release, and reducing the adhesion of dead bacteria to ~1%. This is the first such study to explore an anti-infection surface relying on these multi-tier strategies at the nanoscale.
Madureira, Ana Raquel; Campos, Débora A; Oliveira, Ana; Sarmento, Bruno; Pintado, Maria Manuela; Gomes, Ana Maria
The evaluation of the digestion effects on bioactive solid lipid nanoparticles (SLN) was performed. For this purpose, witepsol and carnauba SLN loaded with rosmarinic acid (RA) were exposed to the simulated gastrointestinal tract (GIT) conditions prevailing in stomach and small intestine. The simulation of intestinal epithelium was made with a dialysis bag and intestinal cell culture lines. Changes on SLN physical properties, RA release and absorption profiles were followed at each step. Combination of digestion pH and enzymes showed a significant effect upon SLN physical properties. Zeta potential values increased at stomach conditions and decreased at small intestine simulation. Also, at intestine, SLN increased their sizes and released 40-60% of RA, maintaining its initial antioxidant activity values. Sustained release of 40% of RA from SLN was also observed in dialysis tube. At CaCo-2 cell line, both types of SLN showed similar absorbed RA % (ca. 30%). Nevertheless, in CaCo-2/HT29x mix cell lines, for carnauba SLN a lower adsorption RA % was observed than for witepsol SLN. Solid lipid nanoparticles protected RA bioactivity (in terms of antioxidant activity) until reaching the intestine. A controlled release of RA from SLN was achieved and a significant absorption was observed at intestinal cells. Overall, SLN produced with witepsol showed a higher stability than carnauba SLN.
Nooli, Mounika; Chella, Naveen; Kulhari, Hitesh; Shastri, Nalini R; Sistla, Ramakrishna
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.
Bhalekar, Mangesh; Upadhaya, Prashant; Madgulkar, Ashwini
Darunavir, an anti-HIV drug having poor solubility in aqueous and lipid medium, illustrates degradation above its melting point, i.e. 74 °C, thus, posing a challenge to dosage formulation. Despite, the drug suffers from poor oral bioavailability (37%) owing to less permeability and being poly-glycoprotein and cyp3A metabolism substrate. The study aimed formulating a SLN system to overcome the formulation and bioavailability associated problems of the drug. Based on the drug solubility and stable dispersion findings, lipid and surfactant were chosen and nanoparticles were prepared using hot-homogenization technique. Optimization of variables such as lipid concentration, oil-surfactant and homogenization cycle was carried and their effect on particle size and entrapment efficiency was studied. Freeze-dried SLN further characterized using SEM, DSC and PXRD analysis revealed complete entrapment of the drug and amorphous nature of the SLN. In vitro pH release studies in 0.1 N HCl and 6.8 pH buffer demonstrated 84 and 80% release at the end of 12th h. The apparent permeability of the SLN across rat intestine was found to be 24 × 10-6 at 37 °C at the end of 30 min while at 4 °C the same was found to be 5.6 × 10-6 prompting involvement of endocytic processes in the uptake of SLN. Accelerated stability studies revealed no prominent changes upon storage.
Silva, A C; Amaral, M H; González-Mira, E; Santos, D; Ferreira, D
Two different solid lipid nanoparticles (SLN)-based hydrogels (HGs) formulations were developed as potential mucoadhesive systems for risperidone (RISP) oral transmucosal delivery. The suitability of the prepared semi-solid formulations for application on oral mucosa was assessed by means of rheological and textural analysis, during 30 days. Plastic flows with thixotropy and high adhesiveness were obtained for all the tested systems, which predict their success for the oral transmucosal application proposed. The SLN remained within the colloidal range after HGs preparation. However, after 30 days of storage, a particle size increase was detected in one type of the HGs formulations. In vitro drug release studies revealed a more pronounced RISP release after SLN hydrogel entrapment, when compared to the dispersions alone. In addition, a pH-dependent release was observed as well. The predicted in vivo RISP release mechanism was Fickian diffusion alone or combined with erosion.
de Oliveira, Jhones Luiz; Campos, Estefânia Vangelie Ramos; Gonçalves da Silva, Camila Morais; Pasquoto, Tatiane; Lima, Renata; Fraceto, Leonardo Fernandes
Solid lipid nanoparticles (SLN) containing the herbicides atrazine and simazine were prepared and characterized, and in vitro evaluation was made of the release kinetics, herbicidal activity, and cytotoxicity. The stability of the nanoparticles was investigated over a period of 120 days, via analyses of particle size, ζ potential, polydispersion, pH, and encapsulation efficiency. SLN showed good physicochemical stability and high encapsulation efficiencies. Release kinetics tests showed that use of SLN modified the release profiles of the herbicides in water. Herbicidal activity assays performed with pre- and postemergence treatment of the target species Raphanus raphanistrum showed the effectiveness of the formulations of nanoparticles containing herbicides. Assays with nontarget organisms (Zea mays) showed that the formulations did not affect plant growth. The results of cytotoxicity assays indicated that the presence of SLN acted to reduce the toxicity of the herbicides. The new nanoparticle formulations enable the use of smaller quantities of herbicide and therefore offer a more environmentally friendly method of controlling weeds in agriculture.
Sun, Jiabei; Bi, Chao; Chan, Hok Man; Sun, Shaoping; Zhang, Qingwen; Zheng, Ying
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.
Wencui, Z; Qi, Z; Ying, W; Di, W
Solid lipid nanoparticles (SLN) are colloidal drug carriers and may be suitable for delivery of garlic oil, a nutraceutical with medicinal properties, whose use has been limited by its poor solubility. We tested whether poor solubility of garlic oil would be overcome by complexing with SLN by high-pressure homogenization and ultrasound techniques. The effects of lipid phase, surfactant mixture and loading concentration of garlic oil on particle size and distribution were also investigated. High pressure homogenization technique was used to prepare SLN, using orthogonal experiment method to optimize entrapment efficiency, loading efficiency, and recovery of SLN. Pharmacokinetics of garlic oil loaded solid lipid nanoparticles after oral administration to rats was studied by using LC/MS/MS method. Mean particle size and zeta potential of SLN were, respectively, 106.5 ± 40.3 nm and -30.2 mv. The majority of SLN had a less ordered arrangement of crystals at room temperature, which was beneficial for increasing the drug loading capacity. Drug entrapment efficiency was > 90 percent and showed a relatively long-term physical stability. It was feasible to prepare a lyophilized product with good long-term stability. When 10% trehalose and 5% sucrose were used as cryopreservants, SNL particle size increased from 106.5 nm prior to lyophilisation to 155.3 nm after reconstitution. The garlic oil content in SLN decreased to about 85% (respectively, 34.3 vs. 39.4 mg/mL prior to lyophilisation) due to volatility of garlic oil. Pharmacokinetic studies in rats demonstrated that distribution and elimination of diallyl trisulfide (DATS) and diallyl disulfide (DADS) in garlic oil were rapid. Additionally, elimination of garlic oil-SLN complex is faster than that of garlic oil alone, probably, due to phagocytosis. An SLN complex with garlic oil exhibits characteristics similar to those of parenteral emulsions, even after lyophilization and reconstitution.
Uner, M; Wissing, S A; Yener, G; Müller, R H
This study was performed as a complimentary to our previous study regarding the chemical stability of ascorbyl palmitate (AP) in solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and for comparison, in nanoemulsion (NE) incorporated into a hydrogel produced by high pressure homogenization. AP is known as an effective antioxidant that protects tissue integrity similar to vitamin C. Recently, its moisturizing activity in conventional topical formulations was found to be high. The aim of the present study was to investigate the moisturizing potential of AP in SLN and NLC incorporated into hydrogel as colloidal carrier systems. It has been known that SLN and NLC have occlusive effects, but AP incorporation moisturized skin significantly better than placebo in short-term (p < 0.001) and long-term trials (p < 0.01) for both SLN and NLC. In the second part of the study, SLN and NLC were found to sustain the penetration of AP through excised human skin about 1/2 and 2/3 times compared to NE (p < 0.001 and p < 0.01), respectively, due to the solid state of Witepsol E85 in the lipid phase.
Liu, Jingwen; Meng, Tingting; Yuan, Ming; Wen, Lijuan; Cheng, Bolin; Liu, Na; Huang, Xuan; Hong, Yun; Yuan, Hong; Hu, Fuqiang
Background One of the major obstacles in the treatment of breast cancer is breast cancer stem cells (BCSC) which are resistant to standard chemotherapeutic drugs. It has been proven that microRNA-200c (miR-200c) can restore sensitivity to microtubule-targeting chemotherapeutic drugs by reducing the expression of class III β-tubulin. In this study, combination therapy with miR-200c and paclitaxel (PTX) mediated by lipid nanoparticles was investigated as an alternative strategy against BCSC. Materials and methods A cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane was strategically selected to formulate solid lipid nanoparticles (SLN) for miR-200c delivery. Nanostructured lipid carriers (NLC) with 20 wt% oleic acid were prepared for PTX delivery. Mammospheres, which gained the characteristics of BCSC, were used as a cell model to evaluate the efficiency of combination therapy. Results The cationic SLN could condense anionic miRNA to form SLN/miRNA complexes via charge interactions and could protect miRNA from degradation by ribonuclease. SLN/miR-200c complexes achieved 11.6-fold expression of miR-200c after incubation for 24 hours, compared with that of Lipofectamine™ 2000/miR-200c complexes (*P<0.05). Intracellular drug release assay proved that miRNA can be released from SLN/miRNA complexes efficiently in 12 hours after cellular uptake. After BCSC were transfected with SLN/miR-200c, the expression of class III β-tubulin was effectively downregulated and the cellular cytotoxicity of PTX-loaded NLC (NLC/PTX) against BCSC was enhanced significantly (**P<0.01). Conclusion The results indicated that the cationic SLN could serve as a promising carrier for miRNA delivery. In addition, the combination therapy of miR-200c and PTX revealed a novel therapeutic strategy for the treatment of BCSC. PMID:28003747
Liu, Jingwen; Meng, Tingting; Yuan, Ming; Wen, Lijuan; Cheng, Bolin; Liu, Na; Huang, Xuan; Hong, Yun; Yuan, Hong; Hu, Fuqiang
One of the major obstacles in the treatment of breast cancer is breast cancer stem cells (BCSC) which are resistant to standard chemotherapeutic drugs. It has been proven that microRNA-200c (miR-200c) can restore sensitivity to microtubule-targeting chemotherapeutic drugs by reducing the expression of class III β-tubulin. In this study, combination therapy with miR-200c and paclitaxel (PTX) mediated by lipid nanoparticles was investigated as an alternative strategy against BCSC. A cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane was strategically selected to formulate solid lipid nanoparticles (SLN) for miR-200c delivery. Nanostructured lipid carriers (NLC) with 20 wt% oleic acid were prepared for PTX delivery. Mammospheres, which gained the characteristics of BCSC, were used as a cell model to evaluate the efficiency of combination therapy. The cationic SLN could condense anionic miRNA to form SLN/miRNA complexes via charge interactions and could protect miRNA from degradation by ribonuclease. SLN/miR-200c complexes achieved 11.6-fold expression of miR-200c after incubation for 24 hours, compared with that of Lipofectamine™ 2000/miR-200c complexes (*P<0.05). Intracellular drug release assay proved that miRNA can be released from SLN/miRNA complexes efficiently in 12 hours after cellular uptake. After BCSC were transfected with SLN/miR-200c, the expression of class III β-tubulin was effectively downregulated and the cellular cytotoxicity of PTX-loaded NLC (NLC/PTX) against BCSC was enhanced significantly (**P<0.01). The results indicated that the cationic SLN could serve as a promising carrier for miRNA delivery. In addition, the combination therapy of miR-200c and PTX revealed a novel therapeutic strategy for the treatment of BCSC.
Emami, J.; Mohiti, H.; Hamishehkar, H.; Varshosaz, J.
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
Rompicharla, Sri Vishnu Kiran; Bhatt, Himanshu; Shah, Aashma; Komanduri, Neeraja; Vijayasarathy, Dhanya; Ghosh, Balaram; Biswas, Swati
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.
Guillot, Alexis; Couffin, Anne-Claude; Sejean, Xavier; Navarro, Fabrice; Limberger, Markus; Lehr, Claus-Michael
Contrary to physical characterization techniques for nanopharmaceuticals (shape, size and zeta-potential), the techniques to quantify the free and the entrapped drug remain very few and difficult to transpose in routine analytical laboratories. The application of Solid Phase Extraction (SPE) technique was investigated to overcome this challenge. The separation of free and entrapped drug by SPE was quantitatively validated by High Performance Liquid Chromatography. The developed protocol was implemented to characterize cyclosporine A-loaded 120 nm-sized lipid nanoparticles (LNPs, Lipidot®) dispersed in aqueous buffer. The colloidal stability was assessed by Dynamic Light Scattering (DLS). Validation experiments demonstrated suitable linearity, repeatability, accuracy and specificity to quantify residual free, entrapped and total drug. For the investigated LNPs, the method revealed a very limited shelflife of the formulation when stored in an aqueous buffer at 5°C and even more at elevated temperature. Nevertheless, the DLS measurements confirmed the stability of nanoparticles during SPE in a suitable concentration range. SPE, when successfully validated, represents a valuable tool for drug development and quality control purposes of lipid-based nanopharmaceuticals in an industrial environment.
Severino, Patrícia; Andreani, Tatiana; Jäger, Alessandro; Chaud, Marco V; Santana, Maria Helena A; Silva, Amélia M; Souto, Eliana B
Insulin was used as model protein to developed innovative Solid Lipid Nanoparticles (SLNs) for the delivery of hydrophilic biotech drugs, with potential use in medicinal chemistry. SLNs were prepared by double emulsion with the purpose of promoting stability and enhancing the protein bioavailability. Softisan(®)100 was selected as solid lipid matrix. The surfactants (Tween(®)80, Span(®)80 and Lipoid(®)S75) and insulin were chosen applying a 2(2) factorial design with triplicate of central point, evaluating the influence of dependents variables as polydispersity index (PI), mean particle size (z-AVE), zeta potential (ZP) and encapsulation efficiency (EE) by factorial design using the ANOVA test. Therefore, thermodynamic stability, polymorphism and matrix crystallinity were checked by Differential Scanning Calorimetry (DSC) and Wide Angle X-ray Diffraction (WAXD), whereas the effect of toxicity of SLNs was check in HepG2 and Caco-2 cells. Results showed a mean particle size (z-AVE) width between 294.6 nm and 627.0 nm, a PI in the range of 0.425-0.750, ZP about -3 mV, and the EE between 38.39% and 81.20%. After tempering the bulk lipid (mimicking the end process of production), the lipid showed amorphous characteristics, with a melting point of ca. 30 °C. The toxicity of SLNs was evaluated in two distinct cell lines (HEPG-2 and Caco-2), showing to be dependent on the concentration of particles in HEPG-2 cells, while no toxicity in was reported in Caco-2 cells. SLNs were stable for 24 h in in vitro human serum albumin (HSA) solution. The resulting SLNs fabricated by double emulsion may provide a promising approach for administration of protein therapeutics and antigens. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Aljaeid, Bader Mubarak; Hosny, Khaled Mohamed
Background and objective Miconazole is a broad-spectrum antifungal drug that has poor aqueous solubility (<1 µg/mL); as a result, a reduction in its therapeutic efficacy has been reported. The aim of this study was to formulate and evaluate miconazole-loaded solid lipid nanoparticles (MN-SLNs) for oral administration to find an innovative way to alleviate the disadvantages associated with commercially available capsules. Methods MN-SLNs were prepared by hot homogenization/ultrasonication. The solubility of miconazole in different solid lipids was measured. The effect of process variables, such as surfactant types, homogenization and ultrasonication times, and the charge-inducing agent on the particle size, zeta potential, and encapsulation efficiency were determined. Furthermore, in vitro drug release, antifungal activity against Candida albicans, and in vivo pharmacokinetics were studied in rabbits. Results The MN-SLN, consisting of 1.5% miconazole, 2% Precirol ATO5, 2.5% Cremophor RH40, 0.5% Lecinol, and 0.1% Dicetylphosphate, had an average diameter of 23 nm with a 90.2% entrapment efficiency. Furthermore, the formulation of MN-SLNs enhanced the antifungal activity compared with miconazole capsules. An in vivo pharmacokinetic study revealed that the bioavailability was enhanced by >2.5-fold. Conclusion MN-SLN was more efficient in the treatment of candidiasis with enhanced oral bioavailability and could be a promising carrier for the oral delivery of miconazole. PMID:26869787
Aljaeid, Bader Mubarak; Hosny, Khaled Mohamed
Miconazole is a broad-spectrum antifungal drug that has poor aqueous solubility (<1 µg/mL); as a result, a reduction in its therapeutic efficacy has been reported. The aim of this study was to formulate and evaluate miconazole-loaded solid lipid nanoparticles (MN-SLNs) for oral administration to find an innovative way to alleviate the disadvantages associated with commercially available capsules. MN-SLNs were prepared by hot homogenization/ultrasonication. The solubility of miconazole in different solid lipids was measured. The effect of process variables, such as surfactant types, homogenization and ultrasonication times, and the charge-inducing agent on the particle size, zeta potential, and encapsulation efficiency were determined. Furthermore, in vitro drug release, antifungal activity against Candida albicans, and in vivo pharmacokinetics were studied in rabbits. The MN-SLN, consisting of 1.5% miconazole, 2% Precirol ATO5, 2.5% Cremophor RH40, 0.5% Lecinol, and 0.1% Dicetylphosphate, had an average diameter of 23 nm with a 90.2% entrapment efficiency. Furthermore, the formulation of MN-SLNs enhanced the antifungal activity compared with miconazole capsules. An in vivo pharmacokinetic study revealed that the bioavailability was enhanced by >2.5-fold. MN-SLN was more efficient in the treatment of candidiasis with enhanced oral bioavailability and could be a promising carrier for the oral delivery of miconazole.
Xue, Mei; Zhang, Liang; Yang, Ming-xing; Zhang, Wei; Li, Xiu-min; Ou, Zhi-min; Li, Zhi-peng; Liu, Su-huan; Li, Xue-jun; Yang, Shu-yu
Berberine (BBR) shows very low plasma levels after oral administration due to its poor absorption by the gastrointestinal tract. We have previously demonstrated that BBR showed increased gastrointestinal absorption and enhanced antidiabetic effects in db/db mice after being entrapped into solid lipid nanoparticles (SLNs). However, whether BBR-loaded SLNs (BBR-SLNs) also have beneficial effects on hepatosteatosis is not clear. We investigated the effects of BBR-SLNs on lipid metabolism in the liver using histological staining and reverse transcription polymerase chain reaction analysis. The results showed that oral administration of BBR-SLNs inhibited the increase of body weight and decreased liver weight in parallel with the reduction of serum alanine transaminase and liver triglyceride levels in db/db mice. The maximum drug concentration in the liver was 20-fold higher than that in the blood. BBR-SLNs reduced fat accumulation and lipid droplet sizes significantly in the liver, as indicated by hematoxylin and eosin and Oil Red O staining. The expression of lipogenic genes, including fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD1), and sterol regulatory element-binding protein 1c (SREBP1c) were downregulated, while lipolytic gene carnitine palmitoyltransferase-1 (CPT1) was upregulated in BBR-SLN-treated livers. In summary, we have uncovered an unexpected effect of BBR-SLNs on hepatosteatosis treatment through the inhibition of lipogenesis and the induction of lipolysis in the liver of db/db mice.
Rudolph, Carsten; Rosenecker, Joseph
Solid lipid nanoparticles (SLNs) offer several technological advantages over standard DNA carriers such as cationic lipids or cationic polymers. However, in the absence of endosomolytic agents such as chloroquine, gene-transfer efficiency mediated by SLN-derived gene vectors consisting of optimized lipid composition remains lower compared to those achieved with standard transfection agents. This protocol describes the incorporation of a dimeric human immunodeficiency virus type-1 (HIV-1) TAT peptide into SLN gene vectors to increase gene-transfer efficiency. This results in higher transfection rates than for standard transfection agents in vitro; the ternary SLN-gene vector complexes usually result in transfection levels equal to or higher than those observed with gene vector complexes formulated with branched polyethylenimine (PEI) 25 kDa. One significant advantage of using this method is the low cytotoxicity of the SLN gene vectors. The application of the gene-transfer technique is limited to relatively low plasmid DNA (pDNA) concentrations of the resulting complexes (10 µg/mL). At higher concentrations, the particles tend to aggregate and precipitate. Therefore, their use for in vivo application, which generally requires high pDNA concentrations, is limited.
Xue, Mei; Zhang, Liang; Yang, Ming-xing; Zhang, Wei; Li, Xiu-min; Ou, Zhi-min; Li, Zhi-peng; Liu, Su-huan; Li, Xue-jun; Yang, Shu-yu
Berberine (BBR) shows very low plasma levels after oral administration due to its poor absorption by the gastrointestinal tract. We have previously demonstrated that BBR showed increased gastrointestinal absorption and enhanced antidiabetic effects in db/db mice after being entrapped into solid lipid nanoparticles (SLNs). However, whether BBR-loaded SLNs (BBR-SLNs) also have beneficial effects on hepatosteatosis is not clear. We investigated the effects of BBR-SLNs on lipid metabolism in the liver using histological staining and reverse transcription polymerase chain reaction analysis. The results showed that oral administration of BBR-SLNs inhibited the increase of body weight and decreased liver weight in parallel with the reduction of serum alanine transaminase and liver triglyceride levels in db/db mice. The maximum drug concentration in the liver was 20-fold higher than that in the blood. BBR-SLNs reduced fat accumulation and lipid droplet sizes significantly in the liver, as indicated by hematoxylin and eosin and Oil Red O staining. The expression of lipogenic genes, including fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD1), and sterol regulatory element-binding protein 1c (SREBP1c) were downregulated, while lipolytic gene carnitine palmitoyltransferase-1 (CPT1) was upregulated in BBR-SLN-treated livers. In summary, we have uncovered an unexpected effect of BBR-SLNs on hepatosteatosis treatment through the inhibition of lipogenesis and the induction of lipolysis in the liver of db/db mice. PMID:26346310
Shao, Wenyao; Yan, Mengwen; Chen, Tingting; Chen, Yuqing; Xiao, Zongyuan
This work aims to develop a temperature-controlled continuous solvent emulsification-diffusion process to synthesize all-trans retinoic acid (ATRA)-loaded solid lipid nanoparticles (SLNs) using static mixers. ATRA-loaded SLNs of around 200 nm were obtained when the flow rates of the organic and aqueous phases were 50 ml min-1 and 500 ml min-1, respectively. It was found that the lipid concentration played a dominant role in the size of the obtained SLNs, and higher drug concentration resulted in relatively low entrapment efficiency. The encapsulation of ATRA in the SLNs was effective in improving its stability according to the photo-degradation test. The in vitro release of SLN was slow without an initial burst. This study demonstrates that the solvent emulsification-diffusion technique with static mixing is an effective method of producing SLNs, and could easily be scaled up for industrial applications. Highlights Higher lipid concentration leads to larger SLNs. SLN transformation occurs due to Ostwald ripening. The ATRA-loaded SLNs around 200 nm were successfully produced with static mixers. ATRA-loaded SLNs show better stability towards sunlight. ATRA in SLNs exhibited a relatively slow release rate without a significant initial burst.
Montasser, Imed; Shahgaldian, Patrick; Perret, Florent; Coleman, Anthony W.
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
Ahmadnia, Sara; Moazeni, Mohammad; Mohammadi-Samani, Soliman; Oryan, Ahmad
Cystic echinococcosis (CE) is caused by the larval stage of Echinococcus granulosus, which in this disease the metacestode develop in visceral organs especially liver and lungs. The disease is present worldwide and affects humans as well as herbivores including cattle, sheep, camels, horses and others. Benzimidazole carbamate derivatives, such as mebendazole and albendazole, are currently used for chemotherapeutic treatment of CE in inoperable patients and have to be applied in high doses for extended periods of time, and therefore adverse side effects are frequently observed. This study was designed to evaluate and compare the in vivo effects of 0.5 mg/kg, BID, albendazole sulfoxide (ricobendazole) and two different therapeutic regimens of 0.5 mg/kg BID and 2 mg/kg every 48 h of albendazole sulfoxide loaded solid lipid nanoparticles. Albendazole sulfoxide loaded solid lipid nanoparticles was prepared by solvent diffusion-evaporation method. Fifty Balb/c mice were infected by intraperitoneal injection of protoscoleces and 8 months post infection, the infected mice were treated for 15 days with the above mentioned regimens. They were then euthanized and the size and weight of the cysts as well as their ultrastructural changes were investigated. Although the cysts showed reduced size and weight in the treated animals but these reductions were not statistically significant. The cysts in the animals which received albendazole sulfoxide loaded SLN every 48 h showed more ultrastructural modification. However, these ultrastructural changes should be supported by further biochemical and molecular studies before introducing it as an efficient therapeutic regimen for treatment of human and animal hydatid disease. Copyright © 2013 Elsevier Inc. All rights reserved.
Dang, Hao; Meng, Murtaza Hasan Weiwei; Zhao, Haiwei; Iqbal, Javed; Dai, Rongji; Deng, Yulin; Lv, Fang
Luteolin (LU, 5,7,3',4'-tetrahydroxyflavone) most active compound in Chinese herbal flavones has been acting as a antimicrobial, anti-inflammatory, anti-cancer, and antimutagen. However, its poor bioavailability, hydrophobicity, and pharmacokinetics restrict clinical application. Here in this study, LU-loaded solid lipid nanoparticles have been prepared by hot-microemulsion ultrasonic technique to improve the bioavailability & pharmacokinetics of compound. LU-loaded solid lipid nanoparticle size was confirmed by particle size analyzer with range from 47 to 118 nm, having zepta potential -9.2 mV and polydisperse index 0.247, respectively. Round-shaped SLNPs were obtained by using transmission electron microscope, and encapsulation efficiency 74.80 % was calculated by using HPLC. Both in vitro and vivo studies, LC-MS/MS technique was used for quantification of Luteolin in rat. The T max value of drug with LU-SLNs after the administration was Ten times shorter than pure Luteolin suspension administration. C max value of drug after the administration of LU-SLNs was five times higher than obtained with native drug suspension. Luteolin with SLNs has increased the half-life approximately up to 2 h. Distribution and clearance of drug with SLNs were significantly decreased by 2.16-10.57 fold, respectively. In the end, the relative bioavailability of SLNs has improved about 4.89 compared to Luteolin with SLNs. From this study, it can be concluded that LU-SLNs have not only great potential for improving solubility but also increased the drug concentration in plasma. Furthermore, use of LC-MS/MS for quantification of LU-SLNs in rat plasma is reliable and of therapeutic usefulness, especially for neurodegenerative and cancerous disorders in humans.
Polchi, Alice; Magini, Alessandro; Mazuryk, Jarosław; Tancini, Brunella; Gapiński, Jacek; Patkowski, Adam; Giovagnoli, Stefano; Emiliani, Carla
Recently, the use of mammalian target of rapamycin (mTOR) inhibitors, in particular rapamycin (Rp), has been suggested to improve the treatment of neurodegenerative diseases. However, as Rp is a strong immunosuppressant, specific delivery to the brain has been postulated to avoid systemic exposure. In this work, we fabricated new Rp loaded solid lipid nanoparticles (Rp-SLN) stabilized with polysorbate 80 (PS80), comparing two different methods and lipids. The formulations were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), wide angle X-ray scattering (WAXS), cryo-transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) and particle tracking. In vitro release and short-term stability were assessed. Biological behavior of Rp-SLN was tested in SH-SY5Y neuroblastoma cells. The inhibition of mTOR complex 1 (mTORC1) was evaluated over time by a pulse-chase study compared to free Rp and Rp nanocrystals. Compritol Rp-SLN resulted more stable and possessing proper size and surface properties with respect to cetyl palmitate Rp-SLN. Rapamycin was entrapped in an amorphous form in the solid lipid matrix that showed partial crystallinity with stable Lβ, sub-Lα and Lβ′ arrangements. PS80 was stably anchored on particle surface. No drug release was observed over 24 h and Rp-SLN had a higher cell uptake and a more sustained effect over a week. The mTORC1 inhibition was higher with Rp-SLN. Overall, compritol Rp-SLN show suitable characteristics and stability to be considered for further investigation as Rp brain delivery system. PMID:28335215
Rodenak-Kladniew, Boris; Islan, German A; de Bravo, Margarita G; Durán, Nelson; Castro, Guillermo R
Linalool (LN) is a monoterpene found in essential oils of plants and herbs that produces multiple effects on the mevalonate pathway and interesting antiproliferative activity in cancer cells. However, due to its poor aqueous solubility, an efficient vehicle is needed to improve its administration and bioavailability in physiological media. LN encapsulation in solid lipid nanoparticles (SLN) with different compositions was explored and in vitro tested in two cancer cell lines. SLN of myristyl myristate (MM), cetyl esters (SS) and cetyl palmitate (CP) were prepared by sonication in the presence of Pluronic(®)F68 as surfactant. Nanoparticle size, morphology and distribution were determined by dynamic light scattering in combination with optical and transmission electron microscopy (TEM). SLN showed spherical shape and mean diameters in the range of 90-130nm with narrow size dispersion (PDI values lower than 0.2) and Z potentials around -4.0mV. The encapsulation percentages of LN in SLN were higher than 80% for all tested formulations and exhibited in vitro LN controlled release profiles for at least 72h. The nanoparticles were physicochemically characterized by FTIR, XRD, DSC and TGA, and the incorporation of LN into SLN was higher than 80% in tested matrices. The developed formulations, and in particular SLN (MM)-LN, showed in vitro antiproliferative effects on hepatocarcinoma (HepG2) and lung adenocarcinoma (A549) cell lines in a dose-dependent response, and higher inhibitory effects were found in comparison with free LN. The cellular uptake of SLN was demonstrated by fluorescence microscopy, enhancing the ability of nanoparticles to intracellularly deliver the cargo molecules.
Kharaji, Maryam Heidari; Doroud, Delaram; Taheri, Tahereh; Rafati, Sima
Leishmaniasis is a worldwide disease that leads to high mortality and morbidity in human populations. Today, leishmaniasis is managed via drug therapy. The drugs that are already in clinical use are limited to a number of toxic chemical compounds and their parasite drug resistance is increasing. It is therefore essential, in order to circumvent the current difficulties, to design a new anti-leishmanial drug treatment strategy. Besides producing new, active anti-leishmanial entities, another promising strategy could be developing novel delivery systems and formulations of the existing pharmaceutical ingredients to improve drug efficacy. In the present study, paromomycin sulfate (PM), as one of the promising anti-leishmanial drugs, was formulated in solid lipid nanoparticles (SLN), and its in vitro efficacy was investigated against different strains of Leishmania using a MTT test, Parasite-Rescue-Transformation-Assay, SYTO Green staining, and fluorescent microscope imaging. The results show that PM-loaded SLN is significantly more effective than PM in inhibiting parasite propagation (P < 0.05) and that cytotoxicity of PM-SLN formulations is size dependent. According to our results, delivery of the drugs to the macrophages via nanoparticle utilization seems to be an accessible and practical approach.
Heidari-Kharaji, Maryam; Taheri, Tahereh; Doroud, Delaram; Habibzadeh, Sima; Rafati, Sima
Leishmaniasis is a parasitic disease transmitted through the bite of an infected phlebotomine sand fly and caused by protozoan parasites of the genus Leishmania. There is no available vaccine for leishmaniasis in human, and the current chemotherapy approaches are hampered by different clinical problems. Most of available drugs are confined to a limited number of toxic chemical compounds, which some parasite strains have evolved drug resistance against. Hence, drug discovery and production of a new anti leishmanial compound is essential. One promising strategy is using the nanoparticle delivery systems with the aim of accelerating the efficacy of the available treatments. In the present study, paromomycin sulfate (PM) was formulated in solid lipid nanoparticles (SLN) and the in vivo efficacy was investigated against Leishmania tropica in BALB/c mice model. To do so, the increase in footpad thickness was measured and real-time PCR was performed to quantify the parasite load after infectious challenge. The level of nitric oxide and cytokines including interleukin-4 (IL-4) and gamma interferon (IFN -γ) were assessed. Altogether, the results show that PM loaded into SLN is significantly more effective than PM alone in inhibiting the parasite propagation and switching towards Th1 response.
Ma, Yanhui; Zhang, Xiaolei; Xu, Xiaoxuan; Shen, Liang; Yao, Yao; Yang, Ziyan; Liu, Peishu
Recent advances in the synthesis of multi-functional nanoparticles have opened up tremendous opportunities for the targeted delivery of genes of interest. Cationic solid lipid nanoparticles (SLN) can efficiently bind nucleic acid molecules and transfect genes in vitro. Few reports have combined SLN with therapy using decoy oligodeoxynucleotides (ODN). In the present study, we prepared SLN to encapsulate STAT3 decoy ODN; then, the properties and in vitro behavior of SLN-STAT3 decoy ODN complexes were investigated. SLN-STAT3 decoy ODN complexes were efficiently taken up by human ovarian cancer cells and significantly suppressed cell growth. Blockage of the STAT3 pathway by SLN-STAT3 decoy ODN complexes resulted in an evident induction of cell death, including apoptotic and autophagic death. The mechanism involved the increased expression of cleaved caspase 3, Bax, Beclin-1 and LC3-II and reduced expression of Bcl-2, pro-caspase 3, Survivin, p-Akt and p-mTOR. In addition, SLN-STAT3 decoy ODN complexes inhibited cell invasion by up-regulating E-cadherin expression and down-regulating Snail and MMP-9 expression. These findings confirmed that SLN as STAT3 decoy ODN carriers can induce cell death and inhibit invasion of ovarian cancer cells. We propose that SLN represent a potential approach for targeted gene delivery in cancer therapy. PMID:25923701
Rassu, Giovanna; Soddu, Elena; Posadino, Anna Maria; Pintus, Gianfranco; Sarmento, Bruno; Giunchedi, Paolo; Gavini, Elisabetta
We designed a delivery system to obtain an efficient and optimal nose-to-brain transport of BACE1 siRNA, potentially useful in the treatment of Alzheimer's disease. We selected a cell-penetrating peptide, the short peptide derived from rabies virus glycoprotein known as RVG-9R, to increase the transcellular pathway in neuronal cells. The optimal molar ratio between RVG-9R and BACE1 siRNA was elucidated. The complex between the two was then encapsulated. We propose chitosan-coated and uncoated solid lipid nanoparticles (SLNs) as a nasal delivery system capable of exploiting both olfactory and trigeminal nerve pathways. The coating process had an effect on the zeta potential, obtaining positively-charged nanoparticles, and on siRNA protection. The positive charge of the coating formulation ensured mucoadhesiveness to the particles and also prolonged residence time in the nasal cavity. We studied the cellular transport of siRNA released from the SLNs using Caco-2 as a model of epithelial-like phenotypes. We found that siRNA permeates the monolayer to a greater extent when released from any of the studied formulations than from bare siRNA, and primarily from chitosan-coated SLNs.
Işcan, Y; Wissing, S A; Hekimoğlu, S; Müller, R H
Solid lipid nanoparticles (SLN) for topical delivery were prepared by high pressure homogenization using solid lipids. The lipophilic agents DEET (N,N-diethyl-m-toluamide) and vitamin K were used as model drugs. These topical agents were incorporated into SLN which were characterized. Differential scanning calorimetry studies were performed in order to detect probable interactions in the SLN dispersions. Physical stability of SLN in aqueous dispersions and the effect of drug incorporation into SLN were investigated by photon correlation spectroscopy and zeta potential measurements. Characterization and short-term stability studies showedthat DEET and vitamin K are good candidates for topical SLN formulations.
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
Silva, A C; González-Mira, E; García, M L; Egea, M A; Fonseca, J; Silva, R; Santos, D; Souto, E B; Ferreira, D
The suitability of solid lipid nanoparticles (SLN) for the encapsulation of risperidone (RISP), an antipsychotic lipophilic drug, was assessed for oral administration. The hot high pressure homogenization (HPH) and the ultrasound (US) technique were used as production methods for SLN. All the studies on the SLN formulations were done in parallel, in order to compare the results and conclude about the advantages and limitations of both techniques. The particle sizes were in the nanometer range for all prepared SLN formulations and the zeta potential absolute values were high, predicting good long-term stability. Optical analyses demonstrated the achievement of stable colloidal dispersions. Physicochemical characterization of dispersions and bulk lipids, performed by differential scanning calorimetry (DSC) and X-ray assays, support prediction of occurrence of drug incorporation in the SLN and good long term stability of the systems. The toxicity of SLN with Caco-2 cells and the existence of contaminations derived from the production equipments were assessed by the (4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) assay. The results showed 90% of cell viability after SLN exposure, with no significant differences within all prepared formulations (p > 0.05). From this study, we conclude that SLN can be considered as efficient carriers for RISP encapsulation. Moreover, HPH and US revealed to be both effective methods for SLN production.
Luo, Yangchao; Teng, Zi; Li, Ying; Wang, Qin
The poor stability of solid lipid nanoparticles (SLN) under acidic condition resulted in large aggregation in gastric environment, limiting their application as oral delivery systems. In this study, a series of SLN was prepared to investigate the effects of surfactant/cosurfactant and chitosan coating on their physicochemical properties as well as cellular uptake. SLN was prepared from Compritol 888 ATO using a low-energy method combining the solvent-diffusion and hot homogenization technique. Poloxamer 188 and polyethylene glycol (PEG) were effective emulsifiers to produce SLN with better physicochemical properties than SLN control. Chitosan-coated SLN exhibited the best stability under acidic condition by forming a thick layer around the lipid core, as clearly observed by transmission electron microscope. The intermolecular interactions in different formulations were monitored by Fourier transform infrared spectroscopy. Chitosan coating also significantly improved the mucoadhesive property of SLN as determined by Quartz Crystal Microbalance. In vitro drug delivery assays, cytotoxicity, and cellular uptake of SLN were studied by incorporating coumarin 6 as a fluorescence probe. Overall, chitosan-coated SLN was superior to other formulations and held promising features for its application as a potential oral drug delivery system for hydrophobic drugs.
Yadav, Aarti; Sunkaria, Aditya; Singhal, Nitin; Sandhir, Rajat
Vascular dementia (VaD) is the leading cause of cognitive decline resulting from vascular lesions. Recent studies have shown that mitochondrial dysfunctions and oxidative stress are involved in cognitive decline. The aim of the present study was to evaluate the beneficial effects of resveratrol-loaded solid lipid nanoparticles (R-SLNs) in permanent bilateral common carotid artery occlusion (BCCAO) induced model of VaD. R-SLNs prepared had average size of 286 nm and 91.25% drug encapsulation efficiency with sustained release. Moreover, R-SLNs had 4.5 times higher levels of resveratrol (RSV) in brain compared to when administered as free RSV. Neurobehavioral analyses revealed that R-SLNs administration successfully ameliorated cognitive decline observed in BCCAO rats. Administration of R-SLNs to BCCAO animals showed significant reduction in mitochondrial reactive oxygen species (ROS) generation, lipid peroxidation, and protein carbonyls. In addition, R-SLNs significantly improved redox ratio and Mn-superoxide dismutase (Mn-SOD) activity. R-SLNs administration resulted in significant reduction in hypoxia-inducible factor 1α (HIF-1α) levels, whereas, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) levels were increased after R-SLNs treatment. Taken together, the results demonstrate that R-SLNs could be a novel and promising therapeutic strategy in VaD as well in other age-related neurodegenerative disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.
Kakkar, Vandita; Kaur, Indu Pal
Aluminium, a well established neurotoxicant, is reported to be involved in the aetiology of Alzheimer's disease (AD) due to its easy admittance and accumulation in central nervous system (CNS). Simultaneous curcumin treatment during the induction of neurotoxicity by AlCl(3) is reported to provide protection. However, the therapeutic potential of curcumin in terms of reversing the neuronal damage once induced is limited due to its compromised bioavailability (BA). We prepared solid lipid nanoparticles of curcumin (C-SLNs) with enhanced BA (32-155 times) and investigated its therapeutic role in alleviating behavioural, biochemical and histochemical changes upon oral administration (100mg/kg) of AlCl(3) in male Lacca mice. Adverse effects of AlCl(3) were completely reversed by oral administration of C-SLNs. Treatment with free curcumin showed ≤ 15% recovery in membrane lipids (LPO) and 22% recovery in acetylcholinesterase (AChE) with respect to AlCl(3) treated group. C-SLNs showed significantly better results (97.46% and 73% recovery in LPO and AChE) at a dose of 50mg/kg, and the results were comparable (p ≤ 0.001) to those achieved with rivastigmine. Histopathology of the brain sections of C-SLNs treated groups also indicated significant improvement. Study highlights the potential of C-SLNs for treatment of AD. Copyright © 2011 Elsevier Ltd. All rights reserved.
Pardeshi, Chandrakantsing V; Rajput, Pravin V; Belgamwar, Veena S; Tekade, Avinash R; Surana, Sanjay J
Present investigation deals with intranasal delivery of ropinirole hydrochloride (ROPI HCl), loaded in solid lipid nanoparticles (SLNs). Prime objectives of this experiment are avoidance of hepatic first pass metabolism and to improve therapeutic efficacy in the treatment of Parkinson's disease. SLNs were fabricated by emulsification-solvent diffusion technique. A 3(2)-factorial design approach has been employed to assess the influence of two independent variables, namely Pluronic F-68 and stearylamine concentration on particle size, ζ-potential and entrapment efficiency of prepared SLNs. Prepared samples were further evaluated for in vitro drug diffusion, ex vivo drug permeation, histopathological and stability studies. Differential scanning calorimetry analysis revealed the encapsulation of amorphous form of drug into lipid matrix, while scanning electron microscopy studies indicated the spherical shape. Fabricated SLNs had shown no severe signs of damage on integrity of nasal mucosa. Release pattern of prepared drug-loaded sample was best fitted to zero-order kinetic model with non-Fickian super case II diffusion mechanism. In vivo pharmacodynamic studies were carried out to compare therapeutic efficacy of prepared nasal formulation against marketed oral formulation. Results of analysis of variance demonstrated the significance of suggested model. Three-dimensional response surface plots and regression equations confirmed the corresponding influence of selected independent variables on measured responses. Our findings suggested the feasibility of investigated system for intranasal administration.
Makled, Shaimaa; Nafee, Noha; Boraie, Nabila
Phosphodiesterase type 5 (PDE-5) inhibitors - among which sildenafil citrate (SC) - play a primary role in the treatment of pulmonary hypertension (PH). Yet, SC can be only administered orally or parenterally with lot of risks. Targeted delivery of SC to the lungs via inhalation/nebulization is mandatory. In this study, solid lipid nanoparticles (SLNs) loaded with SC were prepared and characterized in terms of colloidal, morphological and thermal properties. The amount of drug loaded and its release behavior were estimated as a function of formulation variables. The potential of lipid nanocarriers to retain their properties following nebulization and autoclaving was investigated. In addition, toxicity aspects of plain and loaded SLNs on A549 cells were studied with respect to concentration. Spherical SLNs in the size range (100-250nm) were obtained. Particles ensured high encapsulation efficiency (88-100%) and sustained release of the payload over 24h. Cell-based viability experiments revealed a concentration-dependant toxicity for both plain and loaded SLNs recording an IC50 of 516 and 384μg/mL, respectively. Nebulization with jet nebulizer and sterilization via autoclaving affected neither the colloidal stability of SLNs nor the drug entrapment, proving their potential as pulmonary delivery system. Interaction of SLNs with mucin was a function of the emulsifier coating layer. Results yet seeking clinical evidence - might give promises of new therapy for PH of higher safety, better performance and higher patient compliance. Copyright © 2016 Elsevier B.V. All rights reserved.
Kuo, Yung-Chih; Chung, Chiu-Yen
Solid lipid nanoparticles (SLNs) with complex internal phase were fabricated for formulating stavudine (D4T), delavirdine (DLV), and saquinavir (SQV). The lipids including Compritol 888 ATO, tripalmitin, and cacao butter were stabilized by L-α-phospatidylcholine, cholesteryl hemisuccinate, and taurocholate to form SLNs. The results revealed that the morphology of SLNs was spheroidal with shallow surface pits. An increase in the weight percentage of Compritol 888 ATO increased the average diameter of D4T-entrapping SLNs and decreased that of DLV- and SQV-entrapping SLNs. Preservation at 4°C over 6 weeks slightly enhanced the size of SLNs. For a specific drug, an increase in the entrapment efficiency enlarged the nanocarriers. The order of drug in the average particle diameter and in the entrapment efficiency was SQV>DLV>D4T, in general. In addition, the dissolution of the three drugs from SLNs showed the characteristics of sustained release. The order of drug in the cumulative release percentage was D4T>DLV>SQV. SLNs containing Compritol 888 ATO, tripalmitin, and cacao butter are efficient in carrying antiretroviral agents for medicinal application.
Farboud, Effat Sadat; Nasrollahi, Saman Ahmad; Tabbakhi, Zahra
Solid lipid nanoparticles (SLNs) of coenzyme Q10 (CoQ10) were formulated by a high-pressure homogenization method. The best formulation of SLN dispersion consisted of 13% lipid (cetyl palmitate or stearic acid), 8% surfactant (Tween 80 or Tego Care 450), and water. Stability tests, particle size analysis, differential scanning calorimetry, transmission electron microscopy, and release study were conducted to find the best formulation. A simple cream of CoQ10 and a cream containing CoQ10-loaded SLNs were prepared and compared on volunteers aged 20–30 years. SLNs with particle size between 50 nm and100 nm exhibited the most suitable stability. In vitro release profiles of CoQ10 from simple cream, SLN alone, and CoQ10-loaded SLN cream showed prolonged release for SLNs compared with the simple cream, whereas there was no significant difference between SLN alone and SLN in cream. In vitro release studies also demonstrated that CoQ10-loaded SLN and SLN cream possessed a biphasic release pattern in comparison with simple cream. In vivo skin hydration and elasticity studies on 25 volunteers suggested good dermal penetration and useful activity of Q10 on skin as a hydratant and antiwrinkle cream. PMID:21674018
Lai, Francesco; Wissing, Sylvia A; Müller, Rainer H; Fadda, Anna M
The aim of this study was to formulate a new delivery system for ecological pesticides by the incorporation of Artemisia arborescens L essential oil into solid lipid nanoparticles (SLN). Two different SLN formulations were prepared following the high-pressure homogenization technique using Compritol 888 ATO as lipid and Poloxamer 188 or Miranol Ultra C32 as surfactants. The SLN formulation particle size was determined using Photon correlation spectroscopy (PCS) and laser diffraction analysis (LD). The change of particle charge was studied by zeta potential (ZP) measurements, while the melting and recrystallization behavior was studied using differential scanning calorimetry (DSC). In vitro release studies of the essential oil were performed at 35 degrees C. Data showed a high physical stability for both formulations at various storage temperatures during 2 months of investigation. In particular, average diameter of Artemisia arborescens L essential oil-loaded SLN did not vary during storage and increased slightly after spraying the SLN dispersions. In vitro release experiments showed that SLN were able to reduce the rapid evaporation of essential oil if compared with the reference emulsions. Therefore, obtained results showed that the studied SLN formulations are suitable carriers in agriculture.
Severino, Patrícia; Silveira, Elisânia F; Loureiro, Kahynna; Chaud, Marco V; Antonini, Danilo; Lancellotti, Marcelo; Sarmento, Victor Hugo; da Silva, Classius F; Santana, Maria Helena A; Souto, Eliana B
Antimicrobial resistance is a current public health concern, limiting the available therapeutic options used for the treatment of common bacterial infections. The development of new drug entities via biotechnological processes is however expensive and time-consuming. Therefore, old antimicrobial agents have been recovered for clinical use. An example of these drugs is polymyxin, which is known for its serious adverse side effects, such as nephrotoxicity, neurotoxicity and promotion of skin pigmentation. To overcome these limitations, the use of biodegradable nanoparticles has been proposed to allow site-specific targeting, increasing the drug's bioavailability and decreasing its side effects. The aim of this work was the development of an optimized pharmaceutical formulation composed of solid lipid nanoparticles (SLN) loading polymyxin B sulphate (PLX) for the treatment of bacterial infections. The PLX-loaded SLN were produced by a double emulsion method (w/o/w), obtaining particles with a mean size of approximately 200nm, polydispersity of 0.3 and zeta potential of -30mV. The encapsulation efficiency reached values above 90% for all developed formulations. SLN remained stable for a period of 6months of storage at room temperature. The occlusive properties of the SLN was shown to be dependent on the type of lipid, while the antimicrobial properties of PLX-loaded SLN were effective against resistant strains of Pseudomonas aeruginosa. Results from the differential scanning calorimetry (DSC), wide angle X-ray diffraction (WAXD) and small angle X-ray scattering (SAXS) analyses confirmed the crystallinity of the inner SLN matrices, suggesting the capacity of these particles to modify the release profile of the loaded drug. Copyright © 2017. Published by Elsevier B.V.
Anantachaisilp, Suranan; Meejoo Smith, Siwaporn; Treetong, Alongkot; Pratontep, Sirapat; Puttipipatkhachorn, Satit; Rungsardthong Ruktanonchai, Uracha
Lipid nanoparticles are a promising alternative to existing carriers in chemical or drug delivery systems. A key challenge is to determine how chemicals are incorporated and distributed inside nanoparticles, which assists in controlling chemical retention and release characteristics. This study reports the chemical and structural investigation of γ-oryzanol loading inside a model lipid nanoparticle drug delivery system composed of cetyl palmitate as solid lipid and Miglyol 812® as liquid lipid. The lipid nanoparticles were prepared by high pressure homogenization at varying liquid lipid content, in comparison with the γ-oryzanol free systems. The size of the lipid nanoparticles, as measured by the photon correlation spectroscopy, was found to decrease with increased liquid lipid content from 200 to 160 nm. High-resolution proton nuclear magnetic resonance (1H-NMR) measurements of the medium chain triglyceride of the liquid lipid has confirmed successful incorporation of the liquid lipid in the lipid nanoparticles. Differential scanning calorimetric and powder x-ray diffraction measurements provide complementary results to the 1H-NMR, whereby the crystallinity of the lipid nanoparticles diminishes with an increase in the liquid lipid content. For the distribution of γ-oryzanol inside the lipid nanoparticles, the 1H-NMR revealed that the chemical shifts of the liquid lipid in γ-oryzanol loaded systems were found at rather higher field than those in γ-oryzanol free systems, suggesting incorporation of γ-oryzanol in the liquid lipid. In addition, the phase-separated structure was observed by atomic force microscopy for lipid nanoparticles with 0% liquid lipid, but not for lipid nanoparticles with 5 and 10% liquid lipid. Raman spectroscopic and mapping measurements further revealed preferential incorporation of γ-oryzanol in the liquid part rather than the solid part of in the lipid nanoparticles. Simple models representing the distribution of γ-oryzanol and
Pan, Yuanjie; Tikekar, Rohan V; Nitin, N
The overall goal of this study was to characterize the distribution of a model bioactive encapsulant in the lipid domain of SLNs and NLCs and its relationship with loading efficiency and reactivity of the model encapsulant with oxidative stress agents. Distribution of a model bioactive (beta-carotene) was compared to that of a fluorescent dye (Nile red) in SLNs, 10% NLC, 30% NLC, 50% NLC, 70% NLC (the number represents the percentage of liquid lipid within the total lipid amount) and emulsions. Fluorescence imaging shows that the distribution of Nile red in the lipid domain of colloidal carriers was similar to that of beta-carotene in all formulations. Based on the combination of imaging observations and loading efficiency measurements, the results demonstrate that beta-carotene was excluded from the lipid domain in both SLNs and NLCs. The extent of exclusion decreased, while uniformity in the distribution of encapsulant in the lipid domain of colloidal carrier increased with an increase in percentage of liquid lipid content of NLCs. Oxidative stability of the encapsulated beta-carotene in SLN and NLCs (at least until 30% liquid lipid composition) was significantly lower compared to that in emulsion. Only for the NLCs with 50 and 70% liquid lipid content, oxidative stability of the encapsulated compound was significantly higher than that in emulsions. Overall, the results demonstrate that differences in loading efficiency and oxidative stability of beta-carotene in SLNs and NLCs may be explained by the differences in the distribution of beta-carotene. Copyright © 2016 Elsevier B.V. All rights reserved.
Mosallaei, Navid; Mahmoudi, Asma; Ghandehari, Hamidreza; Yellepeddi, Venkata Kashyap; Jaafari, Mahmoud Reza; Malaekeh-Nikouei, Bizhan
7-Ethyl-10-hydroxycamptothecin (SN38) is a biologically active metabolite of irinotecan. Due to the variability of irinotecan metabolism rate to SN38, and poor solubility of this compound in pharmaceutically acceptable solvents, SN38 has not been successfully used in the clinic. In the present study, we prepared solid lipid nanoparticle (SLN) formulations containing SN38 and evaluated the in vitro and in vivo efficacy of these nanoparticles. SLNs and PEGylated SLNs containing SN38 (SLN-SN38 and PEG-SLN-SN38) were prepared using ultrasonication technique. Nanoparticles were characterized for size, zeta potential, and drug encapsulation efficiency. In vitro cytotoxicity of these compounds was evaluated in two colorectal carcinoma cell lines, namely C-26 and HT-116. In vivo antitumor efficacy of the formulations was evaluated in C-26 xenograft tumor mice models. Mice survival was also explored through 60days post IV injection. Mean size of SLN-SN38 and PEG-SLN-SN38 was around 103 and 131nm, respectively. Polydispersity index (PDI) for all the formulations was around 0.2 and zeta potential was negative (-5 to -15mV). Nearly 90% of the drug was encapsulated in SLNs. SLN-SN38 and PEG-SLN-SN38 compared to irinotecan were significantly more toxic to C-26 and HT-116 cell lines after 48h of exposure. Calculation of IC50 suggests higher sensitivity of HT-116 cells than C-26 cells to SLN-SN38 and PEG-SLN-SN38. Tumor inhibitory efficacy presented the highest efficacy in SLN-SN38. However, both SLN-SN38 and PEG-SLN-SN38 carriers showed higher efficiency to inhibit tumors compared to irinotecan (25mg/kg).
Doktorovova, Slavomira; Souto, Eliana B; Silva, Amélia M
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.
Garg, Anuj; Bhalala, Kripal; Tomar, Devendra Singh; Wahajuddin
The present investigation aims to develop lumefantrine loaded binary solid lipid nanoparticles (LF-SLNs) to improve its poor and variable oral bioavailability. The oral bioavailability of LF is poor and variable due to its limited aqueous solubility and P-gp mediated efflux occurring in small intestine. LF-SLNs were prepared using binary lipid mixture of stearic acid and caprylic acid stabilized with TPGS (D-alpha tocopheryl polyethylene glycol 1000 succinate) and Poloxamer 188. Developed LF-SLNs were characterized for particle size distribution, zeta potential, entrapment efficiency, solid state properties and biopharmaceutical properties including in situ intestinal permeability and oral bioavailability. The particle size distribution, zeta potential and entrapment efficiency of optimized batch (LF-SLN7) was found to be 357.7±43.27nm, 25.29±1.15mV and 97.35±0.30%, respectively. DSC thermographs showed loss of crystalline nature of lumefantrine in LF-SLNs. In situ single pass intestinal permeability study (SPIP) study indicated significant enhancement in the effective intestinal permeability of LF from LF-SLN7 as compared to that of control. Pharmacokinetic study also showed significant increase in Cmax and area under curve (AUC0-∞) from LF-SLN7 (3860±521ng/mL and 43181±2557h×ng/mL, respectively) as compared to that of LF-control suspension (1425±563ng/mL and 19586±1537h×ng/mL, respectively). Thus, developed LF-SLNs can be promising to overcome P-gp efflux pump and enhance the oral bioavailability of lumefantrine.
Bhatt, Rahul; Singh, Devendra; Prakash, Atish; Mishra, Neeraj
The objective of the present study was to investigate the potential use of solid lipid nanoparticles (SLNs) as a drug delivery system to enhance the brain-targeting efficiency of rosmarinic acid (RA) following intranasal (i.n.) administration. The RA-loaded SLNs was prepared by the hot homogenization technique, in which glycerol monostearate (GMS) as lipid, tween 80 and soya lecithin were used as surfactant along with hydrogenated soya phosphatidyl choline (HSPC) as a stabilizer, and were characterized for particle size, zeta potential (ZP), in vitro study. Nasal delivery of the developed formulation followed by the study of behavioral (locomotor, narrow beam, body weight) and biochemical parameters (glutathione, lipid peroxidation, catalase and nitrite) in wistar rat was carried out. Optimized RA-loaded SLNs using tween 80 (SLNPRT) have the mean size of (149.2 ± 3.2 nm), ZP (-38.27 mV) entrapment efficiency (61.9 ± 2.2%). 3-NP-treated rat significantly increased behavioral alterations, oxidative damage as compared with the control group. SLNPRT treatment significantly improved behavioral abnormalities and attenuated the oxidative stress in 3NP-treated rats. However, the nasal delivery of SLNPRT produced significant therapeutic action as compared to intravenous application. In the organ distribution study, brain drug concentration was found to be 5.69 µg, in pharmacokinetic study Cmax, tmax, t1/2, AUC values were found to be 0.284 µg/ml, 1.5 h, 3.17 h, and 1.505 µg/ml/h, respectively. The encouraging results confirmed the developed optimized RA-loaded SLNs formulation following the non-invasive nose-to-brain drug delivery that is a promising therapeutic approach for the effective management in Huntington disease.
Wu, Miaojing; Fan, Yanghua; Lv, Shigang; Xiao, Bing; Ye, Minhua; Zhu, Xingen
Glioma is a common malignant brain tumor originating in the central nervous system. Efficient delivery of therapeutic agents to the cells and tissues is a difficult challenge. Co-delivery of anticancer drugs into the cancer cells or tissues by multifunctional nanocarriers may provide a new paradigm in cancer treatment. In this study, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) were constructed for co-delivery of vincristine (VCR) and temozolomide (TMZ) to develop the synergetic therapeutic action of the two drugs. The antitumor effects of these two systems were compared to provide a better choice for gliomatosis cerebri treatment. VCR- and TMZ-loaded SLNs (VT-SLNs) and NLCs (VT-NLCs) were formulated. Their particle size, zeta potential, drug encapsulation efficiency (EE) and drug loading capacity were evaluated. The single TMZ-loaded SLNs and NLCs were also prepared as contrast. Anti-tumor efficacies of the two kinds of carriers were evaluated on U87 malignant glioma cells and mice bearing malignant glioma model. Significantly better glioma inhibition was observed on NLCs formulations than SLNs, and dual drugs displayed the highest antitumor efficacy in vivo and in vitro than all the other formulations used. VT-NLCs can deliver VCR and TMZ into U87MG cells more efficiently, and inhibition efficacy is higher than VT-SLNs. This dual drugs-loaded NLCs could be an outstanding drug delivery system to achieve excellent therapeutic efficiency for the treatment of malignant gliomatosis cerebri.
Das, Surajit; Ng, Wai Kiong; Tan, Reginald B H
In recent years, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are among the popular research topics for the delivery of lipophilic drugs. Although SLNs have demonstrated several beneficial properties as drug-carrier, limited drug-loading and expulsion of drug during storage led to the development of NLCs. However, the superiority of NLCs over SLNs has not been fully established yet due to the contradictory results. In this study, SLNs and NLCs were developed using clotrimazole as model drug. Size, polydispersity index (PI), zeta potential (ZP), drug-loading (L), drug encapsulation efficiency (EE), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffractometry (XRD), drug release and stability of SLNs and NLCs were compared. Critical process parameters exhibited significant impact on the nanoparticles' properties. Size, PI, ZP and EE of the developed SLNs and NLCs were<100 nm, <0.17, <-22 mV and>82%, respectively. SEM images of SLNs and NLCs revealed spherical shaped particles (≈ 100 nm). DSC and XRD studies indicated slight difference between SLNs and NLCs as well as disappearance of the crystalline peak(s) of the encapsulated drug. NLCs demonstrated faster drug release than SLNs at low drug-loading, whereas there was no significant difference in drug release from SLNs and NLCs at high drug-loading. However, sustained/prolonged drug release was observed from both formulations. Furthermore, this study suggests that the drug release experiment should be designed considering the final application (topical/oral/parenteral) of the product. Regarding stability, NLCs showed better stability (in terms of size, PI, EE and L) than SLNs at 25°C. Moreover, there was no significant difference in drug release profile of NLCs after 3 months storage in compare to fresh NLCs, while significant change in drug release rate was observed in case of SLNs. Therefore, NLCs have an edge over SLNs. Copyright © 2012 Elsevier
Chitosan-Coated Cinnamon/Oregano-Loaded Solid Lipid Nanoparticles to Augment 5-Fluorouracil Cytotoxicity for Colorectal Cancer: Extract Standardization, Nanoparticle Optimization, and Cytotoxicity Evaluation.
Kamel, Kamel M; Khalil, Islam A; Rateb, Mostafa E; Elgendy, Hosieny; Elhawary, Seham
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.
Nakasato, Daniele Y; Pereira, Anderson E S; Oliveira, Jhones L; Oliveira, Halley C; Fraceto, Leonardo F
Although the potential toxicity of many metallic and carbon nanoparticles to plants has been reported, few studies have evaluated the phytotoxic effects of polymeric and solid lipid nanoparticles. The present work described the preparation and characterization of chitosan/tripolyphosphate (CS/TPP) nanoparticles and solid lipid nanoparticles (SLN) and evaluated the effects of different concentrations of these nanoparticles on germination of Zea mays, Brassica rapa, and Pisum sativum. CS/TPP nanoparticles presented an average size of 233.6±12.1nm, polydispersity index (PDI) of 0.30±0.02, and zeta potential of +21.4±1.7mV. SLN showed an average size of 323.25±41.4nm, PDI of 0.23±0.103, and zeta potential of -13.25±3.2mV. Nanotracking analysis enabled determination of concentrations of 1.33×10(10) (CS/TPP) and 3.64×10(12) (SLN) nanoparticles per mL. At high concentrations, CS/TPP nanoparticles caused complete inhibition of germination, and thus negatively affected the initial growth of all tested species. Differently, SLN presented no phytotoxic effects. The different size and composition and the opposite charges of SLN and CS/TPP nanoparticles could be associated with the differential phytotoxicity of these nanomaterials. The present study reports the phytotoxic potential of polymeric CS/TPP nanoparticles towards plants, indicating that further investigation is needed on the effects of such formulations intended for future use in agricultural systems, in order to avoid damage to the environment. Copyright © 2017 Elsevier Inc. All rights reserved.
Kumar, Raj; Singh, Ashutosh; Garg, Neha; Siril, Prem Felix
Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (IBP) are among the most prescribed drugs across the globe. However, most NSAIDs are insoluble in water leading them to have poor bioavailability and erratic absorption. Moreover, NSAIDs such as IBP and ketoprofen (KP) have to be administered very frequently due to their short plasma half-life leading to side effects. Controlled release formulations of IBP, KP and nabumetone (NBT) based on solid lipid nanoparticles (SLNs) were successfully synthesised in the present study to solve the above-mentioned challenges that are associated with NSAIDs. SLNs were prepared in two steps; hot-melt homogenization followed by sonication to formulate SLNs with spherical morphology. While capmul® GMS-50K (capmul) was used as the lipid due to the high solubility of the studied drugs in it, gelucire® 50/13 (gelucire) was used as the surfactant. It was found that particle size was directly proportional to drug concentration and inversely proportional to surfactant concentration, volume of water added and temperature of water. Ultrasonication in a pulse mode with optimum duration of 15min was essential to obtain smaller nanoparticles through the formation of a nanoemulsion. Drug loaded SLNs with small particle size and narrow size distribution with good solid loading, encapsulation efficiency and drug loading percentage could be prepared using the optimised conditions. SLNs prepared at the optimised condition were characterized thoroughly by using different techniques such as dynamic light scattering (DLS), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). The cytotoxicity results showed that the prepared SLNs are non-toxic to Raw cell line. The drugs IBP, KP and NBT showed 53, 74 and 69% of percentage entrapment efficiency with
Pardeike, Jana; Hommoss, Aiman; Müller, Rainer H
Solid lipid nanoparticles (SLN) are distinguishable from nanostructured lipid carriers (NLC) by the composition of the solid particle matrix. Both are an alternative carrier system to liposomes and emulsions. This review paper focuses on lipid nanoparticles for dermal application. Production of lipid nanoparticles and final products containing lipid nanoparticles is feasible by well-established production methods. SLN and NLC exhibit many features for dermal application of cosmetics and pharmaceutics, i.e. controlled release of actives, drug targeting, occlusion and associated with it penetration enhancement and increase of skin hydration. Due to the production of lipid nanoparticles from physiological and/or biodegradable lipids, this carrier system exhibits an excellent tolerability. The lipid nanoparticles are a "nanosafe" carrier. Furthermore, an overview of the cosmetic products currently on the market is given and the improvement of the benefit/risk ratio of the topical therapy is shown.
Hwang, Tsong-Long; Aljuffali, Ibrahim A; Hung, Chi-Feng; Chen, Chun-Han; Fang, Jia-You
Cationic solid lipid nanoparticles (cSLNs) are extensively employed as the nanocarriers for drug/gene targeting to tumors and the brain. Investigation into the possible immune response of cSLNs is still lacking. The aim of this study was to evaluate the impact of cSLNs upon the activation of human polymorphonuclear neutrophil cells (PMNs). The cytotoxicity, pro-inflammatory mediators, Ca(2+) mobilization, mitogen-activated protein kinases (MAPKs), and neutrophil extracellular traps (NETs) as the indicators of PMN stimulation were examined in this work. The cSLNs presented a diameter of 195 nm with a zeta potential of 44 mV. The cSLNs could interact with the cell membrane to produce a direct membrane lysis and the subsequent cytotoxicity according to lactate dehydrogenase (LDH) elevation. The interaction of cSLNs with the membrane also triggered a Ca(2+) influx, followed by the induction of oxidative stress and degranulation. The cationic nanoparticles elevated the levels of superoxide anion and elastase by 24- and 9-fold, respectively. The PMN activation by cSLNs promoted the phosphorylation of p38 and Jun-N-terminal kinases (JNK) but not extracellular signal-regulated kinases (ERK). The imaging of scanning electron microscopy (SEM) and immunofluorescence demonstrated the production of NETs by cSLNs. This phenomenon was not significant for the neutral SLNs (nSLNs), although histones in NETs also increased after treatment of nSLNs. Our results suggest an important role of cSLNs in governing the activation of human neutrophils.
Fan, Tingting; Chen, Chunhui; Guo, Han; Xu, Juan; Zhang, Jian; Zhu, Xi; Yang, Yang; Zhou, Zhou; Li, Lian; Huang, Yuan
Designing feasible and effective peptide ligand modified solid lipid nanoparticles (SLNs) to improve oral bioavailability of protein drugs and evaluating the influence of mucus remains important. In the present work, two kinds of peptide ligand modified SLNs loaded with salmon calcitonin (sCT), namely, sCT CSK-SLNs and sCT IRQ-SLNs, were prepared by coupling the peptide ligand CSKSSDYQC (CSK) which was reported to show affinity with goblet cells, or IRQRRRR (IRQ), a cell penetrating peptide, to polyoxyethylene (40) stearate (SA-PEG2000). Compared with unmodified SLNs, CSK or IRQ modified SLNs with better drug protection ability could facilitate the internalization of drug on Caco-2/HT29-MTX co-cultured cells and permeation in excised rat duodenum mucosa. The internalization mechanism of two kinds of peptide ligand modified SLNs was mainly active transport via both clathrin- and caveolae-dependent endocytosis. Although mucus was an impediment to the transport of SLNs, the peptide ligand modified SLNs still showed improved drug absorption. The absolute bioavailability of sCT CSK-SLNs (12.41 ± 3.65%) and sCT IRQ-SLNs (10.05 ± 5.10%) raised to 2.45-fold and 1.98-fold compared with unmodified SLNs (5.07 ± 0.54%), implying the feasibility and effectiveness of CSK and IRQ peptide modification for the enhancement of the oral bioavailability of protein drugs. In summary, the nanoparticles modified with CSK or IRQ peptide ligand could be the potential carriers for the transport of protein drugs across intestinal barriers.
Xie, Shuyu; Yang, Fei; Tao, Yanfei; Chen, Dongmei; Qu, Wei; Huang, Lingli; Liu, Zhenli; Pan, Yuanhu; Yuan, Zonghui
Enrofloxacin-loaded docosanoic acid solid lipid nanoparticles (SLNs) with different physicochemical properties were developed to enhance activity against intracellular Salmonella. Their cellular uptake, intracellular elimination and antibacterial activity were studied in RAW 264.7 cells. During the experimental period, SLN-encapsulated enrofloxacin accumulated in the cells approximately 27.06–37.71 times more efficiently than free drugs at the same extracellular concentration. After incubation for 0.5 h, the intracellular enrofloxacin was enhanced from 0.336 to 1.147 μg/mg of protein as the sizes of nanoparticles were increased from 150 to 605 nm, and from 0.960 to 1.147 μg/mg of protein when the charge was improved from −8.1 to −24.9 mv. The cellular uptake was more significantly influenced by the size than it was by the charge, and was not affected by whether the charge was positive or negative. The elimination of optimal SLN-encapsulated enrofloxacin from the cells was significantly slower than that of free enrofloxacin after removing extracellular drug. The inhibition effect against intracellular Salmonella CVCC541 of 0.24 and 0.06 μg/mL encapsulated enrofloxacin was stronger than 0.6 μg/mL free drug after all of the incubation periods and at 48 h, respectively. Docosanoic acid SLNs are thus considered as a promising carrier for intracellular bacterial treatment. PMID:28112240
Minelli, R; Occhipinti, S; Gigliotti, C L; Barrera, G; Gasco, P; Conti, L; Chiocchetti, A; Zara, G P; Fantozzi, R; Giovarelli, M; Dianzani, U; Dianzani, C
BACKGROUND AND PURPOSE Solid lipid nanoparticles containing cholesteryl butyrate (cholbut SLN) can be a delivery system for the anti-cancer drug butyrate. These nanoparticles inhibit adhesion of polymorphonuclear and tumour cells to endothelial cells and migration of tumour cells, suggesting that they may act as anti-inflammatory and anti-tumour agents. Here we have evaluated the effects of cholbut SLN on tumour cell growth using in vitro and in vivo models. EXPERIMENTAL APPROACH Cholbut SLNs were incubated with cultures of four tumour cell lines, and cell growth was analysed by assessing viability, clonogenic capacity and cell cycle. Effects on intracellular signalling was assessed by Western blot analysis of Akt expression. The in vivo anti-tumour activity was measured in two models of PC-3 cell xenografts in SCID/Beige mice. KEY RESULTS Cholbut SLN inhibited tumour cell line viability, clonogenic activity, Akt phosphorylation and cell cycle progression. In mice injected i.v. with PC3-Luc cells and treated with cholbut SLN, . in vivo optical imaging and histological analysis showed no metastases in the lungs of the treated mice. In another set of mice injected s.c. with PC-3 cells and treated with cholbut SLN when the tumour diameter reached 2 mm, analysis of the tumour dimensions showed that treatment with cholbut SLN substantially delayed tumour growth. CONCLUSION AND IMPLICATIONS Cholbut SLN were effective in inhibiting tumour growth in vitro and in vivo. These effects may involve, in part, inhibition of Akt phosphorylation, which adds another mechanism to the activity of this multipotent drug. PMID:23713413
Ruiz de Garibay, A P; Solinís, M A; del Pozo-Rodríguez, A; Apaolaza, P S; Shen, J S; Rodríguez-Gascón, A
Here, we demonstrate the ability of solid lipid nanoparticle-based non-viral vectors to increase the α-galactosidase A levels of the IMFE1 cell line, an in vitro model for target cells in Fabry disease. For this purpose, vectors containing the pR-M10-αGal A plasmid, which encodes the α-galactosidase A enzyme, were prepared; the in vitro transfection efficacy was studied in IMFE1 cells, and the results were confirmed by RT-PCR. The cellular uptake of the vectors, intracellular disposition of the plasmid, and probable endocytosis pathways of the nanoparticles were also analyzed. The vectors used for the studies carried protamine (P-DNA-SLN), dextran and protamine (D-P-DNA-SLN), or hyaluronic acid of two different molecular weights and protamine (HA150-P-DNA-SLN or HA500-P-DNA-SLN). The new formulations, which presented a particle size in the range of nanometers (from 218 nm to 348 nm) and a positive superficial charge, were able to increase α-galactosidase A activity up to 4-fold in comparison to non treated IMFE1 cells. The most efficient vectors were those that included HA, and no differences due to changes in the molecular weight of HA were detected. The observed lack of colocalization with each of the four different Nile Red-labeled vectors and transferrin or cholera toxin appears to indicate that clathrin- and caveolae-independent pathways may be involved in their cellular uptake. Additionally, colocalization with LysoTracker indicated that the formulations were exposed to lysosomal activity, which may be responsible for the release of the plasmid from the vector. In conclusion, we reveal the potential of SLN-based vectors to efficiently transfect an immortalized Fabry patient cell line.
Eskandani, Morteza; Nazemiyeh, Hossein
Shikonin and some of its derivative have approved apoptotic potential in different human cancer cell lines, and moreover have a dominant fluorescent emission at ∼600nm. Here, to enhance shikonin-Act anti-proliferation properties, it was successfully incorporated in Solid Lipid Nanoparticles (SLNs) by the hot homogenization and entrapment efficiency (EE) of drug in SLNs was determined by ultrafiltration method. Scanning electron microscopy (SEM), laser diffractometry and zeta-sizer indicated that shikonin-Act-SLN were spherical and regular particles in the range of 70-120nm with polydispersity index (PI) of less than 0.10. The physical stability of shikonin-Act-loaded SLN in aqueous dispersion was evaluated in terms of size, PI, EE and drug leakage and the results showed that SLNs were stable upon storing three month. Long term in vitro release of the shikonin-Act was also approved. Cellular uptake of the shikonin-Act-SLN was examined by the in vitro fluorescent microscopy and facs flow cytometry analyses. In vivo rat imaging approved the penetrating capability of shikonin-Act-SLN emission through living tissues. In vitro anti-proliferation and genotoxicity evaluation by MTT and comet assay confirmed that shikonin-Act-SLN showed higher cytotoxic/antitumor potential than intact shikonin in terms of IC50 and DNA damage. This work provide sufficient information about improving of the therapeutic efficacy of the shikonin-Act, and also using of the shikonin-Act-SLN in bio-distribution studies during drug delivery investigation by incorporating in lipidic and colloidal drug delivery particles such as SLNs. Copyright © 2014 Elsevier B.V. All rights reserved.
Amekyeh, Hilda; Billa, Nashiru; Yuen, Kah-Hay; Lim, Sheau Chin Sherlyn
Amphotericin B (AmB) is poorly absorbed from the gastrointestinal tract. Recent studies have suggested enhanced drug absorption from solid lipid nanoparticles (SLN). Little is known of the fate of AmB absorption within the gastrointestinal tract, and no gastrointestinal transit study has yet been performed on AmB-containing nano-formulations. We aimed to investigate the effect of food on the gastrointestinal transit properties of an AmB-containing SLN in rats. Three SLNs containing AmB, paracetamol, or sulfasalazine were formulated using cocoa butter and beeswax as lipid matrices and simultaneously administered orally to Sprague-Dawley rats. Paracetamol and sulfapyridine were used as marker drugs for estimating gastric emptying and cecal arrival, respectively. The pharmacokinetic data generated for paracetamol and sulfapyridine were used in estimating the absorption of the AmB SLNs in the small and large intestines, respectively. A delayed rate of AmB absorption was observed in the fed state; however, the extent of absorption was not affected by food. Specifically, the percentages of AmB absorption during the fasted state in the stomach, small intestine, and colon were not significantly different from absorption within the respective regions in the fed state. In both states, however, absorption was highest in the colon and appeared to be a combination of absorption from the small intestine plus absorption proper within the colon. The study suggests that AmB SLN, irrespective of food status, is slowly but predominantly taken up by the lymph, making the small intestine the most favorable site for the delivery of the AmB SLNs.
Gupta, Biki; Poudel, Bijay Kumar; Pathak, Shiva; Tak, Jin Wook; Lee, Hee Hyun; Jeong, Jee-Heon; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh
Imatinib (IMT), an anticancer agent, inhibits receptor tyrosine kinases and is characterized by poor aqueous solubility, extensive first-pass metabolism, and rapid clearance. The aims of the current study are to prepare imatinib-loaded solid lipid nanoparticles (IMT-SLN) and study the effects of associated formulation variables on particle size and drug encapsulation on IMT-SLN using an experimental design. IMT-SLN was optimized by use of a "combo" approach involving Plackett-Burman design (PBD) and Box-Behnken design (BBD). PBD screening resulted in the determination of organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), and amount of Tween® 20 (Tw20) as three significant variables for particle size (S z), drug loading (DL), and encapsulation efficiency (EE) of IMT-SLN, which were used for optimization by BBD, yielding an optimized criteria of O/A = 0.04, D/L = 0.03, and Tw20 = 2.50% w/v. The optimized IMT-SLN exhibited monodispersed particles with a size range of 69.0 ± 0.9 nm, ζ-potential of -24.2 ± 1.2 mV, and DL and EE of 2.9 ± 0.1 and 97.6 ± 0.1% w/w, respectively. Results of in vitro release study showed a sustained release pattern, presumably by diffusion and erosion, with a higher release rate at pH 5.0, compared to pH 7.4. In conclusion, use of the combo experimental design approach enabled clear understanding of the effects of various formulation variables on IMT-SLN and aided in the preparation of a system which exhibited desirable physicochemical and release characteristics.
Zhao, Yun; Chang, Yue-Xing; Hu, Xiao; Liu, Chun-Yu; Quan, Li-Hui; Liao, Yong-Hong
The objective of this study was to prepare solid lipid nanoparticles (SLNs) for sustained pulmonary delivery of Yuxingcao essential oil (YEO). Three YEO loaded SLNs (SLN-200, SLN-400 and SLN-800) with different particle size were prepared and separated following a high-shear homogenization technique using Compritol 888 ATO as lipid and polyvinyl alcohol as an emulsifier. The particle size, zeta potential, drug encapsulation efficiency and drug loading of the SLNs were determined to be between 171 and 812nm, -17.1 and -19.3mV, between 76.6 and 90.2% and between 2.34 and 3.12%, respectively whereas the in vitro release data showed that the SLNs led to sustained drug release up to 48h. In addition, the SLN suspensions after nebulization conferred the fine particle fractions (<5.4μm) of 67.4-75.8%. Following intratracheal administration to rats, YEO loaded SLNs not only prolonged pulmonary retention up to 24h, but also increased AUC values (15.4, 18.2 and 26.3μg/gh for SLN-200, SLN-400 and SLN-800, respectively) by 4.5-7.7 folds compared to the intratracheally dosed YEO solution and by 257-438 folds to the intravenously dosed YEO solution, respectively. The present results were the first to show that YEO loaded SLNs may sustain YEO inhalation delivery and improve local bioavailability, representing a promising inhalable carrier to attain once daily application. Copyright © 2016. Published by Elsevier B.V.
Ha, Yeonjeong; Katz, Lynn E; Liljestrand, Howard M
The distribution coefficient (Klipw) of fullerene between solid supported lipid membranes (SSLMs) and water was examined using different lipid membrane compositions. Klipw of fullerene was significantly higher with a cationic lipid membrane compared to that with a zwitterionic or anionic lipid membrane, potentially due to the strong interactions between negative fullerene dispersions and positive lipid head groups. The higher Klipw for fullerene distribution to ternary lipid mixture membranes was attributed to an increase in the interfacial surface area of the lipid membrane resulting from phase separation. These results imply that lipid composition can be a critical factor that affects bioconcentration of fullerene. Distribution of fullerene into zwitterionic unsaturated lipid membranes was dominated by the entropy contribution (ΔS) and the process was endothermic (ΔH > 0). This result contrasts the partitioning thermodynamics of highly and moderately hydrophobic chemicals indicating that the lipid-water distribution mechanism of fullerene may be different from that of molecular level chemicals. Potential mechanisms for the distribution of fullerene that may explain these differences include adsorption on the lipid membrane surfaces and partitioning into the center of lipid membranes (i.e., absorption).
Moazeni, Maryam; Kelidari, Hamid Reza; Saeedi, Majid; Morteza-Semnani, Ketayoun; Nabili, Mojtaba; Gohar, Atefeh Abdollahi; Akbari, Jafar; Lotfali, Ensieh; Nokhodchi, Ali
Antifungal therapy results in complications in management due to changes in the patterns of epidemiology and drug susceptibility of invasive fungal infections. In this study, we prepared fluconazole-loaded solid lipid nanoparticles (FLZ-SLNs) and investigated the efficacy of the optimal formulation on fluconazole (FLZ)-resistant strains of several Candida species. FLZ-SLN was produced using probe ultrasonication techniques. The morphology of the obtained SLNs was characterized by field emission scanning electron microscopy. The minimum inhibitory concentrations for the new formulations against fluconazole-resistant strains of Candida were investigated using CLSI document M27-A3. The FLZ-SLNs presented a spherical shape with a mean diameter, zeta potential and entrapment efficiency of 84.8nm, -25mV and 89.6%, respectively. The drug release from FLZ-SLNs exhibited burst release behaviour at the initial stage (the first 30min) followed by a sustained release over 24h FLZ-resistant yeast strains behaved as susceptible strains after treatment with FLZ-SLNs (≤8μg/ml). The MIC50 drug concentrations were 2μg/ml, 1μg/ml and 2μg/ml for FLZ-resistant strains of Candida albicans, Candida parapsilosis and Candida glabrata, respectively. In this study, we evaluated novel delivery systems for combating Candida strains that exhibit low susceptibility against the conventional formulation of FLZ as a first-line treatment. Copyright © 2016 Elsevier B.V. All rights reserved.
Trapani, Adriana; Mandracchia, Delia; Di Franco, Cinzia; Cordero, Héctor; Morcillo, Patricia; Comparelli, Roberto; Cuesta, Alberto; Esteban, Maria Angeles
The primary aim of the present work was to evaluate the in vitro uptake of 6-Coumarin (6COUM) loaded solid lipid nanoparticles (SLN) by two gilthead seabream (Sparus aurata L.) cell types: an established cell line (SAF-1 cells) and the primary cultures of head-kidney (HK)-the main haemopoietic organ in fish, equivalent to mammalian bone marrow-leucocytes. For this purpose, after the physicochemical characterization of SLN, the uptake by those immunocompetent fish cells was evaluated using flow cytometry and confocal microscopy. Concomitantly, the uptake of 6-COUM loaded SLN was compared with that achieved with 6-COUM loaded pectin microparticles (MPs), which were selected as a competitor of the delivery carriers. After SLN and MP physicochemical characterization, the results demonstrated that SAF-1 cells were able to internalize high percentages of 6-COUM SLNs when incubated for 4, 8 and 24h, with the highest SLN concentration tested (10 μg/ml). The ability of HK leucocytes to internalize SLN was also found to vary depending on both incubation time and SLN concentration. The highest values of HK leucocytes internalizing SLN particles (around 16%) were detected at the maximum SLN concentration (20 μg/ml) at incubation times of 4 or 8h. Conversely, HK leucocytes were unable to internalize MPs at any tested concentration and incubation time. A possible mechanism explaining the uptake into cells is proposed. The present work constitutes the first approximation to consider SLN as nanocarriers for delivering biologically active substances to fish.
Pyo, Sung Min; Meinke, Martina; Klein, Anja F; Fischer, Tanja C; Müller, Rainer H
For the post laser treatment of couperosis a new dermal formulation was developed combining three actives: vitamin K1, A1 and rutin, where both vitamins were incorporated into solid lipid nanoparticles (SLN) and the poorly soluble antioxidant rutin formulated as nanocrystal. All three formulations were stable over 6 months either on their own or after their incorporation into a hydrogel. Vitamin A1 at 0.3% in emulsions shows local skin irritation due to very rapid release. By forming SLN, prolonged release with less irritation potential but deeper penetration was achieved in porcine ear skin. Due to the nanosized rutin, the new hydrogel showed clearly increased antioxidant activity, representing a stronger protection potential against reactive oxygen species (ROS), compared to marketed anti-redness products with rutin as raw drug powder or water-soluble derivative. In addition, rutin nanocrystals showed up to 5 times pronounced penetration compared to μm-sized raw drug powder. The orientating in-vivo case study revealed a three to six times faster recovery after laser treatment of couperosis by twice daily application of the new hydrogel, regarding scabbed-over areas and erythema. Continued use of the new gel also showed preventive properties against recurrences of veins for at least 8 month.
Zhang, Dianrui; Tan, Tianwei; Gao, Lei
Oridonin, a lipophilic Chinese medicine, has very low oral bioavailability due to its poor solubility. Solid lipid nanoparticle (SLN) delivery systems of oridonin have been formed using stearic acid, soybean lecithin and pluronic F68 in our studies to overcome this problem. Emulsion evaporation-solidification at low temperature was used to prepare SLN dispersions. The particle size and morphology were examined by transmission electron microscopy (TEM), and the zeta potential was measured by a television micro-electrophoresis apparatus. Process and formulation variables have been studied and optimized on the basis of entrapment efficiency. Differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD) studies were performed to characterize the state of the drug. In vitro release studies were performed in phosphate-buffer solution (PBS) (pH 7.4). The tissue distribution in mice and the pharmacokinetics in rabbits were studied to evaluate the tissue targeted property of SLNs. Stable SLN formulations of oridonin having a mean size range of 15-35 nm and mean zeta potential -45.07 mV were developed. More than 40% oridonin was entrapped in SLNs. DSC and PXRD analysis showed that oridonin is dispersed in SLNs in an amorphous state. The release pattern of the drug was analysed and found to follow the Higuchi equations. In vivo studies demonstrated that oridonin-loaded SLNs obviously increased the concentration of oridonin in liver, lung and spleen, while its distribution in heart and kidney decreased.
Shrotriya, Shilpa; Ranpise, Nisharani; Satpute, Pournima; Vidhate, Bhagvat
Irritant contact dermatitis (ICD) and hyperpigmentation are the problems associated with skin. Topical curcumin (CUR) although effective in hyperpigmentation and ICD, is a challenging molecule due to low-solubility. Encapsulation of CUR into solid lipid nanoparticles (SLNs) makes it amenable to topical dosing as their small size promotes its penetration into the skin. CUR-SLNs were prepared using Precirol ATO5 and Tween-80 by probe ultrasonication method. Further, CUR-SLNs were incorporated into Carbopol gel and investigated for ex-vivo skin permeation, skin deposition and skin irritation studies. The potential of CUR-SLN gel was checked against hyperpigmentation through the inhibition of tyrosinase enzyme. It was further evaluated for possible effects on ICD using BALB/c mice. The optimized CUR-SLN showed the particle size of 51 nm and 93% EE. Ex vivo permeation of CUR-SLN gel exhibited controlled drug release up to 24 h, similarly in vitro drug deposition studies showed potential for skin targeting. In vitro tyrosinase inhibition assay indicates that the formulated gel has potential in skin depigmentation. The gel also confirmed proficient suppression of ear swelling and reduction in skin water content in the BALB/c mouse. Thus, the CUR-SLN gel would be a safe and effective alternative to conventional vehicles for treatment of ICD and pigmentation.
Kuo, Yung-Chih; Cheng, Shih-Jue
Solid lipid nanoparticles (SLNs) conjugated with tamoxifen (TX) and lactoferrin (Lf) were applied to carry anticancer carmustine (BCNU) across the blood-brain barrier (BBB) for enhanced antiproliferation against glioblastoma multiforme (GBM). BCNU-loaded SLNs with modified TX and Lf (TX-Lf-BCNU-SLNs) were used to penetrate a monolayer of human brain-microvascular endothelial cells (HBMECs) and human astrocytes and to target malignant U87MG cells. The surface TX and Lf on TX-Lf-BCNU-SLNs improved the characteristics of sustained release for BCNU. When compared with BCNU-loaded SLNs, TX-Lf-BCNU-SLNs increased the BBB permeability coefficient for BCNU about ten times. In addition, TX-BCNU-SLNs considerably promoted the fluorescent intensity of intracellular acetomethoxy derivative of calcein (calcein-AM) in HBMECs via endocytosis. However, the conjugated Lf could only slightly increase the fluorescence of calcein-AM. Moreover, the order of formulation in the inhibition to U87MG cells was TX-Lf-BCNU-SLNs>TX-BCNU-SLNs>Lf-BCNU-SLNs>BCNU-SLNs. TX-Lf-BCNU-SLNs can be effective in infiltrating the BBB and delivering BCNU to GBM for future chemotherapy application. Copyright © 2015 Elsevier B.V. All rights reserved.
Baek, Jong-Suep; Cho, Cheong-Weon
Paclitaxel (PTX) has been used in the treatment of wide range of cancers but its entry into cancer cell is restricted by p-glycoprotein (p-gp). Also, it was reported that verapamil (VP) could inhibit p-gp efflux. Hence, three kinds of solid lipid nanoparticles (SLN) such as PVS (PTX and VP co-loaded SLN), PSV (PTX loaded SLN, later added VP) and PVSV (PTX and VP co-loaded SLN, later added VP) were prepared to overcome MDR by combination of PTX and VP. PVS was the SLN loaded with both PTX and VP at the same time. PSV was the SLN loaded with PTX and then modified with VP - complexed hydroxypropyl-β-cylcodextrin (HPCD). Finally, PVSV was the SLN loaded with PTX and half of VP at the same time subsequently, modified with half of VP - complexed HPCD. The physicochemical characterizations of PVS, PSV or PVSV such as particle size, zeta potential, encapsulation efficiency or in vitro PTX release were examined. PVSV showed that release of VP was higher than PTX solution in first 15h and sustained release of both VP and PTX. PVSV showed significantly higher cytotoxicity and cellular uptake than that of the PTX solution in MCF-7/ADR resistant cells. Furthermore, PVSV significantly down regulated the expression of p-gp than the PTX solution in MCF-7/ADR resistant cells. Based on these findings, this study indicated that the PVSV exhibited great potential for breast cancer therapy.
Jain, Aviral; Singhai, Priyanka; Gurnany, Ekta; Updhayay, Satish; Mody, Nishi
Blood-brain barrier restricts the uptake of many important hydrophilic drugs and limits their efficacy in the treatment of brain diseases because of the presence of tight junctions, high metabolic capacity, low pinocytic vesicular traffic, and efficient efflux mechanisms. In the present project, transferrin (Tf)-conjugated solid lipid nanoparticles (Tf-SLNs) were investigated for their ability to deliver temozolomide (TMZ) to the brain. SLNs were prepared by an ethanol injection method using hydrogenated soya phosphatidylcholine, triolein, cholesterol and distearoylphosphatidylethanolamine. Conjugation of SLNs with Tf was achieved by incubation of Tf with TMZ-loaded SLNs in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in phosphate buffered saline (pH 7.4) as a cross linker. SLNs preparation were characterized for particle size, polydispersity index, zeta potential, surface morphology, percent drug entrapment efficiency, in vitro drug release, and hemolytic toxicity studies. In vitro cytotoxicity studies were performed on human cancer cell lines. The average size was found to be 221 ± 3.22 nm with entrapment efficiency of 69.83 ± 2.52 and 249 ± 2.61 nm with entrapment efficiency decreased to 64.21 ± 2.27 % for unconjugated SLNs and Tf-SLNs, respectively. Fluorescence studies revealed the enhanced uptake of Tf-SLNs in brain tissue compared with unconjugated SLNs.
Al-Amin, Md; Cao, Jiafu; Naeem, Muhammad; Banna, Hasanul; Kim, Min-Soo; Jung, Yunjin; Chung, Hae Young; Moon, Hyung Ryong; Yoo, Jin-Wook
Hyperpigmentation caused by melanin overproduction is a major skin disorder in humans. Inhibition of tyrosinase, a key regulator of melanin production, has been used as an effective strategy to treat hyperpigmentation. In this study, we investigated the use of solid lipid nanoparticles (SLNs) as a highly effective and nontoxic means to deliver a newly synthesized potent tyrosinase inhibitor, MHY498, and to target melanocytes through the skin. MHY498-loaded SLNs (MHY-SLNs) were prepared by an oil-in-water emulsion solvent-evaporation method, and their morphological and physicochemical properties were characterized. MHY-SLNs showed a prolonged drug-release profile and higher skin permeation than that of MHY solution. In an in vivo evaluation of antimelanogenic activity, MHY-SLNs showed a prominent inhibitory effect against ultraviolet B-induced melanogenesis, resulting in no change in the skin color of C57BL/6 mouse, compared with that observed in an MHY solution-treated group and an untreated control group. The antimelanogenic effect of MHY-SLNs was further confirmed through Fontana–Masson staining. Importantly, MHY-SLNs did not induce any toxic effects in the L929 cell line. Overall, these data indicate that MHY-SLNs show promise in the topical treatment of hyperpigmentation. PMID:27980392
Dal Magro, R; Ornaghi, F; Cambianica, I; Beretta, S; Re, F; Musicanti, C; Rigolio, R; Donzelli, E; Canta, A; Ballarini, E; Cavaletti, G; Gasco, P; Sancini, G
Solid lipid nanoparticles (SLN) are colloidal drug delivery systems characterized by higher entrapment efficiency, good scalability of the preparation process and increased sustained prolonged release of the payload compared to other nanocarriers. The possibility to functionalize the surface of SLN with ligands to achieve a site specific targeting makes them attractive to overcome the limited blood-brain barrier (BBB) penetration of therapeutic compounds. SLN are prepared for brain targeting by exploiting the adaptability of warm microemulsion process for the covalent surface modification with an Apolipoprotein E-derived peptide (SLN-mApoE). Furthermore, the influence of the administration route on SLN-mApoE brain bioavailability is here evaluated. SLN-mApoE are able to cross intact a BBB in vitro model. The pulmonary administration of SLN-mApoE is related to a higher confinement in the brain of Balb/c mice compared to the intravenous and intraperitoneal administration routes, without inducing any acute inflammatory reaction in the lungs. These results promote the pulmonary administration of brain-targeted SLN as a feasible strategy for improving brain delivery of therapeutics.
Li, Jian-Chun; Zhang, Wen-Jing; Zhu, Jin-Xiu; Zhu, Na; Zhang, Hong-Min; Wang, Xiu; Zhang, Jin; Wang, Qing-Qing
To investigate the brain delivery in rat by nasal Quetiapine fumarate (QF) loaded with solid lipid nanoparticles in situ gel (QF-SLN-gel). QF-SLN-gel was prepared through micro-emulsion technique. The rat model of schizophrenia was established by intraperitoneal injection of (+)-MK-801, evaluated by stereotypic behavior, Mori's Water Maze (MWM) test and hematoxylin and eosin (HE) staining of hippocampus. The animals were administrated with QF via oral, nasal or tail vein approach and the concentration of QF in blood and brain was determined using high performance liquid chromatography (HPLC). The QF-SLN-gel was even and transparent, having size of 117.8±2.67 d.nm, potential of 57.2±0.24 mV and EF of 97.6±0.58%. After administration of QF-SLN-gel, the concentration of QF in blood and brain of rats in nasal QF-SLN-gel group was similar with that of rats in tail vein QF group, but significantly higher than that of rats in oral QF group. The hippocampal morphology changes induced by (+)-MK-801 were ameliorated by QF, with advantage of nasal QF-SLN-gel over tail vein QF. The nasal QF-SLN-gel had stable and good brain delivery and could ameliorate the damages in rat model of schizophrenia induced by (+)-MK-801.
Saljoughian, N; Zahedifard, F; Doroud, D; Doustdari, F; Vasei, M; Papadopoulou, B; Rafati, S
The use of an appropriate delivery system has recently emerged as a promising approach for the development of effective vaccination against visceral leishmaniasis (VL). Here, we compare two vaccine delivery systems, namely electroporation and cationic solid-lipid nanoparticle (cSLN) formulation, to administer a DNA vaccine harbouring the L. donovani A2 antigen along with L. infantum cysteine proteinases [CPA and CPB without its unusual C-terminal extension (CPB(-CTE) )] and evaluate their potential against L. infantum challenge. Prime-boost administration of the pcDNA-A2-CPA-CPB(-CTE) delivered by either electroporation or cSLN formulation protects BALB/c mice against L. infantum challenge and that protective immunity is associated with high levels of IFN-γ and lower levels of IL-10 production, leading to a strong Th1 immune response. At all time points, the ratio of IFN-γ: IL-10 induced upon restimulation with rA2-rCPA-rCPB and F/T antigens was significantly higher in vaccinated animals. Moreover, Th2-efficient protection was elicited through a high humoral immune response. Nitric oxide production, parasite burden and histopathological analysis were also in concordance with other findings. Overall, these data indicate that similar to the electroporation delivery system, cSLNs as a nanoscale vehicle of Leishmania antigens could improve immune response, hence indicating the promise of these strategies against visceral leishmaniasis.
Shah, Rohan M; Eldridge, Daniel S; Palombo, Enzo A; Harding, Ian H
Stearic acid-based solid lipid nanoparticles (SLNs) were prepared using the microwave assisted one-pot microemulsions procedure pioneered by our group. In this study, non-steroidal anti-inflammatory drugs (NSAIDs) including indomethacin, ketoprofen and nimesulide were selected as ideal "test" drugs, based on their poor water solubility. The model drugs were incorporated within the SLNs by the microwave-assisted procedure at the time of SLN production. The microwave-produced drug-loaded SLNs were evaluated in terms of their physicochemical characteristics, drug release behavior and their uptake into against A549 cell line (human lung epithelial cells). The microwave-produced drug-loaded SLNs had a small particle size distribution, negative zeta potential and high encapsulation efficiency. The drug release studies were consistent with a core-shell structure of SLNs (probably a drug-loaded shell) which results in biphasic drug release from the SLNs. The drug release kinetics suggested a good fit of the release data to the Makoid-Banakar model and was governed by Fickian diffusion. The drug-loaded SLNs showed concentration-dependent cytotoxicity and reduced IL-6 and IL-8 secretion in lipopolysaccharide-induced cells. All of the above findings suggest that the microwave-produced SLNs could be promising drug carriers of NSAIDs and will further facilitate their development for topical, oral and/or nasal administration. Copyright Â© 2016 Elsevier B.V. All rights reserved.
Kim, Sanghoon; Diab, Roudayna; Joubert, Olivier; Canilho, Nadia; Pasc, Andreea
Newly designed microcapsules (MC) combining a core of solid lipid nanoparticle (SLN) and a mesoporous silica shell have been developed and explored as oral delivery system of curcumin (CU). CU-loaded MC (MC-CU) are 2 μm sized and have a mesoporous silica shell of 0.3 μm thickness with a wormlike structure as characterized by small angle X-ray scattering (SAXS), nitrogen adsorption/desorption and transmission electron microscopy (TEM) measurements. It was found that SLN acts as reservoir of curcumin while the mesoporous shell insures the protection and the controlled release of the drug. MC-CU displayed a pH-dependent in vitro release profile with marked drug retention at pH 2.8. Neutral red uptake assay together with confocal laser scanning microscopy (CLSM) showed a good cell tolerance to MC-CU at relatively high concentration of inert materials. Besides, the cell-uptake test revealed that fluorescent-MC were well internalized into Caco-2 cells, confirming the possibility to use MC for gut cells targeting. These findings suggest that organic core-silica shell microcapsules are promising drug delivery systems with enhanced bioavailability for poorly soluble drugs.
Al-Amin, Md; Cao, Jiafu; Naeem, Muhammad; Banna, Hasanul; Kim, Min-Soo; Jung, Yunjin; Chung, Hae Young; Moon, Hyung Ryong; Yoo, Jin-Wook
Hyperpigmentation caused by melanin overproduction is a major skin disorder in humans. Inhibition of tyrosinase, a key regulator of melanin production, has been used as an effective strategy to treat hyperpigmentation. In this study, we investigated the use of solid lipid nanoparticles (SLNs) as a highly effective and nontoxic means to deliver a newly synthesized potent tyrosinase inhibitor, MHY498, and to target melanocytes through the skin. MHY498-loaded SLNs (MHY-SLNs) were prepared by an oil-in-water emulsion solvent-evaporation method, and their morphological and physicochemical properties were characterized. MHY-SLNs showed a prolonged drug-release profile and higher skin permeation than that of MHY solution. In an in vivo evaluation of antimelanogenic activity, MHY-SLNs showed a prominent inhibitory effect against ultraviolet B-induced melanogenesis, resulting in no change in the skin color of C57BL/6 mouse, compared with that observed in an MHY solution-treated group and an untreated control group. The antimelanogenic effect of MHY-SLNs was further confirmed through Fontana-Masson staining. Importantly, MHY-SLNs did not induce any toxic effects in the L929 cell line. Overall, these data indicate that MHY-SLNs show promise in the topical treatment of hyperpigmentation.
Xue, Jingyi; Wang, Taoran; Hu, Qiaobin; Zhou, Mingyong; Luo, Yangchao
In this work, a new and novel organic solvent-free and synthetic surfactant-free method was reported to fabricate stable solid lipid nanoparticles (SLNs) from stearic acid, sodium caseinate (NaCas) and pectin, as well as water. Melted stearic acid was directly emulsified into an aqueous phase containing NaCas and pectin, followed by pH adjustment and thermal treatment to induce the formation of a compact and dense polymeric coating which stabilized SLNs. The preparation procedures and formulations were comprehensively optimized. The inter- and intra-molecular interactions among three ingredients were characterized by fluorescence and Fourier transform infrared spectroscopies. The stability of as-prepared SLNs was evaluated under simulated gastrointestinal conditions, and compared with traditional SLNs prepared with organic solvents. Our results revealed that the SLNs prepared from this organic solvent-free method had superior physicochemical properties over the traditional SLNs, including smaller size and better stability. Furthermore, redispersible SLNs powders were obtained by nano spray drying, but only the SLNs prepared by organic solvent-free method had sub-micron scale, uniform and spherical morphology. The organic solvent-free preparation method was proved to be a promising approach to prepare stable and uniform SLNs for potential oral delivery applications. Copyright © 2017 Elsevier B.V. All rights reserved.
Picone, Pasquale; Bondi, Maria L; Montana, Giovanna; Bruno, Andreina; Pitarresi, Giovanna; Giammona, Gaetano; Di Carlo, Marta
Oxidative stress and dysfunctional mitochondria are among the earliest events in AD, triggering neurodegeneration. The use of natural antioxidants could be a neuroprotective strategy for blocking cell death. Here, the antioxidant action of ferulic acid (FA) on different paths leading to degeneration of recombinant beta-amyloid peptide (rAbeta42) treated cells was investigated. Further, to improve its delivery, a novel drug delivery system (DDS) was used. Solid lipid nanoparticles (SLNs), empty or containing ferulic acid (FA-SNL), were developed as DDS. The resulting particles had small colloidal size and highly negative surface charge in water. Using neuroblastoma cells and rAbeta42 oligomers, it was demonstrated that free and SLNs-loaded FA recover cell viability. FA treatment, in particular if loaded into SLNs, decreased ROS generation, restored mitochondrial membrane potential (Deltapsi(m)) and reduced cytochrome c release and intrinsic pathway apoptosis activation. Further, FA modulated the expression of Peroxiredoxin, an anti-oxidative protein, and attenuated phosphorylation of ERK1/2 activated by Abeta oligomers.
Martins, Susana; Tho, Ingunn; Reimold, Isolde; Fricker, Gert; Souto, Eliana; Ferreira, Domingos; Brandl, Martin
For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded solid lipid nanoparticles (SLN), prepared by hot high pressure homogenisation, were designed. Incorporation of camptothecin in the hydrophobic and acidic environment of SLN matrix was chosen to stabilise the lactone ring, which is essential for its antitumour activity, and for avoiding premature loss of drug on the way to target camptothecin to the brain. A multivariate approach was used to assess the influence of the qualitative and quantitative composition on the physicochemical properties of camptothecin-loaded SLN in comparison to plain SLN. Mean particle sizes of ≤200 nm, homogenous size distributions and high encapsulation efficiencies (>90%) were achieved for the most suitable formulations. In vitro release studies in plasma, showed a prolonged release profile of camptothecin from SLN, confirming the physical stability of the particles under physiological pH. A higher affinity of the SLN to the porcine brain capillary endothelial cells (BCEC) was shown in comparison to macrophages. MTT studies in BCEC revealed a moderate decrease in the cell viability of camptothecin, when incorporated in SLN compared to free camptothecin in solution. In vivo studies in rats showed that fluorescently labelled SLN were detected in the brain after i.v. administration. This study indicates that the camptothecin-loaded SLN are a promising drug brain delivery system worth to explore further for brain tumour therapy.
Li, Jian-Chun; Zhang, Wen-Jing; Zhu, Jin-Xiu; Zhu, Na; Zhang, Hong-Min; Wang, Xiu; Zhang, Jin; Wang, Qing-Qing
To investigate the brain delivery in rat by nasal Quetiapine fumarate (QF) loaded with solid lipid nanoparticles in situ gel (QF-SLN-gel). QF-SLN-gel was prepared through micro-emulsion technique. The rat model of schizophrenia was established by intraperitoneal injection of (+)-MK-801, evaluated by stereotypic behavior, Mori’s Water Maze (MWM) test and hematoxylin and eosin (HE) staining of hippocampus. The animals were administrated with QF via oral, nasal or tail vein approach and the concentration of QF in blood and brain was determined using high performance liquid chromatography (HPLC). The QF-SLN-gel was even and transparent, having size of 117.8±2.67 d.nm, potential of 57.2±0.24 mV and EF of 97.6±0.58%. After administration of QF-SLN-gel, the concentration of QF in blood and brain of rats in nasal QF-SLN-gel group was similar with that of rats in tail vein QF group, but significantly higher than that of rats in oral QF group. The hippocampal morphology changes induced by (+)-MK-801 were ameliorated by QF, with advantage of nasal QF-SLN-gel over tail vein QF. The nasal QF-SLN-gel had stable and good brain delivery and could ameliorate the damages in rat model of schizophrenia induced by (+)-MK-801. PMID:26770349
Liu, Wei; Hu, Meiling; Liu, Wenshuang; Xue, Chengbin; Xu, Huibi; Yang, XiangLiang
The purpose of this study was to investigate solid lipid nanoparticles (SLN) hydrogel for transdermal iontophoretic drug delivery. Triamcinolone acetonide acetate (TAA), a glucocorticoids compound, was employed as the model drug. SLN containing the drug triamcinolone acetonide acetate (TAA-SLN) and their carbopol gel with stable physicochemical properties were prepared. The use of TAA-SLN carbopol gel as a vehicle for the transdermal iontophoretic delivery of TAA was evaluated in vitro using horizontal diffusion cells fitted with porcine ear skin. We found that the TAA-SLN gel possessed good stability, rheological properties, and high electric conductance. Transdermal penetration of TAA from TAA-SLN gel cross the skin tissue was significantly enhanced by iontophoresis. The enhancement of the cumulative penetration amount and the steady-state penetration flux of the penetrated drug were related to the particle size of TAA-SLN and the characteristics of the applied pulse electric current, such as density, frequency, and on/off interval ratio. These results indicated that SLN carbopol gel could be used as a vehicle for transdermal iontophoretic drug delivery under suitable electric conditions.
Pooja, Deep; Tunki, Lakshmi; Kulhari, Hitesh; Reddy, Bharathi B; Sistla, Ramakrishna
This data article contains the data related to the research article "Characterization, biorecognitive activity and stability of WGA grafted lipid nanostructures for the controlled delivery of rifampicin" (Pooja et al. 2015) . In the present study, SLN were prepared by a single emulsification-solvent evaporation method and the various steps of SLN preparation are shown in a flow chart. The preparation of SLN was optimized for various formulation variables including type and quantity of lipid, surfactant, amount of co-surfactant and volume of organic phase. Similarly, effect of variables related to homogezation, sonication and stirring processes, on the size and surface potential of SLN was determined and optimized.
Bhushan, Shashi; Kakkar, Vandita; Pal, Harish Chandra; Mondhe, D M; Kaur, Indu Pal
AP9-cd, a novel lignan composition from Cedrus deodara has significant anticancer potential, and to further enhance its activity, it was lucratively encumbered into solid lipid nanoparticles (SLNs). These nanoparticles were formulated by micro-emulsion technique with 70% drug trap competence. AP9-cd-SLNs were regular, solid, globular particles in the range of 100-200 nm, which were confirmed by electron microscopic studies. Moreover, AP9-cd-SLNs were found to be stable for up to six months in terms of color, particle size, zeta potential, drug content and entrapment. AP9-cd-SLNs have 30-50% higher cytotoxic and apoptotic potential than the AP9-cd alone. The augmented anticancer potential of AP9-cd-SLNs was observed in cytotoxic IC50 value, apoptosis signaling cascade and in Ehrlich ascites tumor (EAT) model. AP9-cd-SLNs induce apoptosis in Molt-4 cells via both intrinsic and extrinsic pathway. Moreover, the dummy nanoparticles (SLNs without AP9-cd) did not have any cytotoxic effect in cancer as well as in normal cells. Consequently, SLNs of AP9-cd significantly augment the apoptotic and antitumor potential of AP9-cd. The present study provides a podium for ornamental the remedial latent via novel delivery systems like solid lipid nanoparticles. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Andreozzi, Erica; Seo, Jai Woong; Ferrara, Katherine; Louie, Angelique
Solid lipid nanoparticles (SLNs) are sub-micron (1–1000 nm) colloidal carriers developed in the last decade as an alternative system to traditional carriers (emulsions, liposomes and polymeric nanoparticles) for intravenous applications.(1) Because of their potential as drug carriers, there is much interest in understanding the in vivo biodistribution of SLNs following intravenous (i.v) injection. Positron Emission Tomography (PET) is an attractive method for investigating biodistribution but requires a radiolabeled compound. In this work, we describe a method to radiolabel SLN for in vivo PET studies. A copper specific chelator, 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N‴-tetraacetic acid (BAT), conjugated with a synthetic lipid,(2) was incorporated into the SLN. Following incubation with 64CuCl2 for 1 hr at 25 °C in 0.1 M NH4OAc buffer (pH 5.5), the SLNs (~150 nm) were successfully radiolabeled with 64Cu (66.5% radiolabeling yield), exhibiting >95% radiolabeled particles following purification. The 64Cu-SLNs were delivered intravenously to mice and imaged with PET at 0.5, 3, 20, and 48 hr post injection. Gamma counting was utilized post imaging to confirm organ distributions. Tissue radioactivity (% injected dose/gram, %ID/g) obtained by quantitative analysis of the images suggests that the 64Cu-SLNs are circulating in the bloodstream after 3 hr (blood half life ~1.4 hr), but are almost entirely cleared by 48 hr. PET and gamma counting confirm approximately 5–7 %ID/g 64Cu-SLNs remaining in the liver at 48 hr post injection. Stability assays confirm that copper remains associated with the SLN over the 48 hr time period and that the biodistribution patterns observed are not from free, dissociated copper. Our results indicate that SLNs can be radiolabeled with 64Cu and their biodistribution can be quantitatively evaluated by in vivo PET imaging and ex vivo gamma counting. PMID:21388194
Pooja, Deep; Tunki, Lakshmi; Kulhari, Hitesh; Reddy, Bharathi B.; Sistla, Ramakrishna
This data article contains the data related to the research article “Characterization, biorecognitive activity and stability of WGA grafted lipid nanostructures for the controlled delivery of rifampicin” (Pooja et al. 2015) . In the present study, SLN were prepared by a single emulsification-solvent evaporation method and the various steps of SLN preparation are shown in a flow chart. The preparation of SLN was optimized for various formulation variables including type and quantity of lipid, surfactant, amount of co-surfactant and volume of organic phase. Similarly, effect of variables related to homogezation, sonication and stirring processes, on the size and surface potential of SLN was determined and optimized. PMID:26759823
Khallaf, Rasha A; Salem, Heba F; Abdelbary, Ahmed
The effective treatment of skin carcinoma is warranted for targeting the chemotherapeutic agents into tumor cells and avoiding unwanted systemic absorption. This work was dedicated to the purpose of engineering highly penetrating shell-enriched nanoparticles that were loaded with a hydrophilic chemotherapeutic agent, 5-fluorouracil (5-FU). Varying ratios of lecithin and poloxamer188 were used to produce shell-enriched nanoparticles by enabling the formation of reversed micelles within this region of the SLN. The localization of 5-FU within the shell region of the SLN, was confirmed using 5-FU nanogold particles as a tracer. SLN were introduced within sodium carboxy methylcellulose hydrogel, and then applied onto the skin of mice-bearing Ehrlich's ascites carcinoma. The mice were treated with the gel twice daily for 6 weeks. The transmission electron microscope (TEM) revealed the formation of uniform nanoparticles, which captured reversed micelles within their shell region. The SLNs' had particle size that ranged from 137 ± 5.5 nm to 800 ± 53.6, zeta potential of -19.70 ± 0.40 mV and entrapment efficiency of 47.92 ± 2.34%. The diffusion of the drug-loaded SLN (269.37 ± 10.92 μg/cm(2)) was doubled when compared with the free drug (122 ± 3.09 μg/cm(2)) when both diffused through a hydrophobic membrane. SLN-treated mice exhibited reduced inflammatory reactions, with reduced degrees of keratosis, in addition to reduced symptoms of angiogenesis compared to 5-FU-treated mice. SLN possesses the capacity to be manipulated to entrap and release hydrophilic antitumor drugs with ease.
Yousry, Carol; Fahmy, Rania Hassan; Essam, Tamer; El-Laithy, Hanan M; Elkheshen, Seham A
A microbiological multidistrict-based survey from different Egyptian governorates was conducted to determine the most prevalent causative agents of ocular infections in the Egyptian population. Antibiotic sensitivity testing was then performed to identify the most potent antimicrobial agent. Vancomycin (VCM) proved the highest activity against gram-positive Staphylococcus bacteria, which are the most commonly isolated causative agents of ocular infection. However, topically applied VCM suffers from poor ocular bioavailability because of its high molecular weight and hydrophilicity. The aim of the present study was to develop VCM-loaded solid lipid nanoparticles (SLNs) using water-in-oil-in-water (W/O/W) double emulsion, solvent evaporation technique to enhance ocular penetration and prolong ophthalmic residence of VCM. Two consecutive full factorial designs (2(4) followed by 3(2)) were adopted to study the effect of different formulation and process parameters on SLN formulation. The lipid type and structure, polyvinyl alcohol (PVA) molecular weight and concentration, sonication time, as well as lipid:drug ratio were studied as independent variables. The formulated SLN formulae were evaluated for encapsulation efficiency (EE%), particle size (PS), and zeta potential as dependent variables. The statistically-optimized SLN formula (1:1 ratio of glyceryltripalmitate:VCM with 1% low molecular weight PVA and 1 min sonication time) had average PS of 277.25 nm, zeta potential of -20.45, and 19.99% drug encapsulation. Scanning and transmission electron micrographs showed well-defined, spherical, homogenously distributed particles. The present study suggests that VCM incorporation into SLNs is successfully achievable; however, further studies with different nanoencapsulation materials and techniques would be valuable for improving VCM encapsulation.
Shah, Kumar A; Joshi, Medha D; Patravale, Vandana B
The objective of the present investigation was to fabricate glyceryl monostearate SLN by employing a biocompatible microemulsion as a template. Biocompatible excipients such as Tween 20 (as a surfactant) and Transcutol P (a cosourfactant) (at different K(m) ratios) were selected for the fabrication of microemulsions. Pseudo-ternary phase diagrams were plotted to identify the area of the microemulsion existence. Glyceryl monostearate SLN were fabricated by dispersing the microemulsion (maintained at 65 degrees C) into cold water (maintained at 2-3 degrees C). The particle size of the SLN was determined by photon correlation spectroscopy. Tretinoin, a lipophilic anti-acne agent was incorporated into SLN as a model drug. The encapsulation efficiency of tretinoin in the SLN was determined by using Nanosep ultrafilteration device at different lipid loads viz. 1%, 1.5% and 2%. Glyceryl monostearate SLN fabricated from biocompatible microemulsion template exhibited average particle size of 175 nm and polydispersity index of 0.833. Tretinoin could be successfully incorporated into SLN and the encapsulation efficiency ranged from 37-48% at different lipid loads.
Kunasekaran, Viveksarathi; Krishnamoorthy, Kannan
The objective of this study was to select best method for the development of rasagiline mesylate (RM) loaded nanoscale solid lipid particles using analytic hierarchy process (AHP). Improper method selection may lead to waste of time, loss of material and financial resources. One of the possibilities to overcome these difficulties, AHP was employed to find the suitable method. In the AHP, a decision of hierarchy was constructed with a goal, criteria, sub-criteria, and alternatives. After constructing the AHP, the expert choice software was used to compute the overall priority of criteria, sub-criteria and alternatives. The best alternative selected was based on the highest priority. Nanoscale solid lipid particles of RM was formulated by the selected microemulsion method (M4) and it shows the particle size, polydispersity index and zeta potential were within acceptable limits. Drug content and entrapment efficiency of the RM-solid lipid nanoparticles were 97.26% and 86.57%, respectively. This study concludes that the AHP was viable and effective tool for selecting a most suitable method for the fabrication of RM loaded nanoscale solid lipid particles.
da Silva, Camila Morais Gonçalves; Pasquoto, Tatiane; de Lima, Renata; Fraceto, Leonardo Fernandes
15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, has physiological properties including pronounced anti-inflammatory activity, though it binds strongly to serum albumin. The use of solid lipid nanoparticles (SLN) can improve therapeutic properties increasing drug efficiency and availability. 15d-PGJ2-SLN was therefore developed and investigated in terms of its immunomodulatory potential. 15d-PGJ2-SLN and unloaded SLN were physicochemically characterized and experiments in vivo were performed. Animals were pretreated with 15d-PGJ2-SLN at concentrations of 3, 10 or 30 μg·kg-1 before inflammatory stimulus with carrageenan (Cg), lipopolysaccharide (LPS) or mBSA (immune response). Interleukins (IL-1β, IL-10 and IL-17) levels were also evaluated in exudates. The 15d-PGJ2-SLN system showed good colloidal parameters and encapsulation efficiency of 96%. The results showed that the formulation was stable for up to 120 days with low hemolytic effects. The 15d-PGJ2-SLN formulation was able to reduce neutrophil migration in three inflammation models tested using low concentrations of 15d-PGJ2. Additionally, 15d-PGJ2-SLN increased IL-10 levels and reduced IL-1β as well as IL-17 in peritoneal fluid. The new 15d-PGJ2-SLN formulation highlights perspectives of a potent anti-inflammatory system using low concentrations of 15d-PGJ2. PMID:27575486
Marto, Joana; Sangalli, Cecilia; Capra, Priscilla; Perugini, Paola; Ascenso, Andreia; Gonçalves, Lídia; Ribeiro, Helena
N-Acetyl-d-glucosamine (NAG) has been recently considered for topical treatment of hyperpigmentation disorders due to its inhibitory effect on thyrosinase enzymes in melanocytes. NAG is a precursor of hyaluronic acid, increasing its amount in skin, and consequently, preserving the skin hydration and elasticity. It may also act as an emulsion stabilizer. Solid lipid nanoparticles (SLN) are advanced delivery systems successfully used in pharmaceutical and cosmetic formulations for the improvement of active molecules penetration into the skin. Therefore, this work aimed to develop and characterize stable and scalable topical formulations containing NAG-loaded SLN. NAG was incorporated in SLN which were prepared by two high shear homogenizers and characterized regarding its morphology and particle size by transmission electron microscopy and photon correlation spectroscopy, respectively. Oil emulgel and hydrogel were used as carriers of NAG-loaded SLN. Several parameters were evaluated, including the droplet size distribution, rheology, pH and topical delivery by different techniques. It was observed that SLN size was significantly dependent on NAG incorporation and homogenization process. Most tested SLN parameters appeared to be quite suitable, that is, spherical and well-defined SLN with approximately 258 nm and -30 mV. Hereafter, both gels containing SLN presented a pseudoplastic flow. Emulgel formulation containing NAG-loaded SLN allowed a higher NAG permeation through the SC compared to the respective control (about 0.8 μgcm(-2 )h(-1)). According to the results obtained, it can be suggested that NAG acts as an emulsion stabilizer. This stabilization was also particularly dependent on the homogenizer type which is quite important for scale-up process. This study demonstrated the potential of scalable SLN formulations to improve NAG topical delivery contributing to the improvement of skin properties on several skin disorders.
Schöler, N; Olbrich, C; Tabatt, K; Müller, R H; Hahn, H; Liesenfeld, O
After intravenous (i.v.) injection, solid lipid nanoparticles (SLN) interact with mononuclear cells. Murine peritoneal macrophages were incubated with SLN formulations consisting of Dynasan 114 coated with different surfactants. The present study was performed to examine the impact of surfactants, which are important surface defining components of SLN, on viability and cytokine production by macrophages. Cytotoxicity, as assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) test, was strongly influenced by the surfactant used being marked with cetylpyridinium chloride- (CPC-) coated SLN at a concentration of 0.001% and further increased at SLN concentrations of 0.01 and 0.1%. All other SLN formulations -- containing Poloxamine 908 (P908), Poloxamer 407 (P407), Poloxamer 188 (P188), Solutol HS15 (HS15), Tween 80 (T80), Lipoid S75 (S75), sodium cholate (SC), or sodium dodecylsulfate (SDS) -- when used at the same concentrations reduced cell viability only slightly. None of the SLN formulations tested induced cytokine production but a concentration-dependent decrease of IL-6 production was observed, which appeared to be associated with cytotoxic effects. IL-12 and TNF-alpha were detected neither in supernatants of macrophages treated with SLN at any concentration nor in those of untreated cells. In contrast to the type of surfactant, the size of SLN was found neither to affect cytotoxicity of SLN nor to result in induction or digression of cytokine production by macrophages. In conclusion, testing the effects of surfactants on SLN on activity of macrophages is a prerequisite prior to in vivo use of SLN.
Wang, Taoran; Hu, Qiaobin; Zhou, Mingyong; Xia, Yan; Nieh, Mu-Ping; Luo, Yangchao
Solid lipid nanoparticles (SLNs) have gained tremendous attraction as carriers for controlled drug delivery. Despite numerous advances in the field, one long-standing historical challenge for their practical applications remains unmet: redispersibility after drying. In this work, a novel design of SLNs using a layer-by-layer (LbL) technique was developed and the formulations were optimized by surface response methodology (Box-Behnken design). To the best of our knowledge, this is the first study reporting the fabrication of SLNs from all natural ingredients in the absence of any synthetic surfactants or coatings. The SLNs were prepared by a combined solvent-diffusion and hot homogenization method, with soy lecithin as natural emulsifier (first layer), followed by the subsequent coating with sodium caseinate (second layer) and pectin (third layer), both of which are natural food biopolymers. The adsorption of pectin coating onto caseinate was reinforced by hydrophobic and electrostatic interactions induced by a pH-driven process along with thermal treatment. The innovative nano spray drying technology was further explored to obtain ultra-fine powders of SLNs. Compared to uncoated or single-layer coated SLNs powders, which showed severe aggregation after spray drying, the well-separated particles with spherical shape and smooth surface were obtained for layer-by-layer (LbL) SLNs, which were redispersible into water without variation of dimension, shape and morphology. The SLNs were characterized by Fourier transform infrared and high-performance differential scanning calorimetry for their physical properties. The LbL-coated SLNs based on all natural ingredients have promising features for future applications as drug delivery systems, overcoming the major obstacles in conventional spray drying and redispersing SLNs-based formulations. Copyright © 2016 Elsevier B.V. All rights reserved.
Ramalingam, Prakash; Ko, Young Tag
Despite the therapeutic effects of resveratrol, its clinical application is restricted by its poor oral bioavailability, low water solubility, and instability. Solid lipid nanoparticles (SLNs)-based drug delivery systems have been shown to provide excellent support for the delivery of hydrophobic drugs. The poor stability and burst release behavior in stomach acidic pH conditions of SLNs result in increased aggregation of the particles in the gastrointestinal environment, limiting the success of these particles as an oral delivery system for hydrophobic drugs. N-trimethyl chitosan (TMC) graft palmitic acid (PA) (TMC-g-PA) mucoadhesive copolymer was hypothesized to be a promising candidate for the surface modification of PA-decorated resveratrol-loaded SLNs to stabilize SLNs and circumvent all the above mentioned obstacles. TMC and TMC-g-PA copolymers were therefore synthesized and characterized by (1)H-nuclear magnetic resonance ((1)H NMR) and Fourier-transformed infra-red (FT-IR) spectroscopy. Resveratrol-loaded SLNs (SLRNs) that comprised Precirol ATO 5, PA, Gelucire 50/13, Tween 80, and resveratrol as well as TMC-g-PA SLRNs were formulated and characterized in terms of physicochemical properties, stability, cytotoxicity, and in vitro and in vivo effects. The in vitro release studies of TMC-g-PA SLRNs demonstrated negligible release of resveratrol in simulated gastric and sustained release in simulated intestinal conditions and the relative bioavailability of resveratrol was furthermore found to be 3.8-fold higher from TMC-g-PA SLRNs than that from resveratrol suspension. Overall, the findings reported here indicate that TMC-g-PA SLRNs represent a potential oral drug delivery system for resveratrol.
Sampaio, A C; Mendes, R J; Castro, P G; Silva, A M
Solid lipid nanoparticles (SLNs) are used as carriers for drug delivery, and are high biocompatible and designed to endure in the host organism. Despite its current industrial production is low, many of these substances are available on the market, and much more are in the production pipeline. As a result, many of them will end in aquatic systems raising the question whether they can pose a risk to aquatic biota and the associated ecological processes. Microbial decomposers of plant litter, play a key role in forested streams being responsible for the energy flow between terrestrial and aquatic environments. Here, we investigated the effects of SLNs on alder leaf litter decomposition by aquatic microbes. Alder leaves were immersed in a stream of Northeast Portugal to allow microbial colonization before being exposed in microcosms of two types of SLNs at two concentrations for 42 days. Results showed that rates of leaf decomposition decreased with exposure to SLNs. Bacterial biomass was not inhibited by SLNs, and cultivable fungi densities remained constant (SLN-A) or increased (SLN-C) compared with control microcosms. The type and concentration of SLNs influenced differently the leaf colonization by fungi as well as fungal sporulation rate. These effects were accompanied by changes in the community extraenzymatic profile: the activities of alkaline phosphatase, acidic phosphatase, Naphthol-AS-BI-phosphohydrolase (P cycle) and lipases increased in the SLNs microcosms. This study provided the first evidence of the adverse effects of the release of SLNs to streams on leaf litter decomposition. Those effects seem to depend on the composition and concentration of SLNs, as well on the microbial target group, or enzyme. Thus, prior to massive industrial production of these nanomaterials, some measures should be taken to avoid environmental impact affecting the microbial communities responsible for detritus decomposition. Copyright © 2016 Elsevier Inc. All rights reserved.
Yasir, Mohd; Sara, Udai Vir Singh
In the present study, haloperidol (HP)-loaded solid lipid nanoparticles (SLNs) were prepared to enhance the uptake of HP to brain via intranasal (i.n.) delivery. SLNs were prepared by a modified emulsification–diffusion technique and evaluated for particle size, zeta potential, drug entrapment efficiency, in vitro drug release, and stability. All parameters were found to be in an acceptable range. In vitro drug release was found to be 94.16±4.78% after 24 h and was fitted to the Higuchi model with a very high correlation coefficient (R2=0.9941). Pharmacokinetics studies were performed on albino Wistar rats and the concentration of HP in brain and blood was measured by high performance liquid chromatography. The brain/blood ratio at 0.5 h for HP-SLNs i.n., HP sol. i.n. and HP sol. i.v. was 1.61, 0.17 and 0.031, respectively, indicating direct nose-to-brain transport, bypassing the blood–brain barrier. The maximum concentration (Cmax) in brain achieved from i.n. administration of HP-SLNs (329.17±20.89 ng/mL, Tmax 2 h) was significantly higher than that achieved after i.v. (76.95±7.62 ng/mL, Tmax 1 h), and i.n. (90.13±6.28 ng/mL, Tmax 2 h) administration of HP sol. The highest drug-targeting efficiency (2362.43%) and direct transport percentage (95.77%) was found with HP-SLNs as compared to the other formulations. Higher DTE (%) and DTP (%) suggest that HP-SLNs have better brain targeting efficiency as compared to other formulations. PMID:26579417
Yasir, Mohd; Sara, Udai Vir Singh
In the present study, haloperidol (HP)-loaded solid lipid nanoparticles (SLNs) were prepared to enhance the uptake of HP to brain via intranasal (i.n.) delivery. SLNs were prepared by a modified emulsification-diffusion technique and evaluated for particle size, zeta potential, drug entrapment efficiency, in vitro drug release, and stability. All parameters were found to be in an acceptable range. In vitro drug release was found to be 94.16±4.78% after 24 h and was fitted to the Higuchi model with a very high correlation coefficient (R (2)=0.9941). Pharmacokinetics studies were performed on albino Wistar rats and the concentration of HP in brain and blood was measured by high performance liquid chromatography. The brain/blood ratio at 0.5 h for HP-SLNs i.n., HP sol. i.n. and HP sol. i.v. was 1.61, 0.17 and 0.031, respectively, indicating direct nose-to-brain transport, bypassing the blood-brain barrier. The maximum concentration (C max) in brain achieved from i.n. administration of HP-SLNs (329.17±20.89 ng/mL, T max 2 h) was significantly higher than that achieved after i.v. (76.95±7.62 ng/mL, T max 1 h), and i.n. (90.13±6.28 ng/mL, T max 2 h) administration of HP sol. The highest drug-targeting efficiency (2362.43%) and direct transport percentage (95.77%) was found with HP-SLNs as compared to the other formulations. Higher DTE (%) and DTP (%) suggest that HP-SLNs have better brain targeting efficiency as compared to other formulations.
Wang, Wenrui; Zhu, Rongrong; Xie, Qian; Li, Ang; Xiao, Yu; Li, Kun; Liu, Hui; Cui, Daxiang; Chen, Yihan; Wang, Shilong
Curcumin has shown considerable pharmacological activity, including anti-inflammatory, but its poor bioavailability and rapid metabolization have limited its application. The purpose of the present study was to formulate curcumin-solid lipid nanoparticles (curcumin-SLNs) to improve its therapeutic efficacy in an ovalbumin (OVA)-induced allergic rat model of asthma. A solvent injection method was used to prepare the curcumin-SLNs. Physiochemical properties of curcumin-SLNs were characterized, and release experiments were performed in vitro. The pharmacokinetics in tissue distribution was studied in mice, and the therapeutic effect of the formulation was evaluated in the model. The prepared formulation showed an average size of 190 nm with a zeta potential value of -20.7 mV and 75% drug entrapment efficiency. X-ray diffraction analysis revealed the amorphous nature of the encapsulated curcumin. The release profile of curcumin-SLNs was an initial burst followed by sustained release. The curcumin concentrations in plasma suspension were significantly higher than those obtained with curcumin alone. Following administration of the curcumin-SLNs, all the tissue concentrations of curcumin increased, especially in lung and liver. In the animal model of asthma, curcumin-SLNs effectively suppressed airway hyperresponsiveness and inflammatory cell infiltration and also significantly inhibited the expression of T-helper-2-type cytokines, such as interleukin-4 and interleukin-13, in bronchoalveolar lavage fluid compared to the asthma group and curcumin-treated group. These observations implied that curcumin-SLNs could be a promising candidate for asthma therapy.
Shi, Li-Li; Lu, Jia; Cao, Yue; Liu, Jiang-Yan; Zhang, Xiao-Xue; Zhang, Hongjian; Cui, Jing-Hao; Cao, Qing-Ri
The purpose of this study was to prepare the positively charged chitosan (CS)- or hydroxypropyl trimethyl ammonium chloride chitosan (HACC)-modified solid lipid nanoparticles (SLNs) loading docetaxel (DTX), and to evaluate their properties in vitro and in vivo. The DTX-loaded SLNs (DTX-SLNs) were prepared through an emulsion solvent evaporation method and further modified with CS or HACC (CS-DTX-SLNs or HACC-DTX-SLNs) via noncovalent interactions. The gastrointestinal (GI) stability, dissolution rate, physicochemical properties and cytotoxicities of SLNs were investigated. In addition, the GI mucosa irritation and oral bioavailability of SLNs were also evaluated in rats. The HACC-DTX-SLNs were highly stable in simulated gastric and intestinal fluids (SGF and SIF). By contrast, the CS-DTX-SLNs were less stable in SIF than in SGF. The drug dissolution remarkably increased when DTX was incorporated into the SLNs, which may be attributed to the change in the crystallinity of DTX and some molecular interactions that occurred between DTX and the carriers. The SLNs showed low toxicity in Caco-2 cells and no GI mucosa irritations were observed in rats. A 2.45-fold increase in the area under the curve of DTX was found in the HACC-DTX-SLN group compared with the DTX group after the modified SLNs were orally administered to rats. However, the oral absorption of DTX-SLN or CS-DTX-SLN group showed no significant difference compared with that of DTX group. The positively charged HACC-DTX-SLNs with a stable particle size could provide the enhanced oral bioavailability of DTX in rats.
Zhang, Xiaoyun; Qiao, Hua; Chen, Ying; Li, Lin; Xia, Huxiong; Shi, Yanbin
Low molecular weight heparin-modified isoliquiritigenin-loaded solid lipid nanoparticle (LMWH-ISL-SLN) was developed for injective application. The morphological observation, particle diameter and zeta potential of LMWH-ISL-SLN were characterized using transmission electron microscopy (TEM) and a Malvern Zetasizer. Its entrapment efficiency (EE) and drug loading (DL) were determined by ultracentrifuge. The in-vitro release experiments were performed by dialysis technique. The cytotoxic effects of LMWH-ISL-SLN on Hep-G2 cell lines were determined using an MTT assay. Pharmacokinetic and tissue distribution studies were conducted in kunming mice after intravenous administration of LMWH-ISL-SLN. The average drug entrapment efficiency for LMWH-ISL-SLN was (99.80 ± 3.27)%, drug loading was (18.68 ± 1.51)%, mean particle size was (217.53 ± 4.86) nm and zeta potential was (–18.24 ± 2.47) mV. The in-vitro release experiments demonstrated isoliquiritigenin release from LMWH-ISL-SLN was in line with Weibull’s distribution law. Hemolysis test and dose-related toxic effects proved that LMWH-ISL-SLN was a safe and non toxic product when given by intravenous injection. The pharmacokinetics results of LMWH-ISL-SLN showed that the area under the concentration-time curve (AUC0→∞)of LMWH-ISL-SLN was greater than that for the isoliquiritigenin solution in plasma. Tissue distribution study indicated that ISL were mainly distributed in the liver and lung. In conclusion, low molecular weight heparin-modified SLN system is a promising carrier for the intravenous delivery of ISL. PMID:27980562
Apaolaza, P S; Del Pozo-Rodríguez, A; Solinís, M A; Rodríguez, J M; Friedrich, U; Torrecilla, J; Weber, B H F; Rodríguez-Gascón, A
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.
Wang, Wenrui; Zhu, Rongrong; Xie, Qian; Li, Ang; Xiao, Yu; Li, Kun; Liu, Hui; Cui, Daxiang; Chen, Yihan; Wang, Shilong
Curcumin has shown considerable pharmacological activity, including anti-inflammatory, but its poor bioavailability and rapid metabolization have limited its application. The purpose of the present study was to formulate curcumin-solid lipid nanoparticles (curcumin-SLNs) to improve its therapeutic efficacy in an ovalbumin (OVA)-induced allergic rat model of asthma. A solvent injection method was used to prepare the curcumin-SLNs. Physiochemical properties of curcumin-SLNs were characterized, and release experiments were performed in vitro. The pharmacokinetics in tissue distribution was studied in mice, and the therapeutic effect of the formulation was evaluated in the model. The prepared formulation showed an average size of 190 nm with a zeta potential value of −20.7 mV and 75% drug entrapment efficiency. X-ray diffraction analysis revealed the amorphous nature of the encapsulated curcumin. The release profile of curcumin-SLNs was an initial burst followed by sustained release. The curcumin concentrations in plasma suspension were significantly higher than those obtained with curcumin alone. Following administration of the curcumin-SLNs, all the tissue concentrations of curcumin increased, especially in lung and liver. In the animal model of asthma, curcumin-SLNs effectively suppressed airway hyperresponsiveness and inflammatory cell infiltration and also significantly inhibited the expression of T-helper-2-type cytokines, such as interleukin-4 and interleukin-13, in bronchoalveolar lavage fluid compared to the asthma group and curcumin-treated group. These observations implied that curcumin-SLNs could be a promising candidate for asthma therapy. PMID:22888226
Dianzani, Chiara; Foglietta, Federica; Ferrara, Benedetta; Rosa, Arianna Carolina; Muntoni, Elisabetta; Gasco, Paolo; Della Pepa, Carlo; Canaparo, Roberto; Serpe, Loredana
AIM To improve anti-inflammatory activity while reducing drug doses, we developed a nanoformulation carrying dexamethasone and butyrate. METHODS Dexamethasone cholesteryl butyrate-solid lipid nanoparticles (DxCb-SLN) were obtained with the warm microemulsion method. The anti-inflammatory activity of this novel nanoformulation has been investigated in vitro (cell adhesion to human vascular endothelial cells and pro-inflammatory cytokine release by lipopolysaccharide-induced polymorphonuclear cells) and in vivo (disease activity index and cytokine plasma concentrations in a dextran sulfate sodium-induced mouse colitis) models. Each drug was also administered separately to compare its effects with those induced by their co-administration in SLN at the same concentrations. RESULTS DxCb-SLN at the lowest concentration tested (Dx 2.5 nmol/L and Cb 0.1 μmol/L) were able to exert a more than additive effect compared to the sum of the individual effects of each drug, inducing a significant in vitro inhibition of cell adhesion and a significant decrease of pro-inflammatory cytokine (IL-1β and TNF-α) in both in vitro and in vivo models. Notably, only the DxCb nanoformulation administration was able to achieve a significant cytokine decrease compared to the cytokine plasma concentration of the untreated mice with dextran sulfate sodium-induced colitis. Specifically, DxCb-SLN induced a IL-1β plasma concentration of 61.77% ± 3.19%, whereas Dx or Cb used separately induced a concentration of 90.0% ± 2.8% and 91.40% ± 7.5%, respectively; DxCb-SLN induced a TNF-α plasma concentration of 30.8% ± 8.9%, whereas Dx or Cb used separately induced ones of 99.5% ± 4.9% and 71.1% ± 10.9%, respectively. CONCLUSION Our results indicate that the co-administration of dexamethasone and butyrate by nanoparticles may be beneficial for inflammatory bowel disease treatment. PMID:28694660
Apaolaza, Paola Stephanie; Delgado, Diego; del Pozo-Rodríguez, Ana; Gascón, Alicia Rodríguez; Solinís, M Ángeles
The introduction of therapeutic genes in target tissues is considered as a novel tool for the treatment of several diseases. We have developed nanoparticles consisting on SLNs, protamine (P) and hyaluronic acid (HA) as carrier for gene therapy. Stable complexes positively charged and with a particle size ranging from 240 nm to 340 nm were obtained. Transfection studies in ARPE-19 and HEK-293 cells showed the versatility of vectors to efficiently transfect cells with different division rate, widening the potential applications of SLN-based vectors. In ARPE 19cells, the incorporation of P and HA induced almost a 7-fold increase in the transfection capacity of SLNs. The CD44 inhibition studies suggested the participation of this receptor in the internalization of the vectors in this cell line. The intracellular disposition of DNA showed that the HA is able to modulate the high degree of condensation of DNA due to the protamine inside the cells; an important fact, if the vector is uptaken via non-degradative endocytosis. Besides, the therapeutic plasmid which encodes the protein retinoschisin was employed achieving a positive transfection in ARPE-19 cells, showing a promising application of this new non-viral system for the treatment of X-linked juvenile retinoschisis by gene therapy.
Mojahedian, Mohammad M; Daneshamouz, Saeid; Samani, Soliman Mohammadi; Zargaran, Arman
Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) are novel medicinal carriers for controlled drug release and drug targeting in different roots of administration such as parenteral, oral, ophthalmic and topical. These carriers have some benefits such as increased drug stability, high drug payload, the incorporation of lipophilic and hydrophilic drugs, and no biotoxicity. Therefore, due to the cost-efficient, proportionally increasable, and reproducible preparation of SLN/NLC and the avoidance of organic solvents used, the warm microemulsion quenching method was selected from among several preparation methods for development in this research. To prepare the warm O/W microemulsion, lipids (distearin, stearic acid, beeswax, triolein alone or in combination with others) were melted at a temperature of 65°C. After that, different ratios of Tween60 (10-22.5%) and glyceryl monostearate (surfactant and co-surfactant) and water were added, and the combination was stirred. Then, 1-butanol (co-surfactant) was added dropwise until a clear microemulsion was formed and titration continued to achieve cloudiness (to obtain the microemulsion zone). The warm o/w microemulsions were added dropwise into 4°C water (1:5 volume ratio) while being stirred at 400 or 600 rpm. Lipid nanosuspensions were created upon the addition of the warm o/w microemulsion to the cold water. The SLN were obtained over a range of concentrations of co-surfactants and lipids and observed for microemulsion stability (clearness). For selected preparations, characterization involved also determination of mean particle size, polydispersity and shape. According to the aim of this study, the optimum formulations requiring the minimum amounts of 1-butanol (1.2%) and lower temperatures for creation were selected. Mono-disperse lipid nanoparticles were prepared in the size range 77 ± 1 nm to 124 ± 21 nm according to a laser diffraction particle size analyzer and transmission electron
Fàbregas, Anna; Sánchez-Hernández, Noemí; Ticó, Josep Ramon; García-Montoya, Encarna; Pérez-Lozano, Pilar; Suñé-Negre, Josep M; Hernández-Munain, Cristina; Suñé, Carlos; Miñarro, Montserrat
Solid lipid nanoparticles (SLNs) are being considered as a new approach for therapeutics for many known diseases. In addition to drug delivery, their use as non-viral vectors for gene delivery can be achieved by the inclusion of cationic lipids, which provide a positive surface potential that favours binding to the DNA backbone. This work is based on the idea that the optimization of the components is required as the first step in simplifying the qualitative and quantitative composition of SLNs as much as possible without affecting the essential properties that define SLNs as optimal non-viral vectors for gene delivery. We selected the best lipids and surfactants in terms of particle size and zeta potential and characterized the properties of the resulting nanoparticles using X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). The SLNs had a particle size of approximately 120 nm and a positive surface charge of 42 mV. In addition, we analysed the main physicochemical characteristics of the bulk components of the nanoparticles using X-ray diffraction (XRD), differential scanning calorimetry (DSC) and mass spectrometry (MS). The suitability of the optimized SLNs for DNA binding was evaluated after the lyophilisation process using a carboxyl-terminal region of the TCERG1 gene, a human factor that has been implicated in several diseases. We show that the SLNs presented high efficiency in the binding of DNA, and importantly, they presented no toxicity when assayed in an in vivo system.
Venishetty, Vinay Kumar; Chede, Raghavendra; Komuravelli, Rojarani; Adepu, Laxminarayana; Sistla, Ramakrishna; Diwan, Prakash V
Solid lipid nanoparticles are most promising delivery systems for the enhancement of bioavailability of highly lipophilic drugs those prone to the first pass metabolism. But burst release of drug from solid lipid nanoparticles in acidic environment such as gastric milieu precludes its usage as oral delivery system. Studies on SLN revealed intraduodenal administration as an alternative route for SLN administration. But clinically it is an inappropriate route for repeated administration of drugs to patients. Hence, we prepared N-carboxymethyl chitosan (MCC) coated carvedilol loaded SLN to protect the rapid release of carvedilol in acidic environment. Positively charged carvedilol loaded SLN were developed using monoglyceride as lipid and soya lecithin and poloxamer 188 as surfactants and stearylamine as charge modifier. These SLN were characterized for particle size, zeta potential, entrapment efficiency, crystallinity and stability studies. Further these SLN were coated with N-carboxymethyl chitosan and confirmed by change in zetapotential and X-ray Photon Spectroscopic analysis. Effect of polymer coating on drug release profiles were studied simulated gastric and intestinal fluids. Effect of polymer coating on oral bioavailability of carvedilol loaded SLN were studied in rats after oral administration. MCC coated SLN improved the bioavailability of carvedilol compared uncoated SLN after oral administration. Insignificant difference in bioavailability was observed compared to intraduodenal administration of SLN. Hence, MCC coated SLN is a novel strategy to avoid intrduodenal administration.
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
Gupta, Shweta; Kesarla, Rajesh; Chotai, Narendra; Misra, Ambikanandan
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
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.
Gupta, Shweta; Kesarla, Rajesh; Chotai, Narendra; Misra, Ambikanandan; Omri, Abdelwahab
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.
Asnawi, Syalwati; Aziz, Azila A.; Aziz, Ramlan A.
A new delivery system for insect repellent is proposed by the incorporation of geranium oil into solid lipid nanoparticle (SLN). A variety of solvents which act as co-surfactants, were introduced to increase the particle size of GE-SLN. Ethanol, which has a high boiling point and a long chain alcohol produced larger particle than dichloromethane. The structure of SLN was not stable when methanol and acetone were used as co-solvents. Concentration of solvents can also influence the size of SLN. In vitro release experiments showed that SLN was able to reduce the rapid evaporation of geranium oil.
Das, Surajit; Ng, Wai Kiong; Tan, Reginald B H
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.
Das, Surajit; Kiong Ng, Wai; Tan, Reginald B. H.
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.
Gokce, Evren H; Korkmaz, Emrah; Tuncay-Tanrıverdi, Sakine; Dellera, Eleonora; Sandri, Giuseppina; Bonferoni, M Cristina; Ozer, Ozgen
Background The effective delivery of coenzyme Q10 (Q10) to the skin has several benefits in therapy for different skin pathologies. However, the delivery of Q10 to deeper layers of skin is challenging due to low aqueous solubility of Q10. Liposomes and solid lipid nanoparticles (SLN) have many advantages to accomplish the requirements in topical drug delivery. This study aims to evaluate the influence of these nanosystems on the effective delivery of Q10 into the skin. Methods Q10-loaded liposomes (LIPO-Q10) and SLNs (SLN-Q10) were prepared by thin film hydration and high shear homogenization methods, respectively. Particle size (PS), polydispersity index (PI), zeta potential (ZP), and drug entrapment efficiency were determined. Differential scanning calorimetry analysis and morphological transmission electron microscopy (TEM) examination were conducted. Biocompatibility/cytotoxicity studies of Q10-loaded nanosystems were performed by means of cell culture (human fibroblasts) under oxidative conditions. The protective effect of formulations against production of reactive oxygen species were comparatively evaluated by cytofluorometry studies. Results PS of uniform SLN-Q10 and LIPO-Q10 were determined as 152.4 ± 7.9 nm and 301.1 ± 8.2 nm, respectively. ZPs were −13.67 ± 1.32 mV and −36.6 ± 0.85 mV in the same order. The drug entrapment efficiency was 15% higher in SLN systems. TEM studies confirmed the colloidal size. SLN-Q10 and LIPO-Q10 showed biocompatibility towards fibroblasts up to 50 μM of Q10, which was determined as suitable for cell proliferation. The mean fluorescence intensity % depending on ROS production determined in cytofluorometric studies could be listed as Q10 ≥ SLN-Q10 > LIPO-Q10. Conclusion The LIPO-Q10 system was able to enhance cell proliferation. On the contrary, SLN-Q10 did not show protective effects against ROS accumulation. As a conclusion, liposomes seem to have advantages over SLN in terms of effective delivery of Q10 to skin
Cassano, Roberta; Ferrarelli, Teresa; Mauro, Maria Vittoria; Cavalcanti, Paolina; Picci, Nevio; Trombino, Sonia
The present article reports the preparation, characterization and performance evaluation of solid lipid nanoparticles (SLNs) based on polyoxyethylene-40 stearate (PEG-40 stearate) for the administration of antifungal agents such as ketoconazole and clotrimazole. These nanoparticles could be useful in the treatment of vaginal infections sustained by Candida albicans. In particular, PEG-40 stearate was made to react with acryloyl chloride in order to introduce an easily polymerizable moiety for the creation of a second shell and to ensure a slow drug release. In addition, the differences on the release profiles between PEG-40 stearate-based nanoparticles, PEG-40 stearate acrylate based and polymerized ones, were analyzed under conditions, simulating the typical environment of Candida albicans infection. Then, the antifungal activity of nanoparticles was also evaluated in terms of minimal inhibitory concentration. Moreover, the nanoparticles were submitted to in vitro studies for evaluating the drug permeability at the site of action. Results ind