Comparison of the anti-diabetic effects of resveratrol, gliclazide and losartan in streptozotocin-induced experimental diabetes.

PubMed

Yazgan, Ümit Can; Taşdemir, Ezel; Bilgin, Hakkı Murat; Deniz Obay, Basra; Şermet, Abdurrahman; Elbey, Bilal

2015-01-01

The aim of this study was to compare the effect of the resveratrol with gliclazide and losartan in streptozotocin induced diabetic rats. Adult male Wistar albino rats were divided into five groups of seven rats each. Diabetes was induced with a single intraperitoneal (i.p.) injection of streptozotocin (55 mg/kg). Rats with blood glucose levels above 250 mg/dl after 48 h of streptozotocin injection were included in the diabetic group. Gliclazide and resveratrol were administered for 3 weeks at 5 mg/kg per day and losartan was administered for 3 weeks at 30 mg/kg per day in an oral aqueous suspension. At the end of the third week all rats were euthanized and fasting blood glucose, HbA1c and the metabolic activity of the hepatic enzymes hexokinase and glucose-6 phosphate dehydrogenase were measured in tail blood and liver specimens. All parameters were quantified using an ELISA plate reader. Resveratrol and gliclazide significantly reduced both blood glucose levels and HbA1c levels in diabetic rats (p < 0.001). However, losartan did not exhibit the same effects (p < 0.05). The enzymatic activity of the liver enzymes hexokinase, glucose-6 phosphate dehydrogenase, fructose 1,6-biphosphatase, pyruvate kinase and glucose-6 phosphatase were enhanced by resveratrol and gliclazide, while losartan treatment was not associated with significant changes in liver carbohydrate metabolism. Resveratrol was not effective in improving liver carbohydrate metabolism relative to gliclazide, a drug widely used to treat diabetes. Dose-response profile of resveratrol remains indeterminate and additional studies may be necessary to determine effective dosing in diabetes.

Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: a mechanistic study.

PubMed

Proks, Peter; de Wet, Heidi; Ashcroft, Frances M

2014-11-01

Sulfonylureas, which stimulate insulin secretion from pancreatic β-cells, are widely used to treat both type 2 diabetes and neonatal diabetes. These drugs mediate their effects by binding to the sulfonylurea receptor subunit (SUR) of the ATP-sensitive K(+) (KATP) channel and inducing channel closure. The mechanism of channel inhibition is unusually complex. First, sulfonylureas act as partial antagonists of channel activity, and second, their effect is modulated by MgADP. We analyzed the molecular basis of the interactions between the sulfonylurea gliclazide and Mg-nucleotides on β-cell and cardiac types of KATP channel (Kir6.2/SUR1 and Kir6.2/SUR2A, respectively) heterologously expressed in Xenopus laevis oocytes. The SUR2A-Y1206S mutation was used to confer gliclazide sensitivity on SUR2A. We found that both MgATP and MgADP increased gliclazide inhibition of Kir6.2/SUR1 channels and reduced inhibition of Kir6.2/SUR2A-Y1206S. The latter effect can be attributed to stabilization of the cardiac channel open state by Mg-nucleotides. Using a Kir6.2 mutation that renders the KATP channel insensitive to nucleotide inhibition (Kir6.2-G334D), we showed that gliclazide abolishes the stimulatory effects of MgADP and MgATP on β-cell KATP channels. Detailed analysis suggests that the drug both reduces nucleotide binding to SUR1 and impairs the efficacy with which nucleotide binding is translated into pore opening. Mutation of one (or both) of the Walker A lysines in the catalytic site of the nucleotide-binding domains of SUR1 may have a similar effect to gliclazide on MgADP binding and transduction, but it does not appear to impair MgATP binding. Our results have implications for the therapeutic use of sulfonylureas. © 2014 Proks et al.

Preparation and characterization of cross-linked excipient of coprocessed xanthan gum-acacia gum as matrix for sustained release tablets

NASA Astrophysics Data System (ADS)

Surini, Silvia; Wati, Dina Risma; Syahdi, Rezi Riadhi

2018-02-01

Sustained release tablet is solid dosage form which is designed to release drugs slowly in the body. This research was intended to prepare and characterize the cross-linked excipients of co-processed xanthan gum-acacia gum (CL-Co-XGGA) as matrices for sustained release tablets with gliclazide as a model drug. CL-Co-XGGA excipients were cross-linked materials of co-processed excipients of xanthan gum-acacia gum (Co-XGGA) using sodium trimetaphosphate. Co-processed excipients of xanthan gum-acacia gum were prepared in the ratio of each excipient 1:2, 1:1 and 2:1. Co-XGGA and CL-Co-XGGA excipients were characterized physically, chemically and functionally. Then, the sustained release (SR) tablets were formulated by wet granulation method using CL-Co-XGGA excipients as matrices. Also, the dissolution study of the gliclazide SR tablets was carried out in phosphate buffer medium pH 7,4 containing sodium lauryl sulphate 0.2% for 12 hours. The results showed that the degree of substitution (DS) of CL-Co-XGGA 1:2, 1:1, 2:1 excipients were respectively 0.067, 0.082 and 0.08. Besides that, the excipients gel strengths were 14.03, 17.27 and 20,70 gF, respectively. The cross-linked excipients had improved flow properties and swelling capability compared to the Co-XGGA excipients. The results of the gliclazide SR tablets evaluations showed that all tablets were passed all tablet requirements. Moreover, the gliclazide release from SR tablets F1 - F6 revealed the sustained release profile, which was following zero order kinetics (F1, F2, F3, F6) and Higuchi kinetics (F4 and F5). It could be concluded that the obtained CL-Co-XGGA excipients might be used as matrices for sustained release tablets and could retard drug release up to 8 until 32 hours.

A Rare Reason of Hyperinsulinism: Munchausen Syndrome by Proxy.

PubMed

Akın, Onur; Yeşilkaya, Ediz; Sari, Erkan; Akar, Çağdaş; Başbozkurt, Gökalp; Macit, Enis; Aydin, Ibrahim; Taşlipinar, Abdullah; Gül, Hüsamettin

2016-01-01

Hyperinsulinism, one of the most important causes of hypoglycaemia, can be congenital or acquired. Rarely, drug toxicity can be a reason for hyperinsulinism. In the context of Munchausen syndrome by proxy (MSP), toxicity usually occurs in children due to drug administration by a parent or caregiver. A 7-year-old girl was referred to our department due to a hyperglycaemic period and hypoglycaemic episodes. On admission, gliclazide was initiated due to her hyperglycaemia, which we attributed to maturity onset diabetes of the young. However, during follow-up, hypoglycaemic levels were detected. Despite cessation of gliclazide, hypoglycaemic seizures occurred. Even with the medications administered, hypoglycaemia could not be prevented. During follow-up, the mother's affect, characterized by anxiety and interest in her daughter's medical care, appeared discordant with the situation. Due to our suspicion of MSP, we discovered toxic levels of gliclazide in the blood and urine samples which had been sent to the toxicology laboratory to search for hypoglycaemic agents. The patient was isolated, and all medications were stopped. After isolation, her hypoglycaemia disappeared, and she became hyperglycaemic (250 mg/dl). Physicians should consider the possibility of MSP in hyperinsulinaemic patients with discordant laboratory results and clinical symptoms, even if the child's parents display great concern. © 2016 S. Karger AG, Basel.

The Hypoglycemic Risk of Glyburide (Glibenclamide) Compared with Modified-Release Gliclazide.

PubMed

Clemens, Kristin K; McArthur, Eric; Dixon, Stephanie N; Fleet, Jamie L; Hramiak, Irene; Garg, Amit X

2015-08-01

The risk for hypoglycemia when taking glyburide compared with modified-release gliclazide remains to be established in older adults in routine care. We investigated the risk of a hospital encounter with hypoglycemia following a new prescription for glyburide compared with modified-release gliclazide. In 2 population-based matched retrospective cohort studies in Ontario, Canada, between 2002 and 2011, we examined older adults who were newly prescribed glyburide or gliclazide as monotherapy or in the presence of metformin. Our primary outcome was a hospital encounter with hypoglycemia assessed within 90 days. The baseline characteristics between matched groups were similar. Initiating glyburide vs. gliclazide as monotherapy was associated with a higher risk for a hospital encounter with hypoglycemia (69 patients of 4374 taking glyburide [1.58%] vs. 8 patients of 4374 taking gliclazide [0.18%], absolute risk increase 1.40% [95% CI 1.01% to 1.79%], number needed to harm 71 [55 to 99], odds ratio 8.63 [95% CI 4.15 to 17.93], p<0.0001). Similar findings were noted when glyburide vs. gliclazide was initiated in the presence of metformin (110 patients of 8038 taking glyburide [1.37%] vs. 19 patients of 8038 taking gliclazide [0.24%], absolute risk increase 1.13% [95% CI 0.86% to 1.40%], number needed to harm 77 [71 to 116], odds ratio 6.06 [95% CI 3.68 to 9.97], p<0.0001). Glyburide was associated with a higher risk for hypoglycemia than modified-release gliclazide. The results of our studies may help to convince healthcare professionals who use glyburide to consider modified-release gliclazide as a safer alternative. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Fluorescence Spectroscopic Studies on the Complexation of Antidiabetic Drugs with Glycosylated Serum Albumin

NASA Astrophysics Data System (ADS)

Seedher, N.; Kanojia, M.

2013-11-01

Glycosylation decreases the association constant values and hence the binding affinity of human serum albumin (HSA) for the antidiabetic drugs under study. The percentage of HAS-bound drug at physiological temperature was only about 21-38 % as compared to 46-74 % for non-glycosylated HSA. Thus the percentage of free drug available for an antihyperglycemic effect was about double (62-79 %) compared to the values for non-glycosylated HSA. Much higher free drug concentrations available for pharmacological effect can lead to the risk of hypoglycemia. Hydrophobic interactions were predominantly involved in the binding. In the binding of gliclazide, hydrogen bonding and electrostatic interactions were involved. Site specificity for glycosylated HSA was the same as that for non-glycosylated HSA; gliclazide and repaglinide bind only at site II whereas glimepiride and glipizide bind at both sites I and II. Glycosylation, however, caused conformational changes in albumin, and the binding region within site II was different for glycosylated and non-glycosylated albumin. Stern-Volmer analysis also indicated the conformational changes in albumin as a result of glycosylation and showed that the dynamic quenching mechanism was valid for fluorescence of both glycosylated and non-glycosylated HSA.

Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications.

PubMed

Kawabata, Yohei; Wada, Koichi; Nakatani, Manabu; Yamada, Shizuo; Onoue, Satomi

2011-11-25

The poor oral bioavailability arising from poor aqueous solubility should make drug research and development more difficult. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. To complete development works within a limited amount of time, the establishment of a suitable formulation strategy should be a key consideration for the pharmaceutical development of poorly water-soluble drugs. In this article, viable formulation options are reviewed on the basis of the biopharmaceutics classification system of drug substances. The article describes the basic approaches for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Literature-based examples of the formulation options for poorly water-soluble compounds and their practical application to marketed products are also provided. Classification of drug candidates based on their biopharmaceutical properties can provide an indication of the difficulty of drug development works. A better understanding of the physicochemical and biopharmaceutical properties of drug substances and the limitations of each delivery option should lead to efficient formulation development for poorly water-soluble drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

Using resonance light scattering and UV/vis absorption spectroscopy to study the interaction between gliclazide and bovine serum albumin.

PubMed

Zhang, Qiu-Ju; Liu, Bao-Sheng; Li, Gai-Xia; Han, Rong

2016-08-01

At different temperatures (298, 310 and 318 K), the interaction between gliclazide and bovine serum albumin (BSA) was investigated using fluorescence quenching spectroscopy, resonance light scattering spectroscopy and UV/vis absorption spectroscopy. The first method studied changes in the fluorescence of BSA on addition of gliclazide, and the latter two methods studied the spectral change in gliclazide while BSA was being added. The results indicated that the quenching mechanism between BSA and gliclazide was static. The binding constant (Ka ), number of binding sites (n), thermodynamic parameters, binding forces and Hill's coefficient were calculated at three temperatures. Values for the binding constant obtained using resonance light scattering and UV/vis absorption spectroscopy were much greater than those obtained from fluorescence quenching spectroscopy, indicating that methods monitoring gliclazide were more accurate and reasonable. In addition, the results suggest that other residues are involved in the reaction and the mode 'point to surface' existed in the interaction between BSA and gliclazide. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

[A new method for safety monitoring of natural dietary supplements--quality profile].

PubMed

Wang, Juan; Wang, Li-Ping; Yang, Da-Jin; Chen, Bo

2008-07-01

A new method for safety monitoring of natural dietary supplements--quality profile was proposed. It would convert passive monitoring of synthetic drug to active, and guarantee the security of natural dietary supplements. Preliminary research on quality profile was completed by high performance liquid chromatography (HPLC) and mass spectrometry (MS). HPLC was employed to analyze chemical constituent profiles of natural dietary supplements. The separation was completed on C18 column with acetonitrile and water (0.05% H3PO4) as mobile phase, the detection wavelength was 223 nm. Based on HPLC, stability of quality profile had been studied, and abnormal compounds in quality profile had been analyzed after addition of phenolphthalein, sibutramine, rosiglitazone, glibenclamide and gliclazide. And by MS, detector worked with ESI +, capillary voltage: 3.5 kV, cone voltage: 30 V, extractor voltage: 4 V, RF lens voltage: 0.5 V, source temperature: 105 degrees C, desolvation temperature: 300 degrees C, desolvation gas flow rate: 260 L/h, cone gas flow rate: 50 L/h, full scan mass spectra: m/z 100-600. Abnormal compound in quality profile had been analyzed after addition of N-mono-desmethyl sibutramine. Quality profile based on HPLC had good stability (Similarity > 0.877). Addition of phenolphthalein, sibutramine, rosiglitazone, glibenclamide and gliclazide in natural dietary supplements could be reflected by HPLC, and addition of N-mono-desmethyl sibutramine in natural dietary supplements could be reflected by MS. Quality profile might monitor adulteration of natural dietary supplements, and prevent addition of synthetic drug after "approval".

Insoluble drug delivery strategies: review of recent advances and business prospects

PubMed Central

Kalepu, Sandeep; Nekkanti, Vijaykumar

2015-01-01

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects. PMID:26579474

Development of novel gastroretentive floating particulate drug delivery system of gliclazide.

PubMed

Awasthi, Rajendra; Kulkarni, Giriraj T

2012-09-01

The objective of present project was to improve the dissolution profile of gliclazide by developing floating alginate beads using various biodegradable polymers like gelatin, pectin and hydroxypropylmethylcellulose (HPMC). The floating beads were prepared by a simple ionotropic gelatin method using calcium carbonate as gas generating agent. The developed beads were characterized by Fourier transform infrared spectroscopy analysis, differential scanning calorimetry, X-ray diffraction analysis and scanning electron microscopy (SEM). The prepared beads showed good in vitro floatation, which was dependent on the concentration of gas-forming agent. SEM photomicrographs confirmed that the developed beads were spherical in shape and had particle size in the range of 730 to 890 μm. The incorporation efficiency was found to be in the range of 59.96 to 85.1%. The cumulative percent drug release from the beads after 10 h dissolution study at pH 1.2 and pH 5.8 was in the range of 33 to 46% and 82 to 95% respectively. The concentration of the gas generating agent was found to influence the release rate. The mechanism of drug release was Fickian diffusion with swelling. The in vivo sub-acute hypoglycemic study in high fat diet induced diabetic C57BL/6J mice demonstrated significant (p < 0.05) hypoglycemic effect over a period of 12 h and 24 h, respectively, with HPMC and pectin beads. A significant (p & 0.05) reduction in fasting and non-fasting blood glucose levels, reduction in fasting plasma insulin level and a significant improvement in glucose tolerance were observed in animals treated with formulations. The developed beads were suitable carriers for improving the systemic absorption of gliclazide and maintaining reduced blood glucose levels.

Gliclazide inhibits diabetic neuropathy irrespective of blood glucose levels in streptozotocin-induced diabetic rats.

PubMed

Qiang, X; Satoh, J; Sagara, M; Fukuzawa, M; Masuda, T; Miyaguchi, S; Takahashi, K; Toyota, T

1998-08-01

N-acetylcysteine and pentoxifylline, free radical scavengers and inhibitors of tumor necrosis factor-alpha (TNF-alpha) production, inhibit the development of peripheral neuropathy in streptozotocin (STZ)-induced diabetic rats. This study was designed to elucidate the effect of gliclazide, an oral hypoglycemic sulfonylurea, on diabetic neuropathy, because it has been indicated to be a free radical scavenger and TNF-alpha inhibitor. Rats were fed with powder chow mixed with gliclazide or glibenclamide as a control ad libitum. Blood glucose levels and body weight were remarkably higher and lower in diabetic than in nondiabetic rats, respectively, while gliclazide and glibenclamide had no effect on these in both diabetic and nondiabetic rats throughout a 24-week experiment. Serum lipoperoxide levels and lipopolysaccharide (LPS)-induced serum TNF-alpha activities were significantly increased in diabetic rats, whereas these were significantly inhibited in gliclazide-treated rats. Motor nerve conduction velocity (MNCV) of the tibial nerve significantly slowed in diabetic rats compared with nondiabetic rats. On the other hand, the slowed MNCV was significantly inhibited in gliclazide-treated diabetic rats after 16 experimental weeks. Morphometric analysis showed that gliclazide prevented decreased myelinated fiber area (P < .05), increased fiber density (P < .001), and decreased axon/myelin ratio (P < .05) in diabetic rats. Glibenclamide treatment did not affect serum lipoperoxide, TNF-alpha, MNCV, or nerve morphology in this experiment. These results indicate that gliclazide has a beneficial effect on peripheral neuropathy in STZ-induced diabetic rats, irrespective of blood glucose levels.

Population PKPD modelling of the long-term hypoglycaemic effect of gliclazide given as a once-a-day modified release (MR) formulation

PubMed Central

Frey, N; Laveille, C; Paraire, M; Francillard, M; Holford, N H G; Jochemsen, Roeline

2003-01-01

Aims To study the relationship between the pharmacokinetics (PK) of gliclazide and its long-term pharmacodynamic (PD) effect in a large population of Type 2 diabetic patients and to identify factors predicting intersubject variability. Methods A PKPD database of 634 Type 2 diabetic patients with a total of 5258 fasting plasma glucose (FPG) samples was built up from the data collected during the clinical development of a modified release formulation of gliclazide (gliclazide MR). The PKPD analysis used a nonlinear mixed effect modelling approach. A mixture model was used to identify patients with a FPG response to treatment. In patients identified as responders, the decrease in FPG was related to gliclazide exposure (AUC) by an Emax relationship. An effect compartment was used to describe the link between PK and PD. A linear disease-progression model was used to assess the glycaemic deterioration observable over several months of treatment. Simulations were performed to evaluate the predictive performance of the PKPD model and to illustrate the time course of the antidiabetic effect of gliclazide MR. Results Disease state was found to be the main explanatory factor for intersubject variability in response to gliclazide. The percentage of responders to gliclazide, used as monotherapy, increased inversely to the number of classes of antidiabetic agents received prior to entry in the studies. In responders, the initial dose (30 mg) of the gliclazide MR dosing regimen induced half of the maximum hypoglycaemic effect. The equilibration half-life between the PK and PD steady states was 3 weeks (intersubject variability of 84%). The rate of disease progression was 0.84 mmol l−1 year−1 (intersubject variability 143%). The PKPD model adequately predicted the FPG profiles of 234 patients who received the current formulation of gliclazide. Simulation of a 1-year parallel dose ranging clinical trial illustrated the influence of dose, time and type of previous antidiabetic treatment on the percentage of patients with clinically significant improvement of blood glucose control. Conclusions This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its long-term hypoglycaemic effect, and has established that the intersubject variability in response is mostly related to disease state. These results underline the clinical interest of quickly increasing the dose of gliclazide MR according to the response to treatment in order to achieve effective blood glucose control. PMID:12580986

Simultaneous Rapid Determination of the Solubility and Diffusion Coefficients of a Poorly Water-Soluble Drug Based on a Novel UV Imaging System.

PubMed

Lu, Yan; Li, Mingzhong

2016-01-01

The solubility and diffusion coefficient are two of the most important physicochemical properties of a drug compound. In practice, both have been measured separately, which is time consuming. This work utilizes a novel technique of UV imaging to determine the solubility and diffusion coefficients of poorly water-soluble drugs simultaneously. A 2-step optimal method is proposed to determine the solubility and diffusion coefficients of a poorly water-soluble pharmaceutical substance based on the Fick's second law of diffusion and UV imaging measurements. Experimental results demonstrate that the proposed method can be used to determine the solubility and diffusion coefficients of a drug with reasonable accuracy, indicating that UV imaging may provide a new opportunity to accurately measure the solubility and diffusion coefficients of a poorly water-soluble drug simultaneously and rapidly. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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

PubMed

Göke, Katrin; Bunjes, Heike

2017-08-30

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

21 CFR 201.319 - Water-soluble gums, hydrophilic gums, and hydrophilic mucilloids (including, but not limited to...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Water-soluble gums, hydrophilic gums, and... Specific Labeling Requirements for Specific Drug Products § 201.319 Water-soluble gums, hydrophilic gums... been associated with the ingestion of water-soluble gums, hydrophilic gums, and hydrophilic mucilloids...

Crosslinked hydrogels-a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs.

PubMed

Sun, Dajun D; Lee, Ping I

2014-02-01

Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.

Crosslinked hydrogels—a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs

PubMed Central

Sun, Dajun D.; Lee, Ping I.

2014-01-01

Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs. PMID:26579361

Electrospinning of calcium phosphate-poly (d,l-lactic acid) nanofibers for sustained release of water-soluble drug and fast mineralization

PubMed Central

Fu, Qi-Wei; Zi, Yun-Peng; Xu, Wei; Zhou, Rong; Cai, Zhu-Yun; Zheng, Wei-Jie; Chen, Feng; Qian, Qi-Rong

2016-01-01

Calcium phosphate-based biomaterials have been well studied in biomedical fields due to their outstanding chemical and biological properties which are similar to the inorganic constituents in bone tissue. In this study, amorphous calcium phosphate (ACP) nanoparticles were prepared by a precipitation method, and used for preparation of ACP-poly(d,l-lactic acid) (ACP-PLA) nanofibers and water-soluble drug-containing ACP-PLA nanofibers by electrospinning. Promoting the encapsulation efficiency of water-soluble drugs in electrospun hydrophobic polymer nanofibers is a common problem due to the incompatibility between the water-soluble drug molecules and hydrophobic polymers solution. Herein, we used a native biomolecule of lecithin as a biocompatible surfactant to overcome this problem, and successfully prepared water-soluble drug-containing ACP-PLA nanofibers. The lecithin and ACP nanoparticles played important roles in stabilizing water-soluble drug in the electrospinning composite solution. The electrospun drug-containing ACP-PLA nanofibers exhibited fast mineralization in simulated body fluid. The ACP nanoparticles played the key role of seeds in the process of mineralization. Furthermore, the drug-containing ACP-PLA nanofibers exhibited sustained drug release which simultaneously occurred with the in situ mineralization in simulated body fluid. The osteoblast-like (MG63) cells with spreading filopodia were well observed on the as-prepared nanofibrous mats after culturing for 24 hours, indicating a high cytocompatibility. Due to the high biocompatibility, sustained drug release, and fast mineralization, the as-prepared composite nanofibers may have potential applications in water-soluble drug loading and release for tissue engineering. PMID:27785016

Mesoporous materials and nanocrystals for enhancing the dissolution behavior of poorly water-soluble drugs.

PubMed

Santos, Helder A; Peltonen, Leena; Limnell, Tarja; Hirvonen, Jouni

2013-01-01

Advanced drug delivery formulations are presently recognized as promising tools for overcoming the adverse physicochemical properties of conventional drug molecules, such as poor water solubility, which often leads to poor drug bioavailability. Oral drug delivery is considered as the easiest and most convenient route of drug administration. However, via the current trends utilizing combinatorial chemistry and high throughput screening in drug development, new drug molecules are moving towards lipophilic and poorly water-soluble large molecules, and the oral delivery route is becoming increasingly challenging. In this context, formulation of poorly soluble and/or permeable drugs using mesoporous materials and nanocrystals technology have proven to be highly successful due to the greater surface/volume ratio of these systems, resulting in improvements in dissolution and bioavailability, as well as enhanced drug permeability. This review addresses the issues of poorly water-soluble drugs with a major focus on recent developments in the application of the mesoporous materials (e.g., porous silicon and silica) and nanocrystals in drug delivery applications. In addition, we present several recent examples of the significant potential of these materials for the pharmaceutical field.

APPLICATION OF VARIOUS POLYMERS AND POLYMERS BASED TECHNIQUES USED TO IMPROVE SOLUBILITY OF POORLY WATER SOLUBLE DRUGS: A REVIEW.

PubMed

Muhammad Sarfraz, Rai; Bashir, Sajid; Mahmood, Asif; Ahsan, Haseeb; Riaz, Humayun; Raza, Hina; Rashid, Zermina; Atif Raza, Syed; Asad Abrar, Muhammad; Abbas, Khawar; Yasmeen, Tahira

2017-03-01

Solubility is concerned with solute and solvent to form a homogenous mixture. If solubility of a drug is low, then usually it is difficult to achieve desired therapeutic level of drug. Most of the newly developed entities have solubility problems and encounter difficulty in dissolution. Basic aim of solubility enhancement is to achieve desired therapeutic'level of drug to produce required pharmacological response. Different techniques are being used to enhance the solubility of water insoluble drugs. These techniques include particle size reduction, spray drying, kneading method, solvent evaporation method, salt formation, microemulsions, co-solven- cy, hydrosols, prodrug approach, supercritical fluid process, hydrogel micro particles etc. Selection of solubility improving method depends on drug properties, site of absorption, and required dosage form characteristics. Variety of polymers are also used to enhance solubility of these drugs like polyethylene glycol 300, polyvinyl pyrrolidone, chitosan, β-cyclodextrins etc.

Formulation of a poorly water-soluble drug in sustained-release hollow granules with a high viscosity water-soluble polymer using a fluidized bed rotor granulator.

PubMed

Asada, Takumi; Yoshihara, Naoki; Ochiai, Yasushi; Kimura, Shin-Ichiro; Iwao, Yasunori; Itai, Shigeru

2018-04-25

Water-soluble polymers with high viscosity are frequently used in the design of sustained-release formulations of poorly water-soluble drugs to enable complete release of the drug in the gastrointestinal tract. Tablets containing matrix granules with a water-soluble polymer are preferred because tablets are easier to handle and the multiple drug-release units of the matrix granules decreases the influences of the physiological environment on the drug. However, matrix granules with a particle size of over 800 μm sometimes cause a content uniformity problem in the tableting process because of the large particle size. An effective method of manufacturing controlled-release matrix granules with a smaller particle size is desired. The aim of this study was to develop tablets containing matrix granules with a smaller size and good controlled-release properties, using phenytoin as a model poorly water-soluble drug. We adapted the recently developed hollow spherical granule granulation technology, using water-soluble polymers with different viscosities. The prepared granules had an average particle size of 300 μm and sharp particle size distribution (relative width: 0.52-0.64). The values for the particle strength of the granules were 1.86-1.97 N/mm 2 , and the dissolution profiles of the granules were not affected by the tableting process. The dissolution profiles and the blood concentration levels of drug released from the granules depended on the viscosity of the polymer contained in the granules. We succeeded in developing the desired controlled-release granules, and this study should be valuable in the development of sustained-release formulations of poorly water-soluble drugs. Copyright © 2018 Elsevier B.V. All rights reserved.

Supercritical fluid particle design for poorly water-soluble drugs (review).

PubMed

Sun, Yongda

2014-01-01

Supercritical fluid particle design (SCF PD) offers a number of routes to improve solubility and dissolution rate for enhancing the bioavailability of poorly water-soluble drugs, which can be adopted through an in-depth knowledge of SCF PD processes and the molecular properties of active pharmaceutical ingredients (API) and drug delivery system (DDS). Combining with research experiences in our laboratory, this review focuses on the most recent development of different routes (nano-micron particles, polymorphic particles, composite particles and bio-drug particles) to improve solubility and dissolution rate of poorly water-soluble drugs, covering the fundamental concept of SCF and the principle of SCF PD processes which are typically used to control particle size, shape, morphology and particle form and hence enable notable improvement in the dissolution rate of the poorly water-soluble drugs. The progress of the industrialization of SCF PD processes in pharmaceutical manufacturing environment with scaled-up plant under current good manufacturing process (GMP) specification is also considered in this review.

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

PubMed

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

2018-06-06

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

Improved intestinal absorption of a poorly water-soluble oral drug using mannitol microparticles containing a nanosolid drug dispersion.

PubMed

Nishino, Yukiko; Kubota, Aya; Kanazawa, Takanori; Takashima, Yuuki; Ozeki, Tetsuya; Okada, Hiroaki

2012-11-01

A nozzle for a spray dryer that can prepare microparticles of water-soluble carriers containing various nanoparticles in a single step was previously developed in our laboratory. To enhance the solubility and intestinal absorption of poorly water-soluble drugs, we used probucol (PBL) as a poorly water-soluble drug, mannitol (MAN) as a water-soluble carrier for the microparticles, and EUDRAGIT (EUD) as a polymer vehicle for the solid dispersion. PBL-EUD-acetone-methanol and aqueous MAN solutions were simultaneously supplied through different liquid passages of the spray nozzle and dried together. PBL-EUD solid dispersion was nanoprecipitated in the MAN solution using an antisolvent mechanism and rapidly dried by surrounding it with MAN. PBL in the dispersion vehicle was amorphous and had higher physical stability according to powder X-ray diffraction and differential scanning calorimetry analysis. The bioavailability of PBL in PBL-EUD S-100-MAN microparticles after oral administration in rats was markedly higher (14- and 6.2-fold, respectively) than that of the original PBL powder and PBL-MAN microparticles. These results demonstrate that the composite microparticles containing a nanosized solid dispersion of a poorly water-soluble drug prepared using the spray nozzle developed by us should be useful to increase the solubility and bioavailability of drugs after oral administration. Copyright © 2012 Wiley Periodicals, Inc.

Formulation of thermoresponsive and buccal adhesive in situ gel for treatment of oral thrush containing poorly water soluble drug bifonazole.

PubMed

Patel, Dimendra; Patel, Dipti; Prajapati, Jatin; Patel, Umang; Patel, Vijay

2012-03-01

The aim of the present work is to formulate and evaluate in situ oral topical gels of poorly water soluble drug Bifonazole based on temperature induced systems for the treatment of oral candidiasis. Bifonazole is poorly water soluble and low permeable drug means it's belongs to BCS Class IV. Due to its poor water solubility, it necessary to enhance solubility in water by make complex with Beta- Cyclodextrin (Drug to βCyclo Dextrine ratio is 1:1). After in situ gel preparation done by using Poloxamer (10% and 15%w/w) along with carbopol 934 (0.2 to 1.0% w/w) and Bifonazole - β CD complex (1%w/w). The formulations were evaluated for physiochemical parameter, gelation Temperature, viscosity, gel strength, content uniformity mucoadhesive force, Diffusion Study.

Formulation of thermoresponsive and buccal adhesive in situ gel for treatment of oral thrush containing poorly water soluble drug bifonazole

PubMed Central

Patel, Dimendra; Patel, Dipti; Prajapati, Jatin; Patel, Umang; Patel, Vijay

2012-01-01

The aim of the present work is to formulate and evaluate in situ oral topical gels of poorly water soluble drug Bifonazole based on temperature induced systems for the treatment of oral candidiasis. Bifonazole is poorly water soluble and low permeable drug means it's belongs to BCS Class IV. Due to its poor water solubility, it necessary to enhance solubility in water by make complex with Beta- Cyclodextrin (Drug to βCyclo Dextrine ratio is 1:1). After in situ gel preparation done by using Poloxamer (10% and 15%w/w) along with carbopol 934 (0.2 to 1.0% w/w) and Bifonazole – β CD complex (1%w/w). The formulations were evaluated for physiochemical parameter, gelation Temperature, viscosity, gel strength, content uniformity mucoadhesive force, Diffusion Study. PMID:23066185

Effect of repaglinide and gliclazide on glycaemic control, early-phase insulin secretion and lipid profiles in.

PubMed

Zhang, Hong; Bu, Ping; Xie, Yan-Hong; Luo, Juan; Lei, Min-Xiang; Mo, Zhao-Hui; Liao, Er-Yuan

2011-01-01

Both repaglinide and gliclazide are insulin secretagogues widely used in the treatment of type 2 diabetes. They stimulate insulin secretion through distinct mechanisms and may benefit patients from different aspects. The present study was to evaluate the effects of repaglinide or gliclazide on glycaemic control, insulin secretion, and lipid profiles in type 2 diabetes patients. A total of 47 newly diagnosed type 2 diabetes patients were randomized 1:1 to receive a 4-week treatment with repaglinide or gliclazide. The standard mixed meal tolerance test was performed before and after the treatment. Plasma glucose (PG), insulin concentration, and lipid profiles were measured. The area under insulin concentration curve (AUC(ins)) and the early-phase insulin secretion index (ΔI(30)/ΔG(30)) were calculated. After the trial, fasting and postprandial PG and postprandial insulin improved significantly in both groups (P < 0.05). The maximum insulin concentration occurred earlier in the repaglinide group than that in the gliclazide group. AUC(ins) increased in both groups (P < 0.05), but no significant difference was found between groups. ΔI(30)/ΔG(30) increased in both groups (P < 0.05), especially in the repaglinide group (P < 0.05). Triglyceride and total cholesterol decreased significantly in the repaglinide group in some time points, while no significant change was observed in the gliclazide group. Repaglinide and gliclazide had similar effects on glycaemic control and total insulin secretion, while repaglinide had more effects on improvements in β-cell function and lipid metabolism.

Comparison of repaglinide vs. gliclazide in combination with bedtime NPH insulin in patients with Type 2 diabetes inadequately controlled with oral hypoglycaemic agents.

PubMed

Furlong, N J; Hulme, S A; O'Brien, S V; Hardy, K J

2003-11-01

This open-label randomized controlled clinical trial compared the effect on glycaemic control and weight gain of repaglinide vs. gliclazide combined with bedtime NPH insulin in patients with Type 2 diabetes inadequately controlled with oral hypoglycaemic therapy [HbA1c>7.0% (DCCT aligned assay, normal range 4.6-6.2%)]. Eighty subjects with Type 2 diabetes were randomized to 13 weeks' open-label treatment with repaglinide 4 mg t.i.d. or gliclazide 160 mg b.i.d. in combination with bedtime NPH insulin (initial dose 0.5 units/kg). The fasting blood glucose (FBG) target was < or =6.0 mmol/l. Baseline characteristics were similar for age, sex, weight, BMI, FBG and HbA1c. Glycaemic control improved similarly in both groups-insulin/gliclazide by (mean) 1.0%, from 9.2 to 8.2% (P=0.001) and by 0.9%, from 9.4 to 8.5% in the insulin/repaglinide group (P=0.005) (P=0.83 between groups). Weight gain averaged (mean +/- sem) 4.1 +/- 0.5 and 3.4 +/- 0.4 kg in the insulin/gliclazide and insulin/repaglinide groups, respectively (P<0.0001 for both groups from baseline) (P=0.29 between groups). The mean number of hypoglycaemic episodes experienced per patient was 2.95 +/- 0.82 (insulin/gliclazide) and 2.3 +/- 0.52 (insulin/repaglinide) (P=0.81 between groups). Both treatments were associated with significant improvements in Diabetes Treatment Satisfaction [Diabetes Treatment Satisfaction Questionnaire-potential range 0 (min) to 36 (max)]; in the insulin/gliclazide group, by 4.9 +/- 1.1 points to 33.3 +/- 0.6 (P<0.0001) and by 3.0 +/- 0.9 points to 34.6 +/- 0.4 (P=0.0006) in the insulin/repaglinide group (P=0.29 between groups). Over 13 weeks, both repaglinide and gliclazide, when combined with bedtime NPH insulin produce similar significant improvements in glycaemic control (-1%) and similar weight gain.

Osmotic pellet system comprising osmotic core and in-process amorphized drug in polymer-surfactant layer for controlled delivery of poorly water-soluble drug.

PubMed

Saindane, Nilesh; Vavia, Pradeep

2012-09-01

The aim of the present investigation was to develop controlled porosity osmotic system for poorly water-soluble drug based on drug in polymer-surfactant layer technology. A poorly water-soluble drug, glipizide (GZ), was selected as the model drug. The technology involved core of the pellets containing osmotic agent coated with drug dispersed in polymer and surfactant layer, finally coated with release-retardant layer with pore former. The optimized drug-layer-coated pellets were evaluated for solubility of GZ at different pH conditions and characterized for amorphous nature of the drug by differential scanning calorimetry and X-ray powder diffractometry. The optimized release-retardant layer pellets were evaluated for in vitro drug release at different pH, hydrodynamic, and osmolality conditions. The optimized drug layer showed improvement in solubility (10 times in pH 1.2, 11 times in pH 4.5, and 21 times in pH 6.8), whereas pellets coated with cellulose acetate (15.0%, w/w, weight gain) with pore former triethyl citrate (10.0%, w/w, of polymer) demonstrated zero-order drug release for 24 h at different pH conditions; moreover, retardation of drug release was observed with increment of osmolality. This system could be a platform technology for controlled delivery of poorly water-soluble drugs. Copyright © 2012 Wiley Periodicals, Inc.

A water-soluble, mucoadhesive quaternary ammonium chitosan-methyl-β-cyclodextrin conjugate forming inclusion complexes with dexamethasone.

PubMed

Piras, Anna Maria; Zambito, Ylenia; Burgalassi, Susi; Monti, Daniela; Tampucci, Silvia; Terreni, Eleonora; Fabiano, Angela; Balzano, Federica; Uccello-Barretta, Gloria; Chetoni, Patrizia

2018-03-30

The ocular bioavailability of lipophilic drugs, such as dexamethasone, depends on both drug water solubility and mucoadhesion/permeation. Cyclodextrins and chitosan are frequently employed to either improve drug solubility or prolong drug contact onto mucosae, respectively. Although the covalent conjugation of cyclodextrin and chitosan brings to mucoadhesive drug complexes, their water solubility is restricted to acidic pHs. This paper describes a straightforward grafting of methyl-β-cyclodextrin (MCD) on quaternary ammonium chitosan (QA-Ch60), mediated by hexamethylene diisocyanate. The resulting product is a water-soluble chitosan derivative, having a 10-atom long spacer between the quaternized chitosan and the cyclodextrin. The derivative is capable of complexing the model drug dexamethasone and stable complexes were also observed for the lyophilized products. Furthermore, the conjugate preserves the mucoadhesive properties typical of quaternized chitosan and its safety as solubilizing excipient for ophthalmic applications was preliminary assessed by in vitro cytotoxicity evaluations. Taken as a whole, the observed features appear promising for future processing of the developed product into 3D solid forms, such as controlled drug delivery systems, films or drug eluting medical devices.

Smart polyelectrolyte microcapsules as carriers for water-soluble small molecular drug.

PubMed

Song, Weixing; He, Qiang; Möhwald, Helmuth; Yang, Yang; Li, Junbai

2009-10-15

Heat treatment is introduced as a simple method for the encapsulation of low molecular weight water-soluble drugs within layer-by-layer assembled microcapsules. A water-soluble drug, procainamide hydrochloride, could thus be encapsulated in large amount and enriched by more than 2 orders of magnitude in the assembled PDADMAC/PSS capsules. The shrunk capsules could control the unloading rate of drugs, and the drugs could be easily unloaded using ultrasonic treatment. The encapsulated amount could be quantitatively controlled via the drug concentration in the bulk. We also found that smaller capsules possess higher encapsulation capability.

Calculation of Drug Solubilities by Pharmacy Students.

ERIC Educational Resources Information Center

Cates, Lindley A.

1981-01-01

A method of estimating the solubilities of drugs in water is reported that is based on a principle applied in quantitative structure-activity relationships. This procedure involves correlation of partition coefficient values using the octanol/water system and aqueous solubility. (Author/MLW)

Polymeric Micelles and Alternative Nanonized Delivery Vehicles for Poorly Soluble Drugs

PubMed Central

Lu, Ying; Park, Kinam

2013-01-01

Poorly soluble drugs often encounter low bioavailability and erratic absorption patterns in the clinical setting. Due to the rising number of compounds having solubility issues, finding ways to enhance the solubility of drugs is one of the major challenges in the pharmaceutical industry today. Polymeric micelles, which form upon self-assembly of amphiphilic macromolecules, can act as solubilizing agents for delivery of poorly soluble drugs. This manuscript examines the fundamentals of polymeric micelles through reviews of representative literature and demonstrates possible applications through recent examples of clinical trial developments. In particular, the potential of polymeric micelles for delivery of poorly water-soluble drugs, especially in the areas of oral delivery and in cancer therapy, is discussed. Key considerations in utilizing polymeric micelles’ advantages and overcoming potential disadvantages have been highlighted. Lastly, other possible strategies related to particle size reduction for enhancing solubilization of poorly water-soluble drugs are introduced. PMID:22944304

Dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs with poor water solubility.

PubMed

Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Lee, Kyoung-Ho; Kim, Dong-Jin; Lee, Beom-Jin

2010-05-01

Although the solid dispersion method has been known to increase the dissolution rate of poorly water-soluble drugs by dispersing them in hydrophilic carriers, one obstacle of the solid dispersion method is its limited solubilization capacity, especially for pH-dependent soluble drugs. pH-modified solid dispersion, in which pH modifiers are incorporated, may be a useful method for increasing the dissolution rate of weakly acidic or basic drugs. Sufficient research, including the most recent reports, was undertaken in this review. How could the inclusion of the pH the pH modifiers in the solid dispersion system change drug structural behaviors, molecular interactions, microenvironmental pH, and/or release rate of pH modifiers, relating with the enhanced dissolution of weakly acidic or weakly basic drugs with poor water solubility? These questions have been investigated to determine the dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs. It is believed that step-by-step mechanistic approaches could provide the ultimate solution for solubilizing several poorly water-soluble drugs with pH-dependent solubility from a solid dispersion system, as well as provide ideas for developing future dosage systems.

Enthalpy-entropy compensation for the solubility of drugs in solvent mixtures: paracetamol, acetanilide, and nalidixic acid in dioxane-water.

PubMed

Bustamante, P; Romero, S; Pena, A; Escalera, B; Reillo, A

1998-12-01

In earlier work, a nonlinear enthalpy-entropy compensation was observed for the solubility of phenacetin in dioxane-water mixtures. This effect had not been earlier reported for the solubility of drugs in solvent mixtures. To gain insight into the compensation effect, the behavior of the apparent thermodynamic magnitudes for the solubility of paracetamol, acetanilide, and nalidixic acid is studied in this work. The solubility of these drugs was measured at several temperatures in dioxane-water mixtures. DSC analysis was performed on the original powders and on the solid phases after equilibration with the solvent mixture. The thermal properties of the solid phases did not show significant changes. The three drugs display a solubility maximum against the cosolvent ratio. The solubility peaks of acetanilide and nalidixic acid shift to a more polar region at the higher temperatures. Nonlinear van't Hoff plots were observed for nalidixic acid whereas acetanilide and paracetamol show linear behavior at the temperature range studied. The apparent enthalpies of solution are endothermic going through a maximum at 50% dioxane. Two different mechanisms, entropy and enthalpy, are suggested to be the driving forces that increase the solubility of the three drugs. Solubility is entropy controlled at the water-rich region (0-50% dioxane) and enthalpy controlled at the dioxane-rich region (50-100% dioxane). The enthalpy-entropy compensation analysis also suggests that two different mechanisms, dependent on cosolvent ratio, are involved in the solubility enhancement of the three drugs. The plots of deltaH versus deltaG are nonlinear, and the slope changes from positive to negative above 50% dioxane. The compensation effect for the thermodynamic magnitudes of transfer from water to the aqueous mixtures can be described by a common empirical nonlinear relationship, with the exception of paracetamol, which follows a separate linear relationship at dioxane ratios above 50%. The results corroborate earlier findings with phenacetin. The similar pattern shown by the drugs studied suggests that the nonlinear enthalpy-entropy compensation effect may be characteristic of the solubility of semipolar drugs in dioxane-water mixtures.

Nanonization strategies for poorly water-soluble drugs.

PubMed

Chen, Huabing; Khemtong, Chalermchai; Yang, Xiangliang; Chang, Xueling; Gao, Jinming

2011-04-01

Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor(®) EL). In this review, several major nanonization techniques that seek to overcome these limitations for drug solubilization are presented. Strategies including drug nanocrystals, nanoemulsions and polymeric micelles are reviewed. Finally, perspectives on existing challenges and future opportunities are highlighted. Published by Elsevier Ltd.

Nanosizing of drugs: Effect on dissolution rate

PubMed Central

Dizaj, S. Maleki; Vazifehasl, Zh.; Salatin, S.; Adibkia, Kh.; Javadzadeh, Y.

2015-01-01

The solubility, bioavailability and dissolution rate of drugs are important parameters for achieving in vivo efficiency. The bioavailability of orally administered drugs depends on their ability to be absorbed via gastrointestinal tract. For drugs belonging to Class II of pharmaceutical classification, the absorption process is limited by drug dissolution rate in gastrointestinal media. Therefore, enhancement of the dissolution rate of these drugs will present improved bioavailability. So far several techniques such as physical and chemical modifications, changing in crystal habits, solid dispersion, complexation, solubilization and liquisolid method have been used to enhance the dissolution rate of poorly water soluble drugs. It seems that improvement of the solubility properties ofpoorly water soluble drugscan translate to an increase in their bioavailability. Nowadays nanotechnology offers various approaches in the area of dissolution enhancement of low aqueous soluble drugs. Nanosizing of drugs in the form of nanoparticles, nanocrystals or nanosuspensions not requiring expensive facilities and equipment or complicated processes may be applied as simple methods to increase the dissolution rate of poorly water soluble drugs. In this article, we attempted to review the effects of nanosizing on improving the dissolution rate of poorly aqueous soluble drugs. According to the reviewed literature, by reduction of drug particle size into nanometer size the total effective surface area is increased and thereby dissolution rate would be enhanced. Additionally, reduction of particle size leads to reduction of the diffusion layer thickness surrounding the drug particles resulting in the increment of the concentration gradient. Each of these process leads to improved bioavailability. PMID:26487886

Thermodynamics of Highly Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs-Impact of a Second Drug on the Solution Phase Behavior and Implications for Combination Products.

PubMed

Trasi, Niraj S; Taylor, Lynne S

2015-08-01

There is increasing interest in formulating combination products that contain two or more drugs. Furthermore, it is also common for different drug products to be taken simultaneously. This raises the possibility of interactions between different drugs that may impact formulation performance. For poorly water-soluble compounds, the supersaturation behavior may be a critical factor in determining the extent of oral absorption. The goal of the current study was to evaluate the maximum achievable supersaturation for several poorly water-soluble compounds alone, and in combination. Model compounds included ritonavir, lopinavir, paclitaxel, felodipine, and diclofenac. The "amorphous solubility" for the pure drugs was determined using different techniques and the change in this solubility was then measured in the presence of differing amounts of a second drug. The results showed that "amorphous solubility" of each component in aqueous solution is substantially decreased by the second component, as long as the two drugs are miscible in the amorphous state. A simple thermodynamic model could be used to predict the changes in solubility as a function of composition. This information is of great value when developing co-amorphous or other supersaturating formulations and should contribute to a broader understanding of drug-drug physicochemical interactions in in vitro assays as well as in the gastrointestinal tract. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers.

PubMed

Ahuja, Naveen; Katare, Om Prakash; Singh, Bhupinder

2007-01-01

Role of various water-soluble carriers was studied for dissolution enhancement of a poorly soluble model drug, rofecoxib, using solid dispersion approach. Diverse carriers viz. polyethylene glycols (PEG 4000 and 6000), polyglycolized fatty acid ester (Gelucire 44/14), polyvinylpyrollidone K25 (PVP), poloxamers (Lutrol F127 and F68), polyols (mannitol, sorbitol), organic acid (citric acid) and hydrotropes (urea, nicotinamide) were investigated for the purpose. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. The sign and magnitude of the thermodynamic parameter, Gibbs free energy of transfer, indicated spontaneity of solubilization process. All the solid dispersions showed dissolution improvement vis-à-vis pure drug to varying degrees, with citric acid, PVP and poloxamers as the most promising carriers. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Fickian diffusion. Solid state characterization of the drug-poloxamer binary system using XRD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate.

Positively Charged Nanostructured Lipid Carriers and Their Effect on the Dissolution of Poorly Soluble Drugs.

PubMed

Choi, Kyeong-Ok; Choe, Jaehyeog; Suh, Seokjin; Ko, Sanghoon

2016-05-20

The objective of this study is to develop suitable formulations to improve the dissolution rate of poorly water soluble drugs. We selected lipid-based formulation as a drug carrier and modified the surface using positively charged chitosan derivative (HTCC) to increase its water solubility and bioavailability. Chitosan and HTCC-coated lipid particles had higher zeta-potential values than uncoated one over the whole pH ranges and improved encapsulation efficiency. In vitro drug release showed that all NLC formulations showed higher in vitro release efficiency than drug particle at pH 7.4. Furthermore, NLC formulation prepared with chitosan or HTCC represented good sustained release property. The results indicate that chitosan and HTCC can be excellent formulating excipients of lipid-based delivery carrier for improving poorly water soluble drug delivery.

Solubility Enhancement of a Poorly Water Soluble Drug by Forming Solid Dispersions using Mechanochemical Activation

PubMed Central

Rojas-Oviedo, I.; Retchkiman-Corona, B.; Quirino-Barreda, C. T.; Cárdenas, J.; Schabes-Retchkiman, P. S.

2012-01-01

Mechanochemical activation is a practical cogrinding operation used to obtain a solid dispersion of a poorly water soluble drug through changes in the solid state molecular aggregation of drug-carrier mixtures and the formation of noncovalent interactions (hydrogen bonds) between two crystalline solids such as a soluble carrier, lactose, and a poorly soluble drug, indomethacin, in order to improve its solubility and dissolution rate. Samples of indomethacin and a physical mixture with a weight ratio of 1:1 of indomethacin and lactose were ground using a high speed vibrating ball mill. Particle size was determined by electron microscopy, the reduction of crystallinity was determined by calorimetry and transmission electron microscopy, infrared spectroscopy was used to find evidence of any interactions between the drug and the carrier and the determination of apparent solubility allowed for the corroboration of changes in solubility. Before grinding, scanning electron microscopy showed the drug and lactose to have an average particle size of around 50 and 30 μm, respectively. After high speed grinding, indomethacin and the mixture had a reduced average particle size of around 5 and 2 μm, respectively, showing a morphological change. The ground mixture produced a solid dispersion that had a loss of crystallinity that reached 81% after 30 min of grinding while the drug solubility of indomethacin within the solid dispersion increased by 2.76 fold as compared to the pure drug. Drug activation due to hydrogen bonds between the carboxylic group of the drug and the hydroxyl group of lactose as well as the decrease in crystallinity of the solid dispersion and the reduction of the particle size led to a better water solubility of indomethacin. PMID:23798775

Solubility Enhancement of Raloxifene Using Inclusion Complexes and Cogrinding Method

PubMed Central

Patil, Payal H.; Belgamwar, Veena S.; Patil, Pratibha R.; Surana, Sanjay J.

2013-01-01

The objective of the present work was to enhance the solubility and dissolution of practically water-insoluble drug raloxifene HCl (RLX), for the same two approaches that were used. In the first approach, drug was kneaded with hydroxypropyl-β-cyclodextrin (HPβCD), and in the second one drug was cogrinded with modified guar gum (MGG). The drug-cyclodextrin complex and drug-MGG cogrind mixtures were characterized by differential scanning calorimetry, X-ray diffraction studies, scanning electron microscopy, and Fourier transform infrared spectroscopy. The solubility and dissolution study reveals that solubility and dissolution rate of RLX remarkably increased in both methods. It was concluded that the prepared inclusion complex showed a remarkable increase in solubility and dissolution of poorly water-soluble drug raloxifene. In the cogrinding mixture, a natural modified gum is used as a surfactant and enhances the solubility and dissolution of RLX without requiring addition of organic solvent or high temperature for its preparation; thus, process is less cumbersome and cost effective. But when both methods were compared; HPβCD complexation method showed significant enhancement of drug solubility. PMID:26555984

Effect of hydrotalcite-like compounds on the aqueous solubility of some poorly water-soluble drugs.

PubMed

Ambrogi, Valeria; Fardella, Giuseppe; Grandolini, Giuliano; Nocchetti, Morena; Perioli, Luana

2003-07-01

A new approach of improving drug dissolution properties is described. This method exploits the property of a carrier owing to the hydrotalcite-type anionic clays (HTlc). HTlc is an inorganic layered solid that lodges anionic compounds among its layers. As HTlc dissolves at acidic pH values (pH < 4), the anions intercalated among the layers are promptly released in the medium. In this article some nonsteroidal antiinflammatory drugs were chosen as models of poorly water-soluble drugs. They were intercalated in HTlc and solubility measurements in acidic medium were performed. A remarkable improvement of drug solubility was observed especially in the case of indomethacin. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association

Controlled release systems containing solid dispersions: strategies and mechanisms.

PubMed

Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Park, Jun Bom; Lee, Beom-Jin

2011-10-01

In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system.

Nanoemulsions as self-emulsified drug delivery carriers for enhanced permeability of the poorly water-soluble selective β₁-adrenoreceptor blocker Talinolol.

PubMed

Ghai, Damanjeet; Sinha, Vivek Ranjan

2012-07-01

To enhance the bioavailability of the poorly water-soluble drug talinolol, a self-nanoemulsifying drug delivery system (SNEDDS) comprising 5% (w/v) Brij-721 ethanolic solution (Smix), triacetin, and water, in the ratio of 40:20:40 (% w/w) was developed by constructing pseudo-ternary phase diagrams and evaluated for droplet size, polydispersity index, and surface morphology of nanoemulsions. The effect of nanodrug carriers on drug release and permeability was assessed using stripped porcine jejunum and everted rat gut sac method and compared with hydroalcoholic drug solution, oily solution, and conventional emulsion and suspension. The SNEDDS showed a significant (P < 0.001) increase in drug release, permeability, and in vivo bioavailability as compared to drug suspension. This may be attributed to increased solubility and enhanced permeability of the drug from nanosized emulsion. In this study, a self-nanoemulsifying drug delivery system was utilized to enhance the bioavailability of the poorly water-soluble beta-blocker talinolol. Significant increase in drug release, permeability, and in vivo bioavailability were demonstrated as compared to standard drug suspension. Copyright © 2012 Elsevier Inc. All rights reserved.

Syntheses, structure characterization and dissolution of two novel cocrystals of febuxostat

NASA Astrophysics Data System (ADS)

Kang, Yanlei; Gu, Jianming; Hu, Xiurong

2017-02-01

Febuxostat was investigated due to its significant effect in the treatment of gout. However, its poor water solubility hinder its potential applications. In recent years, cocrystals have increasingly being applied to enhance the drug solubility. To improve the solubility, two cocrystals of Febuxostat were synthesized through the method of cooling crystallization. The prepared cocrystals febuxostat-isonicotinamide(FEB-INA) and febuxostat-arginine(FEB-Arg) were studied by microscopical observation, Powder X-Ray Diffraction(PXRD), Single Crystal X-ray Diffraction, Differential Scanning Calorimetry(DSC), and infrared spectrometry. At the same time, the cocrystals' solubility and dissolution rate were explored. Both the cocrystals showed higher solubility compared to the pure drug. The FEB-Arg cocrystal enhanced about 900 times of solubility compared to the pure drug. The current study proved that cocrystallization can be a better way to enhance the solubility of the poorly water-soluble drug.

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

PubMed

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

2018-06-23

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

A randomized controlled trial to compare the effects of sulphonylurea gliclazide MR (modified release) and the DPP-4 inhibitor vildagliptin on glycemic variability and control measured by continuous glucose monitoring (CGM) in Brazilian women with type 2 diabetes.

PubMed

Vianna, Andre Gustavo Daher; Lacerda, Claudio Silva; Pechmann, Luciana Muniz; Polesel, Michelle Garcia; Marino, Emerson Cestari; Faria-Neto, Jose Rocha

2018-05-01

This study aims to evaluate whether there is a difference between the effects of vildagliptin and gliclazide MR (modified release) on glycemic variability (GV) in women with type 2 diabetes (T2DM) as evaluated by continuous glucose monitoring (CGM). An open-label, randomized study was conducted in T2DM women on steady-dose metformin monotherapy which were treated with 50 mg vildagliptin twice daily or 60-120 mg of gliclazide MR once daily. CGM and GV indices calculation were performed at baseline and after 24 weeks. In total, 42 patients (age: 61.9 ± 5.9 years, baseline glycated hemoglobin (HbA1c): 7.3 ± 0.56) were selected and 37 completed the 24-week protocol. Vildagliptin and gliclazide MR reduced GV, as measured by the mean amplitude of glycemic excursions (MAGE, p = 0.007 and 0.034, respectively). The difference between the groups did not reach statistical significance. Vildagliptin also significantly decreased the standard deviation of the mean glucose (SD) and the mean of the daily differences (MODD) (p = 0.007 and 0.030). Vildagliptin and gliclazide MR similarly reduced the MAGE in women with T2DM after 24 weeks of treatment. Further studies are required to attest differences between vildagliptin and gliclazide MR regarding glycemic variability. Copyright © 2018 Elsevier B.V. All rights reserved.

Novel electrosprayed nanospherules for enhanced aqueous solubility and oral bioavailability of poorly water-soluble fenofibrate

PubMed Central

Yousaf, Abid Mehmood; Mustapha, Omer; Kim, Dong Wuk; Kim, Dong Shik; Kim, Kyeong Soo; Jin, Sung Giu; Yong, Chul Soon; Youn, Yu Seok; Oh, Yu-Kyoung; Kim, Jong Oh; Choi, Han-Gon

2016-01-01

Purpose The purpose of the present research was to develop a novel electrosprayed nanospherule providing the most optimized aqueous solubility and oral bioavailability for poorly water-soluble fenofibrate. Methods Numerous fenofibrate-loaded electrosprayed nanospherules were prepared with polyvinylpyrrolidone (PVP) and Labrafil® M 2125 as carriers using the electrospray technique, and the effect of the carriers on drug solubility and solvation was assessed. The solid state characterization of an optimized formulation was conducted by scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopic analyses. Oral bioavailability in rats was also evaluated for the formulation of an optimized nanospherule in comparison with free drug and a conventional fenofibrate-loaded solid dispersion. Results All of the electrosprayed nanospherule formulations had remarkably enhanced aqueous solubility and dissolution compared with free drug. Moreover, Labrafil M 2125, a surfactant, had a positive influence on the solubility and dissolution of the drug in the electrosprayed nanospherule. Increases were observed as the PVP/drug ratio increased to 4:1, but higher ratios gave no significant increases. In particular, an electrosprayed nanospherule composed of fenofibrate, PVP, and Labrafil M 2125 at the weight ratio of 1:4:0.5 resulted in a particle size of <200 nm with the drug present in the amorphous state. It demonstrated the highest solubility (32.51±2.41 μg/mL), an excellent dissolution (~85% in 10 minutes), and an oral bioavailability ~2.5-fold better than that of the free drug. It showed similar oral bioavailability compared to the conventional solid dispersion. Conclusion Electrosprayed nanospherules, which provide improved solubility and bioavailability, are promising drug delivery tools for oral administration of poorly water-soluble fenofibrate. PMID:26834471

Novel electrosprayed nanospherules for enhanced aqueous solubility and oral bioavailability of poorly water-soluble fenofibrate.

PubMed

Yousaf, Abid Mehmood; Mustapha, Omer; Kim, Dong Wuk; Kim, Dong Shik; Kim, Kyeong Soo; Jin, Sung Giu; Yong, Chul Soon; Youn, Yu Seok; Oh, Yu-Kyoung; Kim, Jong Oh; Choi, Han-Gon

2016-01-01

The purpose of the present research was to develop a novel electrosprayed nanospherule providing the most optimized aqueous solubility and oral bioavailability for poorly water-soluble fenofibrate. Numerous fenofibrate-loaded electrosprayed nanospherules were prepared with polyvinylpyrrolidone (PVP) and Labrafil(®) M 2125 as carriers using the electrospray technique, and the effect of the carriers on drug solubility and solvation was assessed. The solid state characterization of an optimized formulation was conducted by scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopic analyses. Oral bioavailability in rats was also evaluated for the formulation of an optimized nanospherule in comparison with free drug and a conventional fenofibrate-loaded solid dispersion. All of the electrosprayed nanospherule formulations had remarkably enhanced aqueous solubility and dissolution compared with free drug. Moreover, Labrafil M 2125, a surfactant, had a positive influence on the solubility and dissolution of the drug in the electrosprayed nanospherule. Increases were observed as the PVP/drug ratio increased to 4:1, but higher ratios gave no significant increases. In particular, an electrosprayed nanospherule composed of fenofibrate, PVP, and Labrafil M 2125 at the weight ratio of 1:4:0.5 resulted in a particle size of <200 nm with the drug present in the amorphous state. It demonstrated the highest solubility (32.51±2.41 μg/mL), an excellent dissolution (~85% in 10 minutes), and an oral bioavailability ~2.5-fold better than that of the free drug. It showed similar oral bioavailability compared to the conventional solid dispersion. Electrosprayed nanospherules, which provide improved solubility and bioavailability, are promising drug delivery tools for oral administration of poorly water-soluble fenofibrate.

Particle size reduction to the nanometer range: a promising approach to improve buccal absorption of poorly water-soluble drugs

PubMed Central

Rao, Shasha; Song, Yunmei; Peddie, Frank; Evans, Allan M

2011-01-01

Poorly water-soluble drugs, such as phenylephrine, offer challenging problems for buccal drug delivery. In order to overcome these problems, particle size reduction (to the nanometer range) and cyclodextrin complexation were investigated for permeability enhancement. The apparent solubility in water and the buccal permeation of the original phenylephrine coarse powder, a phenylephrine–cyclodextrin complex and phenylephrine nanosuspensions were characterized. The particle size and particle surface properties of phenylephrine nanosuspensions were used to optimize the size reduction process. The optimized phenylephrine nanosuspension was then freeze dried and incorporated into a multi-layered buccal patch, consisting of a small tablet adhered to a mucoadhesive film, yielding a phenylephrine buccal product with good dosage accuracy and improved mucosal permeability. The design of the buccal patch allows for drug incorporation without the need to change the mucoadhesive component, and is potentially suited to a range of poorly water-soluble compounds. PMID:21753876

Particle size reduction to the nanometer range: a promising approach to improve buccal absorption of poorly water-soluble drugs.

PubMed

Rao, Shasha; Song, Yunmei; Peddie, Frank; Evans, Allan M

2011-01-01

Poorly water-soluble drugs, such as phenylephrine, offer challenging problems for buccal drug delivery. In order to overcome these problems, particle size reduction (to the nanometer range) and cyclodextrin complexation were investigated for permeability enhancement. The apparent solubility in water and the buccal permeation of the original phenylephrine coarse powder, a phenylephrine-cyclodextrin complex and phenylephrine nanosuspensions were characterized. The particle size and particle surface properties of phenylephrine nanosuspensions were used to optimize the size reduction process. The optimized phenylephrine nanosuspension was then freeze dried and incorporated into a multi-layered buccal patch, consisting of a small tablet adhered to a mucoadhesive film, yielding a phenylephrine buccal product with good dosage accuracy and improved mucosal permeability. The design of the buccal patch allows for drug incorporation without the need to change the mucoadhesive component, and is potentially suited to a range of poorly water-soluble compounds.

In vitro and in vivo studies on the complexes of glipizide with water-soluble β-cyclodextrin-epichlorohydrin polymers.

PubMed

Nie, Shufang; Zhang, Shu; Pan, Weisan; Liu, Yanli

2011-05-01

The purpose of this study was to evaluate the potential of a newly modified cyclodextrin derivative, water-soluble β-cyclodextrin-epichlorohydrin polymer (β-CDP), as an effective drug carrier to enhance the dissolution rate and oral bioavailability of glipizide as a poorly water-soluble model drug. Inclusion complexes of glipizide with β-CDP were prepared by the co-evaporation method and characterized by phase solubility, dissolution, and differential scanning calorimetry. The solubility curve was classified as type A(L), which indicated the formation of 1:1 complex between glipizide and β-CDP. β-CDP had better properties of increasing the aqueous solubility of glipizide compared with HP-β-CD. The dissolution rate of drug from the β-CDP complexes was significantly greater than that of the corresponding physical mixtures indicating that the formation of amorphous complex increased the solubility of glipizide. Moreover, the increment in drug dissolution rate from the glipizide/β-CDP systems was higher than that from the corresponding ones with HP-β-CD, which indicated that β-CDP could provide greater capability of solubilization for poorly soluble drugs. Furthermore, in vivo study revealed that the bioavailability of glipizide was significantly improved by glipizide /β-CDP inclusion complex after oral administration to beagle dogs.

Solubility of ocular therapeutic agents in self-emulsifying oils. I. Self-emulsifying oils for ocular drug delivery: solubility of indomethacin, aciclovir and hydrocortisone.

PubMed

Czajkowska-Kośnik, Anna; Sznitowska, Małgorzata

2009-01-01

Self-emulsifying drug delivery systems (SEDDS) were prepared by dissolving Cremophor EL, Tween 20, Tween 80 and Span 80 (1% or 5%) in oils (Miglyol 812 or castor oil). Solubilities of three ophthalmic drugs, namely aciclovir, hydrocortisone and indomethacin were determined in these systems. In addition, the effect of a small amount of water (0.5% and 2%) on solubilization properties of the systems was estimated. Of the three substances, indomethacin showed the best solubility in Miglyol while aciclovir was practically insoluble in this oil. The surfactants usually increased drug solubility in the oily phase. Only Tween 20 was found to decrease the solubility of aciclovir and hydrocortisone in Miglyol. Addition of a small amount of water to the oil/surfactant system increased solubility of hydrocortisone, but not of indomethacin. The results of the current study may be utilized to design a suitable composition of SEDDS and allow continuation of research on this type of drug carriers.

Solubilization of poorly water-soluble drugs using solid dispersions.

PubMed

Tran, Thao T-D; Tran, Phuong H-L; Khanh, Tran N; Van, Toi V; Lee, Beom-Jin

2013-08-01

Many new drugs have been discovered in pharmaceutical industry and exposed their surprised potential therapeutic effects. Unfortunately, these drugs possess low absorption and bioavailability since their solubility limitation in water. Solid dispersion (SD) is the current technique gaining so many attractions from scientists due to its effect on improving solubility and dissolution rate of poorly water-soluble drugs. A number of patents including the most recent inventions have been undertaken in this review to address various respects of this strategy in solubilization of poorly watersoluble drugs including type of carriers, preparation methods and view of technologies used to detect SD properties and mechanisms with the aim to accomplish a SD not only effective on enhanced bioavailability but also overcome difficulties associated with stability and production. Future prospects are as well discussed with an only hope that many developments and researches in this field will be successfully reached and contributed to commercial use for treatment as much as possible.

Adverse cardiovascular events during treatment with glyburide (glibenclamide) or gliclazide in a high-risk population.

PubMed

Juurlink, D N; Gomes, T; Shah, B R; Mamdani, M M

2012-12-01

Sulphonylureas promote insulin release by inhibiting pancreatic potassium channels. Older sulphonylureas such as glyburide (glibenclamide), but not newer ones such as gliclazide, antagonize similar channels in myocardium, interfering with the protective effects of ischaemic preconditioning. Whether this imparts a higher risk of adverse cardiac events is unknown. We conducted a population-based cohort study of patients aged 66 years and older who were hospitalized for acute myocardial infarction or who underwent percutaneous coronary intervention between 1 April 2007 and 31 March 2010 while receiving either glyburide or gliclazide. We used a high-dimensional propensity score matching process to ensure similarity of glyburide- and gliclazide-treated patients. The primary outcome was a composite of death or hospitalization for myocardial infarction or heart failure. During the 2-year study period, we matched 1690 patients treated with glyburide to 984 patients treated with gliclazide at the time of hospitalization for acute myocardial infarction or percutaneous coronary intervention. We found no difference in the risk of the composite outcome among patients receiving glyburide (adjusted hazard ratio 1.01; 95% CI 0.86-1.18). We found similar results in secondary analyses of each outcome individually, and in two supplementary analyses (haemorrhage and pneumonia) in which we anticipated no difference between the two patient groups. Among older patients hospitalized for acute myocardial infarction or percutaneous coronary intervention, treatment with glyburide is not associated with an increased risk of future adverse cardiovascular events relative to gliclazide, suggesting that the effect of glyburide on ischaemic preconditioning is of little clinical relevance. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

NASA Astrophysics Data System (ADS)

Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

2017-11-01

Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

Oral formulation strategies to improve solubility of poorly water-soluble drugs.

PubMed

Singh, Abhishek; Worku, Zelalem Ayenew; Van den Mooter, Guy

2011-10-01

In the past two decades, there has been a spiraling increase in the complexity and specificity of drug-receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends. Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends. Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.

Drug-loaded electrospun mats of poly(vinyl alcohol) fibres and their release characteristics of four model drugs

NASA Astrophysics Data System (ADS)

Taepaiboon, Pattama; Rungsardthong, Uracha; Supaphol, Pitt

2006-05-01

Mats of PVA nanofibres were successfully prepared by the electrospinning process and were developed as carriers of drugs for a transdermal drug delivery system. Four types of non-steroidal anti-inflammatory drug with varying water solubility property, i.e. sodium salicylate (freely soluble in water), diclofenac sodium (sparingly soluble in water), naproxen (NAP), and indomethacin (IND) (both insoluble in water), were selected as model drugs. The morphological appearance of the drug-loaded electrospun PVA mats depended on the nature of the model drugs. The 1H-nuclear magnetic resonance results confirmed that the electrospinning process did not affect the chemical integrity of the drugs. Thermal properties of the drug-loaded electrospun PVA mats were analysed by differential scanning calorimetry and thermogravimetric analysis. The molecular weight of the model drugs played a major role on both the rate and the total amount of drugs released from the as-prepared drug-loaded electrospun PVA mats, with the rate and the total amount of the drugs released decreasing with increasing molecular weight of the drugs. Lastly, the drug-loaded electrospun PVA mats exhibited much better release characteristics of the model drugs than drug-loaded as-cast films.

Solid dispersions, part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs.

PubMed

Bikiaris, Dimitrios N

2011-12-01

The absorption of poorly water-soluble drugs, when presented in the crystalline state to the gastrointestinal tract, is typically dissolution rate-limited, and according to BCS these drugs belong mainly to class II. Both dissolution kinetics and solubility are particle size dependent. Nowadays, various techniques are available to the pharmaceutical industry for dissolution rate enhancement of such drugs. Among such techniques, nanosuspensions and drug formulation in solid dispersions are those with the highest interest. This review discusses strategies undertaken over the last 10 years, which have been applied for the dissolution enhancement of poorly water-soluble drugs; such processes include melt mixing, electrospinning, microwave irradiation and the use of inorganic nanoparticles. Many problems in this field still need to be solved, mainly the use of toxic solvents, and for this reason the use of innovative new procedures and materials will increase over the coming years. Melt mixing remains extremely promising for the preparation of SDs and will probably become the most used method in the future for the preparation of solid drug dispersions.

Chirality plays critical roles in enhancing the aqueous solubility of nocathiacin I by block copolymer micelles.

PubMed

Feng, Kun; Wang, Shuzhen; Ma, Hairong; Chen, Yijun

2013-01-01

Although drug solubilization by block copolymer micelles has been extensively studied, the rationale behind the choice of appropriate block copolymer micelles for various poorly water-soluble drugs has been of relatively less concern. The objective of this study was to use methoxy-poly(ethylene glycol)-polylactate micelles (MPEG-PLA) to solubilize glycosylated antibiotic nocathiacin I and to compare the effects of chirality on the enhancement of aqueous solubility. Nocathiacin I-loaded MPEG-PLA micelles with opposite optical property in PLA were synthesized and characterized. The drug release profile, micelle stability and preliminary safety properties of MPEG-PLA micelles were evaluated. Meanwhile, three other poorly water-soluble chiral compound-loaded micelles were also prepared and compared.  The aqueous solubility of nocathiacin I was greatly enhanced by both L- and D-copolymers, with the degree of enhancement appearing to depend on the chirality of the copolymers. Comparison of different chiral compounds confirmed the trend that aqueous solubility of chiral compounds can be more effectively enhanced by block copolymer micelles with specific stereochemical configuration. The present study introduced chiral concept on the selection and preparation of block copolymer micelles for the enhancement of aqueous solubility of poorly water-soluble drugs. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Effects of polyvinylpyrrolidone both as a binder and pore-former on the release of sparingly water-soluble topiramate from ethylcellulose coated pellets.

PubMed

Yang, Meiyan; Xie, Si; Li, Qiu; Wang, Yuli; Chang, Xinyi; Shan, Li; Sun, Lei; Huang, Xiaoli; Gao, Chunsheng

2014-04-25

Delivering sparingly water-soluble drugs from ethylcellulose (EC) coated pellets with a controlled-release pattern remains challenging. In the present study, hydrophilic polyvinylpyrrolidone (PVP) was used both as a binder and a pore-former in EC coated pellets to deliver sparingly water-soluble topiramate, and the key factors that influenced drug release were identified. When the binder PVP content in drug layers below 20% w/w was decreased, the physical state of topiramate changed from amorphous to crystalline, making much difference to drug solubility and dissolution rates while modifying the drug release profile from first-order to zero-order. In addition, without PVP in drug layering solution, drug layered particles were less sticky during layering process, thus leading to a shorter process and higher loading efficiency. Furthermore, PVP level as a pore-former in EC coating layers mainly governed drug release from the coated pellets with the sensitivity ranging from 23% to 29%. PVP leaching rate and water permeability from EC/PVP film increased with the PVP level, which was perfectly correlated with drug release rate. Additionally, drug release from this formulation was independent of pH of release media or of the paddle mixing speed, but inversely proportional to the osmolality of release media above the physiological range. Copyright © 2014. Published by Elsevier B.V.

Synthesis and anti-cancer efficacy of rapid hydrolysed water-soluble paclitaxel pro-drugs.

PubMed

Ryu, Beom-Young; Sohn, Jeong-Sun; Hess, Michael; Choi, Soo-Kyung; Choi, Jae-Kon; Jo, Byung-Wook

2008-01-01

A new series of poly(ethylene glycol)(PEG)-paclitaxel conjugates that increases water solubility of paclitaxel was synthesized. We developed well-designed self-immolating linkers between a drug and a water-soluble polymer moiety which gave an extremely rapid hydrolysis rate to convert a pro-drug into a parent drug without any reduction in drug efficacy. The self-immolating spacer groups were introduced between the solubilizing PEG and C7-OH of paclitaxel in order to control the rate of enzymatic hydrolysis. All these pro-drugs had a water-solubility of 400 mg/ml or more compared with a solubility of about 0.01 mg/ml. The rate of hydrolysis for the pro-drugs in rat plasma showed considerable variation of t((1/2)) ranging from 0.94 min to 42.7 min. To evaluate the anti-tumor efficacy of the pro-drug which had the fastest enzymatic hydrolysis rate, the growth inhibitory effect (IC(50)), the anti-tumor activity and the anti-metastatic potential of the pro-drug were examined. The pro-drug was potent to inhibit the growth of various cancer cell lines, such as human lung, ovarian, colon and melanoma cancer cells. On the development of melanoma lung colonies in C57B/6 mice following intravenous administration of metastatic murine B16/F10 melanoma cells, the pro-drug seems to be more efficacious than paclitaxel. The reduction of the number of melanoma lung colonies was 46.9% (dose: 5 mg/kg) with pure paclitaxel, and 24.5%, and 40.0% with the pro-drug in the dose of 0.71 mg paclitaxel equivalent/kg and 1.42 mg paclitaxel equivalent/kg, respectively.

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

PubMed

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

2018-05-01

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

Cyclodextrin based ternary system of modafinil: Effect of trimethyl chitosan and polyvinylpyrrolidone as complexing agents.

PubMed

Patel, Parth; Agrawal, Y K; Sarvaiya, Jayrajsinh

2016-03-01

Modafinil is an approved drug for the treatment of narcolepsy and have a strong market presence in many countries. The drug is widely consumed for off-label uses and currently listed as a restricted drug. Modafinil has very low water solubility. To enhance the aqueous solubility of modafinil by the formation of a ternary complex with Hydroxypropyl-β-cyclodextrin and two hydrophilic polymers was the main objective of the present study. Pyrrolidone (PVP K30) and a water soluble chitosan derivative, trimethyl chitosan (TMC) were studied by solution state and solid state characterization methods for their discriminatory efficiency in solubility enhancement of modafinil. Phase solubility study depicted the highest complexation efficiency (2.22) of cyclodextrin derivative in the presence of TMC compared to the same in the presence of PVP K30 (0.08) and in the absence of any polymer (0.92). FT-IR analysis of binary and ternary complex expressed comparable contribution of both polymers in formation of inclusion complex. The thermal behaviour of binary and ternary complex, involving individual polymers disclosed the influence of TMC on polymorphism of the drug. DSC study revealed efficiency of TMC to prevent conversion of metastable polymorphic form to stable polymorphic form. Ternary complex, involving TMC enhanced water solubility of the drug 1.5 times more compared to the binary complex of the drug whereas PVP K30 reduced the Solubility. Copyright © 2015 Elsevier B.V. All rights reserved.

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture.

PubMed

Joshi, Hemant N; Tejwani, Ravindra W; Davidovich, Martha; Sahasrabudhe, Vaishali P; Jemal, Mohammed; Bathala, Mohinder S; Varia, Sailesh A; Serajuddin, Abu T M

2004-01-09

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.

Swelling/Floating Capability and Drug Release Characterizations of Gastroretentive Drug Delivery System Based on a Combination of Hydroxyethyl Cellulose and Sodium Carboxymethyl Cellulose

PubMed Central

Chen, Ying-Chen; Ho, Hsiu-O; Liu, Der-Zen; Siow, Wen-Shian; Sheu, Ming-Thau

2015-01-01

The aim of this study was to characterize the swelling and floating behaviors of gastroretentive drug delivery system (GRDDS) composed of hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose (NaCMC) and to optimize HEC/NaCMC GRDDS to incorporate three model drugs with different solubilities (metformin, ciprofloxacin, and esomeprazole). Various ratios of NaCMC to HEC were formulated, and their swelling and floating behaviors were characterized. Influences of media containing various NaCl concentrations on the swelling and floating behaviors and drug solubility were also characterized. Finally, release profiles of the three model drugs from GRDDS formulation (F1-4) and formulation (F1-1) were examined. Results demonstrated when the GRDDS tablets were tested in simulated gastric solution, the degree of swelling at 6 h was decreased for each formulation that contained NaCMC in comparison to those in de-ionized water (DIW). Of note, floating duration was enhanced when in simulated gastric solution compared to DIW. Further, the hydration of tablets was found to be retarded as the NaCl concentration in the medium increased resulting in smaller gel layers and swelling sizes. Dissolution profiles of the three model drugs in media containing various concentrations of NaCl showed that the addition of NaCl to the media affected the solubility of the drugs, and also their gelling behaviors, resulting in different mechanisms for controlling a drug’s release. The release mechanism of the freely water-soluble drug, metformin, was mainly diffusion-controlled, while those of the water-soluble drug, ciprofloxacin, and the slightly water-soluble drug, esomeprazole, were mainly anomalous diffusion. Overall results showed that the developed GRDDS composed of HEC 250HHX and NaCMC of 450 cps possessed proper swelling extents and desired floating periods with sustained-release characteristics. PMID:25617891

Gliclazide-Induced Insulin Autoimmune Syndrome: A Rare Case Report and Review on Literature.

PubMed

Feng, Xiu; Yuan, Lu; Hu, Yun; Zhu, Yunqing; Yang, Fan; Jiang, Lanlan; Yan, Rengna; Luo, Yong; Zhao, Enhui; Liu, Chenxiao; Wang, Ying; Li, Qi; Cao, Xin; Li, Qian; Ma, Jianhua

2016-01-01

Insulin Autoimmune Syndrome (IAS) is a rare condition characterized by the combination of recurrent severely spontaneous hypoglycemia without evidence of exogenous insulin administration, high concentration of total serum insulin, and the presence of a high titer of insulin autoantibody (IAA). But now we describe a case with IAS caused by gliclazide and hardly occuring hypoglycemia. A 70-year-old man with type 2 diabetes presented to our department with poor glycemic control without evidence of hypoglycemia, but the levels of serum insulin and IAA were very high. He had no exogenous insulin administration history. Switching antidiabetic therapy from gliclazide to acarbose and metformin, the patient's serum insulin level and IAA decreased gradually. Accordingly, the glycemic control improved and there was no episode of hypoglycemia. Hence, clinicians should pay more attention to type 2 diabetic patients treated with gliclazide and detect their serum insulin concentration and IAA to exclude or diagnose IAS and perform the best therapeutic regimen to these patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design of biodegradable nanoparticles: a novel approach to encapsulating poorly soluble phytochemical ellagic acid

NASA Astrophysics Data System (ADS)

Bala, I.; Bhardwaj, V.; Hariharan, S.; Sitterberg, J.; Bakowsky, U.; Kumar, M. N. V. Ravi

2005-12-01

Nanosizing of poorly water soluble drugs or incorporating them into nanoparticles to increase their solubility and thereby the bioavailability has become a favoured approach today. This work describes a novel method for encapsulating poorly water soluble phytochemical ellagic acid that is also sparingly soluble/insoluble in routine solvents used to prepare nanoparticles.

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

PubMed

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

2014-09-01

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

Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs.

PubMed

Lukyanov, Anatoly N; Torchilin, Vladimir P

2004-05-07

Polymeric micelles have a whole set of unique characteristics, which make them very promising drug carriers, in particular, for poorly soluble drugs. Our review article focuses on micelles prepared from conjugates of water-soluble polymers, such as polyethylene glycol (PEG) or polyvinyl pyrrolidone (PVP), with phospholipids or long-chain fatty acids. The preparation of micelles from certain polymer-lipid conjugates and the loading of these micelles with various poorly soluble anticancer agents are discussed. The data on the characterization of micellar preparations in terms of their morphology, stability, longevity in circulation, and ability to spontaneously accumulate in experimental tumors via the enhanced permeability and retention (EPR) effect are presented. The review also considers the preparation of targeted immunomicelles with specific antibodies attached to their surface. Available in vivo results on the efficiency of anticancer drugs incorporated into plain micelles and immunomicelles in animal models are also discussed.

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

PubMed

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

2016-07-01

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

Highly water-soluble, porous, and biocompatible boron nitrides for anticancer drug delivery.

PubMed

Weng, Qunhong; Wang, Binju; Wang, Xuebin; Hanagata, Nobutaka; Li, Xia; Liu, Dequan; Wang, Xi; Jiang, Xiangfen; Bando, Yoshio; Golberg, Dmitri

2014-06-24

Developing materials for "Nano-vehicles" with clinically approved drugs encapsulated is envisaged to enhance drug therapeutic effects and reduce the adverse effects. However, design and preparation of the biomaterials that are porous, nontoxic, soluble, and stable in physiological solutions and could be easily functionalized for effective drug deliveries are still challenging. Here, we report an original and simple thermal substitution method to fabricate perfectly water-soluble and porous boron nitride (BN) materials featuring unprecedentedly high hydroxylation degrees. These hydroxylated BNs are biocompatible and can effectively load anticancer drugs (e.g., doxorubicin, DOX) up to contents three times exceeding their own weight. The same or even fewer drugs that are loaded on such BN carriers exhibit much higher potency for reducing the viability of LNCaP cancer cells than free drugs.

Solubility of guaifenesin in the presence of common pharmaceutical additives.

PubMed

Mani, Narasimhan; Jun, H W; Beach, J Warren; Nerurkar, Jayanti

2003-01-01

The aqueous solubility of guaifenesin, a highly water-soluble drug, in the presence of salts, sugars, and cosolvents was determined at 25 degrees C and 40 degrees C. The solubility of drug at both temperatures was reduced with increasing concentrations of salts and sugars. The extent of reduction in drug solubility was dependent on the type of salts and sugars used. The salting-out coefficient of additives was calculated by plotting log-linear solubility profiles of the drug against the concentrations of the additives. The solubility of guaifenesin, a neutral compound, was found to be higher at lower pH values, which could be due to hydrogen-bonding effects. At 25 degrees C, glycerin, PEG 300, and propylene glycol increased the solubility of drug at low solvent concentrations while the solubility was reduced at high concentrations. At 40 degrees C, the solubility of drug was reduced at all concentrations of cosolvents. The thermodynamic events accompanying the solubility process were discussed to explain the solubility phenomena observed in the presence of additives. The reduced aqueous solubility of guaifenesin in the presence of additives greatly improved the entrapment of drug into controlled-release wax microspheres.

Enhancement of solubility and bioavailability of ambrisentan by solid dispersion using Daucus carota as a drug carrier: formulation, characterization, in vitro, and in vivo study.

PubMed

Deshmane, Subhash; Deshmane, Snehal; Shelke, Santosh; Biyani, Kailash

2018-06-01

Ambrisentan is an US FDA approved drug, it is the second oral endothelin A receptor antagonist known for the treatment of pulmonary arterial hypertension, but its oral administration is limited due to its poor water solubility. Hence, the objective of the investigation was focused on enhancement of solubility and bioavailability of ambrisentan by solid dispersion technique using natural Daucus carota extract as drug carrier. Drug carrier was evaluated for solubility, swelling index, viscosity, angle of repose, hydration capacity, and acute toxicity test (LD 50 ). Ambrisentan was studied for the saturation solubility, phase solubility, and Gibbs free energy change. Compatibility of drug and the natural carrier was confirmed by DSC, FTIR, and XRD. Solid dispersions were evaluated for drug content, solubility, morphology, in vitro, and in vivo study. Screening of the natural carrier showed the desirable properties like water solubility, less swelling index, less viscosity, and acute toxicity study revealed no any clinical symptoms of toxicity. Drug and carrier interaction study confirmed the compatibility to consider its use in the formulation. Formed particles were found to be spherical with smooth surface. In vitro studies revealed higher drug release from the solid dispersion than that of the physical mixture. Bioavailability study confirms the increased absorption and bioavailability by oral administration of solid dispersion. Hence, it can be concluded that the natural Daucus carota extract can be the better alternative source for the preparation of solid dispersion and/or other dosage forms for improving solubility and bioavailability.

Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate.

PubMed

Park, Young-Joon; Ryu, Dong-Sung; Li, Dong Xun; Quan, Qi Zhe; Oh, Dong Hoon; Kim, Jong Oh; Seo, Youn Gee; Lee, Young-Im; Yong, Chul Soon; Woo, Jong Soo; Choi, Han-Gon

2009-06-01

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.

Polymeric micelles for multi-drug delivery in cancer.

PubMed

Cho, Hyunah; Lai, Tsz Chung; Tomoda, Keishiro; Kwon, Glen S

2015-02-01

Drug combinations are common in cancer treatment and are rapidly evolving, moving beyond chemotherapy combinations to combinations of signal transduction inhibitors. For the delivery of drug combinations, i.e., multi-drug delivery, major considerations are synergy, dose regimen (concurrent versus sequential), pharmacokinetics, toxicity, and safety. In this contribution, we review recent research on polymeric micelles for multi-drug delivery in cancer. In concurrent drug delivery, polymeric micelles deliver multi-poorly water-soluble anticancer agents, satisfying strict requirements in solubility, stability, and safety. In sequential drug delivery, polymeric micelles participate in pretreatment strategies that "prime" solid tumors and enhance the penetration of secondarily administered anticancer agent or nanocarrier. The improved delivery of multiple poorly water-soluble anticancer agents by polymeric micelles via concurrent or sequential regimens offers novel and interesting strategies for drug combinations in cancer treatment.

Application of mixture experimental design to simvastatin apparent solubility predictions in the microemulsifion formed by self-microemulsifying.

PubMed

Meng, Jian; Zheng, Liangyuan

2007-09-01

Self-microemulsifying drug delivery systems (SMEDDS) are useful to improve the bioavailability of poorly water-soluble drugs by increasing their apparent solubility through solubilization. However, very few studies, to date, have systematically examined the level of drug apparent solubility in o/w microemulsion formed by self-microemulsifying. In this study, a mixture experimental design was used to simulate the influence of the compositions on simvastatin apparent solubility quantitatively through an empirical model. The reduced cubic polynomial equation successfully modeled the evolution of simvastatin apparent solubility. The results were presented using an analysis of response surface showing a scale of possible simvastatin apparent solubility between 0.0024 ~ 29.0 mg/mL. Moreover, this technique showed that simvastatin apparent solubility was mainly influenced by microemulsion concentration and, suggested that the drug would precipitate in the gastrointestinal tract due to dilution by gastrointestinal fluids. Furthermore, the model would help us design the formulation to maximize the drug apparent solubility and avoid precipitation of the drug.

Drug Solubility: Importance and Enhancement Techniques

PubMed Central

Savjani, Ketan T.; Gajjar, Anuradha K.; Savjani, Jignasa K.

2012-01-01

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics. PMID:22830056

Improvement of dissolution behavior of poorly water soluble drugs by biodegradable polymeric submicron carriers containing sparingly methylated β-cyclodextrin.

PubMed

Singhavi, Dilesh J; Khan, Shagufta; Yeole, Pramod G

2013-04-01

The objective of this study was to develop submicron carriers of two drugs that are practically insoluble in water, i.e. meloxicam and aceclofenac, to improve their dissolution behavior. The phase solubility of the drugs was studied using different concentrations of sparingly methylated β-cyclodextrin, Kleptose(®) Crysmeβ (Crysmeb), in the presence and absence of 0.2 % w/v water-soluble chitosan. Drug-loaded submicron particles (SMPs) were prepared using chitosan chlorhydrate and Crysmeb by the ionotropic gelation method. The SMPs were characterized in terms of powder X-ray diffraction, Fourier transforms infrared spectroscopy, size determination, process yield, drug loading, encapsulation efficiency, surface morphology and in vitro release. The drug loading in the SMPs was enhanced in the presence of Crysmeb. The in vitro drug release was found to be enhanced with SMPs prepared using higher concentrations of Crysmeb. These results indicate that SMPs formed from chitosan chlorhydrate and Crysmeb are promising submicron carriers for enhancing the dissolution of meloxicam and aceclofenac.

Biointerfacing polymeric microcapsules for in vivo near-infrared light-triggered drug release

NASA Astrophysics Data System (ADS)

Shao, Jingxin; Xuan, Mingjun; Si, Tieyan; Dai, Luru; He, Qiang

2015-11-01

Seeking safe and effective water-soluble drug carriers is of great significance in nanomedicine. To achieve this goal, we present a novel drug delivery system based on biointerfacing hollow polymeric microcapsules for effectively encapsulating water-soluble antitumor drug and gold nanorod (GNR) functionalization for triggered release of therapeutic drugs on-demand using low power near-infrared (NIR) radiation. The surface of polymeric microcapsules is covered with fluidic lipid bilayers to decrease the permeability of the wall of polymeric capsules. The temperature increase upon NIR illumination deconstructs the structure of the lipid membrane and polyelectrolyte multilayers, which in turn results in the rapid release of encapsulated water-soluble drug. In vivo antitumor tests demonstrate that this microcapsule has the effective ability of inhibiting tumor growth and preventing metastases. Real time in vivo fluorescence imaging results confirm that capsules can be excreted gradually from the animal body which in turn demonstrates the biocompatibility and biodegradation of these biointerfacing GNR-microcapsules. This intelligent system provides a novel anticancer platform with the advantages of controlled release, biological friendliness and credible biosafety.Seeking safe and effective water-soluble drug carriers is of great significance in nanomedicine. To achieve this goal, we present a novel drug delivery system based on biointerfacing hollow polymeric microcapsules for effectively encapsulating water-soluble antitumor drug and gold nanorod (GNR) functionalization for triggered release of therapeutic drugs on-demand using low power near-infrared (NIR) radiation. The surface of polymeric microcapsules is covered with fluidic lipid bilayers to decrease the permeability of the wall of polymeric capsules. The temperature increase upon NIR illumination deconstructs the structure of the lipid membrane and polyelectrolyte multilayers, which in turn results in the rapid release of encapsulated water-soluble drug. In vivo antitumor tests demonstrate that this microcapsule has the effective ability of inhibiting tumor growth and preventing metastases. Real time in vivo fluorescence imaging results confirm that capsules can be excreted gradually from the animal body which in turn demonstrates the biocompatibility and biodegradation of these biointerfacing GNR-microcapsules. This intelligent system provides a novel anticancer platform with the advantages of controlled release, biological friendliness and credible biosafety. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06350g

GSH- and pH-responsive drug delivery system constructed by water-soluble pillar[5]arene and lysine derivative for controllable drug release.

PubMed

Wu, Xuan; Li, Yan; Lin, Chen; Hu, Xiao-Yu; Wang, Leyong

2015-04-21

Novel GSH- and pH-responsive supramolecular vesicles constructed by an amphiphilic inclusion complex formed from water-soluble pillar[5]arene and lysine derivative have been successfully developed, which can efficiently encapsulate anticancer drug MTZ and show rapid MTZ-release in a simulated acidic tumor environment with high GSH concentration, and exhibit potent antitumor activity.

An Intestinal "Transformers"-like Nanocarrier System for Enhancing the Oral Bioavailability of Poorly Water-Soluble Drugs.

PubMed

Chuang, Er-Yuan; Lin, Kun-Ju; Huang, Tring-Yo; Chen, Hsin-Lung; Miao, Yang-Bao; Lin, Po-Yen; Chen, Chiung-Tong; Juang, Jyuhn-Huarng; Sung, Hsing-Wen

2018-06-06

Increasing the intestinal dissolution of orally administered poorly water-soluble drugs that have poor oral bioavailability to a therapeutically effective level has long been an elusive goal. In this work, an approach that can greatly enhance the oral bioavailability of a poorly water-soluble drug such as curcumin (CUR) is developed, using a "Transformers"-like nanocarrier system (TLNS) that can self-emulsify the drug molecules in the intestinal lumen to form nanoemulsions. Owing to its known anti-inflammation activity, the use of CUR in treating pancreatitis is evaluated herein. Structural changes of the TLNS in the intestinal environment to form the CUR-laden nanoemulsions are confirmed in vitro. The therapeutic efficacy of this TLNS is evaluated in rats with experimentally induced acute pancreatitis (AP). Notably, the CUR-laden nanoemulsions that are obtained using the proposed TLNS can passively target intestinal M cells, in which they are transcytosed and then transported into the pancreatic tissues via the intestinal lymphatic system. The pancreases in rats that are treated with the TLNS yield approximately 12 times stronger CUR signals than their counterparts receiving free CUR, potentially improving the recovery of AP. These findings demonstrate that the proposed TLNS can markedly increase the intestinal drug dissolution, making oral delivery a favorable noninvasive means of administering poorly water-soluble drugs.

Solubility and transdermal permeation properties of a dehydroepiandrosterone cyclodextrin complex from hydrophilic and lipophilic vehicles.

PubMed

Ceschel, GianCarlo; Bergamante, Valentina; Maffei, Paola; Lombardi Borgia, Simone; Calabrese, Valeria; Biserni, Stefano; Ronchi, Celestino

2005-01-01

The permeation ability of a compound is due principally to its concentration in the vehicle and to its aptitude to cross the stratum corneum of the skin. In this work ex-vivo permeation studies on newly developed formulations containing dehydroepiandrosterone (DHEA) were carried out to investigate vehicles that increase drug permeation through the skin. To enhance the solubility of DHEA, its complex form with alpha-cyclodextrin was used. In addition, the two forms (pure drug and complex form) were introduced in hydrophilic (water), lipophilic (paraffin oil), and microemulsion vehicles to evaluate the synergic effect of cyclodextrins and microemulsion vehicles on solubility and permeation. From the results, DHEA solubility is notably conditioned by the type of the vehicle used: the highest solubilities (both for pure and complex drug forms) were obtained with microemulsion, followed by paraffin oil and water. Moreover, in all the studied vehicles, the c-DHEA was more soluble than DHEA. Permeation profile fluxes showed very interesting differences. That reflect the varying drug forms (pure drug and complex form), vehicles used, and drug concentrations in the vehicles. The major flux was obtained in complex of DHEA with alpha-cyclodextrins in the microemulsion vehicle. Therefore, this type of vehicle and drug form would be very useful in the development of a topical formulation containing DHEA.

Liposheres as a Novel Carrier for Lipid Based Drug Delivery: Current and Future Directions.

PubMed

Swain, Suryakanta; Beg, Sarwar; Babu, Sitty M

2016-01-01

Researchers are facing challenges to develop robust formulation and to enhance the bioavailability of poorly water-soluble drugs towards clinical applications. The development of new drug molecule alone is not adequate to assure ample pharmacotherapy of various diseases. Considerable results obtained from in vitro studies are not supported by in vivo data due to inadequate plasma drug concentrations. This may occur due to limited drug solubility and absorption. To resolve these problems, development of new drug delivery systems will be a promising approach. One of the promising pharmaceutical strategies is the use of lipospheres drug delivery system to deliver the poorly water-soluble drugs. Therefore, the present review described the methodology for manufacturing of lipospheres and factors influencing the formulation to deliver the drugs to the targeted site. Apart from that, this review also enlisted briefly the various applications of liposphers in medical and biomedical fields and critically discussed the recent patent system.

Carboxylated mesoporous carbon microparticles as new approach to improve the oral bioavailability of poorly water-soluble carvedilol.

PubMed

Zhang, Yanzhuo; Zhi, Zhizhuang; Li, Xue; Gao, Jian; Song, Yaling

2013-09-15

The main objective of this study was to develop carboxylated ordered mesoporous carbon microparticles (c-MCMs) loaded with a poorly water-soluble drug, intended to be orally administered, able to enhance the drug loading capacity and improve the oral bioavailability. A model drug, carvedilol (CAR), was loaded onto c-MCMs via a procedure involving a combination of adsorption equilibrium and solvent evaporation. The physicochemical properties of the drug-loaded composites were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and HPLC. It was found that c-MCM has a high drug loading level up to 41.6%, and higher than that of the mesoporous silica template. Incorporation of CAR in both drug carriers enhanced the solubility and dissolution rate of the drug, compared to the pure crystalline drug. After loading CAR into c-MCMs, its oral bioavailability was compared with the marketed product in dogs. The results showed that the bioavailability of CAR was improved 179.3% compared with that of the commercial product when c-MCM was used as the drug carrier. We believe that the present study will help in the design of oral drug delivery systems for enhanced oral bioavailability of poorly water-soluble drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Self-double-emulsifying drug delivery system (SDEDDS): a new way for oral delivery of drugs with high solubility and low permeability.

PubMed

Qi, Xiaole; Wang, Lishuang; Zhu, Jiabi; Hu, Zhenyi; Zhang, Jie

2011-05-16

Water-in-oil-in-water (w/o/w) double emulsions are potential for enhancing oral bioavailability of drugs with high solubility and low permeability, but their industrial application is limited due to the instability. Herein, we developed a novel formulation, self-double-emulsifying drug delivery systems (SDEDDS) by formulating mixtures of hydrophilic surfactants and water-in-oil (w/o) emulsions, which were easier to be stable through formulations optimization. SDEDDS can spontaneously emulsify to water-in-oil-in-water (w/o/w) double emulsions in the mixed aqueous gastrointestinal environment, with drugs encapsulated in the internal water phase of the double emulsions. We employed SDEDDS to improve the oral absorption of pidotimod, a peptide-like drug with high solubility and low permeability. The optimized pidotimod-SDEDDS were found to be stable up to 6 months under 25°C. Plasma concentration-time profiles from pharmacokinetic studies in rats dosed with SDEDDS showed 2.56-fold (p<0.05) increased absorption of pidotimod, compared to the pidotimod solution. Histopathologic studies confirmed that SDEDDS exerted absorption promoting effect without serious local damages. These studies demonstrate that SDEDDS may be a promising strategy for peroral delivery of peptide and peptidomimetic drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

Application of molecular dynamics simulation to predict the compatability between water-insoluble drugs and self-associating poly(ethylene oxide)-b-poly(epsilon-caprolactone) block copolymers.

PubMed

Patel, Sarthak; Lavasanifar, Afsaneh; Choi, Phillip

2008-11-01

In the present work, molecular dynamics (MD) simulation was applied to study the solubility of two water-insoluble drugs, fenofibrate and nimodipine, in a series of micelle-forming PEO-b-PCL block copolymers with combinations of blocks having different molecular weights. The solubility predictions based on the MD results were then compared with those obtained from solubility experiments and by the commonly used group contribution method (GCM). The results showed that Flory-Huggins interaction parameters computed by the MD simulations are consistent with the solubility data of the drug/PEO-b-PCL systems, whereas those calculated by the GCM significantly deviate from the experimental observation. We have also accounted for the possibility of drug solubilization in the PEO block of PEO-b-PCL.

Spectrophotometric Determination of Poorly Water Soluble Drug Rosiglitazone Using Hydrotropic Solubilization technique.

PubMed

Sherje, A P; Desai, K J

2011-09-01

In the present investigation, hydrotropic solution of urea was employed as a solubilizing agent for spectrophotometric determination of poorly water-soluble drug rosiglitazone maleate. In solubility determination study, it was found that there was more than 14-folds enhancement in solubility of rosiglitazone maleate in a 6M solution of urea. Rosiglitazone maleate obeys Beer's law in concentration range of 5-300 μg/ml. Linearity of rosiglitazone maleate was found in the range of 80-120% of the label claim. The proposed method has been applied successfully to the analysis of the cited drug in pharmaceutical formulations with good accuracy and precision. The method herein described is new, simple, eco-friendly, economic, and accurate and can be utilized in routine analysis of rosiglitazone maleate in bulk drug and tablet dosage form.

Spectrophotometric Determination of Poorly Water Soluble Drug Rosiglitazone Using Hydrotropic Solubilization technique

PubMed Central

Sherje, A. P.; Desai, K. J.

2011-01-01

In the present investigation, hydrotropic solution of urea was employed as a solubilizing agent for spectrophotometric determination of poorly water-soluble drug rosiglitazone maleate. In solubility determination study, it was found that there was more than 14-folds enhancement in solubility of rosiglitazone maleate in a 6M solution of urea. Rosiglitazone maleate obeys Beer's law in concentration range of 5-300 μg/ml. Linearity of rosiglitazone maleate was found in the range of 80-120% of the label claim. The proposed method has been applied successfully to the analysis of the cited drug in pharmaceutical formulations with good accuracy and precision. The method herein described is new, simple, eco-friendly, economic, and accurate and can be utilized in routine analysis of rosiglitazone maleate in bulk drug and tablet dosage form. PMID:22923874

Supersaturation-nucleation behavior of poorly soluble drugs and its impact on the oral absorption of drugs in thermodynamically high-energy forms.

PubMed

Ozaki, Shunsuke; Minamisono, Takuma; Yamashita, Taro; Kato, Takashi; Kushida, Ikuo

2012-01-01

In order to better understand the oral absorption behavior of poorly water-soluble drugs, their supersaturation-nucleation behavior was characterized in fasted state simulated intestinal fluid. The induction time (t(ind)) for nucleation was measured for four model drugs: itraconazole, erlotinib, troglitazone, and PLX4032. Supersaturated solutions were prepared by solvent shift method, and nucleation initiation was monitored by ultraviolet detection. The relationship between t(ind) and degree of supersaturation was analyzed in terms of classical nucleation theory. The defined supersaturation stability proved to be compound specific. Clinical data on oral absorption were investigated for drugs in thermodynamically high-energy forms such as amorphous forms and salts and was compared with in vitro supersaturation-nucleation characteristics. Solubility-limited maximum absorbable dose was proportionate to intestinal effective drug concentrations, which are related to supersaturation stability and thermodynamic solubility. Supersaturation stability was shown to be an important factor in determining the effect of high-energy forms. The characterization of supersaturation-nucleation behavior by the presented method is, therefore, valuable for assessing the potential absorbability of poorly water-soluble drugs. Copyright © 2011 Wiley-Liss, Inc.

21 CFR 201.319 - Water-soluble gums, hydrophilic gums, and hydrophilic mucilloids (including, but not limited to...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Water-soluble gums, hydrophilic gums, and..., carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-1,4 linked) polymannose acetate), guar gum, karaya... active ingredients; required warnings and directions. 201.319 Section 201.319 Food and Drugs FOOD AND...

Solubilization of poorly water-soluble drug carbamezapine in pluronic micelles: effect of molecular characteristics, temperature and added salt on the solubilizing capacity.

PubMed

Kadam, Yogesh; Yerramilli, Usha; Bahadur, Anita

2009-08-01

The solubilization of a poorly water-soluble antiepileptic drug, carbamazepine (CBZ), in a series of micelle-forming PEO-PPO-PEO block copolymers with combinations of blocks having different molecular weight was studied. The drug solubility and micelle-water partition coefficient (P) were determined using UV-vis spectroscopy. Dynamic light scattering on copolymer solutions was used to measure size and polydispersity of nanoaggregates. Solubilization of carbamezapine increased with the rise in temperature and concentration of block copolymers, but no significant increase was observed with added salt (NaCl). The solubilization is also discussed from a thermodynamics viewpoint, by considering the standard free energy of solubilization (DeltaG degrees ).

Polymer brush hexadecyltrimethylammonium bromide (CTAB) modified poly (propylene-g-styrene sulphonic acid) fiber (ZB-1): CTAB/ZB-1 as a promising strategy for improving the dissolution and physical stability of poorly water-soluble drugs.

PubMed

Cao, Jinxu; Yang, Baixue; Wang, Yumei; Wei, Chen; Wang, Hongyu; Li, Sanming

2017-11-01

The feasibility of polymer brush as drug delivery vehicle was demonstrated with the goal of improving the dissolution and physical stability of poorly water-soluble drugs. Polymer brush CTAB/ZB-1 was synthesized by electrostatic interaction using a physical modification method with anionic poly (propylene-g-styrene sulphonic acid) fiber (ZB-1) as the substrate and cationic hexadecyltrimethylammonium bromide (CTAB) as the modifier. The polymer brush structure of CTAB/ZB-1 was validated by atomic force microscopy (AFM) and the channels of brush provided the drug loading sites. Flurbiprofen (FP), a BCS class II representative drug, was selected as the model poorly water-soluble drug to be loaded into this polymer brush. Then the drug loading and release were systematically investigated. Besides, the transformation from crystalline FP to amorphous state was observed by differential scanning calorimeter (DSC). In vitro dissolution in pure water and pH1.2 HCl media with/without 0.1% sodium dodecyl sulfate (SDS) was tested. Moreover, the optimal formulations (namely carrier/drug ratios) were determined. The results demonstrated prominent improvement of dissolution when FP was released from CTAB/ZB-1. After a long time storage, FP remained amorphous in CTAB/ZB-1 according to DSC determinations and performed an approximately equivalent dissolution compared with fresh samples, suggesting the advantage of CTAB/ZB-1 as carrier in enhancing the physical stability of drugs. The study introduced the versatile easily formulated polymer brush CTAB/ZB-1 and demonstrated the potential of polymer brush as an alternative approach for improving the dissolution and physical stability of poorly water-soluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Introduction for Design of Nanoparticle Based Drug Delivery Systems.

PubMed

Edgar, Jun Yan Chan; Wang, Hui

2017-01-01

Conventional drug delivery systems contain numerous limitations such as limited targeting, low therapeutic indices, poor water solubility, and the induction of drug resistances. In order to overcome the drawbacks of conventional pathway of drug delivery, nanoparticle delivery systems are therefore designed and used as the drug carriers. Nanoparticle based drug delivery systems have been rapidly growing and are being applied to various sections of biomedicine. Drug nanocarriers based on dendrimers, liposomes, self-assembling peptides, watersoluble polymers, and block copolymer micelles are the most extensively studied types of drug delivery systems and some of them are being used in clinical therapy. In particular for cancer therapy, antineoplastic drugs are taking advantage of nanoparticulate drug carriers to improve the cure efficacy. Nanoparticle based drug carriers are capable of improving the therapeutic effectiveness of the drugs by using active targeting for the site-specific delivery, passive targeting mechanisms such as enhanced permeability and retention (EPR), de novo synthesis and uptake of low density liposome in cancer cells or by being water-soluble to improve the suboptimal pharmacokinetics in limited water-soluble delivery methods. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Perspectives on Strategies Using Swellable Polymers in Solid Dispersions for Controlled Drug Release.

PubMed

Tran, Thao T D; Tran, Phuong H L

2017-01-01

Poorly water-soluble drugs, which commonly face the issue of poor absorption and low bioavailability, have been under ongoing research of many formulation scientists for the past few decades. Solid dispersion is one of the most effective strategies in concerns for improving bioavailability of poorly water-soluble drugs. Either application of solid dispersions in dissolution enhancement of poorly water-soluble drugs or the use of swellable polymers in controlled drug release has been reported in pharmaceutical designs widely. However, a review of strategies of using swellable polymers in solid dispersion to take a full advantage of these polymers as a current perspective in facilitating drug bioavailability enhancement is still missing. In this review, we aim to provide a summary of techniques used to formulate a swellable polymer in solid dispersion especially a description of a suitable fabrication method in design of a controlled release solid dispersion. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Monoglyceride-based self-assembling copolymers as carriers for poorly water-soluble drugs.

PubMed

Rouxhet, L; Dinguizli, M; Latere Dwan'isa, J P; Ould-Ouali, L; Twaddle, P; Nathan, A; Brewster, M E; Rosenblatt, J; Ariën, A; Préat, V

2009-12-01

To develop self-assembling polymers forming polymeric micelles and increasing the solubility of poorly soluble drugs, amphiphilic polymers containing a hydrophilic PEG moiety and a hydrophobic moiety derived from monoglycerides and polyethers were designed. The biodegradable copolymers were obtained via a polycondensation reaction of polyethylene glycol (PEG), monooleylglyceride (MOG) and succinic anhydride (SA). Polymers with molecular weight below 10,000 g/mol containing a minimum of 40 mol% PEG and a maximum of 10 mol% MOG self-assembled spontaneously in aqueous media upon gentle mixing. They formed particles with a diameter of 10 nm although some aggregation was evident. The critical micellar concentration varied between 3x10(-4) and 4x10(-3) g/ml, depending on the polymer. The cloud point (> or = 66 degrees C) and flocculation point (> or = 0.89 M) increased with the PEG chain length. At a 1% concentration, the polymers increased the solubility of poorly water-soluble drug candidates up to 500-fold. Drug solubility increased as a function of the polymer concentration. HPMC capsules filled with these polymers disintegrated and released model drugs rapidly. Polymer with long PEG chains had a lower cytotoxicity (MTT test) on Caco-2 cells. All of these data suggest that the object polymers, in particular PEG1000/MOG/SA (45/5/50) might be potential candidates for improving the oral biopharmaceutical performance of poorly soluble drugs.

Functionally engineered nanosized particles in pharmaceutics: improved oral delivery of poorly water-soluble drugs.

PubMed

Ozeki, Tetsuya; Tagami, Tatsuaki

2013-01-01

The development of drug nanoparticles has attracted substantial attention because of their potential to improve the dissolution rate and oral availability of poorly water-soluble drugs. This review summarizes the recent articles that discussed nanoparticle-based oral drug delivery systems. The preparation methods were categorized as top-down and bottom-up methods, which are common methods for preparing drug nanoparticles. In addition, methods of handling drug nanoparticles (e.g., one-step preparation of nanocomposites which are microparticles containing drug nanoparticles) were introduced for the effective preservation of drug nanoparticles. The carrier-based preparation of drug nanoparticles was also introduced as a potentially promising oral drug delivery system.

From nanoemulsions to self-nanoemulsions, with recent advances in self-nanoemulsifying drug delivery systems (SNEDDS).

PubMed

Rehman, Fiza Ur; Shah, Kifayat Ullah; Shah, Shefaat Ullah; Khan, Ikram Ullah; Khan, Gul Majid; Khan, Amjad

2017-11-01

Lipid-based drug delivery systems (LBDDS) are the most promising technique to formulate the poorly water soluble drugs. Nanotechnology strongly influences the therapeutic performance of hydrophobic drugs and has become an essential approach in drug delivery research. Self-nanoemulsifying drug delivery systems (SNEDDS) are a vital strategy that combines benefits of LBDDS and nanotechnology. SNEDDS are now preferred to improve the formulation of drugs with poor aqueous solubility. Areas covered: The review in its first part shortly describes the LBDDS, nanoemulsions and clarifies the ambiguity between nanoemulsions and microemulsions. In the second part, the review discusses SNEDDS and elaborates on the current developments and modifications in this area without discussing their associated preparation techniques and excipient properties. Expert opinion: SNEDDS have exhibit the potential to increase the bioavailability of poorly water soluble drugs. The stability of SNEDDS is further increased by solidification. Controlled release and supersaturation can be achieved, and are associated with increased patient compliance and improved drug loads, respectively. Presence of biodegradable ingredients and ease of large-scale manufacturing combined with a lot of 'drug-targeting opportunities' give SNEDDS a clear distinction and prominence over other solubility enhancement techniques.

pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs.

PubMed

Wang, Xue-Qing; Zhang, Qiang

2012-10-01

pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers' dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

Drug carrier systems for solubility enhancement of BCS class II drugs: a critical review.

PubMed

Kumar, Sumit; Bhargava, Deepak; Thakkar, Arti; Arora, Saahil

2013-01-01

Poor aqueous solubility impedes a drug's bioavailability and challenges its pharmaceutical development. Pharmaceutical development of drugs with poor water solubility requires the establishment of a suitable formulation layout among various techniques. Various approaches have been investigated extensively to improve the aqueous solubility and poor dissolution rate of BCS class II and IV drugs. In this literature review, novel formulation options, particularly for class II drugs designed for applications such as micronization, self-emulsification, cyclodextrin complexation, co-crystallisation, super critical fluid technology, solubilisation by change in pH, salt formation, co-solvents, melt granulation, and solid dispersion, liposomal/niosomal formulations, are discussed in detail to introduce biopharmaceutical challenges and recent approaches to facilitate more efficient drug formulation and development.

Enhancing the solubility and bioavailability of poorly water-soluble drugs using supercritical antisolvent (SAS) process.

PubMed

Abuzar, Sharif Md; Hyun, Sang-Min; Kim, Jun-Hee; Park, Hee Jun; Kim, Min-Soo; Park, Jeong-Sook; Hwang, Sung-Joo

2018-03-01

Poor water solubility and poor bioavailability are problems with many pharmaceuticals. Increasing surface area by micronization is an effective strategy to overcome these problems, but conventional techniques often utilize solvents and harsh processing, which restricts their use. Newer, green technologies, such as supercritical fluid (SCF)-assisted particle formation, can produce solvent-free products under relatively mild conditions, offering many advantages over conventional methods. The antisolvent properties of the SCFs used for microparticle and nanoparticle formation have generated great interest in recent years, because the kinetics of the precipitation process and morphologies of the particles can be accurately controlled. The characteristics of the supercritical antisolvent (SAS) technique make it an ideal tool for enhancing the solubility and bioavailability of poorly water-soluble drugs. This review article focuses on SCFs and their properties, as well as the fundamentals of overcoming poorly water-soluble drug properties by micronization, crystal morphology control, and formation of composite solid dispersion nanoparticles with polymers and/or surfactants. This article also presents an overview of the main aspects of the SAS-assisted particle precipitation process, its mechanism, and parameters, as well as our own experiences, recent advances, and trends in development. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug nanoparticles: formulating poorly water-soluble compounds.

PubMed

Merisko-Liversidge, Elaine M; Liversidge, Gary G

2008-01-01

More than 40% of compounds identified through combinatorial screening programs are poorly soluble in water. These molecules are difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues. Formulating these compounds as pure drug nanoparticles is one of the newer drug-delivery strategies applied to this class of molecules. Nanoparticle dispersions are stable and have a mean diameter of less than 1 micron. The formulations consist of water, drug, and one or more generally regarded as safe excipients. These liquid dispersions exhibit an acceptable shelf-life and can be postprocessed into various types of solid dosage forms. Drug nanoparticles have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance, providing the discovery scientist with an alternate avenue for screening and identifying superior analogs. For the toxicologist, the approach provides a means for dose escalation using a formulation that is commercially viable. In the past few years, formulating poorly water-soluble compounds using a nanoparticulate approach has evolved from a conception to a realization whose versatility and applicability are just beginning to be realized.

Vildagliptin has the same safety profile as a sulfonylurea on bone metabolism and bone mineral density in post-menopausal women with type 2 diabetes: a randomized controlled trial.

PubMed

Vianna, Andre Gustavo Daher; de Lacerda, Claudio Silva; Pechmann, Luciana Muniz; Polesel, Michelle Garcia; Marino, Emerson Cestari; Borba, Victoria Zeghbi Cochenski; Barreto, Fellype de Carvalho

2017-01-01

Several antidiabetic therapies affect bone metabolism. Sulfonylureas have the lowest impact on bone among oral antidiabetics. The objective of this study is to compare the effects of vildagliptin and gliclazide modified release (MR) on bone turnover markers (BTMs) and bone mineral density (BMD) in postmenopausal women with uncontrolled type 2 diabetes (T2D). Forty-two postmenopausal women with uncontrolled T2D were randomly allocated into vildagliptin or gliclazide MR (control) groups. The primary endpoint was the change in the BTMs in months 6 and 12 compared with the baseline. The secondary endpoint was the variation in the BMD, which was assessed via dual-energy X-ray absorptiometry at the lumbar spine, femoral neck and total hip at baseline and month 12. After a 12-month treatment, the BTM serum carboxy-terminal telopeptide of type 1 collagen increased 0.001 ± 0.153 ng/mL in the vildagliptin group versus 0.008 ± 0.060 ng/mL in the gliclazide MR group ( p  = 0.858). The serum osteocalcin, serum amino-terminal propeptide of procollagen type I and urinary amino-terminal telopeptide of type 1 collagen remained stable in both groups, and there was no statistically significant difference between the effect of vildagliptin and gliclazide MR on these variables. The lumbar spine BMD did not change in the vildagliptin or gliclazide MR groups after a 12-month treatment (0.000 ± 0.025 g/cm 2 versus -0.008 ± 0.036, respectively, p  = 0.434). Furthermore, there was a similar lack of change in the femoral neck and total hip BMD values in both treatments. Bone turnover markers and BMD remained unchanged after a 12-month treatment in both groups, which suggests that vildagliptin has the same safety profile as gliclazide MR on bone metabolism. Trial Registration ClinicalTrials.gov number NCT01679899.

Parameters influencing the course of passive drug loading into lipid nanoemulsions.

PubMed

Göke, Katrin; Bunjes, Heike

2018-05-01

Passive drug loading can be used to effectively identify suitable colloidal lipid carrier systems for poorly water-soluble drugs. This method comprises incubation of preformed carrier systems with drug powder and subsequent determination of the resulting drug load of the carrier particles. Until now, the passive loading mechanism is unknown, which complicates reliable routine use. In this work, the influence of drug characteristics on the course of passive loading was investigated systematically varying drug surface area and drug solubility. Fenofibrate and flufenamic acid were used as model drugs; the carrier system was a trimyristin nanodispersion. Loading progress was analyzed by UV spectroscopy or by a novel method based on differential scanning calorimetry. While increasing drug solubility by micelle incorporation did not speed up passive loading, a large drug surface area and high water solubility were key parameters for fast loading. Since both factors are crucial in drug dissolution as described by the Noyes-Whitney equation, these findings point to a dissolution-diffusion-based passive loading mechanism. Accordingly, passive loading also occurred when drug and carrier particles were separated by a dialysis membrane. Knowledge of the loading mechanism allows optimizing the conditions for future passive loading studies and assessing the limitations of the method. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of various processes for simultaneous complexation and granulation to incorporate drug-cyclodextrin complexes into solid dosage forms.

PubMed

Gyanani, Vijay; Siddalingappa, Basavaraj; Betageri, Guru V

2015-01-01

Insoluble drugs often formulated with various excipients to enhance the dissolution. Cyclodextrins (CDs) are widely used excipients to improve dissolution profile of poorly soluble drugs. Drug-CD complexation process is complex and often requires multiple processes to produce solid dosage form. Hence, this study explored commonly used granulation processes for simultaneous complexation and granulation. Poorly soluble drugs ibuprofen and glyburide were selected as experimental drugs. Co-evaporation of drug:CD mixture from a solvent followed by wet granulation with water was considered as standard process for comparison. Spray granulation and fluid bed processing (FBP) using drug:CD solution in ethanol were evaluated as an alternative processes. The dissolution data of glyburide tablets indicated that tablets produced by spray granulation, FBP and co-evaporation-granulation have almost identical dissolution profile in water and 0.1% SLS (>70% in water and >60% in SLS versus 30 and 34%, respectively for plain tablet, in 120 min). Similarly, ibuprofen:CD tablets produced by co-evaporation-granulation and FBP displayed similar dissolution profile in 0.01 M HCl (pH 2.0) and buffer pH 5.5 (>90 and 100% versus 44 and 80% respectively for plain tablets, 120 min). Results of this study demonstrated that spray granulation is simple and cost effective process for low dose poorly soluble drugs to incorporate drug:CD complex into solid dosage form, whereas FBP is suitable for poorly soluble drugs with moderate dose.

Design of Chitosan and Its Water Soluble Derivatives-Based Drug Carriers with Polyelectrolyte Complexes

PubMed Central

Wu, Qing-Xi; Lin, Dong-Qiang; Yao, Shan-Jing

2014-01-01

Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail. PMID:25532565

Design of chitosan and its water soluble derivatives-based drug carriers with polyelectrolyte complexes.

PubMed

Wu, Qing-Xi; Lin, Dong-Qiang; Yao, Shan-Jing

2014-12-19

Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail.

Development and characterization of nanostructured mists with potential for actively targeting poorly water-soluble compounds into the lungs.

PubMed

Nesamony, Jerry; Kalra, Ashish; Majrad, Mohamed S; Boddu, Sai Hanuman Sagar; Jung, Rose; Williams, Frederick E; Schnapp, Alaina M; Nauli, Surya M; Kalinoski, Andrea L

2013-10-01

To formulate nanoemulsions (NE) with potential for delivering poorly water-soluble drugs to the lungs. A self nanoemulsifying composition consisting of cremophor RH 40, PEG 400 and labrafil M 2125 CS was selected after screening potential excipients. The solubility of carbamazepine, a poorly water-soluble drug, was tested in the formulation components. Oil-in-water (o/w) NEs were characterized using dynamic light scattering, electrophoretic light scattering, transmission electron microscopy (TEM) and differential scanning calorimetry. NEs were nebulized into a mist using a commercial nebulizer and characterized using laser diffraction and TEM. An aseptic method was developed for preparing sterile NEs. Biocompatibility of the formulation was evaluated on NIH3T3 cells using MTT assay. In vitro permeability of the formulation was tested in zebra fish eggs, HeLa cells, and porcine lung tissue. NEs had neutrally charged droplets of less than 20 nm size. Nebulized NEs demonstrated an o/w nanostructure. The mist droplets were of size less than 5 μm. Sterility testing and cytotoxicity results validated that the NE was biocompatible and sterile. In vitro tests indicated oil nanodroplets penetrating intracellularly through biological membranes. The nanoemulsion mist has the potential for use as a pulmonary delivery system for poorly water-soluble drugs.

The influence of supercritical carbon dioxide (SC-CO2) processing conditions on drug loading and physicochemical properties.

PubMed

Ahern, Robert J; Crean, Abina M; Ryan, Katie B

2012-12-15

Poor water solubility of drugs can complicate their commercialisation because of reduced drug oral bioavailability. Formulation strategies such as increasing the drug surface area are frequently employed in an attempt to increase dissolution rate and hence, improve oral bioavailability. Maximising the drug surface area exposed to the dissolution medium can be achieved by loading drug onto a high surface area carrier like mesoporous silica (SBA-15). The aim of this work was to investigate the impact of altering supercritical carbon dioxide (SC-CO(2)) processing conditions, in an attempt to enhance drug loading onto SBA-15 and increase the drug's dissolution rate. Other formulation variables such as the mass ratio of drug to SBA-15 and the procedure for combining the drug and SBA-15 were also investigated. A model drug with poor water solubility, fenofibrate, was selected for this study. High drug loading efficiencies were obtained using SC-CO(2), which were influenced by the processing conditions employed. Fenofibrate release rate was enhanced greatly after loading onto mesoporous silica. The results highlighted the potential of this SC-CO(2) drug loading approach to improve the oral bioavailability of poorly water soluble drugs. Copyright © 2012 Elsevier B.V. All rights reserved.

Handling of computational in vitro/in vivo correlation problems by Microsoft Excel: V. Predictive absorbability models.

PubMed

Langenbucher, Frieder

2007-08-01

This paper discusses Excel applications related to the prediction of drug absorbability from physicochemical constants. PHDISSOC provides a generalized model for pH profiles of electrolytic dissociation, water solubility, and partition coefficient. SKMODEL predicts drug absorbability, based on a log-log plot of water solubility and O/W partitioning; augmented by additional features such as electrolytic dissociation, melting point, and the dose administered. GIABS presents a mechanistic model of g.i. drug absorption. BIODATCO presents a database compiling relevant drug data to be used for quantitative predictions.

A novel three-dimensional large-pore mesoporous carbon matrix as a potential nanovehicle for the fast release of the poorly water-soluble drug, celecoxib.

PubMed

Zhang, Yanzhuo; Wang, Hong; Li, Chuanjun; Sun, Baoxiang; Wang, Yu; Wang, Siling; Gao, Cunqiang

2014-04-01

A novel mesocellular carbon foam (MSU-FC) with a large pore size and a three-dimensional porous structure for the oral delivery of poorly water-soluble drugs was prepared. The goal of this study was to improve in vitro dissolution and in vivo absorption of celecoxib (CEB), a model drug, by means of novel carbon-based nanoparticles prepared from the MSU-FC matrix. The MSU-FC matrix was synthesized by an inverse replica templating method using mesocellular silica template. A solvent immersion/evaporation method was used to load the drug molecules. The drug-loaded nanoparticles were characterized for morphology, surface area, particle size, mesoporous structure, crystallinity, solubility and dissolution. The effect of MSU-FC on cell viability was measured using the MTT conversion assay. Furthermore, the oral bioavailability of CEB-loaded MSU-FC in fasted rats was compared with that of the marketed product. Our results demonstrate that CEB incorporation into the prepared MSU-FC resulted in an approximately 9-fold increase in aqueous solubility in comparison with crystalline CEB. MSU-FC produced accelerated immediate release of CEB in comparison with crystalline CEB (pure CEB powder or marketed formulation) and the drug-loaded conventional mesoporous carbon particles. The relative bioavailability of CEB for CEB-loaded MSU-FC was 172%. In addition, MSU-FC nanoparticles exhibited very low toxicity. The MSU-FC nanomatrix has been shown to be a promising drug delivery vehicle for improving the dissolution and biopharmaceutical characteristics of poorly water-soluble drugs.

Enhanced solubility and bioavailability of sibutramine base by solid dispersion system with aqueous medium.

PubMed

Li, Dong Xun; Jang, Ki-Young; Kang, Wonku; Bae, Kyoungjin; Lee, Mann Hyung; Oh, Yu-Kyoung; Jee, Jun-Pil; Park, Young-Joon; Oh, Dong Hoon; Seo, Youn Gee; Kim, Young Ran; Kim, Jong Oh; Woo, Jong Soo; Yong, Chul Soon; Choi, Han-Gon

2010-01-01

To develop a novel sibutramine base-loaded solid dispersion with improved solubility bioavailability, various solid dispersions were prepared with water, hydroxypropylmethyl cellulose (HPMC), poloxamer and citric acid using spray-drying technique. The effect of HPMC, poloxamer and citric acid on the aqueous solubility of sibutramine was investigated. The physicochemical properties of solid dispersion were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction. The dissolution and pharmacokinetics in rats of solid dispersion were evaluated compared to the sibutramine hydrochloride monohydrate-loaded commercial product (Reductil). The sibutramine base-loaded solid dispersion gave two type forms. Like conventional solid dispersion system, one type appeared as a spherical shape with smooth surface, as the carriers and drug with relatively low melting point were soluble in water and formed it. The other appeared as an irregular form with relatively rough surface. Unlike conventional solid dispersion system, this type changed no crystalline form of drug. Our results suggested that this type was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting from changing the hydrophobic drug to hydrophilic form. The sibutramine-loaded solid dispersion at the weight ratio of sibutramine base/HPMC/poloxamer/citric acid of 5/3/3/0.2 gave the maximum drug solubility of about 3 mg/ml. Furthermore, it showed the similar plasma concentration, area under the curve (AUC) and C(max) of parent drug, metabolite I and II to the commercial product, indicating that it might give the similar drug efficacy compared to the sibutramine hydrochloride monohydrate-loaded commercial product in rats. Thus, this solid dispersion system would be useful to deliver poorly water-soluble sibutramine base with enhanced bioavailability.

Drug Release Kinetics and Front Movement in Matrix Tablets Containing Diltiazem or Metoprolol/λ-Carrageenan Complexes

PubMed Central

Bonferoni, Maria Cristina; Colombo, Paolo; Zanelotti, Laura; Caramella, Carla

2014-01-01

In this work we investigated the moving boundaries and the associated drug release kinetics in matrix tablets prepared with two complexes between λ-carrageenan and two soluble model drugs, namely, diltiazem HCl and metoprolol tartrate aiming at clarifying the role played by drug/polymer interaction on the water uptake, swelling, drug dissolution, and drug release performance of the matrix. The two studied complexes released the drug with different mechanism indicating two different drug/polymer interaction strengths. The comparison between the drug release behaviour of the complexes and the relevant physical mixtures indicates that diltiazem gave rise to a less soluble and more stable complex with carrageenan than metoprolol. The less stable metoprolol complex afforded an erodible matrix, whereas the stronger interaction between diltiazem and carrageenan resulted in a poorly soluble, slowly dissolving matrix. It was concluded that the different stability of the studied complexes affords two distinct drug delivery systems: in the case of MTP, the dissociation of the complex, as a consequence of the interaction with water, affords a classical soluble matrix type delivery system; in the case of DTZ, the dissolving/diffusing species is the complex itself because of the very strong interaction between the drug and the polymer. PMID:25045689

Drug release kinetics and front movement in matrix tablets containing diltiazem or metoprolol/λ-carrageenan complexes.

PubMed

Bettini, Ruggero; Bonferoni, Maria Cristina; Colombo, Paolo; Zanelotti, Laura; Caramella, Carla

2014-01-01

In this work we investigated the moving boundaries and the associated drug release kinetics in matrix tablets prepared with two complexes between λ-carrageenan and two soluble model drugs, namely, diltiazem HCl and metoprolol tartrate aiming at clarifying the role played by drug/polymer interaction on the water uptake, swelling, drug dissolution, and drug release performance of the matrix. The two studied complexes released the drug with different mechanism indicating two different drug/polymer interaction strengths. The comparison between the drug release behaviour of the complexes and the relevant physical mixtures indicates that diltiazem gave rise to a less soluble and more stable complex with carrageenan than metoprolol. The less stable metoprolol complex afforded an erodible matrix, whereas the stronger interaction between diltiazem and carrageenan resulted in a poorly soluble, slowly dissolving matrix. It was concluded that the different stability of the studied complexes affords two distinct drug delivery systems: in the case of MTP, the dissociation of the complex, as a consequence of the interaction with water, affords a classical soluble matrix type delivery system; in the case of DTZ, the dissolving/diffusing species is the complex itself because of the very strong interaction between the drug and the polymer.

Synthesis and characterization of water-soluble hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins).

PubMed

Buchanan, Charles M; Alderson, Susan R; Cleven, Curtis D; Dixon, Daniel W; Ivanyi, Robert; Lambert, Juanelle L; Lowman, Douglas W; Offerman, Rick J; Szejtli, Jozsef; Szente, Lajos

2002-03-15

We have examined the synthesis of hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins) and the ability of these cyclodextrin ethers to form guest-host complexes with guest molecules. The hydroxybutenyl cyclodextrin ethers were prepared by a base-catalyzed reaction of 3,4-epoxy-1-butene with the parent cyclodextrins in an aqueous medium. Reaction byproducts were removed by nanofiltration before the hydroxybutenyl cyclodextrins were isolated by co-evaporation of water-EtOH. Hydroxybutenyl cyclodextrins containing no unsubstituted parent cyclodextrin typically have a degree of substitution of 2-4 and a molar substitution of 4-7. These hydroxybutenyl cyclodextrins are randomly substituted, amorphous solids. The hydroxybutenyl cyclodextrin ethers were found to be highly water soluble. Complexes of HBen-beta-CD with glibenclamide and ibuprofen were prepared and isolated. In both cases, the guest content of the complexes was large, and a significant increase in the solubility of the free drug was observed. Dissolution of the complexes in pH 1.4 water was very rapid, and significant increases in the solubility of the free drugs were observed. Significantly, after reaching equilibrium concentration, a decrease in the drug concentration over time was not observed.

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

PubMed

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

2017-06-30

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

Phase solubility studies and anti-Trichomonas vaginalis activity evaluations of metronidazole and methylated β-cyclodextrin complexes: Comparison of CRYSMEB and RAMEB.

PubMed

Malli, Sophia; Bories, Christian; Ponchel, Gilles; Loiseau, Philippe M; Bouchemal, Kawthar

2018-06-01

Metronidazole (MTZ) is a 5-nitroimidazole drug used for the treatment of Trichomonas vaginalis parasitic infection. Aqueous formulations containing MTZ are restricted because apparent solubility in water of this drug is low. In this context, two methylated-β-cyclodextrins (CRYSMEB and RAMEB) were used as a tool to increase apparent solubility of MTZ in water. CRYSMEB was limited by its own solubility in water (15% w/w, 12.59 mM), while RAMEB at a concentration of 40% w/w (300.44 mM) allowed a maximal increase of apparent solubility of MTZ (3.426% w/w, 200.19 mM). From our knowledge, this corresponds to the highest enhancement of MTZ apparent aqueous solubility ever reported in the literature using methylated cyclodextrins. In vitro evaluations showed that anti-T. vaginalis activity of MTZ formulated with CRYSMEB and RAMEB was preserved. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of formulation variables and post-compression curing on drug release from a new sustained-release matrix material: polyvinylacetate-povidone.

PubMed

Shao, Z J; Farooqi, M I; Diaz, S; Krishna, A K; Muhammad, N A

2001-01-01

A new commercially available sustained-release matrix material, Kollidon SR, composed of polyvinylacetate and povidone, was evaluated with respect to its ability to modulate the in vitro release of a highly water-soluble model compound, diphenhydramine HCl. Kollidon SR was found to provide a sustained-release effect for the model compound, with certain formulation and processing variables playing an important role in controlling its release kinetics. Formulation variables affecting the release include the level of the polymeric material in the matrix, excipient level, as well as the nature of the excipients (water soluble vs. water insoluble). Increasing the ratio of a water-insoluble excipient, Emcompress, to Kollidon SR enhanced drug release. The incorporation of a water-soluble excipient, lactose, accelerated its release rate in a more pronounced manner. Stability studies conducted at 40 degrees C/75% RH revealed a slow-down in dissolution rate for the drug-Kollidon SR formulation, as a result of polyvinylacetate relaxation. Further studies demonstrated that a post-compression curing step effectively stabilized the release pattern of formulations containing > or = 47% Kollidon SR. The release mechanism of Kollidon-drug and drug-Kollidon-Emcompress formulations appears to be diffusion controlled, while that of the drug-Kollidon-lactose formulation appears to be controlled predominantly by diffusion along with erosion.

Effect of formulation and processing variables on the characteristics of microspheres for water-soluble drugs prepared by w/o/o double emulsion solvent diffusion method.

PubMed

Lee, J; Park, T G; Choi, H

2000-02-25

80% except for acetaminophen, due to its lower solubility in water and higher solubility in corn oil. The release profile of the drug was pH dependent. In acidic medium, the release rate was much slower, however, the drug was released quickly at pH 7.4. Tacrine showed unexpected release profiles, probably due to ionic interaction with polymer matrix and the shell structure and the highest release rate was obtained at pH 2.0. The prepared microspheres had a sponge-like inner structure with or without central hollow core and the surface was dense with no apparent pores.

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

PubMed

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

2015-01-01

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

Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity.

PubMed

Tang, L; Khan, S U; Muhammad, N A

2001-11-01

The purpose of this work is to develop a bio-relevant dissolution method for formulation screening in order to select an enhanced bioavailable formulation for a poorly water-soluble drug. The methods used included a modified rotating disk apparatus for measuring intrinsic dissolution rate of the new chemical entity (NCE) and the USP dissolution method II for evaluating dissolution profiles of the drug in three different dosage forms. The in vitro dissolution results were compared with the in vivo bioavailability for selecting a bio-relevant medium. The results showed that the solubility of the NCE was proportional to the concentration of sodium lauryl sulfate (SLS) in the media. The apparent intrinsic dissolution rate of the NCE was linear to the rotational speed of the disk, which indicated that the dissolution of the drug is a diffusion-controlled mechanism. The apparent intrinsic dissolution rate was also linear to the surfactant concentration in the media, which was interpreted using the Noyes and Whitney Empirical Theory. Three formulations were studied in three different SLS media using the bulk drug as a reference. The dissolution results were compared with the corresponding bioavailability results in dogs. In the 1% SLS--sink conditions--the drug release from all the formulations was complete and the dissolution results were discriminative for the difference in particle size of the drug in the formulations. However, the data showed poor IVIV correlation. In the 0.5% SLS medium--non-sink conditions--the dissolution results showed the same rank order among the tested formulations as the bioavailability. The best IVIV correlation was obtained from the dissolution in 0.25% SLS medium, an over-saturated condition. The conclusions are: a surfactant medium increases the apparent intrinsic dissolution rate of the NCE linearly due to an increase in solubility. A low concentration of surfactant in the medium (0.25%) is more bio-relevant than higher concentrations of surfactant in the media for the poorly water-soluble drug. Creating sink conditions (based on bulk drug solubilities) by using a high concentration of a surfactant in the dissolution medium may not be a proper approach in developing a bio-relevant dissolution method for a poorly water-soluble drug.

Development and evaluation of natural gum-based extended release matrix tablets of two model drugs of different water solubilities by direct compression.

PubMed

Ofori-Kwakye, Kwabena; Mfoafo, Kwadwo Amanor; Kipo, Samuel Lugrie; Kuntworbe, Noble; Boakye-Gyasi, Mariam El

2016-01-01

The study was aimed at developing extended release matrix tablets of poorly water-soluble diclofenac sodium and highly water-soluble metformin hydrochloride by direct compression using cashew gum, xanthan gum and hydroxypropylmethylcellulose (HPMC) as release retardants. The suitability of light grade cashew gum as a direct compression excipient was studied using the SeDeM Diagram Expert System. Thirteen tablet formulations of diclofenac sodium (∼100 mg) and metformin hydrochloride (∼200 mg) were prepared with varying amounts of cashew gum, xanthan gum and HPMC by direct compression. The flow properties of blended powders and the uniformity of weight, crushing strength, friability, swelling index and drug content of compressed tablets were determined. In vitro drug release studies of the matrix tablets were conducted in phosphate buffer (diclofenac: pH 7.4; metformin: pH 6.8) and the kinetics of drug release was determined by fitting the release data to five kinetic models. Cashew gum was found to be suitable for direct compression, having a good compressibility index (ICG) value of 5.173. The diclofenac and metformin matrix tablets produced generally possessed fairly good physical properties. Tablet swelling and drug release in aqueous medium were dependent on the type and amount of release retarding polymer and the solubility of drug used. Extended release of diclofenac (∼24 h) and metformin (∼8-12 h) from the matrix tablets in aqueous medium was achieved using various blends of the polymers. Drug release from diclofenac tablets fitted zero order, first order or Higuchi model while release from metformin tablets followed Higuchi or Hixson-Crowell model. The mechanism of release of the two drugs was mostly through Fickian diffusion and anomalous non-Fickian diffusion. The study has demonstrated the potential of blended hydrophilic polymers in the design and optimization of extended release matrix tablets for soluble and poorly soluble drugs by direct compression.

Application of hot melt extrusion for poorly water-soluble drugs: limitations, advances and future prospects.

PubMed

Lu, Ming; Guo, Zhefei; Li, Yongcheng; Pang, Huishi; Lin, Ling; Liu, Xu; Pan, Xin; Wu, Chuanbin

2014-01-01

Hot melt extrusion (HME) is a powerful technology to enhance the solubility and bioavailability of poorly water-soluble drugs by producing amorphous solid dispersions. Although the number of articles and patents about HME increased dramatically in the past twenty years, there are very few commercial products by far. The three main obstacles limiting the commercial application of HME are summarized as thermal degradation of heat-sensitive drugs at high process temperature, recrystallization of amorphous drugs during storage and dissolving process, and difficulty to obtain products with reproducible physicochemical properties. Many efforts have been taken in recent years to understand the basic mechanism underlying these obstacles and then to overcome them. This article reviewed and summarized the limitations, recent advances, and future prospects of HME.

Assessment of hupu gum for its carrier property in the design and evaluation of solid mixtures of poorly water soluble drug - rofecoxib.

PubMed

Vadlamudi, Harini Chowdary; Raju, Y Prasanna; Asuntha, G; Nair, Rahul; Murthy, K V Ramana; Vulava, Jayasri

2014-01-01

There are no reports about the pharmaceutical applications of hupu gum (HG). Hence the present study was undertaken to test its suitability in the dissolution enhancement of poorly water soluble drug. Rofecoxib (RFB) was taken as model drug. For comparison solid mixtures were prepared with carriers such as poly vinyl pyrrolidone (PVP), sodium starch glycollate (SSG) and guar gum (GG). Physical mixing (PM), co-grinding (CG), kneading (KT) and solvent evaporation (SE) techniques were used to prepare the solid mixtures, using all the carriers in different carrier and drug ratios. The solid mixtures were characterized by powder X-ray diffraction (XRD) and Fourier-transformed infrared spectroscopy (FTIR). There was a significant improvement in the dissolution rate of solid mixtures of HG, when compared with the solid mixtures of other carriers. There was an increase in dissolution rate with increase in concentration of HG upto 1:1 ratio of carrier and drug. No drug-carrier interaction was found by FTIR studies. XRD studies indicated reduction in crystallinity of the drug with increase in HG concentration. Hence HG could be a useful carrier for the dissolution enhancement of poorly water soluble drugs.

Nano-aggregates: emerging delivery tools for tumor therapy.

PubMed

Sharma, Vinod Kumar; Jain, Ankit; Soni, Vandana

2013-01-01

A plethora of formulation techniques have been reported in the literature for site-specific targeting of water-soluble and -insoluble anticancer drugs. Along with other vesicular and particulate carrier systems, nano-aggregates have recently emerged as a novel supramolecular colloidal carrier with promise for using poorly water-soluble drugs in molecular targeted therapies. Nano-aggregates possess some inherent properties such as size in the nanometers, high loading efficiency, and in vivo stability. Nano-aggregates can provide site-specific drug delivery via either a passive or active targeting mechanism. Nano-aggregates are formed from a polymer-drug conjugated amphiphilic block copolymer. They are suitable for encapsulation of poorly water-soluble drugs by covalent conjugation as well as physical encapsulation. Because of physical encapsulation, a maximum amount of drug can be loaded in nano-aggregates, which helps to achieve a sufficiently high drug concentration at the target site. Active transport can be achieved by conjugating a drug with vectors or ligands that bind specifically to receptors being overexpressed in the tumor cells. In this review, we explore synthesis and tumor targeting potential of nano-aggregates with active and passive mechanisms, and we discuss various characterization parameters, ex vivo studies, biodistribution studies, clinical trials, and patents.

Template-directed hydrothermal synthesis of hydroxyapatite as a drug delivery system for the poorly water-soluble drug carvedilol

NASA Astrophysics Data System (ADS)

Zhao, Qinfu; Wang, Tianyi; Wang, Jing; Zheng, Li; Jiang, Tongying; Cheng, Gang; Wang, Siling

2011-09-01

In order to improve the dissolution rate and increase the bioavailability of a poorly water-soluble drug, intended to be administered orally, the biocompatible and bioactive mesoporous hydroxyapatite (HA) was successfully synthesized. In the present study, mesoporous HA nanoparticles were produced using Pluronic block co-polymer F127 and cetyltrimethylammonium bromide (CTAB) as templates by the hydrothermal method. The obtained mesoporous HA was employed as a drug delivery carrier to investigate the drug storage/release properties using carvedilol (CAR) as a model drug. Characterizations of the raw CAR powder, mesoporous HA and CAR-loaded HA were carried out by the scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, N2 adsorption/desorption, thermogravimetric analysis (TGA), and UV-VIS spectrophotometry. The results demonstrated that CAR was successfully incorporated into the mesoporous HA host. In vitro drug release studies showed that mesoporous HA had a high drug load efficiency and provided immediate release of CAR compared with micronized raw drug in simulated gastric fluid (pH 1.2) and intestinal fluid (pH 6.8). Consequently, mesoporous HA is a good candidate as a drug carrier for the oral delivery of poorly water-soluble drugs.

A green and facile preparation approach, licochalcone A capped on hollow gold nanoparticles, for improving the solubility and dissolution of anticancer natural product.

PubMed

Sun, Yi-Wei; Wang, Li-Hong; Meng, Da-Li; Che, Xin

2017-12-01

This study described a valuable drug delivery system for poorly water-soluble anticancer naturalproduct, licochalcone A, isolated from Glycyrrhiza inflata , loaded on hollow gold nanoparticles by green method to improve solubility and dissolution and maintain its natural pharmacological property. Briefly, the formation of hollow gold nanoparticles involves three steps: preparing of silica nanospheres by Stober method, forming of a thick gold shell around the silica templates and etching of silica particles by HF solution. Hollow gold nanoparticles (HGNPs) and drug loaded hollow gold nanoparticles (L-HGNPs) displayed spherical structure and approximately 200nm in size observed by SEM, XRD, EDS and DSC analysis showed that HGNPs were gold hollow structure and crystalline form. The solubility in aqueous solution of licochalcone A was increased obviously to 488.9 μg/ml, compared with free drugs of 136.1 μg/ml. Another interesting finding is that near-infrared (NIR) irradiation increased the speed of solubility of licochalcone A in aqueous solutions, rather than quantity. In short, the method of nano-delivery system combined with poorly water-soluble drug to improve its solubility and dissolution is worth applying to other natural products in order to increase their opportunities in clinical applications.

Development of clinical dosage forms for a poorly water-soluble drug II: formulation and characterization of a novel solid microemulsion preconcentrate system for oral delivery of a poorly water-soluble drug.

PubMed

Li, Ping; Hynes, Sara R; Haefele, Thomas F; Pudipeddi, Madhu; Royce, Alan E; Serajuddin, Abu T M

2009-05-01

The solution of a poorly water-soluble drug in a liquid lipid-surfactant mixture, which served as a microemulsion preconcentrate, was converted into a solid form by incorporating it in a solid polyethylene glycol (PEG) matrix. The solid microemulsion preconcentrates thus formed consisted of Capmul PG8 (propylene glycol monocaprylate) as oil, Cremophor EL (polyoxyl 35 castor oil) as surfactant, and hydrophilic polymer PEG 3350 as solid matrix. The drug (aqueous solubility: 0.17 microg/mL at pH 1-8 and 25 degrees C) was dissolved in a melt of the mixture at 65-70 degrees C and then the hot solution was filled into hard gelatin capsules; the liquid gradually solidified upon cooling below 55 degrees C. The solid system was characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), confocal Raman microscopy (CRM), and the dispersion testing in water. It was confirmed that a solid microemulsion preconcentrate is a two-phase system, where clusters of crystalline PEG 3350 formed the solid structure (m.p. 55-60 degrees C) and the liquid microemulsion preconcentrate dispersed in between PEG 3350 crystals as a separate phase. The drug remained dissolved in the liquid phase. In vitro release testing showed that the preconcentrate dispersed readily in water forming a microemulsion with the drug dissolved in the oil particles (<150 nm) and the presence of PEG 3350 did not interfere with the process of self-microemulsification.

Factors affecting the formation of eutectic solid dispersions and their dissolution behavior.

PubMed

Vippagunta, Sudha R; Wang, Zeren; Hornung, Stefanie; Krill, Steven L

2007-02-01

The objective of this work was to obtain a fundamental understanding of the factors, specifically the properties of poorly water-soluble drugs and water-soluble carriers, which influence predominantly, the formation of eutectic or monotectic crystalline solid dispersion and their dissolution behavior. A theoretical model was applied on five poorly water-soluble drugs (fenofibrate, flurbiprofen, griseofulvin, naproxen, and ibuprofen) having diverse physicochemical properties and water-soluble carrier (polyethylene glycol (PEG) 8000) for the evaluation of these factors. Of these, two drugs, fenofibrate and flurbiprofen, and PEG of different molecular weights (3350, 8000, and 20000), were chosen as model drugs and carriers for further investigation. Experimental phase diagrams were constructed and dissolution testing was performed to assess the performance of the systems. The theoretical model predicted the formation of eutectic or monotectic solid dispersions of fenofibrate, griseofulvin, ibuprofen, and naproxen with PEG, holding the contribution of specific intermolecular interactions between compound and carrier to zero. In the case of the flurbiprofen-PEG eutectic system, intermolecular interactions between drug and polymer needed to be taken into consideration to predict the experimental phase diagram. The results of the current work suggest that the thermodynamic function of melting point and heat of fusion (as a measure of crystal energy of drug) plays a significant role in the formation of a eutectic system. Lipophilicity of the compound (as represented by cLog P) was also demonstrated to have an effect. Specific interactions between drug and carrier play a significant role in influencing the eutectic composition. Molar volume of the drug did not seem to have an impact on eutectic formation. The polymer molecular weight appeared to have an impact on the eutectic composition for flurbiprofen, which exhibits specific interactions with PEG, whereas no such impact of polymer molecular weight on eutectic composition was observed for fenofibrate, which does not exhibit specific interactions with PEG. The impact of polymer molecular weight on dissolution of systems where specific drug-polymer interactions are exhibited was also observed. The current work provides valuable insight into factors affecting formation and dissolution of eutectic systems, which can facilitate the rational selection of suitable water-soluble carriers. Copyright (c) 2006 Wiley-Liss, Inc.

Zero-order release of poorly water-soluble drug from polymeric films made via aqueous slurry casting.

PubMed

Zhang, Lu; Alfano, Joy; Race, Doran; Davé, Rajesh N

2018-05-30

In spite of significant recent interest in polymeric films containing poorly water-soluble drugs, dissolution mechanism of thicker films has not been investigated. Consequently, release mechanisms of poorly water-soluble drugs from thicker hydroxypropyl methylcellulose (HPMC) films are investigated, including assessing thickness above which they exhibit zero-order drug release. Micronized, surface modified particles of griseofulvin, a model drug of BSC class II, were incorporated into aqueous slurry-cast films of different thicknesses (100, 500, 1000, 1500 and 2000 μm). Films 1000 μm and thicker were formed by either stacking two or more layers of ~500 μm, or forming a monolithic thick film. Compared to monolithic thick films, stacked films required simpler manufacturing process (easier casting, short drying time) and resulted in better critical quality attributes (appearance, uniformity of thickness and drug per unit area). Both the film forming approaches exhibited similar release profiles and followed the semi-empirical power law. As thickness increased from 100 μm to 2000 μm, the release mechanism changed from Fickian diffusion to zero-order release for films ≥1000 μm. The diffusional power law exponent, n, achieved value of 1, confirming zero-order release, whereas the percentage drug release varied linearly with sample surface area, and sample thickness due to fixed sample diameter. Thus, multi-layer hydrophilic polymer aqueous slurry-cast thick films containing poorly water-soluble drug particles provide a convenient dosage form capable of zero-order drug release with release time modulated through number of layers. Copyright © 2018 Elsevier B.V. All rights reserved.

Solubility advantage of amorphous pharmaceuticals: II. Application of quantitative thermodynamic relationships for prediction of solubility enhancement in structurally diverse insoluble pharmaceuticals.

PubMed

Murdande, Sharad B; Pikal, Michael J; Shanker, Ravi M; Bogner, Robin H

2010-12-01

To quantitatively assess the solubility advantage of amorphous forms of nine insoluble drugs with a wide range of physico-chemical properties utilizing a previously reported thermodynamic approach. Thermal properties of amorphous and crystalline forms of drugs were measured using modulated differential calorimetry. Equilibrium moisture sorption uptake by amorphous drugs was measured by a gravimetric moisture sorption analyzer, and ionization constants were determined from the pH-solubility profiles. Solubilities of crystalline and amorphous forms of drugs were measured in de-ionized water at 25°C. Polarized microscopy was used to provide qualitative information about the crystallization of amorphous drug in solution during solubility measurement. For three out the nine compounds, the estimated solubility based on thermodynamic considerations was within two-fold of the experimental measurement. For one compound, estimated solubility enhancement was lower than experimental value, likely due to extensive ionization in solution and hence its sensitivity to error in pKa measurement. For the remaining five compounds, estimated solubility was about 4- to 53-fold higher than experimental results. In all cases where the theoretical solubility estimates were significantly higher, it was observed that the amorphous drug crystallized rapidly during the experimental determination of solubility, thus preventing an accurate experimental assessment of solubility advantage. It has been demonstrated that the theoretical approach does provide an accurate estimate of the maximum solubility enhancement by an amorphous drug relative to its crystalline form for structurally diverse insoluble drugs when recrystallization during dissolution is minimal.

Towards improved solubility of poorly water-soluble drugs: cryogenic co-grinding of piroxicam with carrier polymers.

PubMed

Penkina, Anna; Semjonov, Kristian; Hakola, Maija; Vuorinen, Sirpa; Repo, Timo; Yliruusi, Jouko; Aruväli, Jaan; Kogermann, Karin; Veski, Peep; Heinämäki, Jyrki

2016-01-01

Amorphous solid dispersions (SDs) open up exciting opportunities in formulating poorly water-soluble active pharmaceutical ingredients (APIs). In the present study, novel catalytic pretreated softwood cellulose (CPSC) and polyvinylpyrrolidone (PVP) were investigated as carrier polymers for preparing and stabilizing cryogenic co-ground SDs of poorly water-soluble piroxicam (PRX). CPSC was isolated from pine wood (Pinus sylvestris). Raman and Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used for characterizing the solid-state changes and drug-polymer interactions. High-resolution scanning electron microscope (SEM) was used to analyze the particle size and surface morphology of starting materials and final cryogenic co-ground SDs. In addition, the molecular aspects of drug-polymer interactions and stabilization mechanisms are presented. The results showed that the carrier polymer influenced both the degree of amorphization of PRX and stabilization against crystallization. The cryogenic co-ground SDs prepared from PVP showed an enhanced dissolution rate of PRX, while the corresponding SDs prepared from CPSC exhibited a clear sustained release behavior. In conclusion, cryogenic co-grinding provides a versatile method for preparing amorphous SDs of poorly water-soluble APIs. The solid-state stability and dissolution behavior of such co-ground SDs are to a great extent dependent on the carrier polymer used.

Solubilization of the poorly water soluble drug, telmisartan, using supercritical anti-solvent (SAS) process.

PubMed

Park, Junsung; Cho, Wonkyung; Cha, Kwang-Ho; Ahn, Junhyun; Han, Kang; Hwang, Sung-Joo

2013-01-30

Telmisartan is a biopharmaceutical classification system (BCS) class II drug that has extremely low water solubility but is freely soluble in highly alkalized solutions. Few organic solvents can dissolve telmisartan. This solubility problem is the main obstacle achieving the desired bioavailability. Because of its unique characteristics, the supercritical anti-solvent (SAS) process was used to BCS class II drug in a variety of ways including micronization, amorphization and solid dispersion. Solid dispersions were prepared using hydroxypropylmethylcellulose/polyvinylpyrrolidone (HPMC/PVP) at 1:0.5, 1:1, and 1:2 weight ratios of drug to polymer, and pure telmisartan was also treated using the SAS process. Processed samples were characterized for morphology, particle size, crystallinity, solubility, dissolution rate and polymorphic stability. After the SAS process, all samples were converted to the amorphous form and were confirmed to be hundreds nm in size. Solubility and dissolution rate were increased compared to the raw material. Solubility tended to increase with increases in the amount of polymer used. However, unlike the solubility results, the dissolution rate decreased with increases in polymer concentration due to gel layer formation of the polymer. Processed pure telmisartan showed the best drug release even though it had lower solubility compared to other solid dispersions; however, because there were no stabilizers in processed pure telmisartan, it recrystallized after 1 month under severe conditions, while the other solid dispersion samples remained amorphous form. We conclude that after controlling the formulation of solid dispersion, the SAS process could be a promising approach for improving the solubility and dissolution rate of telmisartan. Copyright © 2012 Elsevier B.V. All rights reserved.

Inclusion Complexes of a New Family of Non-Ionic Amphiphilic Dendrocalix[4]arene and Poorly Water-Soluble Drugs Naproxen and Ibuprofen.

PubMed

Khan, Khalid; Badshah, Syed Lal; Ahmad, Nasir; Rashid, Haroon Ur; Mabkhot, Yahia

2017-05-11

The inclusion complexes of a new family of nonionic amphiphilic calix[4]arenes with the anti-inflammatory hydrophobic drugs naproxen (NAP) and ibuprofen (IBP) were investigated. The effects of the alkyl chain's length and the inner core of calix[4]arenes on the interaction of the two drugs with the calix[4]arenes were explored. The inclusion complexes of Amphiphiles 1a - c with NAP and IBP increased the solubility of these drugs in aqueous media. The interaction of 1a - c with the drugs in aqueous media was investigated through fluorescence, molecular modeling, and ¹H-NMR analysis. TEM studies further supported the formation of inclusion complexes. The length of lipophilic alkyl chains and the intrinsic cyclic nature of cailx[4]arene derivatives 1a - c were found to have a significant impact on the solubility of NAP and IBP in pure water.

Cyclodextrin based nanosponges for pharmaceutical use: a review.

PubMed

Tejashri, Gursalkar; Amrita, Bajaj; Darshana, Jain

2013-09-01

Nanosponges are a novel class of hyper-crosslinked polymer based colloidal structures consisting of solid nanoparticles with colloidal sizes and nanosized cavities. These nano-sized colloidal carriers have been recently developed and proposed for drug delivery, since their use can solubilize poorly water-soluble drugs and provide prolonged release as well as improve a drug's bioavailability by modifying the pharmacokinetic parameters of actives. Development of nanosponges as drug delivery systems, with special reference to cyclodextrin based nanosponges, is presented in this article. In the current review, attempts have been made to illustrate the features of cyclodextrin based nanosponges and their applications in pharmaceutical formulations. Special emphasis has been placed on discussing the methods of preparation, characterization techniques and applications of these novel drug delivery carriers for therapeutic purposes. Nanosponges can be referred to as solid porous particles having a capacity to load drugs and other actives into their nanocavity; they can be formulated as oral, parenteral, topical or inhalation dosage forms. Nanosponges offer high drug loading compared to other nanocarriers and are thus suitable for solving issues related to stability, solubility and delayed release of actives. Controlled release of the loaded actives and solubility enhancement of poorly water-soluble drugs are major advantages of nanosponge drug delivery systems.

Effect of cyclodextrin complexation on the aqueous solubility and solubility/dose ratio of praziquantel.

PubMed

Maragos, Stratos; Archontaki, Helen; Macheras, Panos; Valsami, Georgia

2009-01-01

Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound like PZQ could behave as BCS-Class I (highly soluble/highly permeable) drug. Phase solubility and the kneading and lyophilization techniques were used for inclusion complex preparation; solubility was determined by UV spectroscopy. The ability of the water soluble polymer polyvinylpyrolidone (PVP) to increase the complexation and solubilization efficiency of beta-CD and HP-beta-CD for PZQ was examined. Results showed significant improvement of PZQ solubility in the presence of both cyclodextrins but no additional effect in the presence of PVP. The solubility/dose ratios values of PZQ-cyclodextrin complexes calculated considering the low (150 mg) and the high dose (600 mg) of PZQ, used in practice, indicate that PZQ complexation with CDs may result in drug dosage forms that would behave as a BCS-Class I depending on the administered dose.

Soluble polymer conjugates for drug delivery.

PubMed

Minko, Tamara

2005-01-01

The use of water-soluble polymeric conjugates as drug carriers offers several possible advantages. These advantages include: (1) improved drug pharmacokinetics; (2) decreased toxicity to healthy organs; (3) possible facilitation of accumulation and preferential uptake by targeted cells; (4) programmed profile of drug release. In this review, we will consider the main types of useful polymeric conjugates and their role and effectiveness as carriers in drug delivery systems.: © 2005 Elsevier Ltd . All rights reserved.

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1).

PubMed

Brough, Chris; Miller, Dave A; Keen, Justin M; Kucera, Shawn A; Lubda, Dieter; Williams, Robert O

2016-02-01

Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

Layer-by-layer assembled thin films and microcapsules of nanocrystalline cellulose for hydrophobic drug delivery.

PubMed

Mohanta, Vaishakhi; Madras, Giridhar; Patil, Satish

2014-11-26

A layer-by-layer (LbL) approach has been employed for the fabrication of multilayer thin films and microcapsules having nanofibrous morphology using nanocrystalline cellulose (NCC) as one of the components of the assembly. The applicability of these nanoassemblies as drug delivery carriers has been explored by the loading of an anticancer drug, doxorubicin hydrochloride, and a water-insoluble drug, curcumin. Doxorubicin hydrochloride, having a good water solubility, is postloaded in the assembly. In the case of curcumin, which is very hydrophobic and has limited solubility in water, a stable dispersion is prepared via noncovalent interaction with NCC prior to incorporation in the LbL assembly. The interaction of various other lipophilic drugs with NCC was analyzed theoretically by molecular docking in consideration of NCC as a general carrier for hydrophobic drugs.

A double-blind, randomized trial, including frequent patient-physician contacts and Ramadan-focused advice, assessing vildagliptin and gliclazide in patients with type 2 diabetes fasting during Ramadan: the STEADFAST study.

PubMed

Hassanein, Mohamed; Abdallah, Khalifa; Schweizer, Anja

2014-01-01

Several observational studies were conducted with vildagliptin in patients with type 2 diabetes mellitus (T2DM) fasting during Ramadan, showing significantly lower incidences of hypoglycemia with vildagliptin versus sulfonylureas, including gliclazide. It was of interest to complement the existing real-life evidence with data from a randomized, double-blind, clinical trial. NCT01758380. This multiregional, double-blind study randomized 557 patients with T2DM (mean glycated hemoglobin [HbA1c], 6.9%), previously treated with metformin and any sulfonylurea to receive either vildagliptin (50 mg twice daily) or gliclazide plus metformin. The study included four office visits (three pre-Ramadan) and multiple telephone contacts, as well as Ramadan-focused advice. Hypoglycemic events were assessed during Ramadan; HbA(1c) and weight were analyzed before and after Ramadan. The proportion of patients reporting confirmed (<3.9 mmol/L and/or severe) hypoglycemic events during Ramadan was 3.0% with vildagliptin and 7.0% with gliclazide (P=0.039; one-sided test), and this was 6.0% and 8.7%, respectively, for any hypoglycemic events (P=0.173). The adjusted mean change pre- to post-Ramadan in HbA(1c) was 0.05%±0.04% with vildagliptin and -0.03%±0.04% with gliclazide, from baselines of 6.84% and 6.79%, respectively (P=0.165). In both groups, the adjusted mean decrease in weight was -1.1±0.2 kg (P=0.987). Overall safety was similar between the treatments. In line with the results from previous observational studies, vildagliptin was shown in this interventional study to be an effective, safe, and well-tolerated treatment in patients with T2DM fasting during Ramadan, with a consistently low incidence of hypoglycemia across studies, accompanied by good glycemic and weight control. In contrast, gliclazide showed a lower incidence of hypoglycemia in the present interventional than the previous observational studies. This is suggested to be linked to the specific circumstances of this study, including frequent patient-physician contacts, Ramadan-focused advice, a recent switch in treatment, and very well-controlled patients, which is different from what is often seen in real life.

A double-blind, randomized trial, including frequent patient–physician contacts and Ramadan-focused advice, assessing vildagliptin and gliclazide in patients with type 2 diabetes fasting during Ramadan: the STEADFAST study

PubMed Central

Hassanein, Mohamed; Abdallah, Khalifa; Schweizer, Anja

2014-01-01

Background Several observational studies were conducted with vildagliptin in patients with type 2 diabetes mellitus (T2DM) fasting during Ramadan, showing significantly lower incidences of hypoglycemia with vildagliptin versus sulfonylureas, including gliclazide. It was of interest to complement the existing real-life evidence with data from a randomized, double-blind, clinical trial. Clinical Trials Identifier NCT01758380. Methods This multiregional, double-blind study randomized 557 patients with T2DM (mean glycated hemoglobin [HbA1c], 6.9%), previously treated with metformin and any sulfonylurea to receive either vildagliptin (50 mg twice daily) or gliclazide plus metformin. The study included four office visits (three pre-Ramadan) and multiple telephone contacts, as well as Ramadan-focused advice. Hypoglycemic events were assessed during Ramadan; HbA1c and weight were analyzed before and after Ramadan. Results The proportion of patients reporting confirmed (<3.9 mmol/L and/or severe) hypoglycemic events during Ramadan was 3.0% with vildagliptin and 7.0% with gliclazide (P=0.039; one-sided test), and this was 6.0% and 8.7%, respectively, for any hypoglycemic events (P=0.173). The adjusted mean change pre- to post-Ramadan in HbA1c was 0.05%±0.04% with vildagliptin and −0.03%±0.04% with gliclazide, from baselines of 6.84% and 6.79%, respectively (P=0.165). In both groups, the adjusted mean decrease in weight was −1.1±0.2 kg (P=0.987). Overall safety was similar between the treatments. Conclusion In line with the results from previous observational studies, vildagliptin was shown in this interventional study to be an effective, safe, and well-tolerated treatment in patients with T2DM fasting during Ramadan, with a consistently low incidence of hypoglycemia across studies, accompanied by good glycemic and weight control. In contrast, gliclazide showed a lower incidence of hypoglycemia in the present interventional than the previous observational studies. This is suggested to be linked to the specific circumstances of this study, including frequent patient–physician contacts, Ramadan-focused advice, a recent switch in treatment, and very well-controlled patients, which is different from what is often seen in real life. PMID:24920915

QSPR analysis of the partitioning of vaporous chemicals in a water-gas phase system and the water solubility of liquid and solid chemicals on the basis of fragment and physicochemical similarity and hybot descriptors.

PubMed

Raevsky, O; Andreeva, E; Raevskaja, O; Skvortsov, V; Schaper, K

2005-01-01

QSPR analyses of the solubility in water of 558 vapors, 786 liquids and 2045 solid organic neutral chemicals and drugs are presented. Simultaneous consideration of H-bond acceptor and donor factors leads to a good description of the solubility of vapors and liquids. A volume-related term was found to have an essential negative contribution to the solubility of liquids. Consideration of polarizability, H-bond acceptor and donor factors and indicators for a few functional groups, as well as the experimental solubility values of structurally nearest neighbors yielded good correlations for liquids. The application of Yalkowsky's "General Solubility Equation" to 1063 solid chemicals and drugs resulted in a correlation of experimental vs calculated log S values with only modest statistical criteria. Two approaches to derive predictive models for solubility of solid chemicals and drugs were tested. The first approach was based on the QSPR for liquids together with indicator variables for different functional groups. Furthermore, a calculation of enthalpies for intermolecular complexes in crystal lattices, based on new H-bond potentials, was carried out for the better consideration of essential solubility- decreasing effects in the solid state, as compared with the liquid state. The second approach was based on a combination of similarity considerations and traditional QSPR. Both approaches lead to high quality predictions with average absolute errors on the level of experimental log S determination.

Limited sampling strategy models for estimating the AUC of gliclazide in Chinese healthy volunteers.

PubMed

Huang, Ji-Han; Wang, Kun; Huang, Xiao-Hui; He, Ying-Chun; Li, Lu-Jin; Sheng, Yu-Cheng; Yang, Juan; Zheng, Qing-Shan

2013-06-01

The aim of this work is to reduce the cost of required sampling for the estimation of the area under the gliclazide plasma concentration versus time curve within 60 h (AUC0-60t ). The limited sampling strategy (LSS) models were established and validated by the multiple regression model within 4 or fewer gliclazide concentration values. Absolute prediction error (APE), root of mean square error (RMSE) and visual prediction check were used as criterion. The results of Jack-Knife validation showed that 10 (25.0 %) of the 40 LSS based on the regression analysis were not within an APE of 15 % using one concentration-time point. 90.2, 91.5 and 92.4 % of the 40 LSS models were capable of prediction using 2, 3 and 4 points, respectively. Limited sampling strategies were developed and validated for estimating AUC0-60t of gliclazide. This study indicates that the implementation of an 80 mg dosage regimen enabled accurate predictions of AUC0-60t by the LSS model. This study shows that 12, 6, 4, 2 h after administration are the key sampling times. The combination of (12, 2 h), (12, 8, 2 h) or (12, 8, 4, 2 h) can be chosen as sampling hours for predicting AUC0-60t in practical application according to requirement.

Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs.

PubMed

Vo, Chau Le-Ngoc; Park, Chulhun; Lee, Beom-Jin

2013-11-01

Over 40% of active pharmaceutical ingredients (API) in development pipelines are poorly water-soluble drugs which limit formulation approaches, clinical application and marketability because of their low dissolution and bioavailability. Solid dispersion has been considered one of the major advancements in overcoming these issues with several successfully marketed products. A number of key references that describe state-of-the-art technologies have been collected in this review, which addresses various pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs according to the four generations of solid dispersions. This article reviews critical aspects and recent advances in formulation, preparation and characterization of solid dispersions as well as in-depth pharmaceutical solutions to overcome some problems and issues that limit the development and marketability of solid dispersion products. Copyright © 2013 Elsevier B.V. All rights reserved.

Ultimate biodegradability and ecotoxicity of orally administered antidiabetic drugs.

PubMed

Markiewicz, Marta; Jungnickel, Christian; Stolte, Stefan; Białk-Bielińska, Anna; Kumirska, Jolanta; Mrozik, Wojciech

2017-07-05

Hypoglycaemic pharmaceuticals are recently more and more frequently detected in the environment. In our previous study, we have shown that even though many of them undergo significant primary degradation some are transformed to stable products or undergo such transformation that a large part of the structure is still preserved. One of the main routes of elimination from wastewaters or surface waters is biodegradation and a lack thereof leads to accumulation in the environment. Within this work we tested the ultimate biodegradability of six oral antidiabetics: metformin and its main metabolite guanylurea, acarbose, glibenclamide, gliclazide, glimepiride and repaglinide. We also compared the experimental results obtained in this and accompanying work with models designed to predict biodegradability and showed that these models are only moderately successful. Additionally, we examined these compounds in acute Daphnia magna test to check if they might pose an ecotoxicological threat. Combining the results of biodegradability and toxicity tests allows a preliminary assessment of their potential environmental impact. Copyright © 2017 Elsevier B.V. All rights reserved.

Core-shell nanofibers of curcumin/cyclodextrin inclusion complex and polylactic acid: Enhanced water solubility and slow release of curcumin.

PubMed

Aytac, Zeynep; Uyar, Tamer

2017-02-25

Core-shell nanofibers were designed via electrospinning using inclusion complex (IC) of model hydrophobic drug (curcumin, CUR) with cyclodextrin (CD) in the core and polymer (polylactic acid, PLA) in the shell (cCUR/HPβCD-IC-sPLA-NF). CD-IC of CUR and HPβCD was formed at 1:2 molar ratio. The successful formation of core-shell nanofibers was revealed by TEM and CLSM images. cCUR/HPβCD-IC-sPLA-NF released CUR slowly but much more in total than PLA-CUR-NF at pH 1 and pH 7.4 due to the restriction of CUR in the core of nanofibers and solubility improvement shown in phase solubility diagram, respectively. Improved antioxidant activity of cCUR/HPβCD-IC-sPLA-NF in methanol:water (1:1) is related with the solubility enhancement achieved in water based system. The slow reaction of cCUR/HPβCD-IC-sPLA-NF in methanol is associated with the shell inhibiting the quick release of CUR. On the other hand, cCUR/HPβCD-IC-sPLA-NF exhibited slightly higher rate of antioxidant activity than PLA-CUR-NF in methanol:water (1:1) owing to the enhanced solubility. To conclude, slow release of CUR was achieved by core-shell nanofiber structure and inclusion complexation of CUR with HPβCD provides high solubility. Briefly, electrospinning of core-shell nanofibers with CD-IC core could offer slow release of drugs as well as solubility enhancement for hydrophobic drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Lipid-based nanocarriers as an alternative for oral delivery of poorly water- soluble drugs: peroral and mucosal routes.

PubMed

Silva, A C; Santos, D; Ferreira, D; Lopes, C M

2012-01-01

The hydrophobic character of most drug molecules and their potential for degradation under the hostile environment of the gastrointestinal tract (GIT) constitutes the main obstacle in the development of a successful oral drug delivery system, since these are related to limitations of bioavailability and absorption processes. However, according to the advantages of the oral route, alternative ways of drug administration in the oral cavity should be considered. In this context, it is essential to have a systematic knowledge of the GIT and the oral cavity components, for a better understanding of the processes taking place during the oral administration of drugs. This review gives an overview of those anatomical and physiological features and elucidates about the current approaches employed to enhance the bioavailability of oral poorly water-soluble drugs. Strategies including the uses of lipid-based nanocarriers, such as nanoemulsions, liposomes and lipid nanoparticles are discussed, considering their ability to improve solubility, dissolution kinetics, absorption and, consequently, biopharmaceutical properties. Some toxicological concerns are also highlighted.

Design of tablets for the delayed and complete release of poorly water-soluble weak base drugs using SBE7M-β-CD as a solubilizing agent.

PubMed

Rao, Venkatramana M; Zannou, Erika A; Stella, Valentino J

2011-04-01

The challenge of designing a delayed-release oral dosage form is significantly increased when the drug substance is poorly water soluble. This manuscript describes the design and characterization of a novel controlled-release film-coated tablet for the pH-triggered delayed and complete release of poorly water-soluble weak base drugs. Delivery of weak bases is specifically highlighted with the use of dipyridamole and prazosin as model compounds. Tailored delayed release is achieved with a combination of an insoluble but semipermeable polymer and an enteric polymer, such as cellulose acetate and hydroxypropyl cellulose phthalate, respectively, as coatings. The extent of the time lag prior to complete release depends on the film-coating composition and thickness. Complete release is achieved by the addition of a cyclodextrin, namely SBE7M-β-CD with or without a pH modifier added to the tablet core to ensure complete solubilization and release of the drug substance. The film-coating properties allow the complex formation/solubilization to occur in situ. Additionally, the drug release rate can be modulated on the basis of the cyclodextrin to drug molar ratio. This approach offers a platform technology for delayed release of potent but poorly soluble drugs and the release can be modulated by adjusting the film-coating composition and thickness and/or the cyclodextrin and pH modifier, if necessary. Copyright © 2010 Wiley-Liss, Inc.

Kinetics of drug release from ointments: Role of transient-boundary layer.

PubMed

Xu, Xiaoming; Al-Ghabeish, Manar; Krishnaiah, Yellela S R; Rahman, Ziyaur; Khan, Mansoor A

2015-10-15

In the current work, an in vitro release testing method suitable for ointment formulations was developed using acyclovir as a model drug. Release studies were carried out using enhancer cells on acyclovir ointments prepared with oleaginous, absorption, and water-soluble bases. Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In oleaginous bases, drug release followed a unique logarithmic-time dependent profile; in both absorption and water-soluble bases, drug release exhibited linearity with respect to square root of time (Higuchi model) albeit differences in the overall release profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was proposed, verified, and compared to Higuchi theory. Furthermore, impact of drug solubility (under various pH conditions) and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Overall, the results suggest that for oleaginous ointments containing dispersed drug particles, kinetics and mechanism of drug release is controlled by expansion of transient boundary layer, and drug release increases linearly with respect to logarithmic time. Published by Elsevier B.V.

Dissolution enhancement of a model poorly water-soluble drug, atorvastatin, with ordered mesoporous silica: comparison of MSF with SBA-15 as drug carriers.

PubMed

Maleki, Aziz; Hamidi, Mehrdad

2016-01-01

The purpose of this study was to develop mesoporous silica materials incorporated with poorly water-soluble drug atorvastatin calcium (AC) in order to improve drug dissolution, and intended to be orally administrated. A comparison between 2D-hexagonal silica nanostructured SBA-15 and mesocellular siliceous foam (MSF) with continuous 3D pore system on drug release rate was investigated. AC-loaded mesoporous silicas were characterized thorough N2 adsorption-desorption analysis, Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and dynamic light scattering (DLS). Results demonstrated a successful incorporation of AC into the silica-based hosts. The results taken from the drug release tests were also analyzed using different parameters, namely similarity factor (f2), difference factor (f1), dissolution efficiency (DE%), mean dissolution rate (MDR) and dissolution time (tm%). It confirmed a significant enhancement in the release profile of atorvastatin calcium with SBA-15, and MSF as drug carrier. Moreover, in comparison with SBA-15, MSF showed faster release rate of AC in enzyme-free simulated gastric fluid (pH 1.2). We believed that our findings can help the use of mesoporous silica materials in improving bioavailability of poorly water-soluble drugs.

Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs.

PubMed

Ozaki, Shunsuke; Kushida, Ikuo; Yamashita, Taro; Hasebe, Takashi; Shirai, Osamu; Kano, Kenji

2013-07-01

The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations. Copyright © 2013 Wiley Periodicals, Inc.

Amino acids as co-amorphous stabilizers for poorly water soluble drugs--Part 1: preparation, stability and dissolution enhancement.

PubMed

Löbmann, Korbinian; Grohganz, Holger; Laitinen, Riikka; Strachan, Clare; Rades, Thomas

2013-11-01

Poor aqueous solubility of an active pharmaceutical ingredient (API) is one of the most pressing problems in pharmaceutical research and development because up to 90% of new API candidates under development are poorly water soluble. These drugs usually have a low and variable oral bioavailability, and therefore an unsatisfactory therapeutic effect. One of the most promising approaches to increase dissolution rate and solubility of these drugs is the conversion of a crystalline form of the drug into its respective amorphous form, usually by incorporation into hydrophilic polymers, forming glass solutions. However, this strategy only led to a small number of marketed products usually because of inadequate physical stability of the drug (crystallization). In this study, we investigated a fundamentally different approach to stabilize the amorphous form of drugs, namely the use of amino acids as small molecular weight excipients that form specific molecular interactions with the drug resulting in co-amorphous forms. The two poorly water soluble drugs carbamazepine and indomethacin were combined with amino acids from the binding sites of the biological receptors of these drugs. Mixtures of drug and the amino acids arginine, phenylalanine, tryptophan and tyrosine were prepared by vibrational ball milling. Solid-state characterization with X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) revealed that the various blends could be prepared as homogeneous, single phase co-amorphous formulations indicated by the appearance of an amorphous halo in the XRPD diffractograms and a single glass transition temperature (Tg) in the DSC measurements. In addition, the Tgs of the co-amorphous mixtures were significantly increased over those of the individual drugs. The drugs remained chemically stable during the milling process and the co-amorphous formulations were generally physically stable over at least 6 months at 40 °C under dry conditions. The dissolution rate of all co-amorphous drug-amino acid mixtures was significantly increased over that of the respective crystalline and amorphous pure drugs. Amino acids thus appear as promising excipients to solve challenges connected with the stability and dissolution of amorphous drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Drug delivery strategies for poorly water-soluble drugs.

PubMed

Fahr, Alfred; Liu, Xiangli

2007-07-01

The drug candidates coming from combinatorial chemistry research and/or the drugs selected from biologically based high-throughput screening are quite often very lipophilic, as these drug candidates exert their pharmacological action at or in biological membranes or membrane-associated proteins. This challenges drug delivery institutions in industry or academia to develop carrier systems for the optimal oral and parenteral administration of these drugs. To mention only a few of the challenges for this class of drugs: their oral bioavailability is poor and highly variable, and carrier development for parenteral administration is faced with problems, including the massive use of surface-active excipients for solubilisation. Formulation specialists are confronted with an even higher level of difficulties when these drugs have to be delivered site specifically. This article addresses the emerging formulation designs for delivering of poorly water-soluble drugs.

Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution process.

PubMed

Kataoka, Makoto; Fukahori, Miho; Ikemura, Atsumi; Kubota, Ayaka; Higashino, Haruki; Sakuma, Shinji; Yamashita, Shinji

2016-04-01

The aim of the present study was to evaluate the effects of gastric pH on the oral absorption of poorly water-soluble drugs using an in vitro system. A dissolution/permeation system (D/P system) equipped with a Caco-2 cell monolayer was used as the in vitro system to evaluate oral drug absorption, while a small vessel filled with simulated gastric fluid (SGF) was used to reflect the gastric dissolution phase. After applying drugs in their solid forms to SGF, SGF solution containing a 1/100 clinical dose of each drug was mixed with the apical solution of the D/P system, which was changed to fasted state-simulated intestinal fluid. Dissolved and permeated amounts on applied amount of drugs were then monitored for 2h. Similar experiments were performed using the same drugs, but without the gastric phase. Oral absorption with or without the gastric phase was predicted in humans based on the amount of the drug that permeated in the D/P system, assuming that the system without the gastric phase reflected human absorption with an elevated gastric pH. The dissolved amounts of basic drugs with poor water solubility, namely albendazole, dipyridamole, and ketoconazole, in the apical solution and their permeation across a Caco-2 cell monolayer were significantly enhanced when the gastric dissolution process was reflected due to the physicochemical properties of basic drugs. These amounts resulted in the prediction of higher oral absorption with normal gastric pH than with high gastric pH. On the other hand, when diclofenac sodium, the salt form of an acidic drug, was applied to the D/P system with the gastric phase, its dissolved and permeated amounts were significantly lower than those without the gastric phase. However, the oral absorption of diclofenac was predicted to be complete (96-98%) irrespective of gastric pH because the permeated amounts of diclofenac under both conditions were sufficiently high to achieve complete absorption. These estimations of the effects of gastric pH on the oral absorption of poorly water-soluble drugs were consistent with observations in humans. In conclusion, the D/P system with the gastric phase may be a useful tool for better predicting the oral absorption of poorly water-soluble basic drugs. In addition, the effects of gastric pH on the oral absorption of poorly water-soluble drugs may be evaluated by the D/P system with and without the gastric phase. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed

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

2016-01-04

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

Consensus Recommendations on Sulfonylurea and Sulfonylurea Combinations in the Management of Type 2 Diabetes Mellitus – International Task Force

PubMed Central

Kalra, Sanjay; Bahendeka, Silver; Sahay, Rakesh; Ghosh, Sujoy; Md, Fariduddin; Orabi, Abbas; Ramaiya, Kaushik; Al Shammari, Sameer; Shrestha, Dina; Shaikh, Khalid; Abhayaratna, Sachitha; Shrestha, Pradeep K.; Mahalingam, Aravinthan; Askheta, Mazen; A. Rahim, Aly Ahmed; Eliana, Fatimah; Shrestha, Hari K.; Chaudhary, Sandeep; Ngugi, Nancy; Mbanya, Jean Claude; Aye, Than Than; Latt, Tint Swe; Akanov, Zhanay A.; Syed, Abbas Raza; Tandon, Nikhil; Unnikrishnan, A. G.; Madhu, S. V.; Jawa, Ali; Chowdhury, Subhankar; Bajaj, Sarita; Das, Ashok Kumar

2018-01-01

For decades, sulfonylureas (SUs) have been important drugs in the antidiabetic therapeutic armamentarium. They have been used as monotherapy as well as combination therapy. Focus on newer drugs and concerns about the risk of severe hypoglycemia and weight gain with some SUs have led to discussion on their safety and utility. It has to be borne in mind that the adverse events associated with SUs should not be ascribed to the whole class, as many modern SUs, such as glimepiride and gliclazide modified release, are associated with better safety profiles. Furthermore, individualization of treatment, using SUs in combination with other drugs, backed with careful monitoring and patient education, ensures maximum benefits with minimal side effects. The current guidelines, developed by experts from Africa, Asia, and the Middle East, promote the safe and smart use of SUs in combination with other glucose-lowering drugs. PMID:29535952

Influence of Physiological Gastrointestinal Surfactant Ratio on the Equilibrium Solubility of BCS Class II Drugs Investigated Using a Four Component Mixture Design

PubMed Central

2017-01-01

The absorption of poorly water-soluble drugs is influenced by the luminal gastrointestinal fluid content and composition, which control solubility. Simulated intestinal fluids have been introduced into dissolution testing including endogenous amphiphiles and digested lipids at physiological levels; however, in vivo individual variation exists in the concentrations of these components, which will alter drug absorption through an effect on solubility. The use of a factorial design of experiment and varying media by introducing different levels of bile, lecithin, and digested lipids has been previously reported, but here we investigate the solubility variation of poorly soluble drugs through more complex biorelevant amphiphile interactions. A four-component mixture design was conducted to understand the solubilization capacity and interactions of bile salt, lecithin, oleate, and monoglyceride with a constant total concentration (11.7 mM) but varying molar ratios. The equilibrium solubility of seven low solubility acidic (zafirlukast), basic (aprepitant, carvedilol), and neutral (fenofibrate, felodipine, griseofulvin, and spironolactone) drugs was investigated. Solubility results are comparable with literature values and also our own previously published design of experiment studies. Results indicate that solubilization is not a sum accumulation of individual amphiphile concentrations, but a drug specific effect through interactions of mixed amphiphile compositions with the drug. This is probably due to a combined interaction of drug characteristics; for example, lipophilicity, molecular shape, and ionization with amphiphile components, which can generate specific drug–micelle affinities. The proportion of each component can have a remarkable influence on solubility with, in some cases, the highest and lowest points close to each other. A single-point solubility measurement in a fixed composition simulated media or human intestinal fluid sample will therefore provide a value without knowledge of the surrounding solubility topography meaning that variability may be overlooked. This study has demonstrated how the amphiphile ratios influence drug solubility and highlights the importance of the envelope of physiological variation when simulating in vivo drug behavior. PMID:28749696

Lipid nanoparticles for administration of poorly water soluble neuroactive drugs.

PubMed

Esposito, Elisabetta; Drechsler, Markus; Mariani, Paolo; Carducci, Federica; Servadio, Michela; Melancia, Francesca; Ratano, Patrizia; Campolongo, Patrizia; Trezza, Viviana; Cortesi, Rita; Nastruzzi, Claudio

2017-09-01

This study describes the potential of solid lipid nanoparticles and nanostructured lipid carriers as nano-formulations to administer to the central nervous system poorly water soluble drugs. Different neuroactive drugs, i.e. dimethylfumarate, retinyl palmitate, progesterone and the endocannabinoid hydrolysis inhibitor URB597 have been studied. Lipid nanoparticles constituted of tristearin or tristearin in association with gliceryl monoolein were produced. The nanoencapsulation strategy allowed to obtain biocompatible and non-toxic vehicles, able to increase the solubility of the considered neuroactive drugs. To improve URB597 targeting to the brain, stealth nanoparticles were produced modifying the SLN surface with polysorbate 80. A behavioural study was conducted in rats to test the ability of SLN containing URB597 given by intranasal administration to alter behaviours relevant to psychiatric disorders. URB597 maintained its activity after nanoencapsulation, suggesting the possibility to propose this kind of vehicle as alternative to unphysiological mixtures usually employed for animal and clinical studies.

Estimation of intragastric solubility of drugs: in what medium?

PubMed

Vertzoni, Maria; Pastelli, Eleni; Psachoulias, Dimitris; Kalantzi, Lida; Reppas, Christos

2007-05-01

To measure the solubility of four drugs in human gastric aspirates, canine gastric aspirates (CGF) and simulated gastric fluids in order to propose a medium for estimating intragastric drug solubility relevant to a bioavailability study in the fasted state. Intragastric environment after administration of water to healthy fasted adults and to healthy fasted dogs (this study) was initially characterized. Solubilities were then measured with the shake-flask method in gastric fluid aspirated after the administration of water to healthy fasted adults and to healthy fasted dogs, in various simulated gastric fluids, i.e. SGF(SLS), SGF(Triton), FaSSGF, FaSSGF(NaCl), and in various HCl solutions with pH values ranging from 1.2 to 2.9. In all cases, FaSSGF performed better than canine aspirates, SGF(SLS), SGF(Triton), or FaSSGF(NaCl) in predicting solubility in HGF. However, its superiority over HCl pH 1.6 was not clear. For ketoconazole, dipyridamole, miconazole, and felodipine deviations of solubility data in FaSSGF from solubility data in HGF were non-significant, 34, -39 and 252%, respectively, whereas the corresponding deviations of data in HCl pH 1.6 from data in HGF were non-significant, 24, 70, and 130%, respectively. Combining data in FaSSGF and HCl pH 1.6 is comparatively the most efficient way to get an estimate of drug solubility in the fasting gastric contents during a bioavailability study. However, accurate estimation of intragastric solubility is limited by the changing environment during intragastric residence of solid particles and the degree of simulation of intragastric composition.

Formulation of poorly water-soluble Gemfibrozil applying power ultrasound.

PubMed

Ambrus, R; Naghipour Amirzadi, N; Aigner, Z; Szabó-Révész, P

2012-03-01

The dissolution properties of a drug and its release from the dosage form have a basic impact on its bioavailability. Solubility problems are a major challenge for the pharmaceutical industry as concerns the development of new pharmaceutical products. Formulation problems may possibly be overcome by modification of particle size and morphology. The application of power ultrasound is a novel possibility in drug formulation. This article reports on solvent diffusion and melt emulsification, as new methods supplemented with drying in the field of sonocrystallization of poorly water-soluble Gemfibrozil. During thermoanalytical characterization, a modified structure was detected. The specific surface area of the drug was increased following particle size reduction and the poor wettability properties could also be improved. The dissolution rate was therefore significantly increased. Copyright © 2011 Elsevier B.V. All rights reserved.

Probing the mechanisms of drug release from amorphous solid dispersions in medium-soluble and medium-insoluble carriers.

PubMed

Sun, Dajun D; Lee, Ping I

2015-08-10

The objective of the current study is to mechanistically differentiate the dissolution and supersaturation behaviors of amorphous drugs from amorphous solid dispersions (ASDs) based on medium-soluble versus medium-insoluble carriers under nonsink dissolution conditions through a direct head-to-head comparison. ASDs of indomethacin (IND) were prepared in several polymers which exhibit different solubility behaviors in acidic (pH1.2) and basic (pH7.4) dissolution media. The selected polymers range from water-soluble (e.g., PVP and Soluplus) and water-insoluble (e.g., ethylcellulose and Eudragit RL PO) to those only soluble in an acidic or basic dissolution medium (e.g., Eudragit E100, Eudragit L100, and HPMCAS). At 20wt.% drug loading, DSC and powder XRD analysis confirmed that the majority of incorporated IND was present in an amorphous state. Our nonsink dissolution results confirm that whether the carrier matrix is medium soluble determines the release mechanism of amorphous drugs from ASD systems which has a direct impact on the rate of supersaturation generation, thus in turn affecting the evolution of supersaturation in amorphous systems. For example, under nonsink dissolution conditions, the release of amorphous IND from medium-soluble carriers is governed by a dissolution-controlled mechanism leading to an initial surge of supersaturation followed by a sharp decline in drug concentration due to rapid nucleation and crystallization. In contrast, the dissolution of IND ASD from medium-insoluble carriers is more gradual as drug release is regulated by a diffusion-controlled mechanism by which drug supersaturation is built up gradually and sustained over an extended period of time without any apparent decline. Since several tested carrier polymers can be switched from soluble to insoluble by simply changing the pH of the dissolution medium, the results obtained here provide unequivocal evidence of the proposed transition of kinetic solubility profiles from the same ASD system induced by changes in the drug release mechanism in dissolution medium of a different pH. Copyright © 2015 Elsevier B.V. All rights reserved.

Sustained ophthalmic delivery of highly soluble drug using pH-triggered inner layer-embedded contact lens.

PubMed

Zhu, Qiang; Cheng, Hongbo; Huo, Yingnan; Mao, Shirui

2018-06-10

In the present work the feasibility of using inner layer-embedded contact lenses (CLs) to achieve sustained release of highly water soluble drug, betaxolol hydrochloride (BH) on the ocular surface was investigated. Blend film of cellulose acetate and Eudragit S100 was selected as the inner layer, while silicone hydrogel was used as outer layer to construct inner layer-embedded contact lenses. Influence of polymer ratio in the blend film on in vitro drug release behavior in phosphate buffered solution or simulated tear fluid was studied and drug-polymer interaction, erosion and swelling of the blend film were characterized to better understand drug-release mechanism. Storage stability of the inner layer-embedded contact lenses in phosphate buffer solution was also conducted, with ignorable drug loss and negligible change in drug release pattern within 30 days. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 240 h in tear fluid, indicating prolonged drug precorneal residence time. In conclusion, cellulose acetate/Eudragit S100 inner layer-embedded contact lenses are quite promising as controlled-release carrier of highly water soluble drug for ophthalmic delivery. Copyright © 2018 Elsevier B.V. All rights reserved.

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

PubMed Central

2015-01-01

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

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

PubMed

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

2016-01-04

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

Facile synthesis of functionalized ionic surfactant templated mesoporous silica for incorporation of poorly water-soluble drug.

PubMed

Li, Jing; Xu, Lu; Yang, Baixue; Wang, Hongyu; Bao, Zhihong; Pan, Weisan; Li, Sanming

2015-08-15

The present paper reported amino group functionalized anionic surfactant templated mesoporous silica (Amino-AMS) for loading and release of poorly water-soluble drug indomethacin (IMC) and carboxyl group functionalized cationic surfactant templated mesoporous silica (Carboxyl-CMS) for loading and release of poorly water-soluble drug famotidine (FMT). Herein, Amino-AMS and Carboxyl-CMS were facilely synthesized using co-condensation method through two types of silane coupling agent. Amino-AMS was spherical nanoparticles, and Carboxyl-CMS was well-formed spherical nanosphere with a thin layer presented at the edge. Drug loading capacity was obviously enhanced when using Amino-AMS and Carboxyl-CMS as drug carriers due to the stronger hydrogen bonding force formed between surface modified carrier and drug. Amino-AMS and Carboxyl-CMS had the ability to transform crystalline state of loaded drug from crystalline phase to amorphous phase. Therefore, IMC loaded Amino-AMS presented obviously faster release than IMC because amorphous phase of IMC favored its dissolution. The application of asymmetric membrane capsule delayed FMT release significantly, and Carboxyl-CMS favored sustained release of FMT due to its long mesoporous channels and strong interaction formed between its carboxyl group and amino group of FMT. Copyright © 2015 Elsevier B.V. All rights reserved.

Dissolution Failure of Solid Oral Drug Products in Field Alert Reports.

PubMed

Sun, Dajun; Hu, Meng; Browning, Mark; Friedman, Rick L; Jiang, Wenlei; Zhao, Liang; Wen, Hong

2017-05-01

From 2005 to 2014, 370 data entries of dissolution failures of solid oral drug products were assessed with respect to the solubility of drug substances, dosage forms [immediate release (IR) vs. modified release (MR)], and manufacturers (brand name vs. generic). The study results show that the solubility of drug substances does not play a significant role in dissolution failures; however, MR drug products fail dissolution tests more frequently than IR drug products. When multiple variables were analyzed simultaneously, poorly water-soluble IR drug products failed the most dissolution tests, followed by poorly soluble MR drug products and very soluble MR drug products. Interestingly, the generic drug products fail dissolution tests at an earlier time point during a stability study than the brand name drug products. Whether the dissolution failure of these solid oral drug products has any in vivo implication will require further pharmacokinetic, pharmacodynamic, clinical, and drug safety evaluation. Food and Drug Administration is currently conducting risk-based assessment using in-house dissolution testing, physiologically based pharmacokinetic modeling and simulation, and post-market surveillance tools. At the meantime, this interim report will outline a general scheme of monitoring dissolution failures of solid oral dosage forms as a pharmaceutical quality indicator. Published by Elsevier Inc.

Caffeine: a potential complexing agent for solubility and dissolution enhancement of celecoxib.

PubMed

Shakeel, Faiyaz; Faisal, Mohammed S

2010-01-01

Complexation of caffeine with the drug celecoxib was used to enhance its solubility as well as in vitro dissolution in the present investigation. Caffeine was extracted from tea leaves using the sublimation method. A molecular complex (1:1) of caffeine-celecoxib was prepared using the solubility method. The solubility of celecoxib in distilled water and the caffeine complex was determined using a HPLC method at a wavelength of 250 nm. Dissolution studies of pure celecoxib, a marketed capsule (Celebrex), and the complex were performed using USP dissolution apparatus I for pure celecoxib and the complex and apparatus II for the capsule in distilled water. The highest solubility (48.32 mg/mL) as well as percent dissolution (90.54%) of celecoxib was obtained with the caffeine-celecoxib complex. The results for solubility and dissolution were highly significant as compared to pure celecoxib and the marketed capsule (p < 0.01). These results suggest that caffeine is a promising complexing agent for solubility as well as dissolution enhancement of the poorly soluble drug celecoxib.

Synthesis of water-soluble, multiple functionalizable dendrons for the conversion of large dendrimers or other molecular objects into potential drug carriers.

PubMed

Müller, Stephan; Schlüter, A Dieter

2005-09-19

The synthesis of dendrons and dendrimers which carry OEG chains and bidentate ligands and/or fluorescence tags is described. The orthogonally protected functional groups of the dendrons allow modification of the substitution pattern and attachment to larger entities. Both dendrons and dendrimers are highly water-soluble. The dendrons should have considerable potential to convert, for example, commercially available, high-generation dendrimers into water-soluble, versatile support materials for antitumor therapy.

Cyclodextrin controlled release of poorly water-soluble drugs from hydrogels.

PubMed

Woldum, Henriette Sie; Larsen, Kim Lambertsen; Madsen, Flemming

2008-01-01

The effect of 2-hydroxypropyl-beta-cyclodextrin and gamma-cyclodextrin on the release of ibuprofen, ketoprofen and prednisolone was studied. Stability constants calculated for inclusion complexes show size dependence for complexes with both cyclodextrins. Hydrogels were prepared by ultraviolet irradiation and release of each model drug was studied. For drugs formulated using cyclodextrins an increase in the achievable concentration and in the release from hydrogels was obtained due to increased solubility, although the solubility of all gamma-cyclodextrin complexes was limited. The load also was increased by adjusting pH for the acidic drugs and this exceeds the increase obtained with gamma-cyclodextrin addition.

Evaluation of diclofenac prodrugs for enhancing transdermal delivery.

PubMed

Lobo, Shabbir; Li, Henan; Farhan, Nashid; Yan, Guang

2014-03-01

Abstract Objective: The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD) and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates and bioconversion rates. In vitro fluxes across human epidermal membrane (HEM) in the Franz diffusion cell were determined on DA-, MD-, ED-, GD- and PD-saturated aqueous solutions. The formation of GD and ED led to the prodrugs with higher aqueous solubilities and lower partition coefficients than those of the parent drug. Prodrugs with improved aqueous solubility showed better fluxes across HEM in aqueous solution than that of the parent drug, with GD showing the highest aqueous solubility and also the highest flux. There is a linear relationship between the aqueous solubility and flux for DA, ED and PD, but GD and MD deviated from the linear line. Diclofenac prodrugs with improved hydrophilicity than the parent drug could be utilized for enhancing transdermal diclofenac delivery.

Mechanism and kinetics of the loss of poorly soluble drugs from liposomal carriers studied by a novel flow field-flow fractionation-based drug release-/transfer-assay.

PubMed

Hinna, Askell Hvid; Hupfeld, Stefan; Kuntsche, Judith; Bauer-Brandl, Annette; Brandl, Martin

2016-06-28

Liposomes represent a versatile drug formulation approach e.g. for improving the water-solubility of poorly soluble drugs but also to achieve drug targeting and controlled release. For the latter applications it is essential that the drug remains associated with the liposomal carrier during transit in the vascular bed. A range of in vitro test methods has been suggested over the years for prediction of the release of drug from liposomal carriers. The majority of these fail to give a realistic prediction for poorly water-soluble drugs due to the intrinsic tendency of such compounds to remain associated with liposome bilayers even upon extensive dilution. Upon i.v. injection, in contrast, rapid drug loss often occurs due to drug transfer from the liposomal carriers to endogenous lipophilic sinks such as lipoproteins, plasma proteins or membranes of red blood cells and endothelial cells. Here we report on the application of a recently introduced in vitro predictive drug transfer assay based on incubation of the liposomal drug carrier with large multilamellar liposomes, the latter serving as a biomimetic model sink, using flow field-flow fractionation as a tool to separate the two types of liposomes. By quantifying the amount of drug remaining associated with the liposomal drug carrier as well as that transferred to the acceptor liposomes at distinct times of incubation, both the kinetics of drug transfer and release to the water phase could be established for the model drug p-THPP (5,10,15,20-tetrakis(4-hydroxyphenyl)21H,23H-porphine). p-THPP is structurally similar to temoporfin, a photosensitizer which is under clinical evaluation in a liposomal formulation. Mechanistic insights were gained by varying the donor-to-acceptor lipid mass ratio, size and lamellarity of the liposomes. Drug transfer kinetics from one liposome to another was found rate determining as compared to redistribution from the outermost to the inner concentric bilayers, such that the overall process could be adequately described by a single 1st order kinetic model. By varying the donor-to-acceptor lipid mass ratio in the range 1:1 to 1:10, a correlation was established between donor-to-acceptor-lipid mass ratio and transfer kinetics, which is regarded essential for scaling to physiological lipid mass ratios. By applying the assay to a series of structurally related model compounds of different bilayer affinity, transfer and release kinetics were established over the whole expected range of liposome bilayer associated drugs in terms of water solubility and lipophilicity. A very rapid transfer and considerable release from liposomes to the water phase was observed for the more water-soluble compounds Sudan II (clogP 5.45) and Sudan III (clogP 6.83). For the more lipophilic compounds, the rate of transfer from the donor liposomes followed the rank order Sudan IV (fastest)>Oil Red O>Sudan Black>p-THPP (slowest). For an equimolar donor-to-acceptor lipid mass ratio, half-lifes of transfer in the range of 12min (Sudan IV) up to 1.5h (p-THPP) were determined. In essence, the results presented here allow for both, mechanistic insights and predictions of drug loss from liposomal carriers upon exposure to biological sinks, which appear more realistic than the commonly employed in vitro release tests. Copyright © 2016 Elsevier B.V. All rights reserved.

Soluble 1:1 complexes and insoluble 3:2 complexes - Understanding the phase-solubility diagram of hydrocortisone and γ-cyclodextrin.

PubMed

Schönbeck, Christian; Madsen, Tobias L; Peters, Günther H; Holm, René; Loftsson, Thorsteinn

2017-10-15

The molecular mechanisms underlying the drug-solubilizing properties of γ-cyclodextrin were explored using hydrocortisone as a model drug. The B S -type phase-solubility diagram of hydrocortisone with γ-cyclodextrin was thoroughly characterized by measuring the concentrations of hydrocortisone and γ-cyclodextrin in solution and the solid phase. The drug-solubilizer interaction was also studied by isothermal titration calorimetry from which a precise value of the 1:1 binding constant (K 11 =4.01mM -1 at 20°C) was obtained. The formation of water-soluble 1:1 complexes is responsible for the initial increase in hydrocortisone solubility while the precipitation of entities with a 3:2 ratio of γ-cyclodextrin:hydrocortisone is responsible for the plateau and the ensuing strong decrease in solubility once all solid hydrocortisone is used up. The complete phase-solubility diagram is well accounted for by a model employing the 1:1 binding constant and the solubility product of the precipitating 3:2 entity (K 32 S =5.51 mM 5 ). For such systems, a small surplus of γ-cyclodextrin above the optimum concentration may result in a significant decrease in drug solubility, and the implications for drug formulations are briefly discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

New spectrophotometric estimation of indomethacin capsules with niacinamide as hydrotropic solubilizing agent.

PubMed

Maheshwari, R K; Rathore, Amit; Agrawal, Archana; Gupta, Megha A

2011-07-01

Hydrotropic solubilization process involves cooperative intermolecular interaction with several balancing molecular forces, rather than either a specific complexation event or a process dominated by a medium effect, such as co-solvency or salting-in. In the present investigation, hydrotropic solution of 2 M niacinamide was employed as the solubilizing agent to solubilize the poorly water-soluble drug, indomethacin, from the capsule dosage form for spectrophotometric determination in ultraviolet region. Hydrotropic agent used did not interfere in the spectrophotometric analysis. In preliminary solubility studies, it was found that there was more than fivefold enhancement in the aqueous solubility of indomethacin (poorly water-soluble drug) in 2 M niacinamide solution as compared to its aqueous solubility at 28 ± 1°C. The proposed method is new, simple, safe, environmentally friendly, economic, accurate and cost-effective and can be successfully employed in routine analysis.

Design and evaluation of self-nanoemulsifying pellets of repaglinide.

PubMed

Desai, N S; Nagarsenker, M S

2013-09-01

The aim of study was to develop self-nanoemulsifying pellets (SNEP) for oral delivery of poorly water soluble drug, repaglinide (RPG). Solubility of RPG in oily phases and surfactants was determined to identify components of self-nanoemulsifying drug delivery system (SNEDDS). The surfactants and cosurfactants were screened for their ability to emulsify oily phase. Ternary phase diagrams were constructed to identify nanoemulsification area for the selected systems. SNEDDS formulations with globule size less than 100 nm were evaluated for in vivo anti-hyperglycemic activity in neonatal streptozotocin rat model. A significant reduction in glucose levels was produced by optimized SNEDDS formulation in comparison to the control group. The optimized SNEDDS formulations were pelletized via extrusion/spheronization technique using microcrystalline cellulose and lactose. SNEP were characterized by X-ray powder diffraction and scanning electron microscopy. X-ray diffraction study indicated loss of crystallinity of RPG in SNEP. The SNEP exhibited good flow properties, mechanical strength and formed nanoemulsion with globule size less than 200 nm. SNEP showed in vitro release of more than 80% RPG in 10 min which was significantly higher than RPG containing reference pellets. In conclusion, our studies illustrated that RPG, a poorly water soluble drug can be successfully formulated into SNEP which can serve as a promising system for the delivery of poorly water soluble drugs.

Biodegradable fibre scaffolds incorporating water-soluble drugs and proteins.

PubMed

Ma, J; Meng, J; Simonet, M; Stingelin, N; Peijs, T; Sukhorukov, G B

2015-07-01

A new type of biodegradable drug-loaded fibre scaffold has been successfully produced for the benefit of water-soluble drugs and proteins. Model drug loaded calcium carbonate (CaCO3) microparticles incorporated into poly(lactic acid-co-glycolic acid) (PLGA) fibres were manufactured by co-precipitation of CaCO3 and the drug molecules, followed by electrospinning of a suspension of such drug-loaded microparticles in a PLGA solution. Rhodamine 6G and bovine serum albumin were used as model drugs for our release study, representing small bioactive molecules and protein, respectively. A bead and string structure of fibres was achieved. The drug release was investigated with different drug loadings and in different pH release mediums. Results showed that a slow and sustained drug release was achieved in 40 days and the CaCO3 microparticles used as the second barrier restrained the initial burst release.

Phase solubility, 1H NMR and molecular modelling studies of bupivacaine hydrochloride complexation with different cyclodextrin derivates

NASA Astrophysics Data System (ADS)

Jug, Mario; Mennini, Natascia; Melani, Fabrizio; Maestrelli, Francesca; Mura, Paola

2010-11-01

A novel method, which simultaneously exploits experimental (NMR) and theoretically calculated data obtained by a molecular modelling technique, was proposed, to obtain deeper insight into inclusion geometry and possible stereoselective binding of bupivacaine hydrochloride with selected cyclodextrin derivatives. Sulphobuthylether-β-cyclodextrin and water soluble polymeric β-cyclodextrin demonstrated to be the best complexing agents for the drug, resulting in formation of the most stable inclusion complexes with the highest increase in aqueous drug solubility. The drug-carrier binding modes with these cyclodextrins and phenomena which may be directly related to the higher stability and better aqueous solubility of complexes formed were discussed in details.

Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs.

PubMed

Dahan, Arik; Hoffman, Amnon

2008-07-02

As a consequence of modern drug discovery techniques, there has been a consistent increase in the number of new pharmacologically active lipophilic compounds that are poorly water soluble. A great challenge facing the pharmaceutical scientist is making these molecules into orally administered medications with sufficient bioavailability. One of the most popular approaches to improve the oral bioavailability of these molecules is the utilization of a lipid based drug delivery system. Unfortunately, current development strategies in the area of lipid based delivery systems are mostly empirical. Hence, there is a need for a simplified in vitro method to guide the selection of a suitable lipidic vehicle composition and to rationalize the delivery system design. To address this need, a dynamic in vitro lipolysis model, which provides a very good simulation of the in vivo lipid digestion process, has been developed over the past few years. This model has been extensively used for in vitro assessment of different lipid based delivery systems, leading to enhanced understanding of the suitability of different lipids and surfactants as a delivery system for a given poorly water soluble drug candidate. A key goal in the development of the dynamic in vitro lipolysis model has been correlating the in vitro data of various drug-lipidic delivery system combinations to the resultant in vivo drug profile. In this paper, we discuss and review the need for this model, its underlying theory, practice and limitations, and the available data accumulated in the literature. Overall, the dynamic in vitro lipolysis model seems to provide highly useful initial guidelines in the development process of oral lipid based drug delivery systems for poorly water soluble drugs, and it predicts phenomena that occur in the pre-enterocyte stages of the intestinal absorption cascade.

N-succinyl-chitosan as a drug carrier: water-insoluble and water-soluble conjugates.

PubMed

Kato, Yoshinori; Onishi, Hiraku; Machida, Yoshiharu

2004-02-01

N-succinyl-chitosan (Suc-Chi) has favourable properties as a drug carrier such as biocompatibility, low toxicity and long-term retention in the body. It was long retained in the systemic circulation after intravenous administration, and the plasma half-lives of Suc-Chi (MW: 3.4 x 10(5); succinylation degree: 0.81 mol/sugar unit; deacetylation degree: 1.0 mol/sugar unit) were ca. 100.3h in normal mice and 43 h in Sarcoma 180-bearing mice. The biodistribution of Suc-Chi into other tissues was trace apart from the prostate and lymph nodes. The maximum tolerable dose for the intraperitoneal injection of Suc-Chi to mice was greater than 2 g/kg. The water-insoluble and water-soluble conjugates could be prepared using a water-soluble carbodiimide and mitomycin C (MMC) or using an activated ester of glutaric MMC. In vitro release characteristics of these conjugates showed similar patterns, i.e. a pH-dependent manner, except that water-insoluble conjugates showed a slightly slower release of MMC than water-soluble ones. The conjugates of MMC with Suc-Chi showed good antitumour activities against various tumours such as murine leukaemias (L1210 and P388), B16 melanoma, Sarcoma 180 solid tumour, a murine liver metastatic tumour (M5076) and a murine hepatic cell carcinoma (MH134). This review summarizes the utilization of Suc-Chi as a drug carrier for macromolecular conjugates of MMC and the therapeutic efficacy of the conjugates against various tumours.

Classification of solid dispersions: correlation to (i) stability and solubility (ii) preparation and characterization techniques.

PubMed

Meng, Fan; Gala, Urvi; Chauhan, Harsh

2015-01-01

Solid dispersion has been a topic of interest in recent years for its potential in improving oral bioavailability, especially for poorly water soluble drugs where dissolution could be the rate-limiting step of oral absorption. Understanding the physical state of the drug and polymers in solid dispersions is essential as it influences both the stability and solubility of these systems. This review emphasizes on the classification of solid dispersions based on the physical states of drug and polymer. Based on this classification, stability aspects such as crystallization tendency, glass transition temperature (Tg), drug polymer miscibility, molecular mobility, etc. and solubility aspects have been discussed. In addition, preparation and characterization methods for binary solid dispersions based on the classification have also been discussed.

Development and validation of in silico models for estimating drug preformulation risk in PEG400/water and Tween80/water systems.

PubMed

Crivori, Patrizia; Morelli, Amedea; Pezzetta, Daniele; Rocchetti, Maurizio; Poggesi, Italo

2007-11-01

Solubility is one of the most important properties of drug candidates for achieving the targeted plasma concentrations following oral dosing. Furthermore, the formulations adopted in the in vivo preclinical studies, for both oral and intravenous administrations, are usually solutions. To formulate compounds sparingly soluble in water, pharmaceutically acceptable cosolvents or surfactants are typically employed to increase solubility. Compounds poorly soluble also in these systems will likely show severe formulation issues. In such cases, relatively high amount of compounds, rarely available in the early preclinical phases, are needed to identify the most appropriate dosing vehicles. Hence, the purpose of this study was to build two computational models which, on the basis of the molecular structure, are able to predict the compound solubility in two vehicle systems (40% PEG400/water and 10% Tween80/water) used in our company as screening tools for anticipating potential formulation issues. The two models were developed using the solubility data obtained from the analysis of approximately 2000 chemically diverse compounds. The structural diversity and the drug-like space covered by these molecules were investigated using the ChemGPS methodology. The compounds were classified (high/low preformulation risk) based on the experimental solubility value range. A combination of descriptors (i.e. logD at two different pH, E-state indices and other 2D structural descriptors) was correlated to these classes using partial least squares discriminant (PLSD) analysis. The overall accuracy of each PLSD model applied to independent sets of compounds was approximately 78%. The accuracy reached when the models were used in combination to identify molecules with low preformulation risk in both systems was 83%. The models appeared a valuable tool for predicting the preformulation risk of drug candidates and consequently for identifying the most appropriate dosing vehicles to be further investigated before the first in vivo preclinical studies. Since only a small number of 2D descriptors is need to evaluate the preformulation risk classes, the models resulted easy to use and characterized by high throughput.

Enhanced encapsulation and bioavailability of breviscapine in PLGA microparticles by nanocrystal and water-soluble polymer template techniques.

PubMed

Wang, Hong; Zhang, Guangxing; Ma, Xueqin; Liu, Yanhua; Feng, Jun; Park, Kinam; Wang, Wenping

2017-06-01

Poly (lactide-co-glycolide) (PLGA) microparticles are widely used for controlled drug delivery. Emulsion methods have been commonly used for preparation of PLGA microparticles, but they usually result in low loading capacity, especially for drugs with poor solubility in organic solvents. In the present study, the nanocrystal technology and a water-soluble polymer template method were used to fabricate nanocrystal-loaded microparticles with improved drug loading and encapsulation efficiency for prolonged delivery of breviscapine. Breviscapine nanocrystals were prepared using a precipitation-ultrasonication method and further loaded into PLGA microparticles by casting in a mold from a water-soluble polymer. The obtained disc-like particles were then characterized and compared with the spherical particles prepared by an emulsion-solvent evaporation method. X-ray powder diffraction (XRPD) and confocal laser scanning microscopy (CLSM) analysis confirmed a highly-dispersed state of breviscapine inside the microparticles. The drug form, loading percentage and fabrication techniques significantly affected the loading capacity and efficiency of breviscapine in PLGA microparticles, and their release performance as well. Drug loading was increased from 2.4% up to 15.3% when both nanocrystal and template methods were applied, and encapsulation efficiency increased from 48.5% to 91.9%. But loading efficiency was reduced as the drug loading was increased. All microparticles showed an initial burst release, and then a slow release period of 28days followed by an erosion-accelerated release phase, which provides a sustained delivery of breviscapine over a month. A relatively stable serum drug level for more than 30days was observed after intramuscular injection of microparticles in rats. Therefore, PLGA microparticles loaded with nanocrystals of poorly soluble drugs provided a promising approach for long-term therapeutic products characterized with preferable in vitro and in vivo performance. Copyright © 2017 Elsevier B.V. All rights reserved.

Nanocarrier for poorly water-soluble anticancer drugs--barriers of translation and solutions.

PubMed

Narvekar, Mayuri; Xue, Hui Yi; Eoh, June Young; Wong, Ho Lun

2014-08-01

Many existing chemotherapeutic drugs, repurposed drugs and newly developed small-molecule anticancer compounds have high lipophilicity and low water-solubility. Currently, these poorly water-soluble anticancer drugs (PWSAD) are generally solubilized using high concentrations of surfactants and co-solvents, which frequently lead to adverse side effects. In recent years, researchers have been actively exploring the use of nanotechnology as an alternative to the solvent-based drug solubilization approach. Several classes of nanocarrier systems (lipid-based, polymer-based and albumin-based) are widely studied for encapsulation and delivery of the existing and new PWSAD. These nanocarriers were also shown to offer several additional advantages such as enhanced tumour accumulation, reduced systemic toxicity and improved therapeutic effectiveness. In this article, the recent nanotechnological advances in PWSAD delivery will be reviewed. The barriers commonly encountered in the development of PWSAD nanoformulations (e.g. formulation issues and nanotoxicity issues) and the strategies to overcome these barriers will also be discussed. It is our goal to provide the pharmaceutical scientists and clinicians with more in-depth information about the nanodelivery approach, thus, more efficacious and safe PWSAD nanoformulations can be developed with improved translational success.

Molecular Dynamics, Recrystallization Behavior, and Water Solubility of the Amorphous Anticancer Agent Bicalutamide and Its Polyvinylpyrrolidone Mixtures.

PubMed

Szczurek, Justyna; Rams-Baron, Marzena; Knapik-Kowalczuk, Justyna; Antosik, Agata; Szafraniec, Joanna; Jamróz, Witold; Dulski, Mateusz; Jachowicz, Renata; Paluch, Marian

2017-04-03

In this paper, we investigated the molecular mobility and physical stability of amorphous bicalutamide, a poorly water-soluble drug widely used in prostate cancer treatment. Our broadband dielectric spectroscopy measurements and differential scanning calorimetry studies revealed that amorphous BIC is a moderately fragile material with a strong tendency to recrystallize from the amorphous state. However, mixing the drug with polymer polyvinylpyrrolidone results in a substantial improvement of physical stability attributed to the antiplasticizing effect governed by the polymer additive. Furthermore, IR study demonstrated the existence of specific interactions between the drug and excipient. We found out that preparation of bicalutamide-polyvinylpyrrolidone mixture in a 2-1 weight ratio completely hinder material recrystallization. Moreover, we determined the time-scale of structural relaxation in the glassy state for investigated materials. Because molecular mobility is considered an important factor governing crystallization behavior, such information was used to approximate the long-term physical stability of an amorphous drug and drug-polymer systems upon their storage at room temperature. Moreover, we found that such systems have distinctly higher water solubility and dissolution rate in comparison to the pure amorphous form, indicating the genuine formulation potential of the proposed approach.

Enhanced encapsulation of metoprolol tartrate with carbon nanotubes as adsorbent

NASA Astrophysics Data System (ADS)

Garala, Kevin; Patel, Jaydeep; Patel, Anjali; Dharamsi, Abhay

2011-12-01

A highly water-soluble antihypertensive drug, metoprolol tartrate (MT), was selected as a model drug for preparation of multi-walled carbon nanotubes (MWCNTs)-impregnated ethyl cellulose (EC) microspheres. The present investigation was aimed to increase encapsulation efficiency of MT with excellent adsorbent properties of MWCNTs. The unique surface area, stiffness, strength and resilience of MWCNTs have drawn much anticipation as carrier for highly water-soluble drugs. Carbon nanotubes drug adsorbate (MWCNTs:MT)-loaded EC microspheres were further optimized by the central composite design of the experiment. The effects of independent variables (MWCNTs:MT and EC:adsorbate) were evaluated on responses like entrapment efficiency (EE) and t 50 (time required for 50% drug release). The optimized batch was compared with drug alone EC microspheres. The results revealed high degree of improvement in encapsulation efficiency for MWCNTs:MT-loaded EC microspheres. In vitro drug release study exhibited complete release form drug alone microspheres within 15 h, while by the same time only 50-60% drug was released for MWCNTs-impregnated EC microspheres. The optimized batch was further characterized by various instrumental analyses such as scanning electron microscopy, powder X-ray diffraction and differential scanning calorimetry. The results endorse encapsulation of MWCNTs:MT adsorbate inside the matrix of EC microspheres, which might have resulted in enhanced encapsulation and sustained effect of MT. Hence, MWCNTs can be utilized as novel carriers for extended drug release and enhanced encapsulation of highly water-soluble drug, MT.

Solid dispersions, part I: recent evolutions and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs.

PubMed

Bikiaris, Dimitrios N

2011-11-01

In recent years, the number of active pharmaceutical ingredients with high therapeutic impact, but very low water solubility, has increased significantly. Thus, a great challenge for pharmaceutical technology is to create new formulations and efficient drug-delivery systems to overcome these dissolution problems. Drug formulation in solid dispersions (SDs) is one of the most commonly used techniques for the dissolution rate enhancement of poorly water-soluble drugs. Generally, SDs can be defined as a dispersion of active ingredients in molecular, amorphous and/or microcrystalline forms into an inert carrier. This review covers literature which states that the dissolution enhancement of SDs is based on the fact that drugs in the nanoscale range, or in amorphous phase, dissolve faster and to a greater extent than micronized drug particles. This is in accordance to the Noyes-Whitney equation, while the wetting properties of the used polymer may also play an important role. The main factors why SD-based pharmaceutical products on the market are steadily increasing over the last few years are: the recent progress in various methods used for the preparation of SDs, the effect of evolved interactions in physical state of the drug and formulation stability during storage, the characterization of the physical state of the drug and the mechanism of dissolution rate enhancement.

Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: III. Impact of drug nanoparticle loading.

PubMed

Krull, Scott M; Moreno, Jacqueline; Li, Meng; Bilgili, Ecevit; Davé, Rajesh N

2017-05-15

Polymer strip films have emerged as a robust platform for poorly water-soluble drug delivery. However, the common conception is that films cannot exceed low drug loadings, mainly due to poor drug stability, slow release, and film brittleness. This study explores the ability to achieve high loadings of poorly water-soluble drug nanoparticles in strip films while retaining good mechanical properties and enhanced dissolution rate. Aqueous suspensions containing up to 30wt% griseofulvin nanoparticles were prepared via wet stirred media milling and incorporated into hydroxypropyl methylcellulose (HPMC) films. Griseofulvin loading in films was adjusted to be between 9 and 49wt% in HPMC-E15 films and 30 and 73wt% in HPMC-E4M films by varying the mixing ratio of HPMC solution-to-griseofulvin suspension. All films exhibited good content uniformity and nanoparticle redispersibility up to 50wt% griseofulvin, while E4M films above 50wt% griseofulvin had slightly worse content uniformity and poor nanoparticle redispersibility. Increasing drug loading in films generally required more time to achieve 100% release during dissolution, although polymer-drug clusters dispersed from E4M films above 50wt% griseofulvin, resulting in similar dissolution profiles. While all films exhibited good tensile strength, a significant decrease in percent elongation was observed above 40-50wt% GF, resulting in brittle films. Copyright © 2017 Elsevier B.V. All rights reserved.

Preparation of Starch/Gelatin Blend Microparticles by a Water-in-Oil Emulsion Method for Controlled Release Drug Delivery.

PubMed

Phromsopha, Theeraphol; Baimark, Yodthong

2014-01-01

Information on the preparation and properties of starch/gelatin blend microparticles with and without crosslinking for drug delivery is presented. The blend microparticles were prepared by the water-in-oil emulsion solvent diffusion method. Glutaraldehyde and methylene blue were used as the crosslinker and the water-soluble drug model, respectively. The blend microparticles were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and UV-Vis spectroscopy. The functional groups of the starch and gelatin blend matrices were determined from the FTIR spectra. Blend microparticles with a nearly spherical shape and internal porous structure were observed from SEM images. The average particle size of the gelatin microparticles depended on the crosslinker ratio but not on the starch/gelatin blend ratio. The in vitro drug release content significantly decreased as the crosslinker ratio increased and the starch blend ratio decreased. The results demonstrated that the starch/gelatin blend microparticles should be a useful controlled release delivery carrier for water-soluble drugs.

Preparation of Starch/Gelatin Blend Microparticles by a Water-in-Oil Emulsion Method for Controlled Release Drug Delivery

PubMed Central

Phromsopha, Theeraphol; Baimark, Yodthong

2014-01-01

Information on the preparation and properties of starch/gelatin blend microparticles with and without crosslinking for drug delivery is presented. The blend microparticles were prepared by the water-in-oil emulsion solvent diffusion method. Glutaraldehyde and methylene blue were used as the crosslinker and the water-soluble drug model, respectively. The blend microparticles were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and UV-Vis spectroscopy. The functional groups of the starch and gelatin blend matrices were determined from the FTIR spectra. Blend microparticles with a nearly spherical shape and internal porous structure were observed from SEM images. The average particle size of the gelatin microparticles depended on the crosslinker ratio but not on the starch/gelatin blend ratio. The in vitro drug release content significantly decreased as the crosslinker ratio increased and the starch blend ratio decreased. The results demonstrated that the starch/gelatin blend microparticles should be a useful controlled release delivery carrier for water-soluble drugs. PMID:24868207

pH-dependent solubility of indomethacin-saccharin and carbamazepine-saccharin cocrystals in aqueous media.

PubMed

Alhalaweh, Amjad; Roy, Lilly; Rodríguez-Hornedo, Naír; Velaga, Sitaram P

2012-09-04

Cocrystals constitute an important class of pharmaceutical solids for their remarkable ability to modulate solubility and pH dependence of water insoluble drugs. Here we show how cocrystals of indomethacin-saccharin (IND-SAC) and carbamazepine-saccharin (CBZ-SAC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND-SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ-SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate. Cocrystal solubility dependence on pH predicted from mathematical models using cocrystal K(sp), and cocrystal component K(a) values, was in excellent agreement with experimental measurements. The cocrystal solubility increase relative to drug was predicted to reach a limiting value for a cocrystal with two acidic components. This limiting value is determined by the ionization constants of cocrystal components. Eutectic constants are shown to be meaningful indicators of cocrystal solubility and its pH dependence. The two contributions to solubility, cocrystal lattice and solvation, were evaluated by thermal and solubility determinations. The results show that solvation is the main barrier for the aqueous solubility of these drugs and their cocrystals, which are orders of magnitude higher than their lattice barriers. Cocrystal increase in solubility is thus a result of decreasing the solvation barrier compared to that of the drug. This work demonstrates the favorable properties of cocrystals and strategies that facilitate their meaningful characterization.

Synthesis, characterization and fluorescent properties of water-soluble glycopolymer bearing curcumin pendant residues.

PubMed

Zhang, Haisong; Yu, Meng; Zhang, Hailei; Bai, Libin; Wu, Yonggang; Wang, Sujuan; Ba, Xinwu

2016-08-01

Curcumin is a potential natural anticancer drug with low oral bioavailability because of poor water solubility. The aqueous solubility of curcumin is enhanced by means of modification with the carbohydrate units. Polymerization of the curcumin-containing monomer with carbohydrate-containing monomer gives the water-soluble glycopolymer bearing curcumin pendant residues. The obtained copolymers (P1 and P2) having desirable water solubility were well-characterized by infrared spectroscopy (IR), nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), UV-Vis absorption spectroscopy, and photoluminescence spectroscopy. The copolymer P2 with a molar ratio of 1:6 (curcumin/carbohydrate) calculated from the proton NMR results exhibits a similar anticancer activity compared to original curcumin, which may serve as a potential chemotherapeutic agent in the field of anticancer medicine.

Development of drug-loaded chitosan hollow nanoparticles for delivery of paclitaxel to human lung cancer A549 cells.

PubMed

Jiang, Jie; Liu, Ying; Wu, Chao; Qiu, Yang; Xu, Xiaoyan; Lv, Huiling; Bai, Andi; Liu, Xuan

2017-08-01

In this study, biodegradable chitosan hollow nanospheres (CHN) were fabricated using polystyrene nanospheres (PS) as templates. CHN were applied to increase the solubility of poorly water-soluble drugs. The lung cancer drug paclitaxel (PTX), which is used as a model drug, was loaded into CHN by the adsorption equilibrium method. The drug-loaded sample (PTX-CHN) offered sustained PTX release and good bioavailability. The state characterization of PTX by differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) showed that the PTX absorbed into CHN existed in an amorphous state. An in vitro toxicity experiment indicated that CHN were nontoxic as carriers of poorly water-soluble drugs. The PTX-CHN produced a marked inhibition of lung cancer A549 cells proliferation and encouraged apoptosis. A cell uptake experiment indicated that PTX-CHN was successfully taken up by lung cancer A549 cells. Furthermore, a degradation experiment revealed that CHN were readily biodegradable. These findings state clearly that CHN can be regarded as promising biomaterials for lung cancer treatment.

Synthesis and Characterization of Water-soluble Conjugates of Cabazitaxel Hemiesters-Dextran.

PubMed

Parhizkar, Elahehnaz; Ahmadi, Fatemeh; Daneshamouz, Saeid; Mohammadi-Samani, Soliman; Sakhteman, Amirhossein; Parhizkar, Golnaz

2017-11-24

Cabazitaxel (CTX) is a second- generation taxane derivative, a class of potent anticancer drugs with very low water solubility. CTX is used in patients with resistant prostate cancer unresponsive to the first generation taxane, docetaxel. Currently marketed formulations of CTX contain high concentrations of surfactant and ethanol, which cause severe hypersensitivity reactions in patients. In order to increase its solubility, two hemiester analogs; CTX-succinate and CTX-glutarate were synthesized and characterized. To improve the solubility of hemiesters even more, dextran as a biocompatible polymer was also conjugated to hemiester analogs. MTT assay was performed on MCF-7 cell line to evaluate the cytotoxicity effect of hemiesters and conjugates. Based on the results, hemiester analogs increased water solubility of the drug up to about 3 and 8 fold. Conjugation to dextran enhanced the CTX solubility to more than 1500 fold. These conjugates released the conjugated CTX in less than 24 hours in a pH dependent manner and showed proper hemocompatibility characteristics. The hemiesters had approximately similar cytotoxicity in comparison with CTX and the dextran conjugates showed higher cytotoxicity effect on MCF-7 cell line. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effect of aminoalkyl methacrylate copolymer E/HCl on in vivo absorption of poorly water-soluble drug.

PubMed

Yoshida, Takatsune; Kurimoto, Ippei; Yoshihara, Keiichi; Umejima, Hiroyuki; Ito, Naoki; Watanabe, Shunsuke; Sako, Kazuhiro; Kikuchi, Akihiko

2013-11-01

This study aimed to investigate in vivo absorption of tacrolimus formulated as a solid dispersion using Eudragit E®/HCl (E-SD). E-SD is an aminoalkyl methacrylate copolymer that can be dissolved under neutral pH conditions. E-SD was used alone as a solid dispersion carrier and/or was mixed with tacrolimus primarily dispersed with hydroxypropylmethylcellulose (HPMC). Tacrolimus was formulated with E-SD at several different ratios. Formulations with tacrolimus/E-SD ratio of 1/3 showed higher in vivo absorption, compared to tacrolimus dispersed in the excipients (primarily HPMC) found in commercially available tacrolimus capsules, using a rat in situ closed loop method. Good correlation was observed between in vitro drug solubility and in vivo drug absorption. In vitro solubility tests and rat oral absorption studies of tacrolimus/HPMC solid dispersion formulations were also conducted after mixing the HPMC dispersion with several ratios of E-SD. E-SD/tacrolimus/HPMC formulations yielded high in vitro drug solubility but comparatively low in vivo absorption. Dog oral absorption studies were conducted using capsules containing a formulation of tacrolimus/E-SD at a ratio of 1/5. The E-SD formulation-containing capsule showed higher in vivo drug absorption than tacrolimus dispersed in the standard HPMC capsule. These studies report enhancement of the in vivo absorption of a poorly water-soluble drug following dispersion with E-SD when compared to formulation in HPMC.

Alginate-caseinate composites: Molecular interactions and characterization of cross-linked beads for the delivery of anticandidals.

PubMed

Khlibsuwan, Rapee; Khunkitti, Watcharee; Pongjanyakul, Thaned

2018-04-19

Polysaccharide-protein composites offer potential utility for the delivery of drugs. The objectives of this work were to investigate the molecular interactions between sodium alginate (SA) and sodium caseinate (SC) in dispersions and films and to characterize calcium alginate (CA) beads mixed with SC for the delivery of fluconazole (FZ) and clotrimazole (CZ). The results demonstrated that SA could interact with SC, which caused a viscosity synergism in the dispersions. Hydrogen bonding between the carboxyl or hydroxyl groups of SA and the amide groups of SC led to the formation of soluble complexes that could reinforce the CA beads prepared by calcium cross-linking. The SC-CA beads provided higher drug entrapment efficiency, lower water uptake and erosion, and slower drug release than for the CA beads. The loaded FZ was an amorphous form, but CZ crystals were embedded in the bead matrix due to the low water solubility of this drug. However, SC micellization could enhance the water solubility and efficacy of CZ against Candida albicans. This finding indicates that SA can interact with SC via hydrogen bonding to form complexes and that the anticandidal-loaded SC-CA beads can be used as drug delivery systems and drug reservoirs in tablets for oral candidiasis. Copyright © 2018 Elsevier B.V. All rights reserved.

Cocrystal solubilization in biorelevant media and its prediction from drug solubilization

PubMed Central

Lipert, Maya P.; Roy, Lilly; Childs, Scott L.

2015-01-01

This work examines cocrystal solubility in biorelevant media, (FeSSIF, fed state simulated intestinal fluid), and develops a theoretical framework that allows for the simple and quantitative prediction of cocrystal solubilization from drug solubilization. The solubilities of four hydrophobic drugs and seven cocrystals containing these drugs were measured in FeSSIF and in acetate buffer at pH 5.00. In all cases, the cocrystal solubility (Scocrystal) was higher than the drug solubility (Sdrug) in both buffer and FeSSIF; however, the solubilization ratio of drug, SRdrug = (SFeSSIF/Sbuffer)drug, was not the same as the solubilization ratio of cocrystal, SRcocrystal = (SFeSSIF/Sbuffer)cocrystal, meaning drug and cocrystal were not solubilized to the same extent in FeSSIF. This highlights the potential risk of anticipating cocrystal behavior in biorelevant media based on solubility studies in water. Predictions of SRcocrystal from simple equations based only on SRdrug were in excellent agreement with measured values. For 1:1 cocrystals, the cocrystal solubilization ratio can be obtained from the square root of the drug solubilization ratio. For 2:1 cocrystals, SRcocrystal is found from (SRdrug)2/3. The findings in FeSSIF can be generalized to describe cocrystal behavior in other systems involving preferential solubilization of a drug such as surfactants, lipids, and other drug solubilizing media. PMID:26390213

pH-Dependent Liquid-Liquid Phase Separation of Highly Supersaturated Solutions of Weakly Basic Drugs.

PubMed

Indulkar, Anura S; Box, Karl J; Taylor, Robert; Ruiz, Rebeca; Taylor, Lynne S

2015-07-06

Supersaturated solutions of poorly aqueous soluble drugs can be formed both in vivo and in vitro. For example, increases in pH during gastrointestinal transit can decrease the aqueous solubility of weakly basic drugs resulting in supersaturation, in particular when exiting the acidic stomach environment. Recently, it has been observed that highly supersaturated solutions of drugs with low aqueous solubility can undergo liquid-liquid phase separation (LLPS) prior to crystallization, forming a turbid solution such that the concentration of the drug in the continuous solution phase corresponds to the amorphous solubility while the colloidal phase is composed of a disordered drug-rich phase. Although it is well established that the equilibrium solubility of crystalline weakly basic drugs follows the Henderson-Hasselbalch relationship, the impact of pH on the LLPS phenomenon or the amorphous solubility has not been explored. In this work, the LLPS concentration of three weakly basic compounds-clotrimazole, nicardipine, and atazanavir-was determined as a function of pH using three different methods and was compared to the predicted amorphous solubility, which was calculated from the pH-dependent crystalline solubility and by estimating the free energy difference between the amorphous and crystalline forms. It was observed that, similar to crystalline solubility, the experimental amorphous solubility at any pH follows the Henderson-Hasselbalch relation and can be predicted if the amorphous solubility of the free base is known. Excellent agreement between the LLPS concentration and the predicted amorphous solubility was observed. Dissolution studies of amorphous drugs showed that the solution concentration can reach the corresponding LLPS concentration at that pH. Solid-state analysis of the precipitated material confirmed the amorphous nature. This work provides insight into the pH-dependent precipitation behavior of poorly water-soluble compounds and provides a fundamental basis with which to understand the performance of supersaturating dosage forms.

A novel strategy to design sustained-release poorly water-soluble drug mesoporous silica microparticles based on supercritical fluid technique.

PubMed

Li-Hong, Wang; Xin, Che; Hui, Xu; Li-Li, Zhou; Jing, Han; Mei-Juan, Zou; Jie, Liu; Yi, Liu; Jin-Wen, Liu; Wei, Zhang; Gang, Cheng

2013-09-15

The organic solvent solution immersion method was often used to achieve the loading of the drugs into mesoporous silica, but the drugs that have loaded into the pores of the mesoporous silica would inevitable migrate from the inside to the external surface or near the outside surface during the process of drying. Hence, it often leads to the pores of mesoporous materials not be fully utilized, and results in a low drug loading efficiency and a fast releasing rate. The purpose of this study was to develop a novel drug loading strategy to avoid soluble component migration during the process of drying, then, to prepare poorly water-soluble drug mesoporous silica microparticles with higher drug loading efficiency and longer sustained-release time. Ibuprofen was used as model drug. The microparticles were prepared by a novel method based on mesoporous silica and supercritical fluid (SCF) technique. The drug-loaded mesoporous silica microparticles prepared by SCF technique were analyzed by thermogravimetric analysis (TGA), N2 adsorption/desorption, scanning electron microscopy (SEM), powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). In vitro releasing study was used to evaluate the sustained-release effect of the drug-loaded microparticles. By virtue of the high diffusibility and the high dissolving capacity of the supercritical carbon dioxide (SCF-CO2), the poorly water-soluble drugs, ibuprofen, entered the pores of the mesoporous silica. The amount and the depth of ibuprofen entered the pores of the mesoporous silica by SCF technique were both larger than those by the solution immersion method. It was found that ibuprofen loaded into the mesoporous silica by SCF technique was amorphous and the largest amount of the ibuprofen loaded into the mesoporous silica by SCF technique could reach 386 mg/g (w/w, ibuprofen/SiO2), it was more than that by the solution immersion method. In vitro releasing study showed that the sustained-release effect of ibuprofen in the samples prepared by SCF technique was 50% in 15 min and 90% in 60 min. It was longer than that prepared by the solution immersion method. Present study showed that sustained-release poorly water-soluble drug mesoporous silica microparticle based on SCF technique has twofold advantages. One is the larger drug loading amount in internal pores of the mesoporous silica, the other is the longer drug releasing time. Copyright © 2013 Elsevier B.V. All rights reserved.

In vitro characterization of a novel polymeric system for preparation of amorphous solid drug dispersions.

PubMed

Mahmoudi, Zahra N; Upadhye, Sampada B; Ferrizzi, David; Rajabi-Siahboomi, Ali R

2014-07-01

Preparation of amorphous solid dispersions using polymers is a commonly used formulation strategy for enhancing the solubility of poorly water-soluble drugs. However, often a single polymer may not bring about a significant enhancement in solubility or amorphous stability of a poorly water-soluble drug. This study describes application of a unique and novel binary polymeric blend in preparation of solid dispersions. The objective of this study was to investigate amorphous solid dispersions of glipizide, a BCS class II model drug, in a binary polymeric system of polyvinyl acetate phthalate (PVAP) and hypromellose (hydroxypropyl methylcellulose, HPMC). The solid dispersions were prepared using two different solvent methods: rotary evaporation (rotavap) and fluid bed drug layering on sugar spheres. The performance and physical stability of the dispersions were evaluated with non-sink dissolution testing, powder X-ray diffraction (PXRD), and modulated differential scanning calorimetry (mDSC). PXRD analysis demonstrated an amorphous state for glipizide, and mDSC showed no evidence of phase separation. Non-sink dissolution testing in pH 7.5 phosphate buffer indicated more than twofold increase in apparent solubility of the drug with PVAP-HPMC system. The glipizide solid dispersions demonstrated a high glass transition temperature (Tg) and acceptable chemical and physical stability during the stability period irrespective of the manufacturing process. In conclusion, the polymeric blend of PVAP-HPMC offers a unique formulation approach for developing amorphous solid dispersions with the flexibility towards the use of these polymers in different ratios and combined quantities depending on drug properties.

Development of Self Emulsifying Formulations of Poorly Soluble Naproxen for Enhanced Drug Delivery.

PubMed

Penjuri, Subhash C B; Saritha, Damineni; Ravouru, Nagaraju; Poreddy, Srikanth R

2016-01-01

The objective of this investigation was to develop a self emulsifying drug delivery system (SEDDS) of naproxen, a poorly water soluble drug, which could improve its solubility and oral bioavailability. The recent patents on SEDDS of abiraterone acetate (WO2014/009434 A1) and tamoxifen (WO2013/0080083) helped in selecting the naproxen and excipients. Phase diagrams were constructed and the formulations were taken from the micro emulsion region. Formulations were subjected to thermodynamic stability, dispersibility and precipitation tests for optimization. Physico chemical characterization was carried out by FTIR and DSC studies. The selected SEDDS consisted of IPM+labrafac lipophile WL 1349, tween 80, PEG 400 and naproxen. The optimized formulation has globule size- 187.6 nm, zeta potential- -9.81 mv, viscosity- 1.772 cps and infinite dilution ability. In vitro drug release was 98.21% and was found to be significantly different from the marketed product and plain drug. After oral administration in rats the SEDDS of naproxen showed anti inflammatory activity (69.82%) which was much improved as compared to the marketed formulation. The Cmax, AUC0t of naproxen was boosted with SEDDS to 133.63 g/ml and 698.29 hr. g/ml respectively. The optimized formulation was found to be stable for 6 months during stability studies conducted according to the ICH Q1A (R2) guidelines. Thus this developed self emulsifying drug delivery system may be a useful tool to enhance the solubility of oral poorly water soluble drug naproxen. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Hydrotropic Solubilization of Lipophilic Drugs for Oral Delivery: The Effects of Urea and Nicotinamide on Carbamazepine Solubility–Permeability Interplay

PubMed Central

Beig, Avital; Lindley, David; Miller, Jonathan M.; Agbaria, Riad; Dahan, Arik

2016-01-01

Hydrotropy refers to increasing the water solubility of otherwise poorly soluble compound by the presence of small organic molecules. While it can certainly increase the apparent solubility of a lipophilic drug, the effect of hydrotropy on the drugs’ permeation through the intestinal membrane has not been studied. The purpose of this work was to investigate the solubility–permeability interplay when using hydrotropic drug solubilization. The concentration-dependent effects of the commonly used hydrotropes urea and nicotinamide, on the solubility and the permeability of the lipophilic antiepileptic drug carbamazepine were studied. Then, the solubility–permeability interplay was mathematically modeled, and was compared to the experimental data. Both hydrotropes allowed significant concentration-dependent carbamazepine solubility increase (up to ∼30-fold). A concomitant permeability decrease was evident both in vitro and in vivo (∼17-fold for nicotinamide and ∼9-fold for urea), revealing a solubility–permeability tradeoff when using hydrotropic drug solubilization. A relatively simplified simulation approach based on proportional opposite correlation between the solubility increase and the permeability decrease at a given hydrotrope concentration allowed excellent prediction of the overall solubility–permeability tradeoff. In conclusion, when using hydrotropic drug solubilization it is prudent to not focus solely on solubility, but to account for the permeability as well; achieving optimal solubility–permeability balance may promote the overall goal of the formulation to maximize oral drug exposure. PMID:27826241

Exploring oral nanoemulsions for bioavailability enhancement of poorly water-soluble drugs.

PubMed

Kotta, Sabna; Khan, Abdul Wadood; Pramod, Kannissery; Ansari, Shahid H; Sharma, Rakesh Kumar; Ali, Javed

2012-05-01

More than 40% of new chemical entities discovered are poorly water soluble and suffer from low oral bioavailability. In recent years, nanoemulsions are receiving increasing attention as a tool of delivering these low-bioavailable moieties in an efficient manner. This review gives a brief description about how oral nanoemulsions act as a tool to improve the bioavailability of poorly water-soluble drugs. The recurrent confusion found in the literature regarding the theory behind the formation of nanoemulsions is clarified, along with the difference between nanoemulsion and lyotropic 'microemulsion' phase. This paper gives a clear-cut idea about all possible methods for the preparation of nanoemulsions and the advantages and disadvantages of each method are described. A description of the stability problems of nanoemulsions and their prevention methods is also provided, in addition to a comprehensive update on the patents and research works done in the arena of oral nanoemulsions. Low-energy emulsification techniques can also produce stable nanoemulsions. It is guaranteed that oral nanoemulsions can act as a potential tool for the delivery of poorly water-soluble therapeutic moieties in a very efficient manner.

Preparation and investigation of mefenamic acid - polyethylene glycol - sucrose ester solid dispersions.

PubMed

Fülöp, Ibolya; Gyéresi, Árpád; Kiss, Lóránd; Deli, Mária A; Croitoru, Mircea Dumitru; Szabó-Révész, Piroska; Aigner, Zoltán

2015-12-01

Mefenamic acid (MA) is a widely used non-steroidal antiinflammatory (NSAID) drug. The adverse effects typical of NSAIDs are also present in the case of MA, partly due to its low water solubility. The aim of this study was to increase the water solubility of MA in order to influence its absorption and bioavailability. Solid dispersions of MA were prepared by the melting method using polyethylene glycol 6000 and different types (laurate, D-1216; palmitate, P-1670; stearate, S-1670) and amounts of sucrose esters as carriers. The X-ray diffraction results show that MA crystals were not present in the products. Dissolution tests carried out in artificial intestinal juice showed that the product containing 10 % D-1216 increased water solubility about 3 times. The apparent permeability coefficient of MA across human Caco-2 intestinal epithelial cell layers was high and, despite the difference in solubility, there was no further increase in drug penetration in the presence of the applied additives.

Enhancing the Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs Using Monoolein Cubosomes.

PubMed

Ali, Md Ashraf; Kataoka, Noriko; Ranneh, Abdul-Hackam; Iwao, Yasunori; Noguchi, Shuji; Oka, Toshihiko; Itai, Shigeru

2017-01-01

Monoolein cubosomes containing either spironolactone (SPI) or nifedipine (NI) were prepared using a high-pressure homogenization technique and characterized in terms of their solubility and oral bioavailability. The mean particle size, polydispersity index (PDI), zeta potential, solubility and encapsulation efficiency (EE) values of the SPI- and NI-loaded cubosomes were determined to be 90.4 nm, 0.187, -13.4 mV, 163 µg/mL and 90.2%, and 91.3 nm, 0.168, -12.8 mV, 189 µg/mL and 93.0%, respectively, which were almost identical to those of the blank cubosome. Small-angle X-ray scattering analyses confirmed that the SPI-loaded, NI-loaded and blank cubosomes existed in the cubic space group Im3̄m. The lattice parameters of the SPI- and NI-loaded cubosomes were 147.6 and 151.6 Å, respectively, making them almost identical to that of blank cubosome (151.0 Å). The in vitro release profiles of the SPI- and NI-loaded cubosomes showed that they released less than 5% of the drugs into various media over 12-48 h, indicating that most of the drug remained encapsulated within the cubic phase of their lipid bilayer. Furthermore, the in vivo pharmacokinetic results suggested that these cubosomes led to a considerable increase in the systemic oral bioavailability of the drugs compared with pure dispersions of the same materials. Notably, the stability results indicated that the mean particle size and PDI values of these cubosomes were stable for at least 4 weeks. Taken together, these results demonstrate that monoolein cubosomes represent promising drug carriers for enhancing the solubility and oral bioavailability of poorly water-soluble drugs.

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

PubMed

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

2015-07-01

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

Water-soluble carbon nanotube compositions for drug delivery and medicinal applications

DOEpatents

Tour, James M.; Lucente-Schultz, Rebecca; Leonard, Ashley; Kosynkin, Dmitry V.; Price, Brandi Katherine; Hudson, Jared L.; Conyers, Jr., Jodie L.; Moore, Valerie C.; Casscells, S. Ward; Myers, Jeffrey N.; Milas, Zvonimir L.; Mason, Kathy A.; Milas, Luka

2014-07-22

Compositions comprising a plurality of functionalized carbon nanotubes and at least one type of payload molecule are provided herein. The compositions are soluble in water and PBS in some embodiments. In certain embodiments, the payload molecules are insoluble in water. Methods are described for making the compositions and administering the compositions. An extended release formulation for paclitaxel utilizing functionalized carbon nanotubes is also described.

Microfluidics based manufacture of liposomes simultaneously entrapping hydrophilic and lipophilic drugs.

PubMed

Joshi, Sameer; Hussain, Maryam T; Roces, Carla B; Anderluzzi, Giulia; Kastner, Elisabeth; Salmaso, Stefano; Kirby, Daniel J; Perrie, Yvonne

2016-11-30

Despite the substantial body of research investigating the use of liposomes, niosomes and other bilayer vesicles for drug delivery, the translation of these systems into licensed products remains limited. Indeed, recent shortages in the supply of liposomal products demonstrate the need for new scalable production methods for liposomes. Therefore, the aim of our research has been to consider the application of microfluidics in the manufacture of liposomes containing either or both a water soluble and a lipid soluble drug to promote co-delivery of drugs. For the first time, we demonstrate the entrapment of a hydrophilic and a lipophilic drug (metformin and glipizide respectively) both individually, and in combination, using a scalable microfluidics manufacturing system. In terms of the operating parameters, the choice of solvents, lipid concentration and aqueous:solvent ratio all impact on liposome size with vesicle diameter ranging from ∼90 to 300nm. In terms of drug loading, microfluidics production promoted high loading within ∼100nm vesicles for both the water soluble drug (20-25% of initial amount added) and the bilayer embedded drug (40-42% of initial amount added) with co-loading of the drugs making no impact on entrapment efficacy. However, co-loading of glipizide and metformin within the same liposome formulation did impact on the drug release profiles; in both instances the presence of both drugs in the one formulation promoted faster (up to 2 fold) release compared to liposomes containing a single drug alone. Overall, these results demonstrate the application of microfluidics to prepare liposomal systems incorporating either or both an aqueous soluble drug and a bilayer loaded drug. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative Effectiveness of DPP-4 Inhibitors Versus Sulfonylurea for the Treatment of Type 2 Diabetes in Routine Clinical Practice: A Retrospective Multicenter Real-World Study.

PubMed

Fadini, Gian Paolo; Bottigliengo, Daniele; D'Angelo, Federica; Cavalot, Franco; Bossi, Antonio Carlo; Zatti, Giancarlo; Baldi, Ileana; Avogaro, Angelo

2018-06-01

DPP-4 inhibitors (DPP4i) and sulfonylureas are popular second-line therapies for type 2 diabetes (T2D), but there is a paucity of real-world studies comparing their effectiveness in routine clinical practice. This was a multicenter retrospective study on diabetes outpatient clinics comparing the effectiveness of DPP4i versus gliclazide extended release. The primary endpoint was change from baseline in HbA1c. Secondary endpoints were changes in fasting plasma glucose, body weight, and systolic blood pressure. Automated software extracted data from the same clinical electronic chart system at all centers. Propensity score matching (PSM) was used to generate comparable cohorts to perform outcome analysis. We included data on 2410 patients starting DPP4i and 1590 patients starting gliclazide (mainly 30-60 mg/day). At baseline, the two groups differed in disease duration, body weight, blood pressure, HbA1c, fasting glucose, HDL cholesterol, triglycerides, liver enzymes, eGFR, prevalence of microangiopathy, and use of metformin. Among DPP4i molecules, no difference in glycemic effectiveness was detected. In matched cohorts (n = 1316/group), patients starting DPP4i, as compared with patients starting gliclazide, experienced greater reductions in HbA1c (- 0.6% versus - 0.4%; p < 0.001), fasting glucose (- 14.1 mg/dl versus - 8.8 mg/dl; p = 0.007), and body weight (- 0.4 kg versus - 0.1 kg; p = 0.006) after an average 6 months follow-up. DPP4i improved glucose control more than gliclazide, especially in patients who had failed with other glucose-lowering medications or were on basal insulin. This large retrospective real-world study shows that, in routine clinical practice, starting a DPP4i allows better glycemic control than starting low-dose gliclazide. The Italian Diabetes Society, with external support from AstraZeneca.

Design of an expert system for the development and formulation of push-pull osmotic pump tablets containing poorly water-soluble drugs.

PubMed

Zhang, Zhi-hong; Dong, Hong-ye; Peng, Bo; Liu, Hong-fei; Li, Chun-lei; Liang, Min; Pan, Wei-san

2011-05-30

The purpose of this article was to build an expert system for the development and formulation of push-pull osmotic pump tablets (PPOP). Hundreds of PPOP formulations were studied according to different poorly water-soluble drugs and pharmaceutical acceptable excipients. The knowledge base including database and rule base was built based on the reported results of hundreds of PPOP formulations containing different poorly water-soluble drugs and pharmaceutical excipients and the experiences available from other researchers. The prediction model of release behavior was built using back propagation (BP) neural network, which is good at nonlinear mapping and learning function. Formulation design model was established based on the prediction model of release behavior, which was the nucleus of the inference engine. Finally, the expert system program was constructed by VB.NET associating with SQL Server. Expert system is one of the most popular aspects in artificial intelligence. To date there is no expert system available for the formulation of controlled release dosage forms yet. Moreover, osmotic pump technology (OPT) is gradually getting consummate all over the world. It is meaningful to apply expert system on OPT. Famotidine, a water insoluble drug was chosen as the model drug to validate the applicability of the developed expert system. Copyright © 2011 Elsevier B.V. All rights reserved.

Multi-Layer Self-Nanoemulsifying Pellets: an Innovative Drug Delivery System for the Poorly Water-Soluble Drug Cinnarizine.

PubMed

Shahba, Ahmad Abdul-Wahhab; Ahmed, Abid Riaz; Alanazi, Fars Kaed; Mohsin, Kazi; Abdel-Rahman, Sayed Ibrahim

2018-04-25

Beside their solubility limitations, some poorly water-soluble drugs undergo extensive degradation in aqueous and/or lipid-based formulations. Multi-layer self-nanoemulsifying pellets (ML-SNEP) introduce an innovative delivery system based on isolating the drug from the self-nanoemulsifying layer to enhance drug aqueous solubility and minimize degradation. In the current study, various batches of cinnarizine (CN) ML-SNEP were prepared using fluid bed coating and involved a drug-free self-nanoemulsifying layer, protective layer, drug layer, moisture-sealing layer, and/or an anti-adherent layer. Each layer was optimized based on coating outcomes such as coating recovery and mono-pellets%. The optimized ML-SNEP were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), in vitro dissolution, and stability studies. The optimized ML-SNEP were free-flowing, well separated with high coating recovery. SEM showed multiple well-defined coating layers. The acidic polyvinylpyrrolidone:CN (4:1) solution presented excellent drug-layering outcomes. DSC and XRD confirmed CN transformation into amorphous state within the drug layer. The isolation between CN and self-nanoemulsifying layer did not adversely affect drug dissolution. CN was able to spontaneously migrate into the micelles arising from the drug-free self-nanoemulsifying layer. ML-SNEP showed superior dissolution compared to Stugeron® tablets at pH 1.2 and 6.8. Particularly, on shifting to pH 6.8, ML-SNEP maintained > 84% CN in solution while Stugeron® tablets showed significant CN precipitation leaving only 7% CN in solution. Furthermore, ML-SNEP (comprising Kollicoat® Smartseal 30D) showed robust stability and maintained > 97% intact CN within the accelerated storage conditions. Accordingly, ML-SNEP offer a novel delivery system that combines both enhanced solubilization and stabilization of unstable poorly soluble drugs.

Self-association and cyclodextrin solubilization of drugs.

PubMed

Loftsson, Thorsteinn; Magnúsdóttir, Auethur; Másson, Már; Sigurjónsdóttir, Jóhanna F

2002-11-01

Phase-solubility diagrams are frequently used to calculate stoichiometry of drug/cyclodextrin complexes. Linear diagrams (A(L)-type systems) are thought to indicate that the complexes are first order with respect to cyclodextrin and first or higher order with respect to the drug. Positive deviation from linearity (A(P)-type systems) are thought to indicate formation of complexes that are first order with respect to the drug but second or higher order with respect to cyclodextrin. The phase solubility of several different compounds, i.e., cholesterol, ibuprofen, diflunisal, alprazolam, 17beta-estradiol and diethylstilbestrol, and various charged and uncharged cyclodextrins was investigated. Phase-solubility diagrams of cholesterol in aqueous cyclodextrin solutions were all of A(P) type. However, the phase-solubility diagrams obtained with charged cyclodextrins could not be fitted to complexes of second or higher order with respect to cyclodextrin. The phase-solubility diagrams of ibuprofen and diflunisal were of A(L) type with slope greater than unity indicating formation of 2:1 drug/cyclodextrin complexes. However, Job's plots and space filling docking studies indicated that 1:1 complexes were formed. These and other observations show that stoichiometry of drug/cyclodextrin complexes cannot be derived from simple phase-solubility studies. Furthermore, the results indicate that drug/cyclodextrin complexes can self-associate to form water-soluble aggregates, which then can further solubilize the drug through non-inclusion complexation. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2307-2316, 2002

Combined Effects of Supersaturation Rates and Doses on the Kinetic-Solubility Profiles of Amorphous Solid Dispersions Based on Water-Insoluble Poly(2-hydroxyethyl methacrylate) Hydrogels.

PubMed

Schver, Giovanna C R M; Lee, Ping I

2018-05-07

Under nonsink dissolution conditions, the kinetic-solubility profiles of amorphous solid dispersions (ASDs) based on soluble carriers typically exhibit so-called "spring-and-parachute" concentration-time behaviors. However, the kinetic-solubility profiles of ASDs based on insoluble carriers (including hydrogels) are known to show sustained supersaturation during nonsink dissolution through a matrix-regulated diffusion mechanism by which the supersaturation of the drug is built up gradually and sustained over an extended period without any dissolved polymers acting as crystallization inhibitors. Despite previous findings demonstrating the interplay between supersaturation rates and total doses on the kinetic-solubility profiles of soluble amorphous systems (including ASDs based on dissolution-regulated releases from soluble polymer carriers), the combined effects of supersaturation rates and doses on the kinetic-solubility profiles of ASDs based on diffusion-regulated releases from water-insoluble carriers have not been investigated previously. Thus, the objective of this study is to examine the impacts of total doses and supersaturation-generation rates on the resulting kinetic-solubility profiles of ASDs based on insoluble hydrogel carriers. We employed a previously established ASD-carrier system based on water-insoluble-cross-linked-poly(2-hydroxyethyl methacrylate) (PHEMA)-hydrogel beads and two poorly water soluble model drugs: the weakly acidic indomethacin (IND) and the weakly basic posaconazole (PCZ). Our results show clearly for the first time that by using the smallest-particle-size fraction and a high dose (i.e., above the critical dose), it is indeed possible to significantly shorten the duration of sustained supersaturation in the kinetic-solubility profile of an ASD based on a water-insoluble hydrogel carrier, such that it resembles the spring-and-parachute dissolution profiles normally associated with ASDs based on soluble carriers. This generates sufficiently rapid initial supersaturation buildup above the critical supersaturation, resulting in more rapid precipitation. Above this smallest-particle-size range, the matrix-diffusion-regulated nonlinear rate of drug release gets slower, which results in a more modest rate of supersaturation buildup, leading to a maximum supersaturation below the critical-supersaturation level without appreciable precipitation. The area-under-the-curve (AUC) values of the in vitro kinetic-solubility concentration-time profiles were used to correlate the corresponding trends in dissolution enhancement. There are observed monotonic increases in AUC values with increasing particle sizes for high-dose ASDs based on water-insoluble hydrogel matrixes, as opposed to the previously reported AUC maxima at some intermediate supersaturation rates or doses in soluble amorphous systems, whereas in the case of low-dose ASDs (i.e., below the critical dose levels), crystallization would be negligible, leading to sustained supersaturation with all particle sizes (i.e., eventually reaching the same maximum supersaturation) and the smallest particle size reaching the maximum supersaturation the fastest. As a result, the smallest particle sizes yield the largest AUC values in the case of low-dose ASDs based on water-insoluble hydrogel matrixes. In addition to probing the interplay between the supersaturation-generation rates and total doses in ASDs based on insoluble hydrogel carriers, our results further support the fact that through either increasing the hydrogel-particle size or lowering the total dose to achieve maximum supersaturation still below the critical-supersaturation level, it is possible to avoid drug precipitation so as to maintain sustained supersaturation.

Highly porous drug-eluting structures

PubMed Central

Elsner, Jonathan J.; Kraitzer, Amir; Grinberg, Orly; Zilberman, Meital

2012-01-01

For many biomedical applications, there is need for porous implant materials. The current article focuses on a method for preparation of drug-eluting porous structures for various biomedical applications, based on freeze drying of inverted emulsions. This fabrication process enables the incorporation of any drug, to obtain an “active implant” that releases drugs to the surrounding tissue in a controlled desired manner. Examples for porous implants based on this technique are antibiotic-eluting mesh/matrix structures used for wound healing applications, antiproliferative drug-eluting composite fibers for stent applications and local cancer treatment, and protein-eluting films for tissue regeneration applications. In the current review we focus on these systems. We show that the release profiles of both types of drugs, water-soluble and water-insoluble, are affected by the emulsion's formulation parameters. The former's release profile is affected mainly through the emulsion stability and the resulting porous microstructure, whereas the latter's release mechanism occurs via water uptake and degradation of the host polymer. Hence, appropriate selection of the formulation parameters enables to obtain desired controllable release profile of any bioactive agent, water-soluble or water-insoluble, and also fit its physical properties to the application. PMID:23507890

Antisolvent crystallization of a cardiotonic drug in ionic liquids: Effect of mixing on the crystal properties

NASA Astrophysics Data System (ADS)

de Azevedo Jacqueline, Resende; Fabienne, Espitalier; Jean-Jacques, Letourneau; Inês, Ré Maria

2017-08-01

LASSBio-294 (3,4-methylenedioxybenzoyl-2-thienylhydrazon) is a poorly soluble drug which has been proposed to have major advantages over other cardiotonic drugs. Poorly water soluble drugs present limited bioavailability due to their low solubility and dissolution rate. An antisolvent crystallization processing can improve the dissolution rate by decreasing the crystals particle size. However, LASSBio-294 is also poorly soluble in organic solvents and this operation is limited. In order to open new perspectives to improve dissolution rate, this work has investigated LASSBio-294 in terms of its antisolvent crystallization in 1-ethyl-3-methylimidazolium methyl phosphonate [emim][CH3O(H)PO2] as solvent and water as antisolvent. Two modes of mixing are tested in stirred vessel with different pre-mixers (Roughton or T-mixers) in order to investigate the mixing effect on the crystal properties (crystalline structure, particle size distribution, residual solvent and in vitro dissolution rate). Smaller drug particles with unchanged crystalline structure were obtained. Despite the decrease of the elementary particles size, the recrystallized particles did not achieve a better dissolution profile. However, this study was able to highlight a certain number of findings such as the impact of the hydrodynamic conditions on the crystals formation and the presence of a gel phase limiting the dissolution rate.

Application of carrier and plasticizer to improve the dissolution and bioavailability of poorly water-soluble baicalein by hot melt extrusion.

PubMed

Zhang, Yilan; Luo, Rui; Chen, Yi; Ke, Xue; Hu, Danrong; Han, Miaomiao

2014-06-01

The objective of this study was to develop a suitable formulation for baicalein (a poorly water-soluble drug exhibiting high melting point) to prepare solid dispersions using hot melt extrusion (HME). Proper carriers and plasticizers were selected by calculating the Hansen solubility parameters, evaluating melting processing condition, and measuring the solubility of obtained melts. The characteristic of solid dispersions prepared by HME was evaluated. The dissolution performance of the extrudates was compared to the pure drug and the physical mixtures. Physicochemical properties of the extrudates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Relative bioavailability after oral administration in beagle dogs was assessed. As a result, Kollidon VA64 and Eudragit EPO were selected as two carriers; Cremophor RH was used as the plasticizer. The dissolution of all the extrudates was significantly improved. DSC and PXRD results suggested that baicalein in the extrudates was amorphous. FTIR spectroscopy revealed the interaction between drug and polymers. After oral administration, the relative bioavailability of solid dispersions with VA64 and EPO was comparative, about 2.4- and 2.9-fold greater compared to the pure drug, respectively.

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs.

PubMed

Censi, Roberta; Di Martino, Piera

2015-10-15

Drugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they can be a challenge to ensure physicochemical stability for the entire shelf life of the drug product. Since clinical failures of polymorph drugs have not been uncommon, and some of them have been entirely unexpected, the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug. In the past, the polymorphism of many drugs was detected fortuitously or through manual time consuming methods; today, drug crystal engineering, in particular, combinatorial chemistry and high-throughput screening, makes it possible to easily and exhaustively identify stable polymorphic and/or hydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related problems or clinical failures. This review describes the concepts involved, provides examples of drugs characterized by poor solubility for which polymorphism has proven important, outlines the state-of-the-art technologies and discusses the pertinent regulations.

Denatured protein-coated docetaxel nanoparticles: Alterable drug state and cytosolic delivery.

PubMed

Zhang, Li; Xiao, Qingqing; Wang, Yiran; Zhang, Chenshuang; He, Wei; Yin, Lifang

2017-05-15

Many lead compounds have a low solubility in water, which substantially hinders their clinical application. Nanosuspensions have been considered a promising strategy for the delivery of water-insoluble drugs. Here, denatured soy protein isolate (SPI)-coated docetaxel nanosuspensions (DTX-NS) were developed using an anti-solvent precipitation-ultrasonication method to improve the water-solubility of DTX, thus improving its intracellular delivery. DTX-NS, with a diameter of 150-250nm and drug-loading up to 18.18%, were successfully prepared by coating drug particles with SPI. Interestingly, the drug state of DTX-NS was alterable. Amorphous drug nanoparticles were obtained at low drug-loading, whereas at a high drug-loading, the DTX-NS drug was mainly present in the crystalline state. Moreover, DTX-NS could be internalized at high levels by cancer cells and enter the cytosol by lysosomal escape, enhancing cell cytotoxicity and apoptosis compared with free DTX. Taken together, denatured SPI has a strong stabilization effect on nanosuspensions, and the drug state in SPI-coated nanosuspensions is alterable by changing the drug-loading. Moreover, DTX-NS could achieve cytosolic delivery, generating enhanced cell cytotoxicity against cancer cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Dissolution enhancement of efavirenz by solid dispersion and PEGylation techniques

PubMed Central

Madhavi, B. Bindu; Kusum, B.; Chatanya, CH. Krishna; Madhu, M. Naga; Harsha, V. Sri; Banji, David

2011-01-01

Background: Efavirenz is the preferred nonnucleotide reverse transcriptase inhibitor for first-line antiretroviral treatment in many countries. It is orally active and is specific for human immunodeficiency virus type 1. Its effectiveness can be attributed to its long half-life, which is 52–76 h after multiple doses. The drug is having poor water solubility. The formulation of poorly soluble drug for oral delivery will be one of the biggest challenges for formulation scientists in the research field. Among the available approaches, the solid dispersion technique has often proved to be the most commonly used method in improving dissolution and bioavailability of the drugs because of its simplicity and economy in preparation and evaluation. Materials and Methods: Solid dispersions were prepared by solvent evaporation and physical mixture methods by using polyethylene glycol as the hydrophilic carrier and PEGylated product was also prepared. The prepared products were evaluated for various parameters, such as polymer interaction, saturation solubility study, and drug release studies. The drug release data were analyzed by fitting it into various kinetic models. Results: There is an improvement in the dissolution from 16% to 70% with solid dispersion technology. Higuchi model was found to be the best fit model. Conclusion: Solid dispersion is the simple, efficient, and economic method to improve the dissolution of the poorly water-soluble drugs. PMID:23071917

Conjugation of curcumin onto hyaluronic acid enhances its aqueous solubility and stability.

PubMed

Manju, S; Sreenivasan, K

2011-07-01

Polymer-drug conjugates have gained much attention largely to circumvent lower drug solubility and to enhance drug stability. Curcumin is widely known for its medicinal properties including its anticancer efficacy. One of the serious drawbacks of curcumin is its poor water solubility which leads to reduced bioavailability. With a view to address these issues, we synthesized hyaluronic acid-curcumin (HA-Cur) conjugate. The drug conjugate was characterized using FT-IR, NMR, Dynamic light scattering and TEM techniques. The conjugates, interestingly found to assembles as micelles in aqueous phase. The formation of micelles seems to improve the stability of the drug in physiological pH. We also assessed cytotoxicity of the conjugate using L929 fibroblast cells and quantified by MTT assay. Copyright © 2011 Elsevier Inc. All rights reserved.

Lipid nanoparticles for the delivery of poorly water-soluble drugs.

PubMed

Bunjes, Heike

2010-11-01

This review discusses important aspects of lipid nanoparticles such as colloidal lipid emulsions and, in particular, solid lipid nanoparticles as carrier systems for poorly water-soluble drugs, with a main focus on the parenteral and peroral use of these carriers. A short historical background of the development of colloidal lipid emulsions and solid lipid nanoparticles is provided and their similarities and differences are highlighted. With regard to drug incorporation, parameters such as the chemical nature of the particle matrix and the physicochemical nature of the drug, effects of drug partition and the role of the particle interface are discussed. Since, because of the crystalline nature of their lipid core, solid lipid nanoparticles display some additional important features compared to emulsions, their specificities are introduced in more detail. This mainly includes their solid state behaviour (crystallinity, polymorphism and thermal behaviour) and the consequences of their usually non-spherical particle shape. Since lipid nanoemulsions and -suspensions are also considered as potential means to alter the pharmacokinetics of incorporated drug substances, some underlying basic considerations, in particular concerning the drug-release behaviour of such lipid nanodispersions on dilution, are addressed as well. Colloidal lipid emulsions and solid lipid nanoparticles are interesting options for the delivery of poorly water-soluble drug substances. Their specific physicochemical properties need, however, to be carefully considered to provide a rational basis for their development into effective carrier systems for a given delivery task. © 2010 The Author. Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain.

Cocrystal Solubilization in Biorelevant Media and its Prediction from Drug Solubilization.

PubMed

Lipert, Maya P; Roy, Lilly; Childs, Scott L; Rodríguez-Hornedo, Naír

2015-12-01

This work examines cocrystal solubility in biorelevant media (FeSSIF, fed-state simulated intestinal fluid), and develops a theoretical framework that allows for the simple and quantitative prediction of cocrystal solubilization from drug solubilization. The solubilities of four hydrophobic drugs and seven cocrystals containing these drugs were measured in FeSSIF and in acetate buffer at pH 5.00. In all cases, the cocrystal solubility (Scocrystal ) was higher than the drug solubility (Sdrug ) in both buffer and FeSSIF; however, the solubilization ratio of drug, SRdrug = (SFeSSIF /Sbuffer )drug , was not the same as the solubilization ratio of cocrystal, SRcocrystal = (SFeSSIF /Sbuffer )cocrystal , meaning drug and cocrystal were not solubilized to the same extent in FeSSIF. This highlights the potential risk of anticipating cocrystal behavior in biorelevant media based on solubility studies in water. Predictions of SRcocrystal from simple equations based only on SRdrug were in excellent agreement with measured values. For 1:1 cocrystals, the cocrystal solubilization ratio (SR) can be obtained from the square root of the drug SR. For 2:1 cocrystals, SRcocrystal is found from (SRdrug )(2/3) . The findings in FeSSIF can be generalized to describe cocrystal behavior in other systems involving preferential solubilization of a drug such as surfactants, lipids, and other drug solubilizing media. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Polymeric Micelles as Novel Carriers for Poorly Soluble Drugs--A Review.

PubMed

Reddy, B Pavan Kumar; Yadav, Hemant K S; Nagesha, Dattatri K; Raizaday, Abhay; Karim, Abdul

2015-06-01

Polymeric micelles are used as 'smart drug carriers' for targeting certain areas of the body by making them stimuli-sensitive or by attachment of a specific ligand molecule onto their surface. The main aim of using polymeric micelles is to deliver the poorly water soluble drugs. Now-a-days they are used especially in the areas of cancer therapy also. In this article we have reviewed several aspects of polymeric micelles concerning their mechanism of formation, chemical nature, preparation and characterization techniques, and their applications in the areas of drug delivery.

Development of a salt drug with improved solubility: Ethionamide nitrate

NASA Astrophysics Data System (ADS)

Diniz, Luan F.; Carvalho, Paulo S.; de Melo, Cristiane C.; Ellena, Javier

2017-06-01

To avoid drug resistance, an adequate tuberculosis treatment should include not only a first-line drug but also at least one second-line drug such as, for example, Ethionamide (ETH). However, the dissolution rate and oral absorption of ETH is highly limited by its low aqueous solubility. Considering that a salt is in general more soluble than its parent compound, herein we depicted a new supramolecular modification of ETH, an Ethionamide nitrate salt (ETHNO3). This salt is the first ETH structure that has been crystallized with four independent ionic pairs (ETH+NO3-) in the asymmetric unit. In addition to the structural study, the salt formation was also identified on the FT-IR and FT-Raman spectra. The thermal behavior of ETHNO3 was also investigated here together with its solubility profile in three dissolution media (purified water, pH 4.0 and 7.0).

An injectable hybrid nanoparticle-in-oil-in-water submicron emulsion for improved delivery of poorly soluble drugs

NASA Astrophysics Data System (ADS)

Wang, Shuo; Wang, Hua; Liang, Wenquan; Huang, Yongzhuo

2012-04-01

Poor drugability problems are commonly seen in a class of chemical entities with poor solubility in water and oil, and moreover, physicochemical instability of these compounds poses extra challenges in design of dosage forms. Such problems contribute a significant high failure rate in new drug development. A hybrid nanoparicle-in-oil-in-water (N/O/W) submicron emulsion was proposed for improved delivery of poorly soluble and unstable drugs (e.g., dihydroartemisinin (DHA)). DHA is known for its potent antimalarial effect and antitumor activity. However, its insolubility and instability impose big challenges for formulations, and so far, no injectable dosage forms are clinically available yet. Therefore, an injectable DHA N/O/W system was developed. Unlike other widely-explored systems (e.g., liposomes, micelles, and emulsions), in which low drug load and only short-term storage are often found, the hybrid submicron emulsion possesses three-fold higher drug-loading capacity than the conventional O/W emulsion. Of note, it can be manufactured into a freeze-drying form and can render its storage up to 6 months even in room temperature. The in vivo studies demonstrated that the PK profiles were significantly improved, and this injectable system was effective in suppressing tumor growth. The strategy provides a useful solution to effective delivery of such a class of drugs.

Application of transglycosylated stevia and hesperidin as drug carriers to enhance biopharmaceutical properties of poorly-soluble artemisinin.

PubMed

Letchmanan, Kumaran; Shen, Shou-Cang; Ng, Wai Kiong; Tan, Reginald B H

2018-01-01

Biopharmaceutical properties of poorly water-soluble antimalarial drug, Artemisinin (ART), were improved by formulating amorphous solid dispersions with transglycosylated food additives (Hsp-G and Stevia-G) via co-spray drying. Both the formulated ART/Hsp-G and ART/Stevia-G showed superior dissolution properties with a burst release of more than 95% of drug within 5 min, whereas untreated ART dissolved only 4% in 5min. The supersaturation solubility of the formulated ART was enhanced by 2-fold as compared with untreated counterpart. The storage stability tests indicated that these formulations chemically stable at room temperature and under low humidity (<18% RH) conditions. However, high humidity (75% RH) induced re-crystallization and caused changes in the physical appearance of the solid dispersions. In addition, both the food additives and ART formulated samples showed low cytotoxicity to Caco-2 cell line suggesting their good biocompatibility. Thus, the formation of solid dispersions of ART with transglycosylated food additives is a potentially safe and effective approach to enhance the bioavailability of poorly water-soluble ART. Copyright © 2017 Elsevier B.V. All rights reserved.

Dissolution Rate Enhancement of Repaglinide Using Dietary Fiber as a Promising Carrier.

PubMed

Chatap, Vivekanand K; Patil, Savita D

2016-01-01

In present investigation, an innovative attempt has been made to enhance the solubility and dissolution rate of Repaglinide (RPGD) using hydrothermally treated water insoluble dietary bamboo fibers (HVBF) as potential nutraceutical used in the treatment of diabetes mellitus. RPGD was selected as a model drug due to its low aqueous solubility and dissolution rate. Characterization of HVBF demonstrated the outstanding features like high surface area, maximum drug loading and increase dissolution rate and making HVBF as an excellent drug carrier. RHVBF (Repaglinide loaded HVBF) tablets were prepared using direct compression method. Pre and post-compression parameters for blend and tablets were studied and found within acceptable limits. RHVBF and tablet showed significantly improved dissolution rate, when compared with pure crystalline RPGD, physical mixture, RVBF and commercial marketed tablet. This fact was further supported by FT-IR, DSC, XRPD and FESEM studies followed by in-vitro drug release profile. Stability studies showed no changes after exposing to accelerated conditions for a period of 3 months with respect to physical characteristics and in-vitro drug release studies. In a nut shell, it can be concluded that HVBF is a novel, smart and promising carrier for poorly water soluble drugs, when administered orally.

Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels.

PubMed

Sun, Dajun D; Ju, Tzu-chi Rob; Lee, Ping I

2012-05-01

The feasibility of forming solid molecular dispersions of poorly water-soluble drugs in crosslinked poly(2-hydroethyl methacrylate) (PHEMA) hydrogel has recently been reported by our group. The purpose of the present study is to investigate the extent of enhancement of kinetic solubility of amorphous solid dispersions (ASDs) of indomethacin (IND) in crosslinked PHEMA hydrogels as compared with those based on conventional water-soluble polymer carriers. Our results show that under non-sink conditions, the initial solubility enhancement is higher for ASDs based on polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HMPCAS), but the ability to maintain this solubility enhancement at longer times is better for ASDs based on PHEMA over a period of 24h with the extent of solubility enhancement of IND ASDs in PHEMA falling between those in PVP and HPMCAS at 10.0% IND loading after 6h and outperforming those in PVP and HPMCAS at 32.9% IND loading after 8h. The observed kinetic solubility profiles reflect the fact that the amorphous IND is released from PHEMA by a different mechanism than those from water-soluble polymer carriers. In this case, the dissolution of IND ASD from water-soluble PVP and HPMCAS is almost instantaneous, resulting in an initial surge of IND concentration followed by a sharp decline due to the nucleation and crystallization events triggered by the rapid build-up of drug supersaturation. On the other hand, the dissolution of IND ASD from insoluble crosslinked PHEMA hydrogel beads is less rapid as it is regulated by a feedback-controlled diffusion mechanism, thus avoiding a sudden surge of supersaturation in the dissolution medium. The absence of an apparent decline in drug concentration during dissolution from IND-PHEMA ASD further reflects the diminished nucleation and crystallization events during IND dissolution from hydrogel-based solid molecular dispersions. Based on the XRD analyses, a threshold IND loading level of about 34% in PHEMA has been identified, above which amorphous to crystalline transition tends to occur. Also, by selecting the appropriate particle sizes, immediate to controlled release of IND from IND-PHEMA ASD can be readily achieved as the release rate increases with decreasing PHEMA bead size. Furthermore, a robust physical stability has been demonstrated in IND-PHEMA ASD with no drug precipitation for up to 8 months at IND loadings below 16.7% under direct open cup exposure to accelerated stability conditions (40°C/75% RH). Copyright © 2012 Elsevier B.V. All rights reserved.

Defined drug release from 3D-printed composite tablets consisting of drug-loaded polyvinylalcohol and a water-soluble or water-insoluble polymer filler.

PubMed

Tagami, Tatsuaki; Nagata, Noriko; Hayashi, Naomi; Ogawa, Emi; Fukushige, Kaori; Sakai, Norihito; Ozeki, Tetsuya

2018-05-30

3D-printed tablets are a promising new approach for personalized medicine. In this study, we fabricated composite tablets consisting of two components, a drug and a filler, by using a fused deposition modeling-type 3D printer. Polyvinylalcohol (PVA) polymer containing calcein (a model drug) was used as the drug component and PVA or polylactic acid (PLA) polymer without drug was used as the water-soluble or water-insoluble filler, respectively. Various kinds of drug-PVA/PVA and drug-PVA/PLA composite tablets were designed, and the 3D-printed tablets exhibited good formability. The surface area of the exposed drug component is highly correlated with the initial drug release rate. Composite tablets with an exposed top and a bottom covered with a PLA layer were fabricated. These tablets showed zero-order drug release by maintaining the surface area of the exposed drug component during drug dissolution. In contrast, the drug release profile varied for tablets whose exposed surface area changed. Composite tablets with different drug release lag times were prepared by changing the thickness of the PVA filler coating the drug component. These results which used PVA and PLA filler will provide useful information for preparing the tablets with multi-components and tailor-made tablets with defined drug release profiles using 3D printers. Copyright © 2018 Elsevier B.V. All rights reserved.

Improvement of drug loading onto ion exchange resin by cyclodextrin inclusion complex.

PubMed

Samprasit, Wipada; Rojanarata, Theerasak; Akkaramongkolporn, Prasert; Ngawhirunpat, Tanasait; Sila-on, Warisada; Opanasopit, Praneet

2013-11-01

Ion exchange resins have ability to exchange their counter ions for ionized drug in the surrounding medium, yielding "drug resin complex." Cyclodextrin can be applied for enhancement of drug solubility and stability. Cyclodextrin inclusion complex of poorly water-soluble NSAIDs, i.e. meloxicam and piroxicam, was characterized and its novel application for improving drug loading onto an anionic exchange resin, i.e. Dowex® 1×2, was investigated. β-Cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin (HP-β-CD) were used for the preparation of inclusion complex with drugs in solution state at various pH. The inclusion complex was characterized by phase solubility, continuous variation, spectroscopic and electrochemistry methods. Then, the drug with and without cyclodextrin were equilibrated with resin at 1:1 and 1:2 weight ratio of drug and resin. Solubility of the drugs was found to increase with increasing cyclodextrin concentration and pH. The increased solubility was explained predominantly due to the formation of inclusion complex at low pH and the increased ionization of drug at high pH. According to characterization studies, the inclusion complex was successfully formed with a 1:1 stoichiometry. The presence of cyclodextrin in the loading solution resulted in the improvement of drug loading onto resin. Enhancing drug loading onto ion-exchange resin via the formation of cyclodextrin inclusion complex is usable in the development of ion-exchange based drug delivery systems, which will beneficially reduce the use of harmful acidic or basic and organic chemicals.

Solubility and some crystallization properties of conglomerate forming chiral drug guaifenesin in water.

PubMed

Fayzullin, Robert R; Lorenz, Heike; Bredikhina, Zemfira A; Bredikhin, Alexander A; Seidel-Morgenstern, Andreas

2014-10-01

The solubility of 3-(2-methoxyphenoxy)-propane-1,2-diol, the well-known chiral drug guaifenesin 1, in water has been investigated by means of polythermal and isothermal approaches. It was found that the solubilities of racemic and enantiomeric diols rac- and (R)-1 depend strongly on temperature. The ternary phase diagram of the guaifenesin enantiomers in water in the temperature range between 10°C and 40°C was constructed. Clear evidence was obtained that rac-1 crystallizes as a stable conglomerate. The Meyerhoffer coefficient for the guaifenesin-water system is more than two and strongly depends on temperature. Neither crystalline hydrates nor polymorphs were detected within the range of conditions covered. Metastable zone width data with regard to primary nucleation were also collected for rac-1 and (R)-1. On the basis of the knowledge acquired, the resolution of racemic guaifenesin by preferential crystallization from solution could be realized successfully. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Nanoparticulate strategies for effective delivery of poorly soluble therapeutics.

PubMed

Gokce, Evren H; Ozyazici, Mine; Souto, Eliana B

2010-07-01

The pharmacological activity of a drug molecule depends on its ability to dissolve and interact with its biological target, either through dissolution and absorption, or through dissolution and receptor interaction. The low bioavailability that characterizes poorly water-soluble drugs is usually attributed to the dissolution kinetic profile. Novel strategies to effectively deliver these drugs include nanoparticulate approaches that either increase the surface area of the drug or improve the solubility characteristics of the drug. Nanosizing approaches are based on the production of drug nanocrytals dispersed in an aqueous surfactant solution, whereas other possibilities include drug loading in nanoparticles. Promising nanoparticulate approaches include the development of lipid-based nanocarriers to increase drug solubility followed by enhanced bioavailability. To select the best approach there are, however, some critical considerations to take into account, for example the physicochemical properties of the drug, the possibility to scale-up the production process, the toxicological considerations of the use of solvents and cosolvents, the selection of an environmentally sustainable methodology and the development of a more patient-friendly dosage form. This article addresses these relevant questions and provides feasible examples of novel strategies with respect to relevant administration routes.

Vibrational frequencies of anti-diabetic drug studied by terahertz time-domain spectroscopy

NASA Astrophysics Data System (ADS)

Du, S. Q.; Li, H.; Xie, L.; Chen, L.; Peng, Y.; Zhu, Y. M.; Li, H.; Dong, P.; Wang, J. T.

2012-04-01

By using terahertz time-domain spectroscopy, the absorption spectra of seven anti-diabetic pills have been investigated. For gliquidone, glipizide, gliclazide, and glimepiride, an obvious resonance peak is found at 1.37 THz. Furthermore, to overcome the limit of density functional theory that can analyze the normal mode frequencies of the ground state of organic material, we also present a method that relies on pharmacophore recognition, from which we can obtain the resonance peak at 1.37 THz can be attributed to the vibration of sulfonylurea group. The results indicate that the veracity of density functional theory can be increased by combining pharmacophore recognition.

Hydroxypropyl cellulose stabilizes amorphous solid dispersions of the poorly water soluble drug felodipine.

PubMed

Sarode, Ashish L; Malekar, Swapnil A; Cote, Catherine; Worthen, David R

2014-11-04

Overcoming the low oral bioavailability of many drugs due to their poor aqueous solubility is one of the major challenges in the pharmaceutical industry. The production of amorphous solid dispersions (ASDs) of these drugs using hydrophilic polymers may significantly improve their solubility. However, their storage stability and the stability of their supersaturated solutions in the gastrointestinal tract upon administration are unsolved problems. We have investigated the potential of a low viscosity grade of a cellulosic polymer, hydroxypropyl cellulose (HPC-SSL), and compared it with a commonly used vinyl polymer, polyvinylpyrrolidone vinyl acetate (PVP-VA), for stabilizing the ASDs of a poorly water soluble drug, felodipine. The ASDs were produced using hot melt mixing and stored under standard and accelerated stability conditions. The ASDs were characterized using differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy. Drug dissolution and partitioning rates were evaluated using single- and biphasic dissolution studies. The ASDs displayed superior drug dissolution and partitioning as compared to the pure crystalline drug, which might be attributed to the formation of a drug-polymer molecular dispersion, amorphous conversion of the drug, and drug-polymer hydrogen bonding interactions. Late phase separation and early re-crystallization occurred at lower and higher storage temperatures, respectively, for HPC-SSL ASDs, whereas early phase separation, even at low storage temperatures, was noted for PVP-VA ASDs. Consequently, the partitioning rates for ASDs dispersed in HPC-SSL were greater than those of PVP-VA at lower and room temperature storage, whereas the performance of both of the ASDs was similar when stored at higher temperatures. Copyright © 2014. Published by Elsevier Ltd.

Multilayer encapsulated mesoporous silica nanospheres as an oral sustained drug delivery system for the poorly water-soluble drug felodipine.

PubMed

Hu, Liang; Sun, Hongrui; Zhao, Qinfu; Han, Ning; Bai, Ling; Wang, Ying; Jiang, Tongying; Wang, Siling

2015-02-01

We used a combination of mesoporous silica nanospheres (MSN) and layer-by-layer (LBL) self-assembly technology to establish a new oral sustained drug delivery system for the poorly water-soluble drug felodipine. Firstly, the model drug was loaded into MSN, and then the loaded MSN were repeatedly encapsulated by chitosan (CHI) and acacia (ACA) via LBL self-assembly method. The structural features of the samples were studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and nitrogen adsorption. The encapsulating process was monitored by zeta-potential and surface tension measurements. The physical state of the drug in the samples was characterized by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). The influence of the multilayer with different number of layers on the drug release rate was studied using thermal gravimetric analysis (TGA) and surface tension measurement. The swelling effect and the structure changes of the multilayer were investigated to explore the relationship between the drug release behavior and the state of the multilayer under different pH conditions. The stability and mucosa adhesive ability of the prepared nanoparticles were also explored. After multilayer coating, the drug release rate was effectively controlled. The differences in drug release behavior under different pH conditions could be attributed to the different states of the multilayer. And the nanoparticles possessed good stability and strong mucosa adhesive ability. We believe that this combination offers a simple strategy for regulating the release rate of poorly water-soluble drugs and extends the pharmaceutical applications of inorganic materials and polymers. Copyright © 2014 Elsevier B.V. All rights reserved.

The Curious Case of the OZ439 Mesylate Salt: An Amphiphilic Antimalarial Drug with Diverse Solution and Solid State Structures.

PubMed

Clulow, Andrew J; Salim, Malinda; Hawley, Adrian; Gilbert, Elliot P; Boyd, Ben J

2018-05-07

Efforts to develop orally administered drugs tend to place an exceptional focus on aqueous solubility as this is an essential criterion for their absorption in the gastrointestinal tract. In this work we examine the solid state behavior and solubility of OZ439, a promising single-dose cure for malaria being developed as the highly water-soluble mesylate salt. The aqueous phase behavior of the OZ439 mesylate salt was determined using a combination of small angle neutron and X-ray scattering (SANS and SAXS, respectively). It was found that this salt has low solubility at low concentrations with the drug largely precipitated in free base aggregates. However, with increasing concentration these crystalline aggregates were observed to dissociate into cationic micelles and lamellar phases, effectively increasing the dissolved drug concentration. It was also found that the dissolved OZ439 spontaneously precipitated in the presence of biologically relevant anions, which we attribute to the high lattice energies of most of the salt forms of the drug. These findings show that aqueous solubility is not always what it seems in the context of amphiphilic drug molecules and highlights that its use as the principal metric in selecting drug candidates for development can be perilous.

Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems.

PubMed

Thenmozhi, Kathavarayan; Yoo, Young Je

2017-09-01

Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability. Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison. The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated. The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2 h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine. Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.

Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: I. Impact of plasticizer on film properties and dissolution

PubMed Central

Krull, Scott M.; Patel, Hardik V.; Li, Meng; Bilgili, Ecevit; Davé, Rajesh N.

2016-01-01

Recent studies have demonstrated polymer films to be a promising platform for delivery of poorly water-soluble drug particles. However, the impact of critical material attributes, for example plasticizer, on the properties of and drug release from such films has yet to be investigated. In response, this study focuses on the impact of plasticizer and plasticizer concentration on properties and dissolution rate of polymer films loaded with poorly water-soluble drug nanoparticles. Glycerin, triacetin, and polyethylene glycol were selected as film plasticizers. Griseofulvin was used as a model Biopharmaceutics Classification System class II drug and hydroxypropyl methylcellulose was used as a film-forming polymer. Griseofulvin nanoparticles were prepared via wet stirred media milling in aqueous suspension. A depression in film glass transition temperature was observed with increasing plasticizer concentration, along with a decrease in film tensile strength and an increase in film elongation, as is typical of plasticizers. However, the type and amount of plasticizer necessary to produce strong yet flexible films had no significant impact on the dissolution rate of the films, suggesting that film mechanical properties can be effectively manipulated with minimal impact on drug release. Griseofulvin nanoparticles were successfully recovered upon redispersion in water regardless of plasticizer or content, even after up to 6 months’ storage at 40 °C and 75% relative humidity, which contributed to similar consistency in dissolution rate after 6 months’ storage for all films. Good content uniformity (<4% R.S.D. for very small film sample size) was also maintained across all film formulations. PMID:27402100

Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: itraconazole.

PubMed

Taupitz, Thomas; Dressman, Jennifer B; Buchanan, Charles M; Klein, Sandra

2013-04-01

The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®. Copyright © 2012 Elsevier B.V. All rights reserved.

Mixed micelles loaded with silybin-polyene phosphatidylcholine complex improve drug solubility

PubMed Central

Duan, Rui-ling; Sun, Xun; Liu, Jie; Gong, Tao; Zhang, Zhi-rong

2011-01-01

Aim: To prepare a novel formulation of phosphatidylcholine (PC)-bile salts (BS)-mixed micelles (MMs) loaded with silybin (SLB)-PC complex for parenteral applications. Methods: SLB-PC-BS-MMs were prepared using the co-precipitation method. Differential scanning calorimetry (DSC) analysis was used to confirm the formation of the complex and several parameters were optimized to obtain a high quality formulation. The water-solubility, drug loading, particle size, zeta potential, morphology and in vivo properties of the SLB-PC-BS-MMs were determined. Results: The solubility of SLB in water was increased from 40.83±1.18 μg/mL to 10.14±0.36 mg/mL with a high drug loading (DL) of 14.43%±0.44% under optimized conditions. The SLB-PC-BS-MMs were observed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed spherical shapes. The particle size and zeta potential, as measured by photon correlation spectroscopy (PCS), were about 30±4.8 nm and −39±5.0 mV, respectively. In vivo studies showed that incorporation of the SLB-PC complex into PC-BS-MMs led to a prolonged circulation time of the drug. Conclusion: This novel formulation appears to be a good candidate for drug substances that exhibit poor solubility for parenteral administration. PMID:21170082

Development of solid dispersion systems of dapivirine to enhance its solubility.

PubMed

Gorajana, Adinarayana; Ying, Chan Chiew; Shuang, Yeen; Fong, Pooi; Tan, Zhi; Gupta, Jyoti; Talekar, Meghna; Sharma, Manisha; Garg, Sanjay

2013-06-01

Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility. Solid dispersions were prepared by solvent and fusion methods. Dapivirine release from the solid dispersion system was determined by conducting in-vitro dissolution studies. The physicochemical characteristics of the drug and its formulation were studied using Differential Scanning Calorimetry (DSC), powder X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). A significant improvement in drug dissolution rate was observed with the solid dispersion systems. XRD, SEM and DSC results indicated the transformation of pure Dapivirine which exists in crystalline form into an amorphous form in selected solid dispersion formulations. FTIR and HPLC analysis confirmed the absence of drug-excipient interactions. Solid dispersion systems can be used to improve the dissolution rate of Dapivirine. This improvement could be attributed to the reduction or absence of drug crystallinity, existence of drug particles in an amorphous form and improved wettability of the drug.

pH-driven colloidal transformations based on the vasoactive drug nicergoline.

PubMed

Salentinig, Stefan; Tangso, Kristian J; Hawley, Adrian; Boyd, Ben J

2014-12-16

The structure of colloidal self-assembled drug delivery systems can be influenced by intermolecular interactions between drug and amphiphilic molecules, and is important to understand in the context of designing improved delivery systems. Controlling these structures can enable controlled or targeted release systems for poorly water-soluble drugs. Here we present the interaction of the hydrophobic vasoactive drug nicergoline with the internal structure of nanostructured emulsion particles based on the monoglyceride-water system. Addition of this drug leads to modification of the internal bicontinuous cubic structure to generate highly pH-responsive systems. The colloidal structures were characterized with small-angle X-ray scattering and visualized using cryogenic transmission electron microscopy. Reversible transformations to inverse micelles at high pH, vesicles at low pH, and the modification of the spacing of the bicontinuous cubic structure at intermediate pH were observed, and enabled the in situ determination of an apparent pKa for the drug in this system--a difficult task using solution-based approaches. The characterization of this phase behavior is also highly interesting for the design of pH-responsive controlled release systems for poorly water-soluble drug molecules.

Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropylmethylcellulose.

PubMed

Yi, Tao; Wan, Jiangling; Xu, Huibi; Yang, Xiangliang

2008-08-07

The objective of this work was the development of a controlled release system based on self-microemulsifying mixture aimed for oral delivery of poorly water-soluble drugs. HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) of low water solubility and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system (SMES) consisting of ethyl oleate, Cremophor RH 40 and Labrasol. Based on investigation by transmission electron microscopy (TEM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction, differences were found in the particle structure between both types of formulations. In vitro release was performed and characterized by the power law. Nimodipine release from both types of formulations showed a controlled release profile and the two power law parameters, n and K, correlated to the viscosity of HPMC. The parameters were also influenced by the presence of SMES. For the controlled release solid SMES, oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. Thus, it is possible to control the in vitro release of poorly soluble drugs from solid oral dosage forms containing SMES.

Spontaneously self-assembled micelles from poly(ethylene glycol)-b-poly(epsilon-caprolactone-co-trimethylene carbonate) for drug solubilization.

PubMed

Latere, Dwan'Isa J P; Rouxhet, L; Brewster, M E; Préat, V; Ariën, A

2008-03-01

Di-block copolymers composed of polyethylene glycol (PEG) and a second block of (co)polyesters of epsilon-caprolactone (CL) and/or trimethylene carbonate (TMC) were synthesized and characterized. Tin octoate was used as catalyst and polymerization were completed over a period of 24 h with high conversion (> 95%). Self-assembling properties in water were evaluated. All di-block copolymers behave similarly except when PCL served as the second block. Stable crew-cut micelles of about 20 nm were obtained by direct dissolution of the liquid di-block copolymers in water at room temperature. When PCL was present as the second block, no solubilization occurred. Drug encapsulation of poorly water-soluble drugs belonging to biopharmaceutics classification system (BCS) class II (ketoprofen and furosemide) was evaluated. Experimental solubility for these two drugs shows a significant enhancement such that a maximum value of 23.4 mg/ml was obtained for ketoprofen in a 10% w/v micellar solution as compared to 0.14 mg in water. In the case of furosemide, the solubility increased from 0.04 mg/ml in water to about 3.2 mg/ml in a 10% w/v micellar solution. Enzymatic degradation of diblock copolymers was also studied in the presence of Pseudomonas lipase in a phosphate buffer solution (pH 7.4). Results indicated rapid degradation of copolymers containing relatively higher amounts of CL compared to TMC suggesting the potential in vivo degradation.

Preparation and evaluation of self-microemulsifying drug delivery system containing vinpocetine.

PubMed

Cui, Shu-Xia; Nie, Shu-Fang; Li, Li; Wang, Chang-Guang; Pan, Wei-San; Sun, Jian-Ping

2009-05-01

The main purpose of current investigation is to prepare a self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of vinpocetine, a poorly water-soluble drug. Suitable vehicles were screened by determining the solubility of vinpocetine in them. Certain surfactants were selected according to their emulsifying ability with different oils. Ternary phase diagrams were used to identify the efficient self-microemulsifying region and to screen the effect of surfactant/cosurfactant ratio (K(m)). The optimized formulation for in vitro dissolution and bioavailability assessment was oil (ethyl oleate, 15%), surfactant (Solutol HS 15, 50%), and cosurfactant (Transcutol P, 35%). The release rate of vinpocetine from SMEDDS was significantly higher than that of the commercial tablet. Pharmacokinetics and bioavailability of SMEDDS were evaluated. It was found that the oral bioavailability of vinpocetine of SMEDDS was 1.72-fold higher as compared with that of the commercial tablet. These results obtained demonstrated that vinpocetine absorption was enhanced significantly by employing SMEDDS. Therefore, SMEDDS might provide an efficient way of improving oral bioavailability of poorly water-soluble drugs.

Preparation of nanoparticles of poorly water-soluble antioxidant curcumin by antisolvent precipitation methods

NASA Astrophysics Data System (ADS)

Kakran, Mitali; Sahoo, Nanda Gopal; Tan, I.-Lin; Li, Lin

2012-03-01

The objective of this study was to enhance the solubility and dissolution rate of a poorly water-soluble antioxidant, curcumin, by fabricating its nanoparticles with two methods: antisolvent precipitation with a syringe pump (APSP) and evaporative precipitation of nanosuspension (EPN). For APSP, process parameters like flow rate, stirring speed, solvent to antisolvent (SAS) ratio, and drug concentration were investigated to obtain the smallest particle size. For EPN, factors like drug concentration and the SAS ratio were examined. The effects of these process parameters on the supersaturation, nucleation, and growth rate were studied and optimized to obtain the smallest particle size of curcumin by both the methods. The average particle size of the original drug was about 10-12 μm and it was decreased to a mean diameter of 330 nm for the APSP method and to 150 nm for the EPN method. Overall, decreasing the drug concentration or increasing the flow rate, stirring rate, and antisolvent amount resulted in smaller particle sizes. Differential scanning calorimetry studies suggested lower crystallinity of curcumin particles fabricated. The solubility and dissolution rates of the prepared curcumin particles were significantly higher than those the original curcumin. The antioxidant activity, studied by the DPPH free radical-scavenging assay, was greater for the curcumin nanoparticles than the original curcumin. This study demonstrated that both the methods can successfully prepare curcumin into submicro to nanoparticles. However, drug particles prepared by EPN were smaller than those by APSP and hence, showed the slightly better solubility, dissolution rate, and antioxidant activity than the latter.

Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt.

PubMed

Sanphui, Palash; Tothadi, Srinu; Ganguly, Somnath; Desiraju, Gautam R

2013-12-02

Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H···O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.

Oral Delivery of Lipophilic Drugs: The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations

PubMed Central

Beig, Avital; Agbaria, Riad; Dahan, Arik

2013-01-01

The purpose of this study was to investigate the impact of oral cyclodextrin-based formulation on both the apparent solubility and intestinal permeability of lipophilic drugs. The apparent solubility of the lipophilic drug dexamethasone was measured in the presence of various HPβCD levels. The drug’s permeability was measured in the absence vs. presence of HPβCD in the rat intestinal perfusion model, and across Caco-2 cell monolayers. The role of the unstirred water layer (UWL) in dexamethasone’s absorption was studied, and a simplified mass-transport analysis was developed to describe the solubility-permeability interplay. The PAMPA permeability of dexamethasone was measured in the presence of various HPβCD levels, and the correlation with the theoretical predictions was evaluated. While the solubility of dexamethasone was greatly enhanced by the presence of HPβCD (K1∶1 = 2311 M−1), all experimental models showed that the drug’s permeability was significantly reduced following the cyclodextrin complexation. The UWL was found to have no impact on the absorption of dexamethasone. A mass transport analysis was employed to describe the solubility-permeability interplay. The model enabled excellent quantitative prediction of dexamethasone’s permeability as a function of the HPβCD level. This work demonstrates that when using cyclodextrins in solubility-enabling formulations, a tradeoff exists between solubility increase and permeability decrease that must not be overlooked. This tradeoff was found to be independent of the unstirred water layer. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption. PMID:23874557

Recent Advances in Delivery Systems and Therapeutics of Cinnarizine: A Poorly Water Soluble Drug with Absorption Window in Stomach

PubMed Central

Pathak, Kamla

2014-01-01

Low solubility causing low dissolution in gastrointestinal tract is the major problem for drugs meant for systemic action after oral administration, like cinnarizine. Pharmaceutical products of cinnarizine are commercialized globally as immediate release preparations presenting low absorption with low and erratic bioavailability. Approaches to enhance bioavailability are widely cited in the literature. An attempt has been made to review the bioavailability complications and clinical therapeutics of poorly water soluble drug: cinnarizine. The interest of writing this paper is to summarize the pharmacokinetic limitations of drug with special focus on strategies to improvise bioavailability along with effectiveness of novel dosage forms to circumvent the obstacle. The paper provides insight to the approaches to overcome low and erratic bioavailability of cinnarizine by cyclodextrin complexes and novel dosage forms: self-nanoemulsifying systems and buoyant microparticulates. Nanoformulations need to systematically explored in future, for their new clinical role in prophylaxis of migraine attacks in children. Clinical reports have affirmed the role of cinnarizine in migraine prophylaxis. Research needs to be dedicated to develop dosage forms for efficacious bioavailability and drug directly to brain. PMID:25478230

Comparison of insulin sensitivity, glucose sensitivity, and first phase insulin secretion in patients treated with repaglinide or gliclazide.

PubMed

Wu, Chung-Ze; Pei, Dee; Hsieh, An-Tsz; Wang, Kun; Lin, Jiunn-Diann; Lee, Li-Hsiu; Chu, Yi-Min; Hsiao, Fone-Ching; Pei, Chun; Hsia, Te-Lin

2010-03-01

The traditional sulfonylureas with long half-lives have sustained stimulatory effects on insulin secretion compared to the short-acting insulin secretagogue. In this study, we used the frequently sampled intravenous glucose tolerance test (FSIGT) to evaluate the insulin sensitivity (IS), glucose sensitivity (SG), and acute insulin response after glucose load (AIRg) after 4 months treatment with either gliclazide or repaglinide. The design of study was randomizedcrossover. We enrolled 20 patients with new-onset type 2 diabetes (mean age, 49.3 years). Totally three FSIGTs were performed, one before and one after each of the two treatment periods as aforementioned. No significant differences in fasting plasma glucose, insulin, body mass index, blood pressure, glycated hemoglobin, or lipids were noted between the two treatments. After the repaglinide treatment, higher AIRg, lower IS, and lower SG were noted, but they did not reach statistical significance. The disposal index (DI) was also not significantly different between the two treatments. In conclusion, since non-significantly higher DI, AIRg, lower IS and SG were noted after repaglinide treatment, it might be a better treatment for diabetes, relative to gliclazide.

Self-assembly of model graft copolymers of agarose and weak polyelectrolyte-based amphiphilic diblock copolymers: controlled drug release and degradation.

PubMed

Muppalla, Ravikumar; Jewrajka, Suresh K; Prasad, Kamalesh

2013-06-01

Polysaccharide-based copolymers are promising biomaterials due to their biocompatibility and biodegradability. For potential biomedical applications the copolymer as a whole and all the degraded species must be biocompatible and easily removable from the system. In this regards, new model pH-responsive seaweed agarose (Agr) grafted with weak polyelectrolyte-based well-defined amphiphilic block copolymers ca. poly[(methyl methacrylate)-b-(2-dimethylamino)ethyl methacrylate)] (PMMA-b-PDMA) were designed and synthesized to study the self-assembly, degradation, and in vitro hydrophobic/hydrophilic drug release behavior. The graft copolymer solutions display extremely low critical micelle concentration (CMC) and form pH responsive stable micelles. The degradation study of the graft copolymer reveals that the entire degraded components are well soluble/dispersible in water due to formation of mixed micelles. The micelles are also strongly adsorbed on the mica surface owing to electrostatic interaction. One application of the graft copolymer micelles is that it can entrap both hydrophilic and poorly water soluble hydrophobic drugs effectively and exhibit slow release kinetics. The release kinetics of both the hydrophilic and poorly water soluble hydrophobic drugs change with pH as well as with the composition of the graft copolymer. Copyright © 2012 Wiley Periodicals, Inc.

Formulation of poorly water-soluble drugs via coacervation--a pilot study using febantel.

PubMed

De Jaeghere, W; De Geest, B G; Van Bocxlaer, J; Remon, J P; Vervaet, C; Antunes da Fonseca, A

2013-11-01

In this study, febantel was dissolved under increased temperature in a nonionic surfactant Lutrol L44® and subsequently mixed into an aqueous maltodextrin solution. After 8h under static conditions, coacervation or phase separation took place. (1)H NMR spectra and HPLC analysis showed that the upper phase contained mainly all febantel, while no febantel was detected in the lower phase. Fluorescent microscopy showed that maltodextrin is distributed in the lower phase. Coacervation proved to be a promising formulation technology for certain poorly water-soluble drugs, such as febantel. The coacervate phase showed an increase in in vitro dissolution kinetics, compared to Rintal® granules. These results were confirmed in an in vivo study performed on dogs. Febantel and fenbendazole showed a significant increase in plasma concentration compared to Rintal® granules. Further studies have to be performed to transform coacervates into a solid dosage form and to prove broad applicability to other poorly soluble drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer.

PubMed

Katare, Yogesh K; Daya, Ritesh P; Sookram Gray, Christal; Luckham, Roger E; Bhandari, Jayant; Chauhan, Abhay S; Mishra, Ram K

2015-09-08

Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain.

Enhancement of solubility and antidiabetic effects of Repaglinide using spray drying technique in STZ-induced diabetic rats.

PubMed

Varshosaz, Jaleh; Minayian, Mohsen; Ahmadi, Mahdieh; Ghassami, Erfaneh

2017-09-01

The purpose of the study was to enhance the solubility of the poorly water-soluble drug, Repaglinide using spray drying based solid dispersion technique by different carriers including Eudragit E100, hydroxyl propyl cellulose Mw 80 000 and poly vinyl pyrollidone K30. Optimization of the best formulation was carried out according to drug solubility, release profile, particle size and angle of repose of the solid dispersions. The optimized sample was characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The morphology of the dispersions was studied by SEM. The blood glucose lowering effect of spray dried solid dispersions was studied in normal and streptozocin-induced diabetic rats. The results showed that Eudragit E100 in 1:3 ratio could enhance drug solubility by 100-fold. DSC studies indicated a marked change in melting point of the drug possibly due to strong hydrogen bonds between the drug and Eudragit, while FT-IR study did not show obvious interactions between them. According to XRPD results Repaglinide converted to an amorphous state in the spray dried dispersions. Spray dried Repaglinide reduced the blood glucose level significantly during the 8 h of obtaining blood samples in comparison with untreated drug (p < 0.05).

Drugs in breast milk.

PubMed

Hervada, A R; Feit, E; Sagraves, R

1978-09-01

The amount of drug excreted into breast milk is dependent upon the lipid solubility of the medication, the mechanism of transport, the degree of ionization, and change in plasma pH. The higher the lipid solubility, the greater the concentration in human milk. The majority of drugs are transported into mammary blood capillaries by passive diffusion. The rest are transported by reverse pinocytosis. Once the drug has entered the epithelial cells of breast tissue, the drug molecules are excreted into the human milk by active transport, passive diffusion, or apocrine secretion. The amount of free (active) drug available for transport depends on the degree of protein binding the plasma pH. Another factor affecting excretion of drugs is the time when breast feeding occurs. In the 1st few days of life, when colostrum is present, water-soluble drugs pass through the breast more easily than afterwards when milk is produced. Then lipid-soluble drugs cross in higher concentrations. The effect on nursing infants is dependent on the amount excreted into the milk, the total amount absorbed by the infant, and the toxicity of the drug. The use of the following drugs in breast feeding mothers is reviewed: anticoagulants, antihypertensives and diuretics, antimicrobials, drugs affecting the central nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin), marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives, nicotine, iodides, propylthiouracil, theophylline), hormones (insulin, thyroxine, and oral contraceptives), and radiopharmaceuticals.

State of the art of nanocrystals technology for delivery of poorly soluble drugs

NASA Astrophysics Data System (ADS)

Zhou, Yuqi; Du, Juan; Wang, Lulu; Wang, Yancai

2016-09-01

Formulation of nanocrystals is a distinctive approach which can effectively improve the delivery of poorly water-soluble drugs, thus enticing the development of the nanocrystals technology. The characteristics of nanocrystals resulted in an exceptional drug delivery conductance, including saturation solubility, dissolution velocity, adhesiveness, and affinity. Nanocrystals were treated as versatile pharmaceuticals that could be delivered through almost all routes of administration. In the current review, oral, pulmonary, and intravenous routes of administration were presented. Also, the targeting of drug nanocrystals, as well as issues of efficacy and safety, were also discussed. Several methods were applied for nanocrystals production including top-down production strategy (media milling, high-pressure homogenization), bottom-up production strategy (antisolvent precipitation, supercritical fluid process, and precipitation by removal of solvent), and the combination approaches. Moreover, this review also described the evaluation and characterization of the drug nanocrystals and summarized the current commercial pharmaceutical products utilizing nanocrystals technology.

Classification of natural products as sources of drugs according to the biopharmaceutics drug disposition classification system (BDDCS).

PubMed

Li, Ji; Larregieu, Caroline A; Benet, Leslie Z

2016-12-01

Natural products (NPs) are compounds that are derived from natural sources such as plants, animals, and micro-organisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters and enzymes in determining drug bioavailability and disposition. It categorizes drugs into one of four biopharmaceutical classes according to their water solubility and extent of metabolism. The present paper reviews 109 drugs from natural product sources: 29% belong to class 1 (high solubility, extensive metabolism), 22% to class 2 (low solubility, extensive metabolism), 40% to class 3 (high solubility, poor metabolism), and 9% to class 4 (low solubility, poor metabolism). Herein we evaluated the characteristics of NPs in terms of BDDCS class for all 109 drugs as wells as for subsets of NPs drugs derived from plant sources as antibiotics. In the 109 NPs drugs, we compiled 32 drugs from plants, 50% (16) of total in class 1, 22% (7) in class 2 and 28% (9) in class 3, none found in class 4; Meantime, the antibiotics were found 5 (16%) in class 2, 22 (71%) in class 3, and 4 (13%) in class 4; no drug was found in class 1. Based on this classification, we anticipate BDDCS to serve as a useful adjunct in evaluating the potential characteristics of new natural products. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Mathematical model to analyze the dissolution behavior of metastable crystals or amorphous drug accompanied with a solid-liquid interface reaction.

PubMed

Hirai, Daiki; Iwao, Yasunori; Kimura, Shin-Ichiro; Noguchi, Shuji; Itai, Shigeru

2017-04-30

Metastable crystals and the amorphous state of poorly water-soluble drugs in solid dispersions (SDs), are subject to a solid-liquid interface reaction upon exposure to a solvent. The dissolution behavior during the solid-liquid interface reaction often shows that the concentration of drugs is supersaturated, with a high initial drug concentration compared with the solubility of stable crystals but finally approaching the latter solubility with time. However, a method for measuring the precipitation rate of stable crystals and/or the potential solubility of metastable crystals or amorphous drugs has not been established. In this study, a novel mathematical model that can represent the dissolution behavior of the solid-liquid interface reaction for metastable crystals or amorphous drug was developed and its validity was evaluated. The theory for this model was based on the Noyes-Whitney equation and assumes that the precipitation of stable crystals at the solid-liquid interface occurs through a first-order reaction. Moreover, two models were developed, one assuming that the surface area of the drug remains constant because of the presence of excess drug in the bulk and the other that the surface area changes in time-dependency because of agglomeration of the drug. SDs of Ibuprofen (IB)/polyvinylpyrrolidone (PVP) were prepared and their dissolution behaviors under non-sink conditions were fitted by the models to evaluate improvements in solubility. The model assuming time-dependent surface area showed good agreement with experimental values. Furthermore, by applying the model to the dissolution profile, parameters such as the precipitation rate and the potential solubility of the amorphous drug were successfully calculated. In addition, it was shown that the improvement in solubility with supersaturation was able to be evaluated quantitatively using this model. Therefore, this mathematical model would be a useful tool to quantitatively determine the supersaturation concentration of a metastable drug from solid dispersions. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug delivery by water-soluble organometallic cages.

PubMed

Therrien, Bruno

2012-01-01

Until recently, organometallic derivatives were generally viewed as moisture- and air-sensitive compounds, and consequently very challenging to synthesise and very demanding in terms of laboratory requirements (Schlenk techniques, dried solvent, glove box). However, an increasing number of stable, water-soluble organometallic compounds are now available, and organometallic chemistry in aqueous phase is a flourishing area of research. As such, coordination-driven self-assemblies using organometallic building blocks are compatible with water, thus opening new perspectives in bio-organometallic chemistry.This chapter gives a short history of coordination-driven self-assembly, with a special attention to organometallic metalla-cycles, especially those composed of half-sandwich complexes. These metalla-assemblies have been used as sensors, as anticancer agents, as well as drug carriers.

Solubility enhancement of a bisnaphthalimide tumoricidal agent, DMP 840, through complexation.

PubMed

Raghavan, K S; Nemeth, G A; Gray, D B; Hussain, M A

1996-10-01

The purpose of this research was to enhance the aqueous solubility of DMP 840 by complexation with water-soluble and nontoxic agents, and to understand the nature of the interactions involved in complex formation using nuclear magnetic resonance (1H-NMR). The solubility of DMP 840 in water, saline, acetate buffers, and cosolvent mixtures was determined by high-performance liquid chromatography, and the effect of nicotinamide and pyridoxine concentrations on the solubility of DMP 840 was examined by the phase solubility method. 1H-NMR spectra were acquired in deuterated acetate buffer at 400 MHz on a Varian Unity-400 spectrometer. The aqueous solubility of DMP 840 was sensitive to the presence of chloride and acetate anions in solution, and did not improve in the presence of cosolvents. The use of the nontoxic and water-soluble complex-forming agents nicotinamide and pyridoxine, however, resulted in a linear increase in the aqueous solubility of DMP 840 with both ligands. The solubilization appears to be due to formation of 1:1 complexes between DMP 840 and the bioorganic ligands. The complexation constants were 15.57 M-1 for the DMP 840:nicotinamide complex and 13.36 M-1 for the DMP 840:pyridoxine complex. The NMR results indicate that the interaction is a result of vertical or plane-to-plane stacking and the complexation constants were in agreement with that obtained by phase solubility. The results suggest that the aqueous solubility of a poorly water soluble drug substance such as DMP 840 can be significantly enhanced by its complexation with water-soluble and nontoxic agents.

Potential of ordered mesoporous silica for oral delivery of poorly soluble drugs.

PubMed

Vialpando, Monica; Martens, Johan A; Van den Mooter, Guy

2011-08-01

The use of ordered mesoporous silica is one of the more recent and rapidly developing formulation techniques for enhancing the solubility of poorly water-soluble drugs. Their large surface area and pore volume make ordered mesoporous silica materials excellent candidates for efficient drug loading and rapid release. While this new approach offers many promising advantages, further research is still necessary to elucidate the molecular mechanisms and to improve our scientific insight into the behavior of this system. In this review, the significant developments to date are presented and research challenges highlighted. Aspects of downstream processability are discussed in view of their special bulk powder properties and unique pore architecture. Lastly, perspectives for successful oral dosage form development are presented.

Water-Soluble Pd8L4 Self-assembled Molecular Barrel as an Aqueous Carrier for Hydrophobic Curcumin.

PubMed

Bhat, Imtiyaz Ahmad; Jain, Ruchi; Siddiqui, Mujahuddin M; Saini, Deepak K; Mukherjee, Partha Sarathi

2017-05-01

A tetrafacial water-soluble molecular barrel (1) was synthesized by coordination driven self-assembly of a symmetrical tetrapyridyl donor (L) with a cis-blocked 90° acceptor [cis-(en)Pd(NO 3 ) 2 ] (en = ethane-1,2-diamine). The open barrel structure of (1) was confirmed by single crystal X-ray diffraction. The presence of a hydrophobic cavity with large windows makes it an ideal candidate for encapsulation and carrying hydrophobic drug like curcumin in an aqueous medium. The barrel (1) encapsulates curcumin inside its molecular cavity and protects highly photosensitive curcumin from photodegradation. The photostability of encapsulated curcumin is due to the absorption of a high proportion of the incident photons by the aromatic walls of 1 with a high absorption cross-sectional area, which helps the walls to shield the guest even against sunlight/UV radiations. As compared to free curcumin in water, we noticed a significant increase in solubility as well as cellular uptake of curcumin upon encapsulation inside the water-soluble molecular barrel (1) in aqueous medium. Fluorescence imaging confirmed that curcumin was delivered into HeLa cancer cells by the aqueous barrel (1) with the retention of its potential anticancer activity. While free curcumin is inactive toward cancer cells in aqueous medium at room temperature due to negligible solubility, the determined IC 50 value of ∼14 μM for curcumin in aqueous medium in the presence of the barrel (1) reflects the efficiency of the barrel as a potential curcumin carrier in aqueous medium without any other additives. Thus, two major challenges of increasing the bioavailability and stability of curcumin in aqueous medium even in the presence of UV light have been addressed by using a new supramolecular water-soluble barrel (1) as a drug carrier.

Beyond liposomes: Recent advances on lipid based nanostructures for poorly soluble/poorly permeable drug delivery.

PubMed

Teixeira, M C; Carbone, C; Souto, E B

2017-10-01

Solid lipid nanoparticle (SLN), nanostructured lipid carriers (NLC) and hybrid nanoparticles, have gained increasing interest as drug delivery systems because of their potential to load and release drugs from the Biopharmaceutical classification system (BCS) of class II (low solubility and high permeability) and of class IV (low solubility and low permeability). Lipid properties (e.g. high solubilizing potential, biocompatibility, biotolerability, biodegradability and distinct route of absorption) contribute for the improvement of the bioavailability of these drugs for a set of administration routes. Their interest continues to grow, as translated by the number of patents being field worldwide. This paper discusses the recent advances on the use of SLN, NLC and lipid-polymer hybrid nanoparticles for the loading of lipophilic, poorly water-soluble and poorly permeable drugs, being developed for oral, topical, parenteral and ocular administration, also discussing the industrial applications of these systems. A review of the patents filled between 2014 and 2017, concerning the original inventions of lipid nanocarriers, is also provided. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs

PubMed Central

Becker, Lisa F; Schwarz, Dennis H

2014-01-01

Summary Methyl and ethyl thioether groups were introduced at all primary positions of α-, β-, and γ-cyclodextrin by nucleophilic displacement reactions starting from the corresponding per-(6-deoxy-6-bromo)cyclodextrins. Further modification of all 2-OH positions by etherification with iodo terminated triethylene glycol monomethyl ether (and tetraethylene glycol monomethyl ether, respectively) furnished water-soluble hosts. Especially the β-cyclodextrin derivatives exhibit very high binding potentials towards the anaesthetic drugs sevoflurane and halothane. Since the resulting inclusion compounds are highly soluble in water at temperatures ≤37 °C they are good candidates for new aqueous dosage forms which would avoid inhalation anaesthesia. PMID:25550759

Synthesis and evaluation of PEG-O-chitosan nanoparticles for delivery of poor water soluble drugs: ibuprofen.

PubMed

Hassani Najafabadi, Alireza; Abdouss, Majid; Faghihi, Shahab

2014-08-01

Current methods for preparation of PEGylated chitosan have limitations such as harsh de protecting step and several purification cycles. In the present study, a facile new method for conjugating methoxy polyethylene glycol (mPEG) to chitosan under mild condition is introduced to improve water solubility of chitosan and control the release of poor water soluble drugs. The method consists of chitosan modification by grafting the C6 position of chitosan to mPEG which is confirmed by Fourier transformed-infrared (FT-IR) and proton nuclear magnetic resonance ((1)HNMR) analyses. The amine groups at the C2 position of chitosan are protected using sodium dodecylsulfate (SDS) which is removed by dialyzing the precipitation against Tris solution. The chemical structure of the prepared polymer is characterized by FTIR and (1)HNMR. The synthesized polymer is then employed to prepare nanoparticles which are characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), scanning electron microscopy (SEM), and dynamic light scattering (DLS) for their size and morphology. The nanoparticles are used for encapsulation of ibuprofen followed by in vitro release investigation in gastrointestinal and simulated biological fluids. The chitosan nanoparticles are used as control. The PEGylated nanoparticles show a particle size of 80 nm with spherical morphology. The results clearly show that drug release from PEGylated chitosan nanoparticles is remarkably slower than chitosan. In addition, drug encapsulation and encapsulation efficiency in PEGylated nanoparticles are dependent on the amount of drug added to the formulation being significantly higher than chitosan nanoparticles. This study provides an efficient, novel, and facile method for preparing a nano carrier system for delivery of water insoluble drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: I. Impact of plasticizer on film properties and dissolution.

PubMed

Krull, Scott M; Patel, Hardik V; Li, Meng; Bilgili, Ecevit; Davé, Rajesh N

2016-09-20

Recent studies have demonstrated polymer films to be a promising platform for delivery of poorly water-soluble drug particles. However, the impact of critical material attributes, for example plasticizer, on the properties of and drug release from such films has yet to be investigated. In response, this study focuses on the impact of plasticizer and plasticizer concentration on properties and dissolution rate of polymer films loaded with poorly water-soluble drug nanoparticles. Glycerin, triacetin, and polyethylene glycol were selected as film plasticizers. Griseofulvin was used as a model Biopharmaceutics Classification System class II drug and hydroxypropyl methylcellulose was used as a film-forming polymer. Griseofulvin nanoparticles were prepared via wet stirred media milling in aqueous suspension. A depression in film glass transition temperature was observed with increasing plasticizer concentration, along with a decrease in film tensile strength and an increase in film elongation, as is typical of plasticizers. However, the type and amount of plasticizer necessary to produce strong yet flexible films had no significant impact on the dissolution rate of the films, suggesting that film mechanical properties can be effectively manipulated with minimal impact on drug release. Griseofulvin nanoparticles were successfully recovered upon redispersion in water regardless of plasticizer or content, even after up to 6months' storage at 40°C and 75% relative humidity, which contributed to similar consistency in dissolution rate after 6months' storage for all films. Good content uniformity (<4% R.S.D. for very small film sample size) was also maintained across all film formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

The use of surfactants to enhance the solubility and stability of the water-insoluble anticancer drug SN38 into liquid crystalline phase nanoparticles.

PubMed

Ranneh, Abdul-Hackam; Iwao, Yasunori; Noguchi, Shuji; Oka, Toshihiko; Itai, Shigeru

2016-12-30

Cubosomes were used to increase the aqueous solubility of the water insoluble anticancer drug SN38. The results showed that the use of a common cubosome formulation consisting of phytantriol (PHYT) as the matrix amphiphile (PHYT-cubosome) led to a 6-fold increase in the solubility of SN38. However, mean hydrodynamic diameter (D H ) and polydispersity index (PDI) of these PHYT-cubosome particles were 345±49nm and 0.37±0.05, respectively, making them unsuitable for intravenous applications. Several additives were investigated to increase the solubility of SN38 and reduce the D H and PDI values of the resulting particles. Charged additives such as didodecyldimethyl ammonium bromide (DDAB) and sodium dodecyl sulfate (SDS) led to improvements in the physiochemical properties of the cubosomes. Notably, the PHYT-DDAB and PHT-SDS cubosomes led to 15- and 14-fold increases in the aqueous solubility of SN38, respectively. Moreover, the SN38 loaded into the PHYT-DDAB and PHYT-SDS cubosomes was found to be highly stable, with very little hydrolysis to its inactive acid form. In summary, the addition of DDAB and SDS to PHYT-cubosome nanoparticle drug delivery systems not only led to considerable improvements in their physiochemical properties, but also enhanced the aqueous solubility of SN38 and increased its chemical stability. Copyright © 2016 Elsevier B.V. All rights reserved.

Fabrication, Characterization, In vitro Evaluation of Solid Lipid Nanoemulsion of Flunarizine dihydrochloride for Nasal Delivery.

PubMed

Newton, Maria J; Harjot, Kaur

2017-01-01

Flunarizine dihydrochloride (FHC) is used for the prophylaxis to migraine. Flunarizine has solubility problems which is practically insoluble in water and alcohol. Nanoemulsion is the approach to increase the solubility of the insoluble drugs. Nanoemulsions of FHC was prepared which can be given through the alternate route such as nasal drug delivery for migraine. In this research work the solubility of the poorly soluble FHC was successfully improved by preparing it as a nano emulsion. Nanoemulsions can pass through the biological membrane easily so it can be delivered through nasal mucosa by which it may provide a quicker onset of action. The currently available dosage forms are in the form of tablet. The formulations were prepared by using Glycerl Monostearate (GMS), Tween 80 as surfactant and PEG 400: Ethanol as co-surfactant in the distilled water. Nanoemulsions were prepared by step by step procedure. The prepared nanoemulsions were analyzed preliminarily by Master Sizer followed by Zeta Sizer by using the technique Dynamic Photon Correlation Spectroscopy. The best nanoemulsion was subjected to Zeta Potential study. The TEM analysis was carried out on the best formulation to gain the detailed information about the formulation. The best formulation was selected based on the physical appearance, homogenecity of the preparation, Preliminary Master Sizer analysis report, Secondary Zeta Sizer analysis report with Zeta Potential and TEM. The best formulation demonstrated the size in nano range with improved solubility. The FHC nano emulsion was prepared successfully which improved the solubility of the drug. The drug release study on simulated nasal fluid revealed that the preparation is suitable to be delivered through the nasal route. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Rapid identification of illegal synthetic adulterants in herbal anti-diabetic medicines using near infrared spectroscopy

NASA Astrophysics Data System (ADS)

Feng, Yanchun; Lei, Deqing; Hu, Changqin

We created a rapid detection procedure for identifying herbal medicines illegally adulterated with synthetic drugs using near infrared spectroscopy. This procedure includes a reverse correlation coefficient method (RCCM) and comparison of characteristic peaks. Moreover, we made improvements to the RCCM based on new strategies for threshold settings. Any tested herbal medicine must meet two criteria to be identified with our procedure as adulterated. First, the correlation coefficient between the tested sample and the reference must be greater than the RCCM threshold. Next, the NIR spectrum of the tested sample must contain the same characteristic peaks as the reference. In this study, four pure synthetic anti-diabetic drugs (i.e., metformin, gliclazide, glibenclamide and glimepiride), 174 batches of laboratory samples and 127 batches of herbal anti-diabetic medicines were used to construct and validate the procedure. The accuracy of this procedure was greater than 80%. Our data suggest that this protocol is a rapid screening tool to identify synthetic drug adulterants in herbal medicines on the market.

PEG-lipid micelles as drug carriers: physiochemical attributes, formulation principles and biological implication.

PubMed

Gill, Kanwaldeep K; Kaddoumi, Amal; Nazzal, Sami

2015-04-01

PEG-lipid micelles, primarily conjugates of polyethylene glycol (PEG) and distearyl phosphatidylethanolamine (DSPE) or PEG-DSPE, have emerged as promising drug-delivery carriers to address the shortcomings associated with new molecular entities with suboptimal biopharmaceutical attributes. The flexibility in PEG-DSPE design coupled with the simplicity of physical drug entrapment have distinguished PEG-lipid micelles as versatile and effective drug carriers for cancer therapy. They were shown to overcome several limitations of poorly soluble drugs such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Therefore, considerable efforts have been made to exploit the full potential of these delivery systems; to entrap poorly soluble drugs and target pathological sites both passively through the enhanced permeability and retention (EPR) effect and actively by linking the terminal PEG groups with targeting ligands, which were shown to increase delivery efficiency and tissue specificity. This article reviews the current state of PEG-lipid micelles as delivery carriers for poorly soluble drugs, their biological implications and recent developments in exploring their active targeting potential. In addition, this review sheds light on the physical properties of PEG-lipid micelles and their relevance to the inherent advantages and applications of PEG-lipid micelles for drug delivery.

Strategies to enhance the bioavailability of curcumin: a potential antitumor drug

NASA Astrophysics Data System (ADS)

Kumar, Abhishek; Chittigori, Joshna; Li, Lian; Samuelson, Lynne; Sandman, Daniel; Kumar, Jayant

2012-02-01

Curcumin is a polyphenol which has elicited considerable interest for its antioxidant and anti tumor properties. Although curcumin may be used as potential therapeutic drug, it is very sparingly soluble in water which makes it less bioavailable under physiological conditions. We report two approaches to make curcumin more bioavailable. The first approach involves fabricating colloidal dispersions of curcumin in the range of tens of nanometers. The second approach involves functionalization of curcumin with polyethylene glycol (PEG) to render it water dispersible or soluble. Since curcumin is a fluorescent molecule as well as a potential drug, its interactions with cells have been investigated using one and two photon confocal fluorescence imaging. We have also observed strong interaction between curcumin and metal ions, which may have physiological implications.

Development of solid dispersions of artemisinin for transdermal delivery.

PubMed

Shahzad, Yasser; Sohail, Sadia; Arshad, Muhammad Sohail; Hussain, Talib; Shah, Syed Nisar Hussain

2013-11-30

Solid dispersions of the poorly soluble drug artemisinin were developed using polymer blends of polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) with the aim of enhancing solubility and in vitro permeation of artemisinin through skin. Formulations were characterised using a combination of molecular dynamics (MD) simulations, differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR). Solubility of artemisinin was determined in two solvents: de-ionised water and phosphate buffered saline (PBS; pH 7.4), while in vitro drug permeation studies were carried out using rabbit skin as a model membrane. MD simulations revealed miscibility between the drug and polymers. DSC confirmed the molecular dispersion of the drug in the polymer blend. Decrease in crystallinity of artemisinin with respect to polymer content and the absence of specific drug-polymer interactions were confirmed using XRD and FT-IR, respectively. The solubility of artemisinin was dramatically enhanced for the solid dispersions, as was the permeation of artemisinin from saturated solid-dispersion vehicles relative to that from saturated solutions of the pure drug. The study suggests that high energy solid forms of artemisinin could possibly enable transdermal delivery of artemisinin. Copyright © 2013 Elsevier B.V. All rights reserved.

Synthesis and in vitro evaluation of methotrexate conjugated O, N-carboxymethyl chitosan via peptidyl spacers

NASA Astrophysics Data System (ADS)

Li, Dan; Lu, Bo; Zhang, Hong; Huang, Zhijun; Xu, Peihu; Zheng, Hua; Yin, Yihua; Xu, Haixing; Liu, Xia; Lou, Yiceng; Zhang, Xueqiong; Xiong, Fuliang

2014-09-01

The use of methotrexate (MTX), an anticancer drug for the treatment of hematologic malignancies, has been limited in the clinical application due to its poor water solubility, high clearance rate, and lack of target specificity. To solve these problems, O, N-carboxymethyl chitosan-dipeptide-MTX conjugates have been synthesized and characterized by fourier transform infrared radiation spectroscopy and proton nuclear magnetic resonance (1H NMR). All polymeric conjugates showed satisfactory water solubility. The results of the study revealed that drug release and toxicity were affected by employing polymeric conjugation strategy and dipeptide spacers [glycylglycine (Gly-Gly), glycyl- l-phenylalanine (Gly-Phe), glycyl- l-tyrosine (Gly-Tyr)]. It has been found that drugs could be effectively loaded and released when polymeric prodrugs were combined with a dipeptide spacer. In conclusion, O, N-CMCS-dipeptide-MTX polymeric prodrugs could potentially be used as responsive drug delivery systems.

Functionalized graphene oxides for drug loading, release and delivery of poorly water soluble anticancer drug: A comparative study.

PubMed

Karki, Neha; Tiwari, Himani; Pal, Mintu; Chaurasia, Alok; Bal, Rajaram; Joshi, Penny; Sahoo, Nanda Gopal

2018-05-18

In this work, the modification of graphene oxides (GOs) have been done with hydrophilic and biodegradable polymer, polyvinylpyrrolidone (PVP) and other excipient β -cyclodextrin (β-CD) through covalent functionalization for efficient loading and compatible release of sparingly water soluble aromatic anticancer drug SN-38 (7-ethyl-10-hydroxy camptothecin). The drug was loaded onto both GO-PVP and GO-β-CD through the π-π interactions.The release of drug from both the nanocarriers were analyzed in different pH medium of pH 7 (water, neutral medium), pH 5 (acidic buffer) and pH 12 (basic buffer). The loading capacity and the cell killing activity of SN-38 loaded on functionalized GO were investigated comprehensively in human breast cancer cells MCF-7.Our findings shown that the cytotoxicity of SN-38 loaded to the polymer modified GO was comparatively higher than free SN-38. In particular, SN-38 loaded GO-PVP nanocarrier has more cytotoxic effect than GO-β-CD nanocarrier against MCF-7 cells, indicating that SN-38 loaded GO-PVP nanocarrier can be used as promising material for drug delivery and biological applications. Copyright © 2018 Elsevier B.V. All rights reserved.

Functional and unmodified MWNTs for delivery of the water-insoluble drug Carvedilol - A drug-loading mechanism

NASA Astrophysics Data System (ADS)

Li, Yuting; Wang, Tianyi; Wang, Jing; Jiang, Tongying; Cheng, Gang; Wang, Siling

2011-04-01

The purpose of this study was to develop carboxyl multi-wall carbon nanotubes (MWNTs) and unmodified MWNTs loaded with a poorly water-soluble drug, intended to improve the drug loading capacity, dissolubility and study the drug-loading mechanism. MWNTs were modified with a carboxyl group through the acid treatment. MWNTs as well as the resulting functionalized MWNTs were investigated as scaffold for loading the model drug, Carvedilol (CAR), using three different methods (the fusion method, the incipient wetness impregnation method, and the solvent method). The effects of different pore size, specific surface area and physical state were systematically studied using scanning electron microscopy (SEM), thermogravimetric analysis (TGA), Fourier transformation infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), nitrogen adsorption, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The functional MWNTs allowed a higher drug loading than the unmodified preparations. The methods used to load the drug had a marked effect on the drug-loading, dissolution, and physical state of the drug as well as its distribution. In addition, the solubility of the drug was increased when carried by both MWNTs and functional MWNTs, and this might help to improve the bioavailability.

Intrinsic solubility estimation and pH-solubility behavior of cosalane (NSC 658586), an extremely hydrophobic diprotic acid.

PubMed

Venkatesh, S; Li, J; Xu, Y; Vishnuvajjala, R; Anderson, B D

1996-10-01

The selection of cosalane (NSC 658586) by the National Cancer Institute for further development as a potential drug candidate for the treatment of AIDS led to the exploration of the solubility behavior of this extremely hydrophobic drug, which has an intrinsic solubility (S0 approaching 1 ng/ml. This study describes attempts to reliably measure the intrinsic solubility of cosalane and examine its pH-solubility behavior. S0 was estimated by 5 different strategies: (a) direct determination in an aqueous suspension: (b) facilitated dissolution; (c) estimation from the octanol/water partition coefficient and octanol solubility (d) application of an empirical equation based on melting point and partition coefficient; and (e) estimation from the hydrocarbon solubility and functional group contributions for transfer from hydrocarbon to water. S0 estimates using these five methods varied over a 5 x 107-fold range Method (a) yielded the highest values, two-orders of magnitude greater than those obtained by method (b) (facilitated dissolution. 1.4 +/- 0.5 ng/ml). Method (c) gave a value 20-fold higher while that from method (d) was in fair agreement with that from facilitated dissolution. Method (e) yielded a value several orders-of-magnitude lower than other methods. A molecular dynamics simulation suggests that folded conformations not accounted for by group contributions may reduce cosalane's effective hydrophobicity. Ionic equilibria calculations for this weak diprotic acid suggested a 100-fold increase in solubility per pH unit increase. The pH-solubility profile of cosalane at 25 degrees C agreed closely with theory. These studies highlight the difficulty in determining solubility of very poorly soluble compounds and the possible advantage of the facilitated dissolution method. The diprotic nature of cosalane enabled a solubility enhancement of > 107-fold by simple pH adjustment.

Development and optimization of a self-microemulsifying drug delivery system for atorvastatin calcium by using D-optimal mixture design.

PubMed

Yeom, Dong Woo; Song, Ye Seul; Kim, Sung Rae; Lee, Sang Gon; Kang, Min Hyung; Lee, Sangkil; Choi, Young Wook

2015-01-01

In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A D-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the D-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs.

Development and optimization of a self-microemulsifying drug delivery system for ator vastatin calcium by using d-optimal mixture design

PubMed Central

Yeom, Dong Woo; Song, Ye Seul; Kim, Sung Rae; Lee, Sang Gon; Kang, Min Hyung; Lee, Sangkil; Choi, Young Wook

2015-01-01

In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A d-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the d-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs. PMID:26089663

Three new hydrochlorothiazide cocrystals: Structural analyses and solubility studies

NASA Astrophysics Data System (ADS)

Ranjan, Subham; Devarapalli, Ramesh; Kundu, Sudeshna; Vangala, Venu R.; Ghosh, Animesh; Reddy, C. Malla

2017-04-01

Hydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform -infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P21/n, P21/c and P21/n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after 4 h in phosphate buffer, pH 7.4, at 25 °C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HCT suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HCT and cocrystallization can be a promising approach to improve aqueous solubility of drugs.

Increasing the dissolution rate and oral bioavailability of the poorly water-soluble drug valsartan using novel hierarchical porous carbon monoliths.

PubMed

Zhang, Yanzhuo; Che, Erxi; Zhang, Miao; Sun, Baoxiang; Gao, Jian; Han, Jin; Song, Yaling

2014-10-01

In the present study, a novel hierarchical porous carbon monolith (HPCM) with three-dimensionally (3D) ordered macropores (∼ 400 nm) and uniform accessible mesopores (∼ 5.2 nm) was synthesized via a facile dual-templating technique using colloidal silica nanospheres and Poloxamer 407 as templates. The feasibility of the prepared HPCM for oral drug delivery was studied. Valsartan (VAL) was chosen as a poorly water-soluble model drug and loaded into the HPCM matrix using the solvent evaporation method. Scanning electron microscopy (SEM) and specific surface area analysis were employed to characterize the drug-loaded HPCM-based formulation, confirming the successful inclusion of VAL into the nanopores of HPCM. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) demonstrated that the incorporated drug in the HPCM matrix was in an amorphous state and the VAL formulation exhibited good physical stability for up to 6 months. In vitro tests showed that the dissolution rate of HPCM-based formulation was increased significantly compared with that of crystalline VAL or VAL-loaded 3D ordered macroporous carbon monoliths (OMCMs). Furthermore, a pharmacokinetic study in rats demonstrated about 2.4-fold increase in oral bioavailability of VAL in the case of HPCM-based formulation compared with the commercially available VAL preparation (Valzaar(®)). These results therefore suggest that HPCM is a promising carrier able to improve the dissolution rate and oral bioavailability of the poorly water-soluble drug VAL. Copyright © 2014. Published by Elsevier B.V.

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

PubMed

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

2018-06-04

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

[Synthesis and physico-chemical characterisation of some new derivatives of rutoside and clofibric acid].

PubMed

Lupaşcu, D; Profire, Lenuţa; Dănilă, Gh

2006-01-01

Fibrates are drugs with efficacy in reducing blood cholesterol levels and especially, triglyceride plasma levels. Unfortunately, fibrates have a poor water-solubility and showed some adverse reactions at long treatment. The objective of this study was to obtain some new clofibric acid derivatives with rutin; some of these compounds contain a guanidine moiety, known as effective at cardiovascular level. All the compounds are soluble in water.

Naproxen Microparticulate Systems Prepared Using In Situ Crystallisation and Freeze-Drying Techniques.

PubMed

Solaiman, Amanda; Tatari, Adam Keenan; Elkordy, Amal Ali

2017-07-01

Poor drug solubility and dissolution rate remain to be one of the major problems facing pharmaceutical scientists, with approximately 40% of drugs in the industry categorised as practically insoluble or poorly water soluble. This in turn can lead to serious delivery challenges and poor bioavailability. The aim of this research was to investigate the effects of the surfactants, poloxamer 407 (P407) and caprol® PGE 860 (CAP), at various concentrations (0.1, 0.5, 1 and 3% w/v) on the enhancement of the dissolution properties of poorly water-soluble drug, naproxen, using in situ micronisation by solvent change method and freeze-drying. The extent at which freeze-drying influences the dissolution rate of naproxen microcrystals is investigated in this study by comparison with desiccant-drying. All formulations were evaluated and characterised using particle size analysis and morphology, in vitro dissolution studies, differential scanning calorimetry (DSC), and Fourier transform infra-red (FT-IR) spectroscopy. An increase in poloxamer 407 concentration in freeze-dried formulations led to enhancement of drug dissolution compared to desiccator-dried formulations, naproxen/caprol® PGE 860 formulations and untreated drug. DSC and FT-IR results show no significant chemical interactions between drug and poloxamer 407, with only very small changes to drug crystallinity. On the other hand, caprol® PGE 860 showed some interactions with drug components, alterations to the crystal lattice of naproxen, and poor dissolution profiles using both drying methods, making it a poor choice of excipient.

Enhanced oral bioavailability of fenofibrate using polymeric nanoparticulated systems: physicochemical characterization and in vivo investigation

PubMed Central

Yousaf, Abid Mehmood; Kim, Dong Wuk; Oh, Yu-Kyoung; Yong, Chul Soon; Kim, Jong Oh; Choi, Han-Gon

2015-01-01

Background The intention of this research was to prepare and compare various solubility-enhancing nanoparticulated systems in order to select a nanoparticulated formulation with the most improved oral bioavailability of poorly water-soluble fenofibrate. Methods The most appropriate excipients for different nanoparticulated preparations were selected by determining the drug solubility in 1% (w/v) aqueous solutions of each carrier. The polyvinylpyrrolidone (PVP) nanospheres, hydroxypropyl-β-cyclodextrin (HP-β-CD) nanocorpuscles, and gelatin nanocapsules were formulated as fenofibrate/PVP/sodium lauryl sulfate (SLS), fenofibrate/HP-β-CD, and fenofibrate/gelatin at the optimized weight ratios of 2.5:4.5:1, 1:4, and 1:8, respectively. The three solid-state products were achieved using the solvent-evaporation method through the spray-drying technique. The physicochemical characterization of these nanoparticles was accomplished by powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and Fourier-transform infrared spectroscopy. Their physicochemical properties, aqueous solubility, dissolution rate, and pharmacokinetics in rats were investigated in comparison with the drug powder. Results Among the tested carriers, PVP, HP-β-CD, gelatin, and SLS showed better solubility and were selected as the most appropriate constituents for various nanoparticulated systems. All of the formulations significantly improved the aqueous solubility, dissolution rate, and oral bioavailability of fenofibrate compared to the drug powder. The drug was present in the amorphous form in HP-β-CD nanocorpuscles; however, in other formulations, it existed in the crystalline state with a reduced intensity. The aqueous solubility and dissolution rates of the nanoparticles (after 30 minutes) were not significantly different from one another. Among the nanoparticulated systems tested in this study, the initial dissolution rates (up to 10 minutes) were higher with the PVP nanospheres and HP-β-CD nanocorpuscles; however, neither of them resulted in the highest oral bioavailability. Irrespective of relatively retarded dissolution rate, gelatin nanocapsules showed the highest apparent aqueous solubility and furnished the most improved oral bioavailability of the drug (~5.5-fold), owing to better wetting and diminution in crystallinity. Conclusion Fenofibrate-loaded gelatin nanocapsules prepared using the solvent-evaporation method through the spray-drying technique could be a potential oral pharmaceutical product for administering the poorly water-soluble fenofibrate with an enhanced bioavailability. PMID:25784807

Simulated food effects on drug release from ethylcellulose: PVA-PEG graft copolymer-coated pellets.

PubMed

Muschert, Susanne; Siepmann, Florence; Leclercq, Bruno; Carlin, Brian; Siepmann, Juergen

2010-02-01

Food effects might substantially alter drug release from oral controlled release dosage forms in vivo. The robustness of a novel type of controlled release film coating was investigated using various types of release media and two types of release apparatii. Importantly, none of the investigated conditions had a noteworthy impact on the release of freely water-soluble diltiazem HCl or slightly water-soluble theophylline from pellets coated with ethylcellulose containing small amounts of PVA-PEG graft copolymer. In particular, the presence of significant amounts of fats, carbohydrates, surfactants, bile salts, and calcium ions in the release medium did not alter drug release. Furthermore, changes in the pH and differences in the mechanical stress the dosage forms were exposed to did not affect drug release from the pellets. The investigated film coatings allowing for oral controlled drug delivery are highly robust in vitro and likely to be poorly sensitive to classical food effects in vivo.

Formulation development and in vitro evaluation of solidified self-microemulsion in the form of tablet containing atorvastatin calcium.

PubMed

Ali, Kazi Asraf; Mukherjee, Biswajit; Bandyopadhyay, Amal Kumar

2013-11-01

The objective of our present study was to prepare solid self-microemulsion in the form of tablet of a poorly water soluble drug, Atorvastatin calcium (ATNC) to increase the solubility, dissolution rate, and minimize the hazards experienced from liquid emulsions. Self-microemulsifying ATNC tablet was formulated mainly by using self-emulsifying base, solidifying agent silicon dioxide and sodium starch glycolate as tablet disintegrant. Self-emulsifying base containing Transcutol P, Gelucire 44/14, and Lutrol F68 with their ratios in the formulation, were best selected by solubility study and ternary phase diagram in different vehicles. Particle size of microemulsion from tablet, physical parameters of the tablet and drug content has been checked. In vitro drug release rate has been carried out in phosphate buffer medium (pH 6.8). Physicochemical characterization of the drug in the optimized formulation has been performed to check drug-excipient incompatibility, if any. Average particle diameter of the emulsions formed from the tablet was found to be below 100 nm in case of formulation F4 and F5, which indicated microemulsions has been formed. In vitro drug release from the formulations F3, F4, and F5 was found to be >90%, indicated the enhancement of solubility of ATNC compared to parent drug. Differential thermal analysis (DTA), Powder X-ray Diffraction (X-RD) and Fourier transform infra red (FTIR) study proved the identity of the drug in the optimized formulation. The tablet form of self-microemulsifying (SME) drug delivery is good for solubility enhancement.

Fast dissolution of poorly water soluble drugs from fluidized bed coated nanocomposites: Impact of carrier size.

PubMed

Azad, Mohammad; Moreno, Jacqueline; Bilgili, Ecevit; Davé, Rajesh

2016-11-20

Formation of core-shell nanocomposites of Fenofibrate and Itraconazole, model poorly water soluble drugs, via fluidized bed (FB) coating of their well-stabilized high drug loaded nanosuspensions is investigated. Specifically, the extent of dissolution enhancement, when fine carrier particles (sub-50μm) as opposed to the traditional large carrier particles (>300μm) are used, is examined. This allows testing the hypothesis that greatly increased carrier surface area and more importantly, thinner shell for finer carriers at the same drug loading can significantly increase the dissolution rate when spray-coated nanosuspensions are well-stabilized. Fine sub-50μm lactose (GranuLac ® 200) carrier particles were made fluidizable via dry coating with nano-silica, enabling decreased cohesion, fluidization and subsequent nanosuspension coating. For both drugs, 30% drug loaded suspensions were prepared via wet-stirred media milling using hydroxypropyl methyl cellulose and sodium dodecyl sulfate as stabilizers. The stabilizer concentrations were varied to affect the milled particle size and prepare a stable nanosuspension. The suspensions were FB coated onto hydrophilic nano-silica (M-5P) dry coated sub-50μm lactose (GranuLac ® 200) carrier particles or larger carrier particles of median size >300μm (PrismaLac ® 40). The resulting finer composite powders (sub-100μm) based on GranuLac ® 200 were freely flowing, had high bulk density, and had much faster, immediate dissolution of the poorly water-soluble drugs, in particular for Itraconazole. This is attributed to a much higher specific surface area of the carrier and corresponding thinner coating layer for fine carriers as opposed to those for large carrier particles. Copyright © 2016 Elsevier B.V. All rights reserved.

Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs.

PubMed

Serajuddin, A T

1999-10-01

Although there was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of poorly water-soluble drugs, their commercial use has been very limited, primarily because of manufacturing difficulties and stability problems. Solid dispersions of drugs were generally produced by melt or solvent evaporation methods. The materials, which were usually semisolid and waxy in nature, were hardened by cooling to very low temperatures. They were then pulverized, sieved, mixed with relatively large amounts of excipients, and encapsulated into hard gelatin capsules or compressed into tablets. These operations were difficult to scale up for the manufacture of dosage forms. The situation has, however, been changing in recent years because of the availability of surface-active and self-emulsifying carriers and the development of technologies to encapsulate solid dispersions directly into hard gelatin capsules as melts. Solid plugs are formed inside the capsules when the melts are cooled to room temperature. Because of surface activity of carriers used, complete dissolution of drug from such solid dispersions can be obtained without the need for pulverization, sieving, mixing with excipients, etc. Equipment is available for large-scale manufacturing of such capsules. Some practical limitations of dosage form development might be the inadequate solubility of drugs in carriers and the instability of drugs and carriers at elevated temperatures necessary to manufacture capsules.

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons.

PubMed

Chokshi, Rina J; Zia, Hossein; Sandhu, Harpreet K; Shah, Navnit H; Malick, Waseem A

2007-01-01

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.

Investigation of Cyclodextrin-Based Nanosponges for Solubility and Bioavailability Enhancement of Rilpivirine.

PubMed

Rao, Monica R P; Chaudhari, Jagruti; Trotta, Francesco; Caldera, Fabrizio

2018-06-04

Rilpivrine is BCS class II drug used for treatment of HIV infection. The drug has low aqueous solubility (0.0166 mg/ml) and dissolution rate leading to low bioavailability (32%). Aim of this work was to enhance solubility and dissolution of rilpivirine using beta-cyclodextrin-based nanosponges. These nanosponges are biocompatible nanoporous particles having high loading capacity to form supramolecular inclusion and non-inclusion complexes with hydrophilic and lipophilic drugs for solubility enhancement. Beta-cyclodextrin was crosslinked with carbonyl diimidazole and pyromellitic dianhydride to prepare nanosponges. The nanosponges were loaded with rilpivirine by solvent evaporation method. Binary and ternary complexes of drug with β-CD, HP-β-CD, nanosponges, and tocopherol polyethylene glycol succinate were prepared and characterized by phase solubility, saturation solubility in different media, in vitro dissolution, and in vivo pharmacokinetics. Spectral analysis by Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry was performed. Results obtained from spectral characterization confirmed inclusion complexation. Phase solubility studies indicated stable complex formation. Saturation solubility was found to be 10-13-folds higher with ternary complexes in distilled water and 12-14-fold higher in 0.1 N HCl. Solubility enhancement was evident in biorelevant media. Molecular modeling studies revealed possible mode of entrapment of rilpivirine within β-CD cavities. A 3-fold increase in dissolution with ternary complexes was observed. Animal studies revealed nearly 2-fold increase in oral bioavailability of rilpivirine. It was inferred that electronic interactions, hydrogen bonding, and van der Waals forces are involved in the supramolecular interactions.

Crystal engineering of a zwitterionic drug to neutral cocrystals: a general solution for floxacins.

PubMed

Gunnam, Anilkumar; Suresh, Kuthuru; Ganduri, Ramesh; Nangia, Ashwini

2016-10-18

The transformation of zwitterionic Sparfloxacin (SPX) to the neutral form is achieved by cocrystallization. Neutral forms of drugs are important for higher membrane permeability, while zwitterions are more soluble in water. The twin advantages of higher solubility/dissolution rate and good stability of neutral SPX are achieved in a molecular cocrystal compared to its zwitterionic SPX hydrate. The amine-phenol supramolecular synthon drives cocrystal formation, with the paraben ester acting as a "proton migrator" for the ionic to neutral transformation.

Solubility enhancement of miconazole nitrate: binary and ternary mixture approach.

PubMed

Rai, Vineet Kumar; Dwivedi, Harinath; Yadav, Narayan Prasad; Chanotiya, Chandan Singh; Saraf, Shubhini A

2014-08-01

Enhancement of aqueous solubility of very slightly soluble Miconazole Nitrate (MN) is required to widen its application from topical formulation to oral/mucoadhesive formulations. Aim of the present investigation was to enhance the aqueous solubility of MN using binary and ternary mixture approach. Binary mixtures such as solvent deposition, inclusion complexation and solid dispersion were adopted to enhance solubility using different polymers like lactose, beta-cyclodextrin (β-CD) and polyethylene-glycol 6000 (PEG 6000), respectively. Batches of binary mixtures with highest solubility enhancement potentials were further mixed to form ternary mixture by a simple kneading method. Drug polymer interaction and mixture morphology was studied using the Fourier transform infrared spectroscopy and the scanning electron microscopy, respectively along with their saturation solubility studies and drug release. An excellent solubility enhancement, i.e. up to 72 folds and 316 folds of MN was seen by binary and ternary mixture, respectively. Up to 99.5% drug was released in 2 h from the mixtures of MN and polymers. RESULTS revealed that solubility enhancement by binary mixtures is achieved due to surface modification and by increasing wettability of MN. Tremendous increase in solubility of MN by ternary mixture could possibly be due to blending of water soluble polymers, i.e. lactose and PEG 6000 with β-CD which was found to enhance the solubilizing nature of β-CD. Owing to the excellent solubility enhancement potential of ternary mixtures in enhancing MN solubility from 110.4 μg/ml to 57640.0 μg/ml, ternary mixture approach could prove to be promising in the development of oral/mucoadhesive formulations.

Evaluation of synergistic antimicrobial effect of vitamins (A, B1, B2, B6, B12, C, D, E and K) with antibiotics against resistant bacterial strains.

PubMed

Shahzad, Shakeel; Ashraf, M Adnan; Sajid, M; Shahzad, Aqeel; Rafique, Azhar; Mahmood, M Shahid

2018-02-02

Multiple drug resistant super bugs of Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA) are becoming challenge for healthcare professionals. In this study, vitamins were evaluated for synergistic activity with the antibiotics. Synergistic effect between antibiotic and stock solutions of vitamins is evaluated by using Kirby-Bauer disc diffusion assay. Distilled water and propylene glycol were used as solvent for water soluble vitamins and fat-soluble vitamins respectively. The final concentration of 10mg/ml of each water-soluble vitamin B1 (Thiamine), B2 (Riboflavin), B6 (Pyridoxine) B12 (Methylcobalamin), C (Ascorbic acid) and 0.1mg/ml of each fat soluble vitamin A (retinol), D (cholecalciferol) E (αTocopherol) K (Menadione) were used with the antibiotics. The results depicted that vitamin K and E have better synergistic activity with piperacillin-tazobactam, imipenem and doripenem antibiotics against A. baumannii. While vitamin B1, B2 and B12 showed remarkable synergistic activity with linezolid against MRSA. Vitamin B1 was further tested to have better synergism with antibiotics oxacillin, tetracycline, rifampicin and linezolid against MRSA. The fat-soluble vitamins E and K were good in synergism against Gram negative A. baumannii while water soluble vitamins as B1, B2 and B12 were effective against MRSA but not against A. baumannii. This synergistic action of vitamins with the antibiotics can be used as a tool to treat multiple drug resistant super bugs with further evaluation at molecular level. Copyright © 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Synthesis, characterization and biological activity of Rhein-cyclodextrin conjugate

NASA Astrophysics Data System (ADS)

Liu, Manshuo; Lv, Pin; Liao, Rongqiang; Zhao, Yulin; Yang, Bo

2017-01-01

Cyclodextrin conjugate complexation is a useful method to enhance the solubility and absorption of poorly soluble drugs. A series of new Rhein-β-cyclodextrin conjugates (Rh-CD conjugates) have been synthesized and examined. Rhein is covalently linked with the β-CD by amido linkage in a 1:1 molar ratio. The conjugates were characterized by 1H NMR, 13C NMR, HRMS, powder X-ray diffraction (powder XRD) as well as thermogravimetric analysis (TGA). The results reveal that incorporation of β-CD could improve the aqueous solubility of Rhein and the cytotoxicity against hepatocellular carcinoma (HepG2) cell line as well as antibacterial activity against three organisms. The improved biological activity and the satisfactory water solubility of the conjugates will be potentially useful for developing novel drug-cyclodextrin conjugates, such as herbal medicine.

Enhanced effect and mechanism of water-in-oil microemulsion as an oral delivery system of hydroxysafflor yellow A

PubMed Central

Qi, Jianping; Zhuang, Jie; Wu, Wei; Lu, Yi; Song, Yunmei; Zhang, Zhetao; Jia, Jia; Ping, Qineng

2011-01-01

Background: A microemulsion is an effective formulation for improving the oral bioavailability of poorly soluble drugs. In this paper, a water-in-oil (w/o) microemulsion was investigated as a system for enhancing the oral bioavailability of Biopharmaceutic Classification System (BCS) III drugs. Methods: The microemulsion formulation was optimized using a pseudoternary phase diagram, comprising propylene glycol dicaprylocaprate (PG), Cremophor® RH40, and water (30/46/24 w/w). Results: The microemulsion increased the oral bioavailability of hydroxysafflor yellow A which was highly water-soluble but very poorly permeable. The relative bioavailability of hydroxysafflor yellow A microemulsion was about 1937% compared with a control solution in bile duct-nonligated rats. However, the microemulsion showed lower enhanced absorption ability in bile duct-ligated rats, and the relative bioavailability was only 181%. In vitro experiments were further employed to study the mechanism of the enhanced effect of the microemulsion. In vitro lipolysis showed that the microemulsion was digested very quickly by pancreatic lipase. About 60% of the microemulsion was digested within 1 hour. Furthermore, the particle size of the microemulsion after digestion was very small (53.3 nm) and the digested microemulsion had high physical stability. An everted gut sac model demonstrated that cumulative transport of the digested microemulsion was significantly higher than that of the diluted microemulsion. Conclusion: These results suggested that digestion of the microemulsion by pancreatic lipase plays an important role in enhancing oral bioavailability of water-soluble drugs. PMID:21720510

Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates.

PubMed

Alam, Mohd Aftab; Ali, Raisuddin; Al-Jenoobi, Fahad Ibrahim; Al-Mohizea, Abdullah M

2012-11-01

Present article reviews solid dispersion (SD) technologies and other patented inventions in the area of pharmaceutical SDs, which provide stable amorphous SDs. The review briefly compiles different techniques for preparing SDs, their applications, characterization of SDs, types of SDs and also elaborates the carriers used to prepare SDs. The advantages of recently introduced SD technologies such as RightSize(™), closed-cycle spray drying (CSD), Lidose® are summarized. Stability-related issues like phase separation, re-crystallization and methods to curb these problems are also discussed. A patented carrier-screening tool for predicting physical stability of SDs on the basis of drug-carrier interaction is explained. Applications of SD technique in controlled drug delivery systems and cosmetics are explored. Review also summarizes the carriers such as Soluplus®, Neusilin®, Solumer(TM) used to prepare stable amorphous SD. Binary and ternary SDs are found to be more stable and provide better enhancement of solubility or dissolution of poorly water-soluble drugs. The use of surfactants in the carrier system of SD is a recent trend. Surfactants and polymers provide stability against re-crystallization of SDs, surfactants also improve solubility and dissolution of drug.

Predicting the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol mixtures via molecular simulation.

PubMed

Paluch, Andrew S; Parameswaran, Sreeja; Liu, Shuai; Kolavennu, Anasuya; Mobley, David L

2015-01-28

We present a general framework to predict the excess solubility of small molecular solids (such as pharmaceutical solids) in binary solvents via molecular simulation free energy calculations at infinite dilution with conventional molecular models. The present study used molecular dynamics with the General AMBER Force Field to predict the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol solvents. The simulations are able to predict the existence of solubility enhancement and the results are in good agreement with available experimental data. The accuracy of the predictions in addition to the generality of the method suggests that molecular simulations may be a valuable design tool for solvent selection in drug development processes.

Predicting the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol mixtures via molecular simulation

NASA Astrophysics Data System (ADS)

Paluch, Andrew S.; Parameswaran, Sreeja; Liu, Shuai; Kolavennu, Anasuya; Mobley, David L.

2015-01-01

We present a general framework to predict the excess solubility of small molecular solids (such as pharmaceutical solids) in binary solvents via molecular simulation free energy calculations at infinite dilution with conventional molecular models. The present study used molecular dynamics with the General AMBER Force Field to predict the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol solvents. The simulations are able to predict the existence of solubility enhancement and the results are in good agreement with available experimental data. The accuracy of the predictions in addition to the generality of the method suggests that molecular simulations may be a valuable design tool for solvent selection in drug development processes.

Preparation and Pharmacokinetics Evaluation of Solid Self-Microemulsifying Drug Delivery System (S-SMEDDS) of Osthole.

PubMed

Sun, Chaojie; Gui, Yun; Hu, Rongfeng; Chen, Jiayi; Wang, Bin; Guo, Yuxing; Lu, Wenjie; Nie, Xiangjiang; Shen, Qiang; Gao, Song; Fang, Wenyou

2018-05-29

The study was performed aiming to enhance the solubility and oral bioavailability of poorly water-soluble drug osthole by formulating solid self-microemulsifying drug delivery system (S-SMEDDS) via spherical crystallization technique. Firstly, the liquid self-microemulsifying drug delivery system (L-SMEDDS) of osthole was formulated with castor oil, Cremophor RH40, and 1,2-propylene glycol after screening various lipids and emulsifiers. The type and amount of polymeric materials, good solvents, bridging agents, and poor solvents in S-SMEDDS formulations were further determined by single-factor study. The optimal formulation contained 1:2 of ethyl cellulose (EC) and Eudragit S100, which served as matrix forming and enteric coating polymers respectively. Anhydrous ethanol and dichloromethane with a ratio of 5:3 are required to perform as good solvent and bridging agent, respectively, with the addition of 0.08% SDS aqueous solution as poor solvent. The optimized osthole S-SMEDDS had a high yield (83.91 ± 3.31%) and encapsulation efficiency (78.39 ± 2.25%). Secondly, osthole L-SMEDDS was solidified to osthole S-SMEDDS with no significant changes in terms of morphology, particle size, and zeta potential. In vitro release study demonstrated a sustained release of the drug from osthole S-SMEDDS. Moreover, in vivo pharmacokinetic study showed that the T max and mean residence time (MRT (0-t) ) of osthole were significantly prolonged and further confirmed that osthole S-SMEDDS exhibited sustained release effect in rabbits. Comparing with osthole aqueous suspension and L-SMEDDS, osthole S-SMEDDS increased bioavailability by 205 and 152%, respectively. The results suggested that S-SMEDDS was an effective oral solid dosage form, which can improve the solubility and oral bioavailability of poorly water-soluble drug osthole.

Effect of amphiphilic graft co-polymer-carrier on physical stability of bosentan nanocomposite: Assessment of solubility, dissolution and bioavailability.

PubMed

Kendre, Prakash N; Chaudhari, Pravin D

2018-05-01

Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary arterial hypertension (PAH). But the solubility and bioavailability of this drug are poor, which has restricted the design and development of dosage forms for efficient and successful therapy. The present study was carried out to develop nanocomposites using an amphiphilic graft co-polymer (Soluplus®) as a carrier to enhance the solubility and bioavailability of bosentan. The graft co-polymer-based nanocomposite formulation was prepared using the single-emulsion technique. The nanocomposite was characterised in terms of particle size analysis, solubility, percentage entrapment efficiency, drug-loading capacity, surface morphology, drug content, in vitro dissolution, stability and bioavailability. FT-IR study revealed that there was no interaction between the drug and Soluplus®. DSC analysis of the nanocomposite formulation confirmed that the bosentan was completely encapsulated within a Soluplus®. XRD analysis showed that the drug was converted to an amorphous form irreversibly. SEM images showed that the particles were of size 96-129μm and had slightly smooth to rough textured surface. TEM analysis indicated that the diameters of the prepared bosentan nanocomposite after dispersion in distilled water were 13.69-96.78nm. Statistically significant increases in the solubility, dissolution and bioavailability of the drug were observed. It was confirmed that the use of a graft co-polymer carrier-based nanocomposite formulation is a good approach for efficient delivery of bosentan, the solubility and bioavailability being increased manifold. Copyright © 2017 Elsevier B.V. All rights reserved.

Application of melt extrusion in the development of a physically and chemically stable high-energy amorphous solid dispersion of a poorly water-soluble drug.

PubMed

Lakshman, Jay P; Cao, Yu; Kowalski, James; Serajuddin, Abu T M

2008-01-01

Formulation of active pharmaceutical ingredients (API) in high-energy amorphous forms is a common strategy to enhance solubility, dissolution rate and, consequently, oral bioavailability of poorly water-soluble drugs. Amorphous APIs are, however, susceptible to recrystallization and, therefore, there is a need to physically stabilize them as solid dispersions in polymeric carriers. Hot melt extrusion has in recent years gained wide acceptance as a method of choice for the preparation of solid dispersions. There is a potential that the API, the polymer or both may degrade if excessively high temperature is needed in the melt extrusion process, especially when the melting point of the API is high. This report details a novel method where the API was first converted to an amorphous form by solvent evaporation and then melt-extruded with a suitable polymer at a drug load of at least 20% w/w. By this means, melt extrusion could be performed much below the melting temperature of the drug substance. Since the glass transition temperature of the amorphous drug was lower than that of the polymer used, the drug substance itself served as the plasticizer for the polymer. The addition of surfactants in the matrix enhanced dispersion and subsequent dissolution of the drug in aqueous media. The amorphous melt extrusion formulations showed higher bioavailability than formulations containing the crystalline API. There was no conversion of amorphous solid to its crystalline form during accelerated stability testing of dosage forms.

Improving the de-agglomeration and dissolution of a poorly water soluble drug by decreasing the agglomerate strength of the cohesive powder.

PubMed

Allahham, Ayman; Stewart, Peter J; Das, Shyamal C

2013-11-30

Influence of ternary, poorly water-soluble components on the agglomerate strength of cohesive indomethacin mixtures during dissolution was studied to explore the relationship between agglomerate strength and extent of de-agglomeration and dissolution of indomethacin (Ind). Dissolution profiles of Ind from 20% Ind-lactose binary mixtures, and ternary mixtures containing additional dibasic calcium phosphate (1% or 10%; DCP), calcium sulphate (10%) and talc (10%) were determined. Agglomerate strength distributions were estimated by Monte Carlo simulation of particle size, work of cohesion and packing fraction distributions. The agglomerate strength of Ind decreased from 1.19 MPa for the binary Ind mixture to 0.84 MPa for 1DCP:20Ind mixture and to 0.42 MPa for 1DCP:2Ind mixture. Both extent of de-agglomeration, demonstrated by the concentration of the dispersed indomethacin distribution, and extent of dispersion, demonstrated by the particle size of the dispersed indomethacin, were in descending order of 1DCP:2Ind>1DCP:20Ind>binary Ind. The addition of calcium sulphate dihydrate and talc also reduced the agglomerate strength and improved de-agglomeration and dispersion of indomethacin. While not definitively causal, the improved de-agglomeration and dispersion of a poorly water soluble drug by poorly water soluble components was related to the agglomerate strength of the cohesive matrix during dissolution. Copyright © 2013 Elsevier B.V. All rights reserved.

Development of a solidified self-microemulsifying drug delivery system (S-SMEDDS) for atorvastatin calcium with improved dissolution and bioavailability.

PubMed

Yeom, Dong Woo; Son, Ho Yong; Kim, Jin Han; Kim, Sung Rae; Lee, Sang Gon; Song, She Hyon; Chae, Bo Ram; Choi, Young Wook

2016-06-15

To improve the dissolution and oral bioavailability (BA) of atorvastatin calcium (ATV), we previously introduced an optimized self-microemulsifying drug delivery system (SMEDDS) using Capmul(®) MCM (oil), Tween(®) 20 (surfactant), and tetraglycol (cosurfactant). In this study, various solid carriers were employed to develop a solidified SMEDDS (S-SMEDDS): mannitol (M) and lactose (L) as water-soluble carriers, and Sylysia(®) 350 (S) and Aerosil(®) 200 (A) as water-insoluble carriers. Maximum solidifying capacities (SCmax) of water-insoluble carriers were significantly greater than those of water-soluble carriers were. The resultant powders were free flowing with an angle of repose <40° and Carr's index 5-20%, regardless of the solid carrier types. S-SMEDDS with mannitol (S(M)-SMEDDS) or lactose (S(L)-SMEDDS) had a smaller droplet size and greater dissolution than S-SMEDDS with Sylysia(®) 350 (S(S)-SMEDDS) or Aerosil(®) 200 (S(A)-SMEDDS). Following oral administration of various formulations to rats at a dose equivalent to 25mg/kg of ATV, plasma drug levels were measured by LC-MS/MS. The relative BAs (RBAs) of SMEDDS, S(M)-SMEDDS, and S(S)-SMEDDS were 345%, 216%, and 160%, respectively, compared to that of ATV suspension. Additionally, at a reduced dose of ATV equivalent to 5mg/kg, the RBAs of S(M)-SMEDDS and S(S)-SMEDDS compared to that of SMEDDS were 101% and 65%, respectively. These results suggest that S(M)-SEMDDS offers great potential for the development of solid dosage forms with improved oral absorption of drugs with poor water solubility. Copyright © 2016 Elsevier B.V. All rights reserved.

Physicochemical properties of valsartan and the effect of ethyl alcohol, propylene glycol and pH on its solubility.

PubMed

Mbah, C J

2005-11-01

The aqueous solubility and partition coefficient of valsartan were determined at room temperature. The effect of ethyl alcohol, propylene glycol and pH on its solubility was also investigated. It was found that both solvents increased the solubility of the drug in water. The solubilizing power of ethyl alcohol was found to be higher than that of propylene glycol. Valsartan solubility was also observed to increase at high pH values and its lipophilicity wasdemonstrated by the high positive value of the logarithm of partition coefficient.

21 CFR 524.1580e - Nitrofurazone ointment with butacaine sulfate.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Nitrofurazone ointment with butacaine sulfate. 524... ANIMAL DRUGS § 524.1580e Nitrofurazone ointment with butacaine sulfate. (a) Specifications. The drug contains 0.2 percent nitrofurazone and 0.5 percent butacaine sulfate in a water-soluble base. (b) Sponsor...

21 CFR 524.1580e - Nitrofurazone ointment with butacaine sulfate.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Nitrofurazone ointment with butacaine sulfate. 524... ANIMAL DRUGS § 524.1580e Nitrofurazone ointment with butacaine sulfate. (a) Specifications. The drug contains 0.2 percent nitrofurazone and 0.5 percent butacaine sulfate in a water-soluble base. (b) Sponsor...

Drug Release Studies from Caesalpinia pulcherrima Seed Polysaccharide.

PubMed

Jeevanandham, Somasundaram; Dhachinamoorthi, Duraiswamy; Bannoth Chandra Sekhar, Kothapalli

2011-01-01

This study examines the controlled release behavior of both water-soluble (acetaminophen, caffeine, theophylline and salicylic acid) and water insoluble (indomethacin) drugs derived from Caesalpinia pulcherrima seed Gum isolated from Caesalpinia pulcherrima kernel powder. It further investigates the effect of incorporating diluents such as microcrystalline cellulose and lactose on caffeine release. In addition the effect the gum's (polysaccharide) partial cross-linking had on release of acetaminophen was examined. Applying the exponential equation, the soluble drugs mechanism of release was found to be anomalous. The insoluble drugs showed a near case II or zero order release mechanism. The rate of release in descending order was caffeine, acetaminophen, theophylline, salicylic acid and indomethacin. An increase in the release kinetics of the drug was observed on blending with diluents. However, the rate of release varied with the type and amount of blend within the matrix. The mechanism of release due to effect of diluents was found to be anomalous. The rate of drug release decreased upon partial cross-linking and the mechanism of release was found to be of super case II.

Aqueous-core PEG-coated PLA nanocapsules for an efficient entrapment of water soluble anticancer drugs and a smart therapeutic response.

PubMed

Cosco, Donato; Paolino, Donatella; De Angelis, Francesco; Cilurzo, Felisa; Celia, Christian; Di Marzio, Luisa; Russo, Diego; Tsapis, Nicolas; Fattal, Elias; Fresta, Massimo

2015-01-01

Novel PEGylated PLA nanocapsules (PEG-AcPLA nanocapsules), loading high percentage of water soluble drugs have been formulated by using multiple emulsion technique without using conventional stabilizers. In particular, sodium deoxycholate hydrate has been used to obtain nanocapsules having a mean diameter of about 200 nm and a polydispersity index of ∼ 0.1. Gemcitabine hydrochloride (GEM) was used as a model of hydrophilic drug. GEM-loaded PEG-AcPLA nanocapsules demonstrated a high encapsulation efficacy and the drug-release followed a zero-order kinetic. MTT-assay evidenced an increased antitumor effect of GEM-loaded PEG-AcPLA nanocapsules compared to the free drug on different cancer cell lines and confocal laser scanning microscopy showed a significant improvement of cell interaction at 6h of incubation. In vivo anticancer activity of GEM-loaded PEG-AcPLA nanocapsules using two xenograft murine models of human solid tumors further supported the efficacy of this nano-drug, thus providing preliminary results about the potential clinical application of this innovative nanotherapeutic. Copyright © 2014 Elsevier B.V. All rights reserved.

Mechanisms underlying changes in indomethacin solubility with local anesthetics and related basic additives

NASA Astrophysics Data System (ADS)

Shimada, Yohsuke; Tateuchi, Ryo; Chatani, Hitoshi; Goto, Satoru

2018-03-01

Indomethacin (IND), an acidic nonsteroidal anti-inflammatory drug, and lidocaine (LID), a local anesthetic (LA), form a eutectic complex when mixed, with a lower melting point. The aqueous solubility of the mixture is greater than that of IND or LID alone, improving the bioavailability of IND. Therefore, IND and LID can be used to model changes in efficacy caused by physicochemical interactions between drugs. In this study, the intermolecular interactions between IND and structurally similar LAs were examined by measuring solubility and analyzing thermodynamics using differential scanning calorimetry. The results indicate that the solubility of IND (log S'IND) varies with LA hydrophobicity. Reductions in melting point resulting from mixing IND and LAs contributed to changes in IND solubility, attributable to direct intermolecular interactions between IND and the LAs. In addition, binding energy of IND-LA as in water was calculated, and the values were correlating with the solubility of IND in experiments. Understanding these interactions will help address some of the problems encountered in polypharmacy.

Exploiting the Phenomenon of Liquid-Liquid Phase Separation for Enhanced and Sustained Membrane Transport of a Poorly Water-Soluble Drug.

PubMed

Indulkar, Anura S; Gao, Yi; Raina, Shweta A; Zhang, Geoff G Z; Taylor, Lynne S

2016-06-06

Recent studies on aqueous supersaturated lipophilic drug solutions prepared by methods including antisolvent addition, pH swing, or dissolution of amorphous solid dispersions (ASDs) have demonstrated that when crystallization is slow, these systems undergo liquid-liquid phase separation (LLPS) when the concentration of the drug in the medium exceeds its amorphous solubility. Following LLPS, a metastable equilibrium is formed where the concentration of drug in the continuous phase corresponds to the amorphous solubility while the dispersed phase is composed of a nanosized drug-rich phase. It has been reasoned that the drug-rich phase may act as a reservoir, enabling the rate of passive transport of the drug across a membrane to be maintained at the maximum value for an extended period of time. Herein, using clotrimazole as a model drug, and a flow-through diffusion cell, the reservoir effect is demonstrated. Supersaturated clotrimazole solutions at concentrations below the amorphous solubility show a linear relationship between the maximum flux and the initial concentration. Once the concentration exceeds the amorphous solubility, the maximum flux achieved reaches a plateau. However, the duration for which the high flux persists was found to be highly dependent on the number of drug-rich nanodroplets present in the donor compartment. Macroscopic amorphous particles of clotrimazole did not lead to the same reservoir effect observed with the nanodroplets formed through the process of LLPS. A first-principles mathematical model was developed which was able to fit the experimental receiver concentration-time profiles for concentration regimes both below and above amorphous solubility, providing support for the contention that the nanodroplet phase does not directly diffuse across the membrane but, instead, rapidly replenishes the drug in the aqueous phase that has been removed by transport across the membrane. This study provides important insight into the properties of supersaturated solutions and how these might in turn impact oral absorption through effects on passive membrane transport rates.

Development of micro-fibrous solid dispersions of poorly water-soluble drugs in sucrose using temperature-controlled centrifugal spinning.

PubMed

Marano, Stefania; Barker, Susan Anne; Raimi-Abraham, Bahijja Tolulope; Missaghi, Shahrzad; Rajabi-Siahboomi, Ali; Craig, Duncan Q M

2016-06-01

Solid dispersion technology represents a successful approach to addressing the bioavailability issues caused by the low aqueous solubility of many Biopharmaceutics Classification System (BCS) Class II drugs. In this study, the use of high-yield manufacture of fiber-based dispersion is explored as an alternative approach to monolith production methods. A temperature-controlled solvent-free centrifugal spinning process was used to produce sucrose-based microfibers containing the poorly water-soluble drugs olanzapine and piroxicam (both BCS Class II); these were successfully incorporated into the microfibers and the basic characteristics of fiber diameter, glassy behavior, drug loading capacity and drug-sucrose interaction assessment were measured. Scanning electron microscopy revealed that bead-free drug-loaded microfibers with homogenous morphology and diameter in the range of a few micrometers were prepared using our process. Differential scanning calorimetric and X-ray diffraction analyses showed that both drug and carrier were present in the amorphous state in the microfibers, although in the case of piroxicam-loaded microfibers, the presence of small amounts of crystalline drug was observed under polarized light microscopy and in Fourier transform infrared spectra. Drug dissolution performance was evaluated under both sink and non-sink conditions and was found to be significantly enhanced compared to the corresponding crystalline physical mixtures and pure drugs, with evidence of supersaturation behavior noted under non-sink conditions. This study has demonstrated that microfiber-based dispersions may be manufactured by the centrifugal spinning process and may possess characteristics that are favorable for the enhanced dissolution and oral absorption of drugs. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Control of pulmonary absorption of water-soluble compounds by various viscous vehicles.

PubMed

Yamamoto, Akira; Yamada, Keigo; Muramatsu, Hideaki; Nishinaka, Asako; Okumura, Shigeki; Okada, Naoki; Fujita, Takuya; Muranishi, Shozo

2004-09-10

Effects of various viscous vehicles on the pulmonary absorption of water-soluble drugs were examined by an in situ pulmonary absorption experiment. Gelatin, polyvinylacohol (PVA), hydroxypropylcellose (HPC), chondroitin sulfate A sodium salt (CS), polyacrylic acid (PAA), methylcellulose #400 (MC400) and hyaluronic acid sodium salt (HA) were used as models of viscous vehicles. 5(6)-Carboxyfluorescein (CF) and fluorescein isothiocayanate-labeled dextran with an average molecular weight of 4000 (FD4) were used as water-soluble drugs. The plasma concentration of CF was controlled and regulated in the presence of these viscous vehicles, especially gelatin (1-5%) and polyvinyl alcohol (PVA) 1%. In the pharmacokinetic analysis, the Cmax values of CF significantly decreased, and its Tmax values increased in the presence of these viscous vehicles compared with the control. The MRT and MAT values of CF with these vehicles were significantly higher than those without these vehicles. Therefore, these findings indicated that the viscous vehicles were effective to regulate the absorption rate of CF. On the other hand, the pulmonary absorption of FD4 was not so much affected even in the presence of gelatin and PVA, although PVA slightly decreased MRT value, and significantly decreased Tmax value. Furthermore, we examined the release rate of CF from the cellulose tube containing various concentrations of gelatin. The release rate of CF from the cellulose tube with gelatin was inversely related to the viscosity of gelatin. In addition, the release rate of CF was inversely related to DeltaMAT (DeltaMAT = MATgel(MAT with gelatin)-MATsol(MAT without gelatin)) in the presence of varying concentrations of gelatin. These findings indicated that these viscous vehicles were effective to control the pulmonary absorption of CF, a water-soluble drug with low molecular weight and they might be useful to increase the local concentration of drugs in the lung.

Water-Soluble Dinitrosyl Iron Complex (DNIC): a Nitric Oxide Vehicle Triggering Cancer Cell Death via Apoptosis.

PubMed

Wu, Shou-Cheng; Lu, Chung-Yen; Chen, Yi-Lin; Lo, Feng-Chun; Wang, Ting-Yin; Chen, Yu-Jen; Yuan, Shyng-Shiou; Liaw, Wen-Feng; Wang, Yun-Ming

2016-09-19

Nitric oxide (NO) is an important cellular signaling molecule that modulates various physiological activities. Angiogenesis-promoting activities of NO-donor drugs have been explored in both experimental and clinical studies. In this study, a structurally well characterized and water-soluble neutral {Fe(NO)2}(9) DNIC [(S(CH2)2OH)(S(CH2)2NH3)Fe(NO)2] (DNIC 2) was synthesized to serve as a NO-donor species. The antitumor activity of DNIC 2 was determined by MTT assay, confocal imaging, and Annexin-V/PI staining. The IC50 values of DNIC 2 were 18.8, 42.9, and 38.6 μM for PC-3, SKBR-3, and CRL5866 tumor cells, respectively. Moreover, DNIC 2 promoted apoptotic cell death via activation of apoptosis-associated proteins and inhibition of survival associated proteins. In particular, DNIC 2 treatment suppressed PC-3 tumor growth by 2.34- and 19.3-fold at 7 and 21 days, in comparison with the control group. These results indicate that water-soluble DNIC 2 may serve as a promising drug for cancer therapy.

Design of porous microparticles with single-micron size by novel spray freeze-drying technique using four-fluid nozzle.

PubMed

Niwa, Toshiyuki; Shimabara, Hiroko; Kondo, Masahiro; Danjo, Kazumi

2009-12-01

Spray freeze-drying (SFD) process, which is a novel particle design technique previously developed by authors, has been improved by using four-fluid nozzle (4N) instead of conventional two-fluid nozzle (2N) to expand its application in pharmaceutical industry. Aqueous spray solutions of the drug and the polymeric carrier were separately supplied into 4N, and atomized while colliding with each other at the tip of nozzle. The droplets of mixed solutions were directly immersed into liquid nitrogen and immediately frozen to form a suspension. Then, the iced droplets were lyophilized by freeze-dryer to prepare the composite particles of the drug and carrier. This process has been used in the present study to modify and enhance the dissolution profiles of poorly water-soluble drug, phenytoin. Water-soluble and enteric polymeric carriers in pharmaceutical use were used as a dissolution modifier. The SFD composite particles prepared by using 4N were fully characterized compared to those using 2N from morphological and physicochemical perspectives. It was found that the particles have fine porous structure producing vast specific surface area. Further, phenytoin was completely dispersed as amorphous state in the polymeric matrix with higher carrier ratio than phenytoin:carrier = 1:3. The dissolution of phenytoin from the water-soluble carrier-based particles was greatly enhanced because of large effective surface area and disappearance of crystalline. On the other hand, the release profiles from enteric carrier-based particles showed the typical enteric patterns, that is, delayed in acidic medium and accelerated in neutral pH. The results demonstrated that SFD technique using 4N has potential to develop the novel solubilized formulation for poorly water-soluble APIs.

Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV.

PubMed

O'Dowd, Hardwin; Shannon, Dean E; Chandupatla, Kishan R; Dixit, Vaishali; Engtrakul, Juntyma J; Ye, Zhengqi; Jones, Steven M; O'Brien, Colleen F; Nicolau, David P; Tessier, Pamela R; Crandon, Jared L; Song, Bin; Macikenas, Dainius; Hanzelka, Brian L; Le Tiran, Arnaud; Bennani, Youssef L; Charifson, Paul S; Grillot, Anne-Laure

2015-07-09

Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.

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

PubMed

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

2018-01-01

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

Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder.

PubMed

Ghosh, Indrajit; Snyder, Jennifer; Vippagunta, Radha; Alvine, Marilyn; Vakil, Ronak; Tong, Wei-Qin; Vippagunta, Sudha

2011-10-31

Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water-soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 °C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution. Copyright © 2011 Elsevier B.V. All rights reserved.

Influence of type and level of water-soluble additives on drug release and surface and mechanical properties of Surelease films.

PubMed

Rohera, Bhagwan D; Parikh, Nilesh H

2002-11-01

Ethylcellulose in combination with water-soluble additives has been used in the development of microporous membrane-coated dosage forms. In the present study, application of three types of water-soluble additives, namely polyethylene glycols (PEG 400, 3350, and 8000), maltodextrins (Maltrin M150, M100, and M040 in the order of lower to higher average polymer size and molecular weight; dextrose equivalence 16.9, 11.1, and 4.8, respectively), and xylitol, as porosity modifiers in the films of a commercially available aqueous ethylcellulose dispersion (Surelease/E-7-7060 plasticized with glyceryl tricaprylate/caprate) was investigated. The effect of type and level of these additives on drug release characteristics and surface and mechanical properties of the polymeric films was studied. Each additive was incorporated at 20 and 30% levels in the polymeric dispersion based on its solids content. Ibuprofen tablets were coated using the polymeric dispersion with and without additive at 3% w/w coat level in a fluid-bed equipment. The coated tablets were evaluated for their drug release rate, coat reflectivity (gloss), Brinell hardness, and elastic modulus. Differential scanning calorimetric analysis of the films was performed to determine the physico-chemical changes in the applied film-coats. The rate of drug release, hence film porosity, was observed to be dependent on the type and level of the additive added. The molecular weight of the additive and its concentration in the polymeric dispersion had significant influence on the rate of drug release, hardness, and elasticity of the film-coats.

Preparation of novel porous starch microsphere foam for loading and release of poorly water soluble drug.

PubMed

Jiang, Tongying; Wu, Chao; Gao, Yikun; Zhu, Wenquan; Wan, Long; Wang, Zhanyou; Wang, Siling

2014-02-01

Organic porous material is a promising carrier for enhancing the dissolution of poorly water soluble drug. The aim of the present study was to enhance dissolution and oral bioavailability of lovastatin (LV) by preparing a porous starch microsphere foam (PSM) using a novel method, meanwhile, looking into the mechanism of improving dissolution of LV. PSM was prepared by the W/O emulsion-freeze thawing method. The porous structure of PSM was characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis. The adsorption role of nanopores on the drug dissolution and physical state of LV was systematically studied by instrumental analysis, and in vitro and in vivo drug dissolution studies. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate carrier cytotoxicity. The SEM images of PSM showed nanometer-sized pores. Physical state characterization indicated that porous structure effectively limited the degree of crystallinity of LV. The results of in vitro and in vivo tests testified that PSM accelerated the release of LV and enhanced its oral bioavailability in comparison with crude LV and commercial capsules. The loaded PSM powder indicated a good physical stability under storage for 12 months. MTT assay shows PSM has no toxicity for Caco-2 cell. The preparation was a promising method to produce small and uniform PSM with markedly enhanced dissolution rate and oral bioavailability due to the spatial confinement effect of porous structure. The present work demonstrates the significant potential for the use of PSM as a novel delivery system for poorly water soluble drugs.

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

PubMed

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

2015-12-07

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

Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet stirred media milling: a microhydrodynamic view.

PubMed

Afolabi, Afolawemi; Akinlabi, Olakemi; Bilgili, Ecevit

2014-01-23

Wet stirred media milling has proven to be a robust process for producing nanoparticle suspensions of poorly water-soluble drugs. As the process is expensive and energy-intensive, it is important to study the breakage kinetics, which determines the cycle time and production rate for a desired fineness. Although the impact of process parameters on the properties of final product suspensions has been investigated, scant information is available regarding their impact on the breakage kinetics. Here, we elucidate the impact of stirrer speed, bead concentration, and drug loading on the breakage kinetics via a microhydrodynamic model for the bead-bead collisions. Suspensions of griseofulvin, a model poorly water-soluble drug, were prepared in the presence of two stabilizers: hydroxypropyl cellulose and sodium dodecyl sulfate. Laser diffraction, scanning electron microscopy, and rheometry were used to characterize them. Various microhydrodynamic parameters including a newly defined milling intensity factor was calculated. An increase in either the stirrer speed or the bead concentration led to an increase in the specific energy and the milling intensity factor, consequently faster breakage. On the other hand, an increase in the drug loading led to a decrease in these parameters and consequently slower breakage. While all microhydrodynamic parameters provided significant physical insight, only the milling intensity factor was capable of explaining the influence of all parameters directly through its strong correlation with the process time constant. Besides guiding process optimization, the analysis rationalizes the preparation of a single high drug-loaded batch (20% or higher) instead of multiple dilute batches. Copyright © 2013 Elsevier B.V. All rights reserved.

Microemulsions containing long-chain oil ethyl oleate improve the oral bioavailability of piroxicam by increasing drug solubility and lymphatic transportation simultaneously.

PubMed

Xing, Qiao; Song, Jia; You, Xiuhua; Xu, Dongling; Wang, Kexin; Song, Jiaqi; Guo, Qin; Li, Pengyu; Wu, Chuanbin; Hu, Haiyan

2016-09-25

Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long-chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC0-t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME-B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport. Copyright © 2016 Elsevier B.V. All rights reserved.

Membrane Proteins Are Dramatically Less Conserved than Water-Soluble Proteins across the Tree of Life

PubMed Central

Sojo, Victor; Dessimoz, Christophe; Pomiankowski, Andrew; Lane, Nick

2016-01-01

Membrane proteins are crucial in transport, signaling, bioenergetics, catalysis, and as drug targets. Here, we show that membrane proteins have dramatically fewer detectable orthologs than water-soluble proteins, less than half in most species analyzed. This sparse distribution could reflect rapid divergence or gene loss. We find that both mechanisms operate. First, membrane proteins evolve faster than water-soluble proteins, particularly in their exterior-facing portions. Second, we demonstrate that predicted ancestral membrane proteins are preferentially lost compared with water-soluble proteins in closely related species of archaea and bacteria. These patterns are consistent across the whole tree of life, and in each of the three domains of archaea, bacteria, and eukaryotes. Our findings point to a fundamental evolutionary principle: membrane proteins evolve faster due to stronger adaptive selection in changing environments, whereas cytosolic proteins are under more stringent purifying selection in the homeostatic interior of the cell. This effect should be strongest in prokaryotes, weaker in unicellular eukaryotes (with intracellular membranes), and weakest in multicellular eukaryotes (with extracellular homeostasis). We demonstrate that this is indeed the case. Similarly, we show that extracellular water-soluble proteins exhibit an even stronger pattern of low homology than membrane proteins. These striking differences in conservation of membrane proteins versus water-soluble proteins have important implications for evolution and medicine. PMID:27501943

Co-delivery of ibuprofen and gentamicin from nanoporous anodic titanium dioxide layers.

PubMed

Pawlik, Anna; Jarosz, Magdalena; Syrek, Karolina; Sulka, Grzegorz D

2017-04-01

Although single-drug therapy may prove insufficient in treating bacterial infections or inflammation after orthopaedic surgeries, complex therapy (using both an antibiotic and an anti-inflammatory drug) is thought to address the problem. Among drug delivery systems (DDSs) with prolonged drug release profiles, nanoporous anodic titanium dioxide (ATO) layers on Ti foil are very promising. In the discussed research, ATO samples were synthesized via a three-step anodization process in an ethylene glycol-based electrolyte with fluoride ions. The third step lasted 2, 5 and 10min in order to obtain different thicknesses of nanoporous layers. Annealing the as-prepared amorphous layers at the temperature of 400°C led to obtaining the anatase phase. In this study, water-insoluble ibuprofen and water-soluble gentamicin were used as model drugs. Three different drug loading procedures were applied. The desorption-desorption-diffusion (DDD) model of the drug release was fitted to the experimental data. The effects of crystalline structure, depth of TiO 2 nanopores and loading procedure on the drug release profiles were examined. The duration of the drug release process can be easily altered by changing the drug loading sequence. Water-soluble gentamicin is released for a long period of time if gentamicin is loaded in ATO as the first drug. Additionally, deeper nanopores and anatase phase suppress the initial burst release of drugs. These results confirm that factors such as morphological and crystalline structure of ATO layers, and the procedure of drug loading inside nanopores, allow to alter the drug release performance of nanoporous ATO layers. Copyright © 2017 Elsevier B.V. All rights reserved.

Development and characterization of lecithin stabilized glibenclamide nanocrystals for enhanced solubility and drug delivery.

PubMed

Kumar, B Sajeev; Saraswathi, R; Kumar, K Venkates; Jha, S K; Venkates, D P; Dhanaraj, S A

2014-05-01

Novel LNCs (lipid nanocrystals) were developed with an aim to improve the solubility, stability and targeting efficiency of the model drug glibenclamide (GLB). PEG 20000, Tween 80 and soybean lecithin were used as polymer, surfactant and complexing agent, respectively. GLB nanocrystals (NCs) were prepared by precipitation process and complexed using hot and cold melt technique. The LNCs were evaluated by drug loading, saturation solubility (SL), optical clarity, in vitro dissolution, solid state characterization, in vivo and stability analysis. LNCs exhibited a threefold increase in SL and a higher dissolution rate than GLB. The percentage dissolution efficiency was found to decrease with increase in PEG 20000. The average particle size was in the range of 155-842 nm and zeta potential values tend to increase after complexation. X-ray powder diffractometry and differential scanning calorimetry results proved the crystallinity prevailed in the samples. Spherical shaped particles (<1000 nm) with a lipid coat on the surface were observed in scanning electron microscopy analysis. Fourier transform infrared results proved the absence of interaction between drug and polymer and stability study findings proved that LNCs were stable. In vivo study findings showed a decrease in drug concentration to pancreas in male Wistar rats. It can be concluded that LNCs are could offer enhanced solubility, dissolution rate and stability for poorly water soluble drugs. The targeting efficiency of LNCs was decreased and further membrane permeability studies ought to be carried out.

Supercritical fluid processing of drug nanoparticles in stable suspension.

PubMed

Pathak, Pankaj; Meziani, Mohammed J; Desai, Tarang; Foster, Charles; Diaz, Julian A; Sun, Ya-Ping

2007-07-01

Significant effort has been directed toward the development of drug formulation and delivery techniques, especially for the drug of no or poor aqueous solubility. Among various strategies to address the solubility issue, the reduction of drug particle sizes to the nanoscale has been identified as a potentially effective and broadly applicable approach. Complementary to traditional methods, supercritical fluid techniques have found unique applications in the production and processing of drug particles. Here we report the application of a newly developed supercritical fluid processing technique, Rapid Expansion of a Supercritical Solution into a Liquid Solvent, to the nanosizing of potent antiparasitic drug Amphotericin B particles. A supercritical carbon dioxide-cosolvent system was used for the solubilization and processing of the drug. The process produced well-dispersed nanoscale Amphotericin B particles suspended in an aqueous solution, and the suspension was intrinsically stable or could be further stabilized in the presence of water-soluble polymers. The properties of the drug nanoparticles were found to be dependent on the type of cosolvent used. The results on the use of dimethyl sulfoxide and methanol as cosolvents and their effects on the properties of nanosized Amphotericin B particles are presented and discussed.

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

PubMed

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

2012-01-01

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

Development of rectal self-emulsifying suspension of a moisture-labile water-soluble drug.

PubMed

Kauss, Tina; Gaubert, Alexandra; Tabaran, Luc; Tonelli, Giovanni; Phoeung, Thida; Langlois, Marie-Hélène; White, Nick; Cartwright, Anthony; Gomes, Melba; Gaudin, Karen

2018-01-30

Self-emulsifying drug delivery systems, commonly used for oral delivery of poorly soluble compounds, were used to formulate water soluble but moisture labile compounds for rectal application. The objective was to use the oily phase of the system to formulate a liquid, non-aqueous product while obtaining the advantages of self-emulsification, rapid contact with the rectal mucosa and rapid absorption post-administration. Ceftriaxone was used as a model drug and the human bile salt sodium chenodeoxycholate was used as an absorption enhancer. After preliminary screening of 23 excipients, based on their emulsification ability and emulsion fineness in binary and ternary mixtures, a full factorial design was used to screen different formulations of three preselected excipients. The optimal formulation contained 60% of excipients, namely Capryol 90, Kolliphor EL and Kolliphor PS20 in 4 : 6 : 6 ratio and 40% of a powder blend that included 500 mg of ceftriaxone. Characterization of the system showed that it complied with the requirements for rectal administration, in particular rapid emulsification in a small quantity of liquid. Rabbit bioavailability showed rapid absorption of ceftriaxone, achieving 128% bioavailability compared to powder control formulation. These results demonstrated the potential of self-emulsifying formulations for rectal administration of Class 3 BCS drugs. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe

PubMed Central

Rashid, Rehmana; Kim, Dong Wuk; Yousaf, Abid Mehmood; Mustapha, Omer; Din, Fakhar ud; Park, Jong Hyuck; Yong, Chul Soon; Oh, Yu-Kyoung; Youn, Yu Seok; Kim, Jong Oh; Choi, Han-Gon

2015-01-01

Background The objective of this study was to compare the physicochemical characteristics, solubility, dissolution, and oral bioavailability of an ezetimibe-loaded solid self-nanoemulsifying drug delivery system (SNEDDS), surface modified solid dispersion (SMSD), and solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability. Methods For the liquid SNEDDS formulation, Capryol 90, Cremophor EL, and Tween 80 were selected as the oil, surfactant, and cosurfactant, respectively. The nanoemulsion-forming region was sketched using a pseudoternary phase diagram on the basis of reduced emulsion size. The optimized liquid SNEDDS was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray drying technique with various amounts of hydroxypropylcellulose and Tween 80, optimized on the basis of their drug solubility. The SESD formulation was prepared with the same composition of optimized SMSD. The aqueous solubility, dissolution, physicochemical properties, and pharmacokinetics of all of the formulations were investigated and compared with the drug powder. Results The drug existed in the crystalline form in SMSD, but was changed into an amorphous form in SNEDDS and SESD, giving particle sizes of approximately 24, 6, and 11 µm, respectively. All of these formulations significantly improved the aqueous solubility and dissolution in the order of solid SNEDDS ≥ SESD > SMSD, and showed a total higher plasma concentration than did the drug powder. Moreover, SESD gave a higher area under the drug concentration time curve from zero to infinity than did SNEDDS and SMSD, even if they were not significantly different, suggesting more improved oral bioavailability. Conclusion Among the various formulations tested in this study, the SESD system would be strongly recommended as a drug delivery system for the oral administration of ezetimibe with poor water solubility. PMID:26491288

The mechanisms of drug release from solid dispersions in water-soluble polymers.

PubMed

Craig, Duncan Q M

2002-01-14

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. However, despite the publication of numerous original papers and reviews on the subject, the mechanisms underpinning the observed improvements in dissolution rate are not yet understood. In this review the current consensus with regard to the solid-state structure and dissolution properties of solid dispersions is critically assessed. In particular the theories of carrier- and drug-controlled dissolution are highlighted. A model is proposed whereby the release behaviour from the dispersions may be understood in terms of the dissolution or otherwise of the drug into the concentrated aqueous polymer layer adjacent to the solid surface, including a derivation of an expression to describe the release of intact particles from the dispersions. The implications of a deeper understanding of the dissolution mechanisms are discussed, with particular emphasis on optimising the choice of carrier and manufacturing method and the prediction of stability problems.

Modeling and Bio molecular Self-assembly via Molecular Dynamics and Dissipative Particle Dynamics

NASA Astrophysics Data System (ADS)

Rakesh, L.

2009-09-01

Surfactants like materials can be used to increase the solubility of poorly soluble drugs in water and to increase drug bioavailability. A typical case study will be demonstrated using DPD simulation to model the distribution of anti-inflammatory drug molecules. Computer simulation is a convenient approach to understand drug distribution and solubility concepts without much wastage and costly experiments in the laboratory. Often in molecular dynamics (MD) the atoms are represented explicitly and the equation of motion as described by Newtonian dynamics is integrated explicitly. MD has been used to study spontaneous formation of micelles by hydrophobic molecules with amphiphilic head groups in bulk water, as well as stability of pre-configured micelles and membranes. DPD is a state-of the- art mesoscale simulation, it is a more recent molecular dynamics technique, originally developed for simulating complex fluids but lately also applied to membrane dynamics, hemodynamic in biomedical applications. Such fluids pervade industrial research from paints to pharmaceuticals and from cosmetics to the controlled release of drugs. Dissipative particle dynamics (DPD) can provide structural and dynamic properties of fluids in equilibrium, under shear or confined to narrow cavities, at length- and time-scales beyond the scope of traditional atomistic molecular dynamics simulation methods. Mesoscopic particles are used to represent clusters of molecules. The interaction conserves mass and momentum and as a consequence the dynamics is consistent with Navier-Stokes equations. In addition to the conservative forces, stochastic drive and dissipation is introduced to represent internal degrees of freedom in the mesoscopic particles. In this research, an initial study is being conducted using the aqueous solubilization of the nonsteroidal, anti-inflammatory drug is studied theoretically in micellar solution of nonionic (dodecyl hexa(ethylene oxide), C12E6) surfactants possessing the hydrocarbon "tail" and their hydrophilic head groups. We find that, for the surfactants, the aqueous solubility of anti-inflammatory molecules increases linearly with increasing surfactant concentration. In particular, we observed a 10-fold increase in the solubility of anti-inflammatory drugs relative to that in the aqueous buffer upon the addition of 100 mM dodecyltrimethyl ammonium bromide -DTAB.

Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug.

PubMed

Rivard, Colleen; Geller, Melissa; Schnettler, Erica; Saluja, Manju; Vogel, Rachel Isaksson; Saluja, Ashok; Ramakrishnan, Sundaram

2014-11-01

Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo. The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth. Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice. Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Experiments and synthesis of bone-targeting epirubicin with the water-soluble macromolecular drug delivery systems of oxidized-dextran.

PubMed

Yu, Li; Cai, Lin; Hu, Hao; Zhang, Yi

2014-05-01

Epirubicin (EPI) is a broad spectrum antineoplastic drug, commonly used as a chemotherapy method to treat osteosarcoma. However, its application has been limited by many side-effects. Therefore, targeted drug delivery to bone has been the aim of current anti-bone-tumor drug studies. Due to the exceptional affinity of Bisphosphonates (BP) to bone, 1-amino-ethylene-1, 1-dephosphate acid (AEDP) was chosen as the bone targeting moiety for water-soluble macromolecular drug delivery systems of oxidized-dextran (OXD) to transport EPI to bone in this article. The bone targeting drug of AEDP-OXD-EPI was designed for the treatment of malignant bone tumors. The successful conjugation of AEDP-OXD-EPI was confirmed by analysis of FTIR and (1)H-NMR spectra. To study the bone-seeking potential of AEDP-OXD-EPI, an in vitro hydroxyapatite (HAp) binding assay and an in vivo experiment of bone-targeting capacity were established. The effectiveness of AEDP-OXD-EPI was demonstrated by inducing apoptosis and necrosis of MG-63 tumor cell line. The obtained experimental data indicated that AEDP-OXD-EPI is an ideal bone-targeting anti-tumor drug.

Improved oral bioavailability of poorly water-soluble glimepiride by utilizing microemulsion technique

PubMed Central

Li, Haiying; Pan, Tingting; Cui, Ying; Li, Xiaxia; Gao, Jiefang; Yang, Wenzhi; Shen, Shigang

2016-01-01

The objective of this work was to prepare an oil/water glimepiride (GM) microemulsion (ME) for oral administration to improve its solubility and enhance its bioavailability. Based on a solubility study, pseudoternary phase diagrams, and Box–Behnken design, the oil/water GMME formulation was optimized and prepared. GMME was characterized by dynamic laser light scattering, zeta potential, transmission electron microscopy, and viscosity. The in vitro drug release, storage stability, pharmacodynamics, and pharmacokinetics of GMME were investigated. The optimized GMME was composed of Capryol 90 (oil), Cremophor RH40 (surfactant), and Transcutol (cosurfactant), and increased GM solubility up to 544.6±4.91 µg/mL. The GMME was spherical in shape. The particle size and its polydispersity index were 38.9±17.46 nm and 0.266±0.057, respectively. Meanwhile, the GMME was physicochemically stable at 4°C for at least 3 months. The short-term efficacy in diabetic mice provided the proof that blood glucose had a consistent and significant reduction at a dose of 375 µg/kg whether via IP injection or IG administration of GMME. Compared with the glimepiride suspensions or glimepiride-meglumine complex solution, the pharmacokinetics of GMME in Wistar rats via IG administration exhibited higher plasma drug concentration, larger area under the curve, and more enhanced oral bioavailability. There was a good correlation of GMME between the in vitro release values and the in vivo oral absorption. ME could be an effective oral drug delivery system to improve bioavailability of GM. PMID:27540291

Water-soluble loratadine inclusion complex: analytical control of the preparation by microwave irradiation.

PubMed

Nacsa, A; Ambrus, R; Berkesi, O; Szabó-Révész, P; Aigner, Z

2008-11-04

The majority of active pharmaceutical ingredients are poorly soluble in water. The rate-determining step of absorption is the dissolution of these drugs. Inclusion complexation with cyclodextrin derivatives can lead to improved aqueous solubility and bioavailability of pharmacons due to the formation of co-crystals through hydrogen-bonding between the components. Inclusion complexes of loratadine were prepared by a convenient new method involving microwave irradiation and the products were compared with those of a conventional preparation method. Dissolution studies demonstrated that the solubility and rate of dissolution of loratadine increased in both of the methods used. The interactions between the components were investigated by thermal analysis and Fourier Transform Infrared studies. The microwave treatment did not cause any chemical changes in the loratadine molecule.

Predicting the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol mixtures via molecular simulation

PubMed Central

Paluch, Andrew S.; Parameswaran, Sreeja; Liu, Shuai; Kolavennu, Anasuya; Mobley, David L.

2015-01-01

We present a general framework to predict the excess solubility of small molecular solids (such as pharmaceutical solids) in binary solvents via molecular simulation free energy calculations at infinite dilution with conventional molecular models. The present study used molecular dynamics with the General AMBER Force Field to predict the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol solvents. The simulations are able to predict the existence of solubility enhancement and the results are in good agreement with available experimental data. The accuracy of the predictions in addition to the generality of the method suggests that molecular simulations may be a valuable design tool for solvent selection in drug development processes. PMID:25637996

Current trends in the use of vitamin E-based micellar nanocarriers for anticancer drug delivery.

PubMed

Muddineti, Omkara Swami; Ghosh, Balaram; Biswas, Swati

2017-06-01

Owing to the complexity of cancer pathogenesis, conventional chemotherapy can be an inadequate method of killing cancer cells effectively. Nanoparticle-based drug delivery systems have been widely exploited pre-clinically in recent years. Areas covered: Incorporation of vitamin-E in nanocarriers have the advantage of (1) improving the hydrophobicity of the drug delivery system, thereby improving the solubility of the loaded poorly soluble anticancer drugs, (2) enhancing the biocompatibility of the polymeric drug carriers, and (3) improving the anticancer potential of the chemotherapeutic agents by reversing the cellular drug resistance via simultaneous administration. In addition to being a powerful antioxidant, vitamin E demonstrated its anticancer potential by inducing apoptosis in various cancer cell lines. Various vitamin E analogs have proven their ability to cause marked inhibition of drug efflux transporters. Expert opinion: The review discusses the potential of incorporating vitamin E in the polymeric micelles which are designed to carry poorly water-soluble anticancer drugs. Current applications of various vitamin E-based polymeric micelles with emphasis on the use of α-tocopherol, D-α-tocopheryl succinate (α-TOS) and its conjugates such as D-α-tocopheryl polyethylene glycol-succinate (TPGS) in micellar system is delineated. Advantages of utilizing polymeric micelles for drug delivery and the challenges to treat cancer, including multiple drug resistance have been discussed.

Quantitative analysis of the effect of supersaturation on in vivo drug absorption.

PubMed

Takano, Ryusuke; Takata, Noriyuki; Saito, Ryoichi; Furumoto, Kentaro; Higo, Shoichi; Hayashi, Yoshiki; Machida, Minoru; Aso, Yoshinori; Yamashita, Shinji

2010-10-04

The purpose of this study is to clarify the effects of intestinal drug supersaturation on solubility-limited nonlinear absorption. Oral absorption of a novel farnesyltransferase inhibitor (FTI-2600) from its crystalline free base and its HCl salt was determined in dogs. To clarify the contribution of supersaturation on improving drug absorption, in vivo intraluminal concentration of FTI-2600 after oral administration was estimated from the pharmacokinetics data using a physiologically based model. Dissolution and precipitation characteristics of FTI-2600 in a biorelevant media were investigated in vitro using a miniscale dissolution test and powder X-ray diffraction analysis. In the in vitro study, the HCl salt immediately dissolved but precipitated rapidly. The metastable amorphous free base precipitant, which did not convert into the stable crystalline free base in the simulated intestinal fluids for several hours, generated a 5-fold increase in dissolved concentration compared to the equilibrium solubility of the crystalline free base. By computer simulation, the intraluminal drug concentration after administration of the free base was estimated to reach the saturated solubility, indicating solubility-limited absorption. On the other hand, administration of the HCl salt resulted in an increased intraluminal concentration and the plasma concentration was 400% greater than that after administration of the free base. This in vivo/in vitro correlation of the increased drug concentrations in the small intestine provide clear evidence that not only the increase in the dissolution rate, but also the supersaturation phenomenon, improved the solubility-limited absorption of FTI-2600. These results indicate that formulation technologies that can induce supersaturation may be of great assistance to the successful development of poorly water-soluble drugs.

Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate.

PubMed

Fujimoto, Yumi; Hirai, Nobuaki; Takatani-Nakase, Tomoka; Takahashi, Koichi

2016-01-01

The aim of this study was to prepare and evaluate solid dispersion tablets containing a poorly water-soluble drug using porous calcium silicate (PCS) by a wet granulation method. Nifedipine (NIF) was used as the model poorly water-soluble drug. Solid dispersion tablets were prepared with the wet granulation method using ethanol and water by a high-speed mixer granulator. The binder and disintegrant were selected from 7 and 4 candidates, respectively. The dissolution test was conducted using the JP 16 paddle method. The oral absorption of NIF was studied in fasted rats. Xylitol and crospovidone were selected as the binder and disintegrant, respectively. The dissolution rates of NIF from solid dispersion formulations were markedly enhanced compared with NIF powder and physical mixtures. Powder X-ray diffraction (PXRD) confirmed the reduced crystallinity of NIF in the solid dispersion formulations. Fourier transform infrared (FT-IR) showed the physical interaction between NIF and PCS in the solid dispersion formulations. NIF is present in an amorphous state in granules prepared by the wet granulation method using water. The area under the plasma concentration-time curve (AUC) and peak concentration (C(max)) values of NIF after dosing rats with the solid dispersion granules were significantly greater than those after dosing with NIF powder. The solid dispersion formulations of NIF prepared with PCS using the wet granulation method exhibited accelerated dissolution rates and superior oral bioavailability. This method is very simple, and may be applicable to the development of other poorly water-soluble drugs.

Targeted polymeric micelles for delivery of poorly soluble drugs.

PubMed

Torchilin, V P

2004-10-01

Polymeric micelles (micelles formed by amphiphilic block copolymers) demonstrate a series of attractive properties as drug carriers, such as high stability both in vitro and in vivo and good biocompatibility, and can be successfully used for the solubilization of various poorly soluble pharmaceuticals. These micelles can also be used as targeted drug delivery systems. The targeting can be achieved via the enhanced permeability and retention effect (into the areas with the compromised vasculature), by making micelles of stimuli-responsive amphiphilic block copolymers, or by attaching specific targeting ligand molecules to the micelle surface. Immunomicelles prepared by coupling monoclonal antibody molecules to p-nitrophenylcarbonyl groups on the water-exposed termini of the micelle corona-forming blocks demonstrate high binding specificity and targetability. Immunomicelles prepared with cancer-specific monoclonal antibody 2C5 specifically bind to different cancer cells in vitro and demonstrate increased therapeutic activity in vivo. This new family of pharmaceutical carriers can be used for the solubilization and targeted delivery of poorly soluble drugs to various pathological sites in the body.

FULLEROL CYTOTOXICITY AND PHOTOTOXICITY IN HUMAN RETINAL PIGMENT EPITHELIAL CELLS.

EPA Science Inventory

Purpose:

Water-soluble fullerenes [nano-C60 ,fullerol] have recently been shown to exhibit antibacterial and antiviral activity including inhibition of HIV protease. In addition to their potential to be used as drugs, they are also being tested as carriers to deliver drugs...

Mesoporous Silica Molecular Sieve based Nanocarriers: Transpiring Drug Dissolution Research.

PubMed

Pattnaik, Satyanarayan; Pathak, Kamla

2017-01-01

Improvement of oral bioavailability through enhancement of dissolution for poorly soluble drugs has been a very promising approach. Recently, mesoporous silica based molecular sieves have demonstrated excellent properties to enhance the dissolution velocity of poorly water-soluble drugs. Current research in this area is focused on investigating the factors influencing the drug release from these carriers, the kinetics of drug release and manufacturing approaches to scale-up production for commercial manufacture. This comprehensive review provides an overview of different methods adopted for synthesis of mesoporous materials, influence of processing factors on properties of these materials and drug loading methods. The drug release kinetics from mesoporous silica systems, the manufacturability and stability of these formulations are reviewed. Finally, the safety and biocompatibility issues related to these silica based materials are discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Development and characterisation of sustained release solid dispersion oral tablets containing the poorly water soluble drug disulfiram.

PubMed

Shergill, Mandip; Patel, Mina; Khan, Siraj; Bashir, Ayesha; McConville, Christopher

2016-01-30

Administration of drugs via the oral route is the most common and preferred route due to its ease of administration, cost-effectiveness and flexibility in design. However, if the drug being administered has limited aqueous solubility it can result in poor bioavailability. Furthermore, the low pH of the stomach as well as enzymatic activity can result in drugs delivered via the oral route being rapidly metabolised and degraded. Here we demonstrate the development and characterisation of sustained release solid dispersion oral tablets, containing the poorly water-soluble drug disulfiram (DSF). The tablets, which are manufactured from two different polymers (Kolliphor(®) P 188 and P 237) specifically designed for the manufacture of solid dispersions and two different polymers (Kollidon(®) SR and HPMC) specifically designed to provide sustained release, can enhance the solubility of DSF, sustain its release, while protecting it from degradation in simulated gastric fluid (SGF). The paper demonstrates that when using the hot melt method at 80°C the DSF loading capacity of the Kolliphor(®) P 188 and P 237 polymers is approximately 43 and 46% respectively, with the DSF completely in an amorphous state. The addition of 80% Kollidon(®) SR to the formulation completely protected the DSF in SGF for up to 70 min with 16% degradation after 120 min, while 75% degradation occurred after 120 min with the addition of 80% HPMC. The release rate of DSF can be manipulated by both the loading and type of sustained release polymer used, with HPMC providing for a much faster release rate compared to Kollidon(®) SR. Copyright © 2015 Elsevier B.V. All rights reserved.

Conjugation of curcumin onto alginate enhances aqueous solubility and stability of curcumin.

PubMed

Dey, Soma; Sreenivasan, K

2014-01-01

Curcumin is a potential drug for various diseases including cancer. Prime limitations associated with curcumin are low water solubility, rapid hydrolytic degradation and poor bioavailability. In order to redress these issues we developed Alginate-Curcumin (Alg-Ccm) conjugate which was characterized by FTIR and (1)H NMR spectroscopy. The conjugate self-assembled in aqueous solution forming micelles with an average hydrodynamic diameter of 459 ± 0.32 nm and negative zeta potential. The spherical micelles were visualized by TEM. The critical micelle concentration (CMC) of Alg-Ccm conjugate was determined. A significant enhancement in the aqueous solubility of curcumin was observed upon conjugation with alginate. Formation of micelles improved the stability of curcumin in water at physiological pH. The cytotoxic activity of Alg-Ccm was quantified by MTT assay using L-929 fibroblast cells and it was found to be potentially cytotoxic. Hence, Alg-Ccm could be a promising drug conjugate as well as a nanosized delivery vehicle. Copyright © 2013 Elsevier Ltd. All rights reserved.

Ordered mesoporous silica to enhance the bioavailability of poorly water-soluble drugs: Proof of concept in man.

PubMed

Bukara, Katarina; Schueller, Laurent; Rosier, Jan; Martens, Mark A; Daems, Tinne; Verheyden, Loes; Eelen, Siemon; Van Speybroeck, Michiel; Libanati, Cristian; Martens, Johan A; Van Den Mooter, Guy; Frérart, Françoise; Jolling, Koen; De Gieter, Marjan; Bugarski, Branko; Kiekens, Filip

2016-11-01

Formulating poorly water soluble drugs using ordered mesoporous silica materials is an emerging approach to tackle solubility-related bioavailability problems. The current study was conducted to assess the bioavailability-enhancing potential of ordered mesoporous silica in man. In this open-label, randomized, two-way cross-over study, 12 overnight fasted healthy volunteers received a single dose of fenofibrate formulated with ordered mesoporous silica or a marketed product based on micronized fenofibrate. Plasma concentrations of fenofibric acid, the pharmacologically active metabolite of fenofibrate, were monitored up to 96h post-dose. The rate (C max /dose increased by 77%; t max reduced by 0.75h) and extent of absorption (AUC 0-24h /dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. The results of this study serve as a proof of concept in man for this novel formulation approach. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed

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

2017-01-01

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

Particle characterization of poorly water-soluble drugs using a spray freeze drying technique.

PubMed

Kondo, Masahiro; Niwa, Toshiyuki; Okamoto, Hirokazu; Danjo, Kazumi

2009-07-01

A spray freeze drying (SFD) method was developed to prepare the composite particles of poorly water-soluble drug. The aqueous solution dissolved drug and the functional polymer was sprayed directly into liquid nitrogen. Then, the iced droplets were lyophilized with freeze-dryer to prepare solid particles. Tolbutamide (TBM) and hydroxypropylmethylcellulose (HPMC) were used as a model drug and water-soluble polymeric carrier in this study, respectively. The morphological observation of particles revealed that the spherical particles having porous structure could be obtained by optimizing the loading amount of drug and polymer in the spray solution. Especially, SFD method was characterized that the prepared particles had significantly larger specific surface area comparing with those prepared by the standard spray drying technique. The physicochemical properties of the resultant particles were found to be dependent on the concentration of spray solution. When the solution with high content of drug and polymer was used, the particle size of the resulting composite particles increased and they became spherical. The specific surface area of the particles also increased as a result of higher concentration of solution. The evaluation of spray solution indicated that these results were dependent on the viscosity of spray solution. In addition, when composite particles of TBM were prepared using the SFD method with HPMC as a carrier, the crystallinity of TBM decreased as the proportion of HPMC increased. When the TBM : HPMC ratio reached 1 : 5, the crystallinity of the particles completely disappeared. The dissolution tests showed that the release profiles of poorly water-soluble TBM from SFD composite particles were drastically improved compared to bulk TBM. The 70% release time T(70) of composite particles prepared by the SFD method in a solution of pH 1.2 was quite smaller than that of bulk TBM, while in a solution of pH 6.8, it was slightly lower. In addition, the release rates were faster than those of standard spray dried (SD) composite particles for solutions of pH 1.2 and 6.8, respectively. When composite particles were prepared from mixtures with various composition ratios, T(70) was found to decrease as the proportion of HPMC increased; the release rate was faster than that of bulk TBM in a solution of pH 6.8, as well as solution of pH 1.2.

Hydrogel-Based Drug Delivery Systems for Poorly Water-Soluble Drugs.

PubMed

McKenzie, Matthew; Betts, David; Suh, Amy; Bui, Kathryn; Kim, London Doyoung; Cho, Hyunah

2015-11-13

Hydrogels are three-dimensional materials that can withstand a great amount of water incorporation while maintaining integrity. This allows hydrogels to be very unique biomedical materials, especially for drug delivery. Much effort has been made to incorporate hydrophilic molecules in hydrogels in the field of drug delivery, while loading of hydrophobic drugs has not been vastly studied. However, in recent years, research has also been conducted on incorporating hydrophobic molecules within hydrogel matrices for achieving a steady release of drugs to treat various ailments. Here, we summarize the types of hydrogels used as drug delivery vehicles, various methods to incorporate hydrophobic molecules in hydrogel matrices, and the potential therapeutic applications of hydrogels in cancer.

Solubility and dissolution performances of spray-dried solid dispersion of Efavirenz in Soluplus.

PubMed

Lavra, Zênia Maria Maciel; Pereira de Santana, Davi; Ré, Maria Inês

2017-01-01

Efavirenz (EFV), a first-line anti-HIV drug largely used as part of antiretroviral therapies, is practically insoluble in water and belongs to BCS class II (low solubility/high permeability). The aim of this study was to improve the solubility and dissolution performances of EFV by formulating an amorphous solid dispersion of the drug in polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ® ) using spray-drying technique. To this purpose, spray-dried dispersions of EFV in Soluplus ® at different mass ratios (1:1.25, 1:7, 1:10) were prepared and characterized using particle size measurements, SEM, XRD, DSC, FTIR and Raman microscopy mapping. Solubility and dissolution were determined in different media. Stability was studied at accelerated conditions (40 °C/75% RH) and ambient conditions for 12 months. DSC and XRD analyses confirmed the EFV amorphous state. FTIR spectroscopy analyses revealed possible drug-polymer molecular interaction. Solubility and dissolution rate of EFV was enhanced remarkably in the developed spray-dried solid dispersions, as a function of the polymer concentration. Spray-drying was concluded to be a proper technique to formulate a physically stable dispersion of amorphous EFV in Soluplus ® , when protected from moisture.

Characterization and cytotoxicity evaluation of biocompatible amino acid esters used to convert salicylic acid into ionic liquids.

PubMed

Moshikur, Rahman Md; Chowdhury, Md Raihan; Wakabayashi, Rie; Tahara, Yoshiro; Moniruzzaman, Muhammad; Goto, Masahiro

2018-07-30

The technological utility of active pharmaceutical ingredients (APIs) is greatly enhanced when they are transformed into ionic liquids (ILs). API-ILs have better solubility, thermal stability, and the efficacy in topical delivery than solid or crystalline drugs. However, toxicological issue of API-ILs is the main challenge for their application in drug delivery. To address this issue, 11 amino acid esters (AAEs) were synthesized and investigated as biocompatible counter cations for the poorly water-soluble drug salicylic acid (Sal) to form Sal-ILs. The AAEs were characterized using 1 H and 13 C NMR, FTIR, elemental, and thermogravimetric analyses. The cytotoxicities of the AAE cations, Sal-ILs, and free Sal were investigated using mammalian cell lines (L929 and HeLa). The toxicities of the AAE cations greatly increased with inclusion of long alkyl chains, sulfur, and aromatic rings in the side groups of the cations. Ethyl esters of alanine, aspartic acid, and proline were selected as a low cytotoxic AAE. The cytotoxicities of the Sal-ILs drastically increased compared with the AAEs on incorporation of Sal into the cations, and were comparable to that of free Sal. Interestingly, the water miscibilities of the Sal-ILs were higher than that of free Sal, and the Sal-ILs were miscible with water at any ratio. A skin permeation study showed that the Sal-ILs penetrated through skin faster than the Sal sodium salt. These results suggest that AAEs could be used in biomedical applications to eliminate the use of traditional toxic solvents for transdermal delivery of poorly water-soluble drugs. Copyright © 2018 Elsevier B.V. All rights reserved.

Inclusion complex and nanoclusters of cyclodextrin to increase the solubility and efficacy of albendazole.

PubMed

Pacheco, P A; Rodrigues, L N C; Ferreira, J F S; Gomes, A C P; Veríssimo, C J; Louvandini, H; Costa, R L D; Katiki, L M

2018-03-01

Albendazole (ABZ), a benzimidazole widely used to control gastrointestinal parasites, is poorly soluble in water, resulting in variable and incomplete bioavailability. This has favored the appearance ABZ-resistant nematodes and, consequently, an increase in its clinical ineffectiveness. Among the pharmaceutical techniques developed to increase drug efficacy, cyclodextrins (CDs) and other polymers have been extensively used with water-insoluble pharmaceutical drugs to increase their solubility and availability. Our objective was to prepare ABZ formulations, including β-cyclodextrin (βCD) or hydroxypropyl-β-cyclodextrin (HPβCD), associated or not to the water-soluble polymer polyvinylpyrrolidone (PVP). These formulations had their solubility and anthelmintic effect both evaluated in vitro. Also, their anthelmintic efficacy was evaluated in lambs naturally infected with gastrointestinal nematodes (GIN) through the fecal egg count (FEC) reduction test. In vitro, the complex ABZ/HPβCD had higher solubility than ABZ/βCD. The addition of PVP to the complexes increased solubility and dissolution rates more effectively for ABZ/HPβCD than for ABZ/βCD. In vivo, 48 lambs naturally infected with GIN were divided into six experimental groups: control, ABZ, ABZ/βCD, ABZ/βCD-PVP, ABZ/HPβCD, and ABZ/HPβCD-PVP. Each treated animal received 10 mg/kg of body weight (based on the ABZ dose) for three consecutive days. After 10 days of the last administered dose, treatment efficacy was calculated. The efficacy values were as follows: ABZ (70.33%), ABZ/βCD (85.33%), ABZ/βCD-PVP (82.86%), ABZ/HPβCD (78.37%), and ABZ/HPβCD-PVP (43.79%). In vitro, ABZ/HPβCD and ABZ/HPβCD-PVP had high solubility and dissolution rates. In vivo, although the efficacies of ABZ/βCD, ABZ/βCD-PVP, and ABZ/HPβCD increased slightly when compared to pure ABZ, this increase was not significant (P > 0.05).

Study of drug diffusion rate by laser beam deflection technique

NASA Astrophysics Data System (ADS)

Swapna, Mohanachandran Nair. S.; Anitha, Madhu J.; Sankararaman, Sankaranarayana Iyer

2017-06-01

Drug administration is an unavoidable part of treatment. When a drug is administered orally or intravenously, it gets absorbed into the blood stream. The rate and efficiency of absorption depend on the route of administration. When a drug is administered through the oral route, it penetrates the epithelial cells of the intestinal mucosa. The diffusion of the drug into the blood stream depends on various parameters, such as concentration, temperature, and the nature of the mucous membrane. The passive diffusion of drugs is found to obey Fick's law. Water soluble drugs penetrate the cell membrane through aqueous channel or pores. Hence, the study of diffusion of drugs into the water and finally into the blood stream is important. An attempt has been made to study the diffusion of the drug in water as 60% to 80% of human body is water. For the study of drug diffusion in water, a commonly used cough syrup of specific gravity 1.263 is used. It is found that the diffusion rate increases with the concentration of the drug.

Study on Enhanced Dissolution of Azilsartan-Loaded Solid Dispersion, Prepared by Combining Wet Milling and Spray-Drying Technologies.

PubMed

Lu, Tianshu; Sun, Yinghua; Ding, Dawei; Zhang, Qi; Fan, Rui; He, Zhonggui; Wang, Jing

2017-02-01

The purpose of this study was to develop a combination method of wet milling and spray-drying technologies to prepare the solid dispersion and improve the dissolution rate of poorly water-soluble drug candidates. Azilsartan (AZL) was selected as the model drug for its poor water solubility. In the study, AZL-loaded solid dispersion was prepared with polyethylene glycol 6000 (PEG6000) and hydroxypropyl cellulose with super low viscosity (HPC-SL) as stabilizers by using combination of wet grinding and spray-drying methods. The high AZL loading solid dispersion was then characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Besides, dissolution test was carried out by the paddle method and stability investigation was also conducted. As a result, the dissolution rate of the solid dispersion tablets was found to be greater than conventional tablets, but in close agreement with market tablets. Furthermore, the formulation was shown to be stable at 40 ± 2°C and 75 ± 5% for at least 6 months, owing to its decreased particle size, morphology, and its crystal form. It was concluded that the combination of wet milling and spray-drying approaches to prepare solid dispersion would be a prospective method to improve the dissolution rate of poorly water-soluble drugs.

Wax-based sustained release matrix pellets prepared by a novel freeze pelletization technique II. In vitro drug release studies and release mechanisms.

PubMed

Cheboyina, Sreekhar; Wyandt, Christy M

2008-07-09

A novel freeze pelletization technique was evaluated for the preparation of wax-based sustained release matrix pellets. Pellets containing water-soluble drugs were successfully prepared using a variety of waxes. The drug release significantly depended on the wax type used and the aqueous drug solubility. The drug release decreased as the hydrophobicity of wax increased and the drug release increased as the aqueous drug solubility increased. In glyceryl monostearate (GMS) pellets, drug release rate decreased as the loading of theophylline increased. On the contrary, the release rate increased as the drug loading of diltiazem HCl increased in Precirol pellets. Theophylline at low drug loads existed in a dissolved state in GMS pellets and the release followed desorption kinetics. At higher loads, theophylline existed in a crystalline state and the release followed dissolution-controlled constant release for all the waxes studied. However, with the addition of increasing amounts of Brij 76, theophylline release rate increased and the release mechanism shifted to diffusion-controlled square root time kinetics. But the release of diltiazem HCl from Precirol pellets at all drug loads, followed diffusion-controlled square root time kinetics. Therefore, pellets capable of providing a variety of release profiles for different drugs can be prepared using this freeze pelletization technique by suitably modifying the pellet forming matrix compositions.

Evaluation of Matrix Tablets Based on Eudragit®E100/Carbopol®971P Combinations for Controlled Release and Improved Compaction Properties of Water Soluble Model Drug Paracetamol.

PubMed

Obeidat, Wasfy M; Nokhodchi, Ali; Alkhatib, Hatim

2015-10-01

The purpose of this work was to investigate the influence of Eudragit®E100 polymer in modifying the release rates and compaction properties of water soluble model drug paracetamol from Carbopol®971P NF polymer matrix tablets prepared by direct compression. The effects of the ratio of the two polymers, the total polymeric content, and the tablets mechanical strength on paracetamol release rates were investigated. Dissolution studies were conducted using USP XX Π rotating paddle apparatus at 50 rpm and 37°C at three different stages (pH 1.2, 4.8, and 6.8). Results showed that the polymers combination improved significantly the compaction properties of paracetamol tablets as evident by the higher crushing strengths (8.3 ± 0.4 Kp) compared to polymer-free tablets (3.4 ± 0.2 Kp) at intermediate compression pressure of 490 MPa. When combined with Carbopol®971P NF, Eudragit®E100 was found to be capable of extending paracetamol release for more than 12 h compared to 1 h for polymers-free tablets. The combined polymers were able to control paracetamol release in a pH independent pattern. The f2 (similarity factor) analysis showed that the ratio between the polymers and the total polymer concentration exhibited significant impact on drug release rates. In conclusion, Eudragit®E100 when combined with Carbopol®971P NF was capable of improving the compaction and sustained release properties of paracetamol. Korsmeyer-Peppas model was found to be the most suitable for fitting drug release data. The polymer combinations can potentially be used to control the release rates of highly water soluble drugs.

The preparation, characterization, and pharmacokinetic studies of chitosan nanoparticles loaded with paclitaxel/dimethyl-β-cyclodextrin inclusion complexes

PubMed Central

Ye, Ya-Jing; Wang, Yun; Lou, Kai-Yan; Chen, Yan-Zuo; Chen, Rongjun; Gao, Feng

2015-01-01

A novel biocompatible and biodegradable drug-delivery nanoparticle (NP) has been developed to minimize the severe side effects of the poorly water-soluble anticancer drug paclitaxel (PTX) for clinical use. PTX was loaded into the hydrophobic cavity of a hydrophilic cyclodextrin derivative, heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), using an aqueous solution-stirring method followed by lyophilization. The resulting PTX/DM-β-CD inclusion complex dramatically enhanced the solubility of PTX in water and was directly incorporated into chitosan (CS) to form NPs (with a size of 323.9–407.8 nm in diameter) using an ionic gelation method. The formed NPs had a zeta potential of +15.9–23.3 mV and showed high colloidal stability. With the same weight ratio of PTX to CS of 0.7, the loading efficiency of the PTX/DM-β-CD inclusion complex-loaded CS NPs was 30.3-fold higher than that of the PTX-loaded CS NPs. Moreover, it is notable that PTX was released from the DM-β-CD/CS NPs in a sustained-release manner. The pharmacokinetic studies revealed that, compared with reference formulation (Taxol®), the PTX/DM-β-CD inclusion complex-loaded CS NPs exhibited a significant increase in AUC0→24h (the area under the plasma drug concentration–time curve over the period of 24 hours) and mean residence time by 2.7-fold and 1.4-fold, respectively. Therefore, the novel drug/DM-β-CD inclusion complex-loaded CS NPs have promising applications for the significantly improved delivery and controlled release of the poorly water-soluble drug PTX or its derivatives, thus possibly leading to enhanced therapeutic efficacy and less severe side effects. PMID:26170666

Ionic liquid-in-oil microemulsion as a potential carrier of sparingly soluble drug: characterization and cytotoxicity evaluation.

PubMed

Moniruzzaman, Muhammad; Tamura, Miki; Tahara, Yoshiro; Kamiya, Noriho; Goto, Masahiro

2010-11-15

Pharmaceutical industries have posed challenges in the topical and transdermal administration of drugs which are poorly soluble or insoluble in water and most of organic solvents. In an approach to overcome this limitation, ionic liquid-in-oil (IL/o) microemulsions (MEs) were employed to increase the solubility of a sparingly soluble drug to enhance its topical and transdermal delivery. The formulation of MEs was composed of a blend of nonionic surfactants, polyoxyethylene sorbitan monooleate (Tween-80) and sorbitan laurate (Span-20), isopropyl myristate (IPM) as an oil phase, and IL [C(1)mim] [(CH(3)O)(2)PO(2)] (dimethylimidazolium dimethylphosphate) as a pseudophase. Among various weight ratios of Tween-80 to Span-20 investigated in the ME systems, the ratio 3:2 showed excellent solubility and skin permeation enhancing effect for acyclovir (ACV) used as a model sparingly soluble drug. The size and size distribution of the ME droplets with and without drug were determined by dynamic light scattering. The permeability study of ACV incorporated in IL droplets as well as other formulations was performed into and across the Yucatan micropig (YMP) porcine skin, and the use of IL/o MEs has been shown to dramatically increase ACV administration. Finally, the cytotoxicity of the new carrier was evaluated in vitro using the reconstructed human epidermal model LabCyte™ EPI-MODEL12. It was found that the cell viability of IL/o MEs containing 4wt% IL was over 80% compared to Dulbecco's Phosphate-Buffered Salines, indicating low cytotoxicity of the carrier. Taken together these results, it can be assumed that IL-assisted nonaqueous ME could serve as a versatile and efficient nanodelivery system for insoluble or sparingly soluble drug molecules that require solubilizing agents for delivery. Copyright © 2010 Elsevier B.V. All rights reserved.

Membrane Proteins Are Dramatically Less Conserved than Water-Soluble Proteins across the Tree of Life.

PubMed

Sojo, Victor; Dessimoz, Christophe; Pomiankowski, Andrew; Lane, Nick

2016-11-01

Membrane proteins are crucial in transport, signaling, bioenergetics, catalysis, and as drug targets. Here, we show that membrane proteins have dramatically fewer detectable orthologs than water-soluble proteins, less than half in most species analyzed. This sparse distribution could reflect rapid divergence or gene loss. We find that both mechanisms operate. First, membrane proteins evolve faster than water-soluble proteins, particularly in their exterior-facing portions. Second, we demonstrate that predicted ancestral membrane proteins are preferentially lost compared with water-soluble proteins in closely related species of archaea and bacteria. These patterns are consistent across the whole tree of life, and in each of the three domains of archaea, bacteria, and eukaryotes. Our findings point to a fundamental evolutionary principle: membrane proteins evolve faster due to stronger adaptive selection in changing environments, whereas cytosolic proteins are under more stringent purifying selection in the homeostatic interior of the cell. This effect should be strongest in prokaryotes, weaker in unicellular eukaryotes (with intracellular membranes), and weakest in multicellular eukaryotes (with extracellular homeostasis). We demonstrate that this is indeed the case. Similarly, we show that extracellular water-soluble proteins exhibit an even stronger pattern of low homology than membrane proteins. These striking differences in conservation of membrane proteins versus water-soluble proteins have important implications for evolution and medicine. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Xanthoceraside hollow gold nanoparticles, green pharmaceutics preparation for poorly water-soluble natural anti-AD medicine.

PubMed

Meng, Da-Li; Shang, Lei; Feng, Xiao-He; Huang, Xing-Fei; Che, Xin

2016-06-15

In order to increase the solubility of poorly water-soluble natural product, xanthoceraside, an effective anti-AD compound from Xanthoceras sorbifolia Bunge, and maintain its natural property, the xanthoceraside hollow gold nanoparticles were successively prepared by green ultrasonic method with silica spheres as templates and HF solution as selective etching solvent. Hollow gold nanoparticles and drug-loaded hollow gold nanoparticles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The solubilities of xanthoceraside loaded on hollow gold nanoparticles were increased obviously from 3.0μg/ml and 2.5μg/ml to 12.7μg/ml and 10.7μg/ml at 25°C and 37°C, respectively. The results of XRD and DSC indicated that the reason for this increase was mainly due to the amorphous state of xanthoceraside loaded on the hollow gold nanoparticles. In summary, the method of loading xanthoceraside onto hollow gold nanoparticles was a green and useful strategy to improve the solubility and dissolution of poorly water-soluble natural products and worth to applying to other natural products. Copyright © 2016 Elsevier B.V. All rights reserved.

Nasal Drug Absorption from Powder Formulations: Effect of Fluid Volume Changes on the Mucosal Surface.

PubMed

Tanaka, Akiko; Furubayashi, Tomoyuki; Enomura, Yuki; Hori, Tomoki; Shimomura, Rina; Maeda, Chiaki; Kimura, Shunsuke; Inoue, Daisuke; Kusamori, Kosuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

2017-01-01

The effect of changes in the mucosal fluid volume on the nasal drug absorption of powder formulations was evaluated using warfarin (WF), piroxicam (PXC), and norfloxacin (NFX) as model drugs. Lactose and sodium chloride (NaCl), which are water soluble and small-sized chemicals that increase osmotic pressure after dissolution, were used as excipients to change the mucosal fluid volume. The in vitro study using a Madin-Darby canine kidney (MDCK) cell monolayer indicated that lactose and NaCl, sprayed over the surface of air interface monolayers, increased the fluid volume on the monolayer surface and enhanced the transepithelial transport of the model drugs. The in vivo animal study indicated that the nasal absorption of PXC is enhanced by lactose and NaCl after nasal administration of the powder formulations. This is likely due to the enhanced dissolution of PXC on fluid-rich nasal mucosa and an increase in the effective surface area for drug permeation, which lead to better nasal absorption. However, both excipients failed to increase the nasal absorption of WF and NFX. To clarify the mechanism of the drug-dependent effect of lactose and NaCl, the nasal residence of the formulation was examined using FD70 as a non-absorbable marker. The nasal clearance of FD70 was enhanced by lactose and NaCl, leading to a decrease in the nasal drug absorption. Lactose and NaCl caused no damage to the nasal tissue. These results indicate that the addition of water-soluble excipients such as lactose to powder formulations can enhance the nasal absorption of highly permeable but poorly soluble drugs.

Sodium alginate as a potential carrier in solid dispersion formulations to enhance dissolution rate and apparent water solubility of BCS II drugs.

PubMed

Borba, Paola Aline Amarante; Pinotti, Marihá; de Campos, Carlos Eduardo Maduro; Pezzini, Bianca Ramos; Stulzer, Hellen Karine

2016-02-10

The solid dispersion technique is the most effective method for improving the dissolution rate of poorly water-soluble drugs, however it depends on a suitable carrier selection. The work explored the use of the biopolymer sodium alginate (SA) as a potential carrier in solid dispersions (SD). The data demonstrated that SA was able to improve the biopharmaceutical properties of the BCS II drug telmisartan (TEL) of low solubility even using relative small drug:polymer ratio. A solid state grinding process was used to prepare the solid dispersions (SD) during 45 min. The SD were prepared in different proportions of drug and carrier of 1:1, 1:3, 1:5, 1:7 and 1:9 (mass/mass). DSC, XRPD, FTIR and Raman confirmed the presence of molecular interactions between TEL and the carrier. FTIR supports the presence of hydrogen bonds between TEL and the carrier. SD_1:5, SD_1:7 and SD_1:9 enhanced the dissolution rate of the drug releasing more than 80% of the drug in just 30 min (83%, 84% and 87%). The the t-test results demonstrated equal dissolution efficiency values for SD_1:7 and Micardis(®), however the similarity (f2) and difference (f1) fit factors showed that the SD and Micardis(®) are statistically different. The physical stability studies demonstrated that SD using sodium alginate as a carrier remained unchanged during the period of 90 days at room temperature, showing that the sodium alginate acts as a good anti plasticizer agent, preventing the drug recrystallization. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prodrugs for transdermal drug delivery - trends and challenges.

PubMed

Ita, Kevin B

2016-09-01

Prodrugs continue to attract significant interest in the transdermal drug delivery field. These moieties can confer favorable physicochemical properties on transdermal drug delivery candidates. Alkyl chain lengthening, pegylation are some of the strategies used for prodrug synthesis. It is usually important to optimize partition coefficient, water and oil solubilities of drugs. In this review, progress made in the field of prodrugs for percutaneous penetration is highlighted and the challenges discussed.

Studying of drug solubility in water and alcohols using drug-ammonium ionic liquid-compounds.

PubMed

Halayqa, Mohammad; Pobudkowska, Aneta; Domańska, Urszula; Zawadzki, Maciej

2018-01-01

Synthesis of three mefenamic acid (MEF) derivatives - ionic liquid compounds composed of MEF in an anionic form and ammonium cation (choline, MEF1), or {di(2-hydroxyethyl)dimethyl ammonium (MEF2)}, or {tri(2-hydroxyethyl)methyl ammonium compound (MEF3)} is presented. The basic thermal properties of pure compounds i.e. fusion temperatures, and the enthalpy of fusion of these compounds have been measured with differential scanning microcalorimetry technique (DSC). Molar volumes have been calculated with the Barton group contribution method. The solubilities of MEF1, MEF2 and MEF3 using the dynamic method were measured at constant pH in a range of temperature from (290 to 370) K in three solvents: water, ethanol and 1-octanol. The experimental solubility data have been correlated by means of three commonly known G E equations: the Wilson, NRTL and UNIQUAC with the assumption that the systems studied here present simple eutectic behaviour. The activity coefficients of pharmaceuticals at saturated solutions in each binary mixture were calculated from the experimental data. The formation of MEF-ionic liquid compounds greatly increases the solubility in water in comparison with pure MEF or complexes with 2-hydroxypropyl-β-cyclodextrin. The development of these compounds formulations will assist in medication taking into account oral solid or gel medicines. Copyright © 2017 Elsevier B.V. All rights reserved.

Preparation and physicochemical characterization of acyclovir cocrystals with improved dissolution properties.

PubMed

Bruni, Giovanna; Maietta, Mariarosa; Maggi, Lauretta; Mustarelli, Piercarlo; Ferrara, Chiara; Berbenni, Vittorio; Milanese, Chiara; Girella, Alessandro; Marini, Amedeo

2013-11-01

Acyclovir is a well-known antiviral agent. It can be administered in very high doses (from 200 to 1000 mg even three-four times daily). It has absorption problems mainly due to its poor solubility in water (about 0.2 g/100 mL at 25°C) and its oral bioavailability is approximately 15%-20% with a half-life of about 3 h. To improve acyclovir solubility and/or its dissolution properties, two cocrystals of this drug were successfully produced with glutaric acid (AGA1:1) and fumaric acid (AFA1:1) as conformers, using a cogrinding method. Their effective formation was investigated by a broad range of techniques: thermal analysis, Fourier transform infrared spectroscopy, X-ray powder diffraction, solid state nuclear magnetic resonance, and scanning electron microscopy coupled with energy dispersive X-ray spectrometry. The water solubility of the AGA1:1 cocrystal was not improved in comparison to acyclovir, while AFA1:1 showed a slight increased solubility at equilibrium. The main difference was detected in terms of intrinsic dissolution rates (IDR). The IDR of the new phases were much faster compared with acyclovir, particularly at neutral pH. AFA1:1 showed the most rapid dissolution behavior in water; within 10 min, the drug was released completely, while just 60% of acyclovir was dissolved in 1 h. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Solubility of drugs in the presence of gelatin: effect of drug lipophilicity and degree of ionization.

PubMed

Kallinteri, P; Antimisiaris, S G

2001-06-19

The solubility of seven drugs (nitrofurantoin, chlorothiazide, phenobarbital, prednisolone, griseofulvin, diazepam and piroxicam) in the absence and presence of gelatin was measured, at three different pH values (3.7, 5.0 and 7.0) at 37 degrees C. Drugs studied had different physicochemical properties (log P, pK(a), aqueous solubility) and their solubility in presence of 0.1 and 0.5% (w/v) hydrolyzed (and in some cases common) gelatin was estimated. Results show that the solubility of all drugs is significantly enhanced, especially in the presence of 0.5% gelatin. This gelatin-induced enhancement in drug solubility is higher in the pH in which acidic drugs are less ionized, especially for the less lipophilic acidic drugs (nitrofurantoin, chlorothiazide). In all cases, drug solubility in presence of gelatin is correlated with their aqueous solubility. Therefore, the established relationships between aqueous and gelatin solubility can be employed to derive an estimate of the drug solubility in presence of gelatin once its aqueous solubility is known. With the exception of piroxicam which is highly ionized and phenobarbital which is relatively soluble, there seems to be a tendency for larger gelatin-induced increases in solubility as drug lipophilicity increases or aqueous solubility decreases.

Polysaccharides based nanomaterials for targeted anti-cancer drug delivery.

PubMed

Dheer, Divya; Arora, Divya; Jaglan, Sundeep; Rawal, Ravindra K; Shankar, Ravi

2017-01-01

Polysaccharides, an important class of biological polymers, are effectively bioactive, nontoxic, hydrophilic, biodegradable and offer a wide diversity in structure and properties. These can be easily modified chemically and biochemically to enhance the bioadhesion with biological tissues, better stability and can improve bioavailability of drugs. Most of the chemotherapeutic drugs have a narrow therapeutic index, slow drug delivery systems and poor water solubility that usually proves toxic to human bodies. The inherent biocompatibility of these biopolymers have shown enhancement of solubility of some chemotherapeutic drugs which also leads to the preparation of nanomaterials for the delivery of antibiotics, anticancer, proteins, peptides and nucleic acids using several routes of administration. Recently, synthesis and research on polysaccharides based nanomaterials have gained enormous attention as one of the most applicable resources in nanomedicine area. This review article will provide a specific emphasis on polysaccharides as natural biomaterials for targeted anticancer drug delivery system.

Synthesis of novel fluorescently labeled water-soluble fullerenes and their application to its cellar uptake and distribution properties

NASA Astrophysics Data System (ADS)

Hashimoto, Akiko; Yamanaka, Takehiro; Takamura-Enya, Takeji

2017-12-01

Fullerene is a well-known carbon nanomaterial, which can be potentially used for drug manufacture or delivery. Despite several successful examples of utilizing fullerene derivatives as drug candidate materials, their low water solubility under physiological conditions negatively affects the cell penetration efficiency after treatment. In this work, we successfully synthesized two fullerene derivatives with covalently attached fluorescein and boron dipyrromethene (BODIPY) fluorophore moieties, which exhibited cellular uptake and intracellular localization. While both fluorophores decreased their fluorescence intensity in the vicinity of fullerene, the cellar uptake of the fluorescein-modified fullerene was detected via fluorescence microscopy observations. Moreover, decreases in the fluorescence intensities of the intact fluorescein and BODIPY species were observed when both fluorophores and fullerene coexisted in aqueous media.

Substituent effect on the thermodynamic solubility of structural analogs: relative contribution of crystal packing and hydration.

PubMed

Ozaki, Shunsuke; Nakagawa, Yoshiaki; Shirai, Osamu; Kano, Kenji

2014-11-01

Thermodynamic analysis of the solubility of benzoylphenylurea (BPU) derivatives was conducted to investigate the relative importance of crystal packing and hydration for improving solubility with minor structural modification. The contribution of crystal packing to solubility was evaluated from the change in Gibbs energy on the transition from the crystalline to liquid state. Hydration Gibbs energy was estimated using a linear free-energy relationship between octanol-water partition coefficients and gas-water partition coefficients. The established solubility model satisfactorily explained the relative thermodynamic solubility of the model compounds and revealed that crystal packing and hydration equally controlled solubility of the structural analogs. All hydrophobic substituents were undesirable for solubility in terms of hydration, as expected. On the other hand, some of these hydrophobic substituents destabilized crystal packing and improved the solubility of the BPU derivatives when their impact on crystal packing exceeded their negative influence on hydration. The replacement of a single substituent could cause more than a 10-fold enhancement in thermodynamic solubility; this degree of improvement was comparable to that generally achieved by amorphous formulations. Detailed analysis of thermodynamic solubility will allow us to better understand the true substituent effect and design drug-like candidates efficiently. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Adsorption and biodegradation of antidiabetic pharmaceuticals in soils.

PubMed

Mrozik, Wojciech; Stefańska, Justyna

2014-01-01

Pharmaceuticals are emerging contaminants in the natural environment. Most studies of the environmental fate of these chemicals focus on their behavior in wastewater treatment processes and in sewage sludge. Little is known about their behavior in soils. In this study adsorption and biodegradation of four antidiabetic pharmaceuticals - glimepiride, glibenclamide, gliclazide and metformin - were examined in three natural soils. The sorption of sulfonylurea derivatives was high (higher than sulfonylurea herbicides for example), whereas metformin showed high mobility. Desorption rates were highest for metformin. Sorption isotherms in two of three soils fitted best to the Freundlich model. Despite their high affinity to for soil surfaces, biodegradation studies revealed that transformation of the drugs occurred. Biodegradation results were described by pseudo-first order kinetics with half-life values from 5 to over 120 d (under aerobic conditions) and indicate that none of the tested drugs can be classified as quickly biodegradable. Biodegradation under anoxic conditions was much slower; often degrading by less than 50% during time of the experiment. Copyright © 2013 Elsevier Ltd. All rights reserved.

Carrier characteristics influence the kinetics of passive drug loading into lipid nanoemulsions.

PubMed

Göke, Katrin; Bunjes, Heike

2018-05-01

Passive loading as a novel screening approach is a material-saving tool for the efficient selection of a suitable colloidal lipid carrier system for poorly water soluble drug candidates. This method comprises incubation of preformed carrier systems with drug powder and subsequent determination of the resulting drug load of the carrier particles after removal of excess drug. For reliable routine use and to obtain meaningful loading results, information on the kinetics of the process is required. Passive loading proceeds via a dissolution-diffusion-based mechanism, where drug surface area and drug water solubility are key parameters for fast passive loading. While the influence of the drug characteristics is mostly understood, the influence of the carrier characteristics remains unknown. The aim of this study was to examine how the lipid nanocarriers' characteristics, i.e. the type of lipid, the lipid content and the particle size, influence the kinetics of passive loading. Fenofibrate was used as model drug and the loading progress was analyzed by UV spectroscopy. The saturation solubility in the nanocarrier particles, i.e. the lipid type, did not influence the passive loading rate constant. Low lipid content in the nanocarrier and a small nanocarrier particle size both increased passive loading speed. Both variations increase the diffusivity of the nanocarrier particles, which is the primary cause for fast loading at these conditions: The quicker the carrier particles diffuse, the higher is the speed of passive loading. The influence of the diffusivity of the lipid nanocarriers and the effect of drug dissolution rate were included in an overall mechanistic model developed for similar processes (A. Balakrishnan, B.D. Rege, G.L. Amidon, J.E. Polli, Surfactant-mediated dissolution: contributions of solubility enhancement and relatively low micelle diffusivity, J. Pharm. Sci. 93 (2004) 2064-2075). The resulting mechanistic model gave a good estimate of the speed of passive loading in nanoemulsions. Whilst the drug's characteristics - apart from drug surface area - are basically fixed, the lipid nanocarriers can be customized to improve passive loading speed, e.g. by using small nanocarrier particles. The knowledge of the loading mechanism now allows the use of passive loading for the straightforward, material-saving selection of suitable lipid drug nanocarriers. Copyright © 2017 Elsevier B.V. All rights reserved.

Improved Dissolution and Oral Bioavailability of Celecoxib by a Dry Elixir System.

PubMed

Cho, Kwan Hyung; Jee, Jun-Pil; Yang, Da A; Kim, Sung Tae; Kang, Dongjin; Kim, Dae-Young; Sim, Taeyong; Park, Sang Yeob; Kim, Kyeongsoon; Jang, Dong-Jin

2018-02-01

The purpose of this study was to develop and evaluate a dry elixir (DE) system for enhancing the dissolution rate and oral bioavailability of celecoxib. DE system has been used for improving solubility, oral bioavailability of poorly water-soluble drugs. The encapsulated drugs or solubilized drugs in the matrix are rapidly dissolved due to the co-solvent effect, resting in both an enhanced dissolution and bioavailability. DEs containing celecoxib were prepared by spray-drying method and characterized by morphology, drug/ethanol content, drug crystallinity, dissolution rate and oral bioavailability. The ethanol content and drug content in DE system could be easily altered by controlling the spraydrying conditions. The dissolution profile of celecoxib from DE proved to be much higher than that of celecoxib powder due to the nano-structured matrix, amorphous state and encapsulated ethanol. The bioavailability of celecoxib from DEs was compared with celecoxib powder alone and commercial product (Celebrex®) in rats. In particular, blood concentrations of celecoxib form DE formulation were much greater than those of native celecoxib and market product. The data demonstrate that the DE system could provide an useful solid dosage form to enhance the solubility, dissolution rate and oral bioavailability of celecoxib.

Impact of polymer type on bioperformance and physical stability of hot melt extruded formulations of a poorly water soluble drug.

PubMed

Mitra, Amitava; Li, Li; Marsac, Patrick; Marks, Brian; Liu, Zhen; Brown, Chad

2016-05-30

Amorphous solid dispersion formulations have been widely used to enhance bioavailability of poorly soluble drugs. In these formulations, polymer is included to physically stabilize the amorphous drug by dispersing it in the polymeric carrier and thus forming a solid solution. The polymer can also maintain supersaturation and promote speciation during dissolution, thus enabling better absorption as compared to crystalline drug substance. In this paper, we report the use of hot melt extrusion (HME) to develop amorphous formulations of a poorly soluble compound (FaSSIF solubility=1μg/mL). The poor solubility of the compound and high dose (300mg) necessitated the use of amorphous formulation to achieve adequate bioperformance. The effect of using three different polymers (HPMCAS-HF, HPMCAS-LF and copovidone), on the dissolution, physical stability, and bioperformance of the formulations was demonstrated. In this particular case, HPMCAS-HF containing HME provided the highest bioavailability and also had better physical stability as compared to extrudates using HPMCAS-LF and copovidone. The data demonstrated that the polymer type can have significant impact on the formulation bioperformance and physical stability. Thus a thorough understanding of the polymer choice is imperative when designing an amorphous solid dispersion formulation, such that the formulation provides robust bioperformance and has adequate shelf life. Copyright © 2016 Elsevier B.V. All rights reserved.

Development of self-nanoemulsifying drug delivery system for oral bioavailability enhancement of valsartan in beagle dogs.

PubMed

Li, Zhenbao; Zhang, Wenjuan; Gao, Yan; Xiang, Rongwu; Liu, Yan; Hu, Mingming; Zhou, Mei; Liu, Xiaohong; Wang, Yongjun; He, Zhonggui; Sun, Yinghua; Sun, Jin

2017-02-01

Valsartan, an angiotensin II receptor antagonist, is widely used to treat high blood pressure in the clinical setting. However, its poor water solubility results in the low oral bioavailability. The aim of this study was to improve dissolution rate and oral bioavailability by developing a self-nanoemulsifying drug delivery system. Saturation solubility of valsartan in various oils, surfactants, and cosurfactants was investigated, and the optimized formulation was determined by central composite design-response surface methodology. The shape of resultant VAL-SNEDDS was spherical with an average diameter of about 27 nm. And the drug loading efficiency is approximately 14 wt%. Differential scanning calorimetry and XRD studies disclosed the molecular or amorphous state of valsartan in VAL-SNEDDS. The dissolution study indicated that the self-nanoemulsifying drug delivery systems (SNEDDS) exhibited significantly enhanced dissolution compared with market capsules (Diovan®) in various media. Furthermore, the stability of formulation revealed that valsartan SNEDDS was stable under low temperature and accelerated test condition. Furthermore, the pharmacokinetics demonstrated that C max and AUC (0-∞) of SNEDDS capsules were about three- and twofold higher than Diovan® in beagle dogs, respectively. Meanwhile, the safety evaluation implied that VAL-SNEDDS was innocuous to beagle dogs during 15 days of continuous administration. Our results suggested that VAL-SNEDDS was a potential and safe delivery system with enhanced dissolution rate and oral bioavailability, as well as offered a strategy for the engineering of poorly water-soluble drugs in the clinical setting.

Enhanced delivery of fixed-dose combination of synergistic antichagasic agents posaconazole-benznidazole based on amorphous solid dispersions.

PubMed

Figueirêdo, Camila Bezerra Melo; Nadvorny, Daniela; Vieira, Amanda Carla Quintas de Medeiros; Schver, Giovanna Christinne Rocha de Medeiros; Soares Sobrinho, José Lamartine; Rolim Neto, Pedro José; Lee, Ping I; Soares, Monica Felts de La Roca

2018-07-01

Posaconazole (PCZ) and benznidazole (BNZ) are known to show synergetic effect in treating the acute and chronic phases of Chagas disease, a neglected parasitic disease. However, as both compounds are poorly water soluble, the development of amorphous solid dispersions (ASDs) of a PCZ/BNZ fixed-dose combination in a water-soluble polymer becomes an attractive option to increase their apparent solubility and dissolution rate, potentially improving their oral bioavailability. The initial approach was to explore solvent evaporated solid dispertion (SD) systems for a PCZ/BNZ 50:50 (wt%) combination at several total drug loading levels (from SD with 10% to 50% drug loading) in water-soluble carriers, including polyvinylpyrrolidone (PVP K-30) and vinylpyrrolidone-vinyl acetate copolymer (PVPVA 64). Based on comparison of non-sink in vitro dissolution performance, ASD systems based on PVPVA was identified as the most effective carrier for a 50:50 (w/w %) fixed-dose combination of PCZ/BNZ to increase their apparent solubility and dissolution rate, mainly at 10% drug loading, which shows more expressive values of area under the curve (AUC) (7336.04 ± 3.77 min.μL/mL for PCZ and 15,795.02 ± 7.29 min.μL/mL for BNZ). Further characterization with polarized microscopy, powder X-ray diffraction, and thermal analysis reveals that there exists a threshold drug loading level at about 30% PCZ/BNZ, below which ASDs are obtained and above which a certain degree of crystallinity tends to result. Moreover, infrared spectroscopic analysis reveals the lack of hydrogen bonding interactions between the drugs (PCZ and BNZ) and the polymer (PVPVA) in the ASD, this is also confirmed through molecular dynamics simulations. The molecular modeling results further show that even in the absence of meaningful hydrogen bonding interactions, there is a greater tendency for PVPVA to interact preferentially with PCZ and BNZ through electrostatic interactions thereby contributing to the stability of the system. Thus, the present SD system has the advantage of presenting a fixed-dese combination of two synergistic antichagasic agents PCZ and BNZ together in amorphous form stabilized in the PVPVA matrix with enhanced dissolution, potentially improving their bioavailability and therapeutic activity in treating Chagas disease. Copyright © 2018 Elsevier B.V. All rights reserved.

An ionic liquid-in-water microemulsion as a potential carrier for topical delivery of poorly water soluble drug: Development, ex-vivo and in-vivo evaluation.

PubMed

Goindi, Shishu; Kaur, Ramanpreet; Kaur, Randeep

2015-11-30

In this paper, we report an ionic liquid-in-water (IL/w) microemulsion (ME) formulation which is able to solubilize etodolac (ETO), a poorly water soluble drug for topical delivery using BMIMPF6 (1-butyl-3-methylimidazolium hexafluorophosphate) as IL, Tween 80 as surfactant and ethanol as co-surfactant. The prepared ME was characterized for physicochemical parameters, subjected to ex-vivo permeation studies as well as in-vivo pharmacodynamic evaluation. The ex-vivo drug permeation studies through rat skin was performed using Franz-diffusion cell and the IL/w based ME showed maximum mean cumulative percent permeation of 99.030±0.921% in comparison to oil-in-water (o/w) ME (61.548±1.875%) and oily solution (48.830±2.488%) of ETO. In-vivo anti-arthritic and anti-inflammatory activities of the prepared formulations were evaluated using different rodent models and the results revealed that ETO loaded IL/w based ME was found to be more effective in controlling inflammation than oily solution, o/w ME and marketed formulation of ETO. Histopathological studies also demonstrated that IL/w based ME caused no anatomical and pathological changes in the skin. Copyright © 2015 Elsevier B.V. All rights reserved.

Preparation and characterization of silica xerogels as carriers for drugs.

PubMed

Czarnobaj, K

2008-11-01

The aim of the present study was to utilize the sol-gel method to synthesize different forms of xerogel matrices for drugs and to investigate how the synthesis conditions and solubility of drugs influence the change of the profile of drug release and the structure of the matrices. Silica xerogels doped with drugs were prepared by the sol-gel method from a hydrolyzed tetraethoxysilane (TEOS) solution containing two model compounds: diclofenac diethylamine, (DD)--a water-soluble drug or ibuprofen, (IB)--a water insoluble drug. Two procedures were used for the synthesis of sol-gel derived materials: one-step procedure (the sol-gel reaction was carried out under acidic or basic conditions) and the two-step procedure (first, hydrolysis of TEOS was carried out under acidic conditions, and then condensation of silanol groups was carried out under basic conditions) in order to obtain samples with altered microstructures. In vitro release studies of drugs revealed a similar release profile in two steps: an initial diffusion-controlled release followed by a slower release rate. In all the cases studied, the released amount of DD was higher and the released time was shorter compared with IB for the same type of matrices. The released amount of drugs from two-step prepared xerogels was always lower than that from one-step base-catalyzed xerogels. One-step acid-catalyzed xerogels proved unsuitable as the carriers for the examined drugs.

Lipid-associated Oral Delivery: Mechanisms and Analysis of Oral Absorption Enhancement

PubMed Central

Rezhdo, Oljora; Speciner, Lauren; Carrier, Rebecca L.

2016-01-01

The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented. PMID:27520734

Pharmaceutical applications of cyclodextrins: basic science and product development.

PubMed

Loftsson, Thorsteinn; Brewster, Marcus E

2010-11-01

Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach. This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin-containing formulations. There are currently a number of marketed products that make use of these functional solubilizing excipients and new product introduction continues to demonstrate their high added value. The ability to predict whether cyclodextrins will be of benefit in creating a dosage form for a particular drug candidate requires a good working knowledge of the properties of cyclodextrins, their mechanism of solubilization and factors that contribute to, or detract from, the biopharmaceutical characteristics of the formed complexes. We provide basic science information as well as data on the development of drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important tool in the formulator's armamentarium to improve apparent solubility and dissolution rate for poorly water-soluble drug candidates. The continued interest and productivity of these materials bode well for future application and their currency as excipients in research, development and drug product marketing. © 2010 The Authors. Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain.

Structural Elucidation of Poloxamer 237 and Poloxamer 237/Praziquantel Solid Dispersions: Impact of Poly(Vinylpyrrolidone) over Drug Recrystallization and Dissolution.

PubMed

Orlandi, Silvina; Priotti, Josefina; Diogo, Hermínio P; Leonardi, Dario; Salomon, Claudio J; Nunes, Teresa G

2018-04-01

Praziquantel (PZQ) is the recommended, effective, and safe treatment against all forms of schistosomiasis. Solid dispersions (SDs) in water-soluble polymers have been reported to increase solubility and bioavailability of poorly water-soluble drugs like PZQ, generally due to the amorphous form stabilization. In this work, poloxamer (PLX) 237 and poly(vinylpyrrolidone) (PVP) K30 were evaluated as potential carriers to revert PZQ crystallization. Binary and ternary SDs were prepared by the solvent evaporation method. PZQ solubility increased similarly with PLX either as binary physical mixtures or SDs. Such unpredicted data correlated well with crystalline PZQ and PLX as detected by solid-state NMR (ssNMR) and differential scanning calorimetry in those samples. Ternary PVP/PLX/PZQ SDs showed both ssNMR broad and narrow superimposed signals, thus revealing the presence of amorphous and crystalline PZQ, respectively, and exhibited the highest PZQ dissolution efficiency (up to 82% at 180 min). SDs with PVP provided a promising way to enhance solubility and dissolution rate of PZQ since PLX alone did not prevent recrystallization of amorphous PZQ. Based on ssNMR data, novel evidences on PLX structure and molecular dynamics were also obtained. As shown for the first time using ssNMR, propylene glycol and ethylene glycol constitute the PLX amorphous and crystalline components, respectively.

Solid state properties and drug release behavior of co-amorphous indomethacin-arginine tablets coated with Kollicoat® Protect.

PubMed

Petry, Ina; Löbmann, Korbinian; Grohganz, Holger; Rades, Thomas; Leopold, Claudia S

2017-10-01

A promising approach to improve the solubility of poorly water-soluble drugs and to overcome the stability issues related to the plain amorphous form of the drugs, is the formulation of drugs as co-amorphous systems. Although polymer coatings have been proven very useful with regard to tablet stability and modifying drug release, there is little known on coating co-amorphous formulations. Hence, the aim of the present study was to investigate whether polymer coating of co-amorphous formulations is possible without inducing recrystallization. Tablets containing either a physical mixture of crystalline indomethacin and arginine or co-amorphous indomethacin-arginine were coated with a water soluble polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® Protect) and stored at 23°C/0% RH and 23°C/75% RH. The solid state properties of the coated tablets were analyzed by XRPD and FTIR and the drug release behavior was tested for up to 4h in phosphate buffer pH 4.5. The results showed that the co-amorphous formulation did not recrystallize during the coating process or during storage at both storage conditions for up to three months, which confirmed the high physical stability of this co-amorphous system. Furthermore, the applied coating could partially inhibit recrystallization of indomethacin during drug release testing, as coated tablets reached a higher level of supersaturation compared to the respective uncoated formulations and showed a lower decrease of the dissolved indomethacin concentration upon precipitation. Thus, the applied coating enhanced the AUC of the dissolution curve of the co-amorphous tablets by about 30%. In conclusion, coatings might improve the bioavailability of co-amorphous formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery.

PubMed

Pozzoli, Michele; Traini, Daniela; Young, Paul M; Sukkar, Maria B; Sonvico, Fabio

2017-09-01

The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus ® (BASF, Germany) using a freeze-drying technique, in order to improve dissolution and absorption through the nasal route. The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray. The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus-BUD formulation. The freeze-dried Soluplus-BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334 ± 0.0178 m 2 /g. The calorimetric analysis confirmed an interaction between BUD and Soluplus and X-ray powder diffraction the amorphous status of the drug. The freeze-dried formulation (LYO) showed faster release compared to both water-based suspension and dry powder commercial products. Furthermore, a LYO formulation, bulked with calcium carbonate (LYO-Ca), showed suitable aerodynamic characteristics for nasal drug delivery. The permeation across RPMI 2650 nasal cell model was higher compared to a commercial water-based BUD suspension. Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.

Alkyl polyglucoside vs. ethoxylated surfactant-based microemulsions as vehicles for two poorly water-soluble drugs: physicochemical characterization and in vivo skin performance.

PubMed

Pajić, Nataša Z Bubić; Todosijević, Marija N; Vuleta, Gordana M; Cekić, Nebojša D; Dobričić, Vladimir D; Vučen, Sonja R; Čalija, Bojan R; Lukić, Milica Ž; Ilić, Tanja M; Savić, Snežana D

2017-12-20

Two types of biocompatible surfactants were evaluated for their capability to formulate skin-friendly/non-irritant microemulsions as vehicles for two poorly water-soluble model drugs differing in properties and concentrations: alkyl polyglucosides (decyl glucoside and caprylyl/capryl glucoside) and ethoxylated surfactants (glycereth-7-caprylate/ caprate and polysorbate 80). Phase behavior, structural inversion and microemulsion solubilization potential for sertaconazole nitrate and adapalene were found to be highly dependent on the surfactants structure and HLB value. Performed characterization (polarized light microscopy, pH, electrical conductivity, rheological, FTIR and DSC measurements) indicated a formulation containing glycereth- 7-caprylate/caprate as suitable for incorporation of both drugs, whereas alkyl polyglucoside-based systems did not exhibit satisfying solubilization capacity for sertaconazole nitrate. Further, monitored parameters were strongly affected by sertaconazole nitrate incorporation, while they remained almost unchanged in adapalene-loaded vehicles. In addition, results of the in vivo skin performance study supported acceptable tolerability for all investigated formulations, suggesting selected microemulsions as promising carriers worth exploring further for effective skin delivery of model drugs.

pH-responsive supramolecular vesicles based on water-soluble pillar[6]arene and ferrocene derivative for drug delivery.

PubMed

Duan, Qunpeng; Cao, Yu; Li, Yan; Hu, Xiaoyu; Xiao, Tangxin; Lin, Chen; Pan, Yi; Wang, Leyong

2013-07-17

The drug delivery system based on supramolecular vesicles that were self-assembled by a novel host-guest inclusion complex between a water-soluble pillar[6]arene (WP6) and hydrophobic ferrocene derivative in water has been developed. The inclusion complexation between WP6 and ferrocene derivative in water was studied by (1)H NMR, UV-vis, and fluorescence spectroscopy, which showed a high binding constant of (1.27 ± 0.42) × 10(5) M(-1) with 1:1 binding stoichiometry. This resulting inclusion complex could self-assemble into supramolecular vesicles that displayed a significant pH-responsive behavior in aqueous solution, which were investigated by fluorescent probe technique, dynamic laser scattering, and transmission electron microscopy. Furthermore, the drug loading and in vitro drug release studies demonstrated that these supramolecular vesicles were able to encapsulate mitoxantrone (MTZ) to achieve MTZ-loaded vesicles, which particularly showed rapid MTZ release at low-pH environment. More importantly, the cellular uptake of these pH-responsive MTZ-loaded vesicles by cancer cells was observed by living cell imaging techniques, and their cytotoxicity assay indicated that unloaded vesicles had low toxicity to normal cells, which could dramatically reduce the toxicity of MTZ upon loading of MTZ. Meanwhile, MTZ-loaded vesicles exhibited comparable anticancer activity in vitro as free MTZ to cancer cells under examined conditions. This study suggests that such supramolecular vesicles have great potential as controlled drug delivery systems.

Assessment of the effeCt of lIfestyle iNtervention plus water-soluble ciNnAMon extract On loweriNg blood glucose in pre-diabetics, a randomized, double-blind, multicenter, placebo controlled trial: study protocol for a randomized controlled trial.

PubMed

Crawford, Paul; Thai, Chuong; Obholz, Joshua; Schievenin, Jeffrey; True, Mark; Shah, Sachin A; Hallgren, John; Clark, Jill; Sharon, Danny

2016-01-05

The World Health Organization predicts that by 2030 diabetes will be the seventh leading cause of death in the world. Multiple studies have tried to determine if cinnamon is an effective treatment for diabetes. Cinnamon extract is an insulin sensitizer, protects mesangial cells, decreases inflammatory markers, and lowers glucose, lipids, and blood pressure in patients with type 2 diabetes, so we developed a protocol to study whether ingestion of water-soluble cinnamon extract prevents progression from pre-diabetes to diabetes. This is a randomized, double-blind, placebo-controlled trial comparing cinnamon extract versus placebo in subjects with pre-diabetes who have committed to participate in a lifestyle change program. The trial will be conducted at five sites and will include 428 subjects who take cinnamon extract or placebo for 1 year. Follow-up for these subjects will be for a total of 2 years (nine study visits). The primary outcomes to be assessed are 1) conversion of patients from pre-diabetes to diabetes and 2) impact of water-soluble cinnamon extract on hepatic transaminases, renal function, and QT interval on electrocardiogram. Secondary outcomes include changes in HbA1c, lipids, waist circumference, weight, blood pressure, and fasting plasma glucose. The trial protocol has been approved by the Institutional Review Board of the US Air Force 59th Medical Wing, Wilford Hall Ambulatory Surgical Center (Protocol FWH20110035H). Investigator-sponsored Investigational New Drug status (114078) was granted by the US Food and Drug Administration. This study will provide high-quality evidence of the efficacy of water-soluble cinnamon extract in conjunction with lifestyle intervention for preventing patients with pre-diabetes from converting to diabetes. Additionally, it will provide important safety information about water-soluble cinnamon extract. ClinicalTrials.gov Identifier: NCT01301521 , 18 February 2011.

High throughput method to characterize acid-base properties of insoluble drug candidates in water.

PubMed

Benito, D E; Acquaviva, A; Castells, C B; Gagliardi, L G

2018-05-30

In drug design experimental characterization of acidic groups in candidate molecules is one of the more important steps prior to the in-vivo studies. Potentiometry combined with Yasuda-Shedlovsky extrapolation is one of the more important strategy to study drug candidates with low solubility in water, although, it requires a large number of sequences to determine pK a values at different solvent-mixture compositions to, finally, obtain the pK a in water (pwwK a ) by extrapolation. We have recently proposed a method which requires only two sequences of additions to study the effect of organic solvent content in liquid chromatography mobile phases on the acidity of the buffer compounds usually dissolved in it along wide ranges of compositions. In this work we propose to apply this method to study thermodynamic pwwK a of drug candidates with low solubilities in pure water. Using methanol/water solvent mixtures we study six pharmaceutical drugs at 25 °C. Four of them: ibuprofen, salicylic acid, atenolol and labetalol, were chosen as members of carboxylic, amine and phenol families, respectively. Since these compounds have known pwwK a values, they were used to validate the procedure, the accuracy of Yasuda-Shedlovsky and other empirical models to fit the behaviors, and to obtain pwwK a by extrapolation. Finally, the method is applied to determine unknown thermodynamic pwwK a values of two pharmaceutical drugs: atorvastatin calcium and the two dissociation constants of ethambutol. The procedure proved to be simple, very fast and accurate in all of the studied cases. Copyright © 2018 Elsevier B.V. All rights reserved.

G5 PAMAM dendrimer versus liposome: a comparison study on the in vitro transepithelial transport and in vivo oral absorption of simvastatin.

PubMed

Qi, Rong; Zhang, Heran; Xu, Lu; Shen, Wenwen; Chen, Cong; Wang, Chao; Cao, Yini; Wang, Yunan; van Dongen, Mallory A; He, Bing; Wang, Siling; Liu, George; Banaszak Holl, Mark M; Zhang, Qiang

2015-07-01

This study compared formulation effects of a dendrimer and a liposome preparation on the water solubility, transepithelial transport, and oral bioavailability of simvastatin (SMV). Amine-terminated G5 PAMAM dendrimer (G5-NH2) was chosen to form SMV/G5-NH2 molecular complexes, and SMV-liposomes were prepared by using a thin film dispersion method. The effects of these preparations on the transepithelial transport were investigated in vitro using Caco-2 cell monolayers. Results indicated that the solubility and transepithelial transport of SMV were significantly improved by both formulations. Pharmacokinetic studies in rats also revealed that both the SMV/G5-NH2 molecular complexes and the SMV-liposomes significantly improved the oral bioavailability of SMV with the liposomes being more effective than the G5-NH2. The overall better oral absorption of SMV-liposomes as compared to SMV/G5-NH2 molecular complexes appeared to arise from better liposomal solubilization and encapsulation of SMV and more efficient intracellular SMV delivery. Various carrier systems have been designed to enhance drug delivery via the oral route. In this study, the authors compared G5 PAMAM dendrimers to liposome preparations in terms of solubility, transepithelial transport, and oral bioavailability of this poorly water-soluble drug. This understanding has improved our knowledge in the further development of drug carrier systems. Copyright © 2015 Elsevier Inc. All rights reserved.

Predictability of drug release from water-insoluble polymeric matrix tablets.

PubMed

Grund, Julia; Körber, Martin; Bodmeier, Roland

2013-11-01

The purpose of this study was to extend the predictability of an established solution of Fick's second law of diffusion with formulation-relevant parameters and including percolation theory. Kollidon SR (polyvinyl acetate/polyvinylpyrrolidone, 80/20 w/w) matrix tablets with various porosities (10-30% v/v) containing model drugs with different solubilities (Cs=10-170 mg/ml) and in different amounts (A=10-90% w/w) were prepared by direct compression and characterized by drug release and mass loss studies. Drug release was fitted to Fick's second law to obtain the apparent diffusion coefficient. Its changes were correlated with the total porosity of the matrix and the solubility of the drug. The apparent diffusion coefficient was best described by a cumulative normal distribution over the range of total porosities. The mean of the distribution coincided with the polymer percolation threshold, and the minimum and maximum of the distribution were represented by the diffusion coefficient in pore-free polymer and in aqueous medium, respectively. The derived model was verified, and the applicability further extended to a drug solubility range of 10-1000 mg/ml. The developed mathematical model accurately describes and predicts drug release from Kollidon SR matrix tablets. It can efficiently reduce experimental trials during formulation development. Copyright © 2013 Elsevier B.V. All rights reserved.

Dual Activity of Hydroxypropyl-β-Cyclodextrin and Water-Soluble Carriers on the Solubility of Carvedilol.

PubMed

Zoghbi, Abdelmoumin; Geng, Tianjiao; Wang, Bo

2017-11-01

Carvedilol (CAR) is a non-selective α and β blocker categorized as class II drug with low water solubility. Several recent studies have investigated ways to overcome this problem. The aim of the present study was to combine two of these methods: the inclusion complex using hydroxypropyl-β-cyclodextrin (HPβCD) with solid dispersion using two carriers: Poloxamer 188 (PLX) and Polyvinylpyrrolidone K-30 (PVP) to enhance the solubility, bioavailability, and the stability of CAR. Kneading method was used to prepare CAR-HPβCD inclusion complex (KD). The action of different carriers separately and in combination on Carvedilol solubility was investigated in three series. CAR-carrier and KD-carrier solid dispersions were prepared by solvent evaporation method. In vitro dissolution test was conducted in three different media: double-distilled water (DDW), simulative gastric fluid (SGF), and PBS pH 6.8 (PBS). The interactions between CAR, HPβCD, and different carriers were explored by Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometry (XRD), and differential scanning colorimetry (DSC). The results showed higher solubility of CAR in KD-PVP solid dispersions up to 70, 25, and 22 fold compared to pure CAR in DDW, SGF, and PBS, respectively. DSC and XRD analyses indicated an improved degree of transformation of CAR in KD-PVP solid dispersion from crystalline to amorphous state. This study provides a new successful combination of two polymers with the dual action of HPβCD and PLX/PVP on water solubility and bioavailability of CAR.

Cocrystal Transition Points: Role of Cocrystal Solubility, Drug Solubility, and Solubilizing Agents.

PubMed

Lipert, Maya P; Rodríguez-Hornedo, Naír

2015-10-05

In this manuscript we bring together concepts that are relevant to the solubilization and thermodynamic stability of cocrystals in the presence of drug solubilizing agents. Simple equations are derived that allow calculation of cocrystal solubilization and transition point solubility. Analysis of 10 cocrystals in 6 different solubilizing agents shows that cocrystal solubilization is quantitatively predicted from drug solubilization. Drug solubilizing agents such as surfactants and lipid-based media are also shown to induce cocrystal transition points, where drug and cocrystal solubilities are equal, and above which the cocrystal solubility advantage over drug is eliminated. We have discovered that cocrystal solubility at the transition point (S*) is independent of solubilizing agent, and can be predicted from knowledge of only the aqueous solubilities of drug and cocrystal. For 1:1 cocrystals, S* = (Scocrystal,aq)(2)/Sdrug,aq. S* is a key indicator of cocrystal thermodynamic stability and establishes the upper solubility limit below which cocrystal is more soluble than the constituent drug. These findings have important implications to tailor cocrystal solubility and stability in pharmaceutical formulations from commonly available drug solubility descriptors.

APTES-modified mesoporous silicas as the carriers for poorly water-soluble drug. Modeling of diflunisal adsorption and release

NASA Astrophysics Data System (ADS)

Geszke-Moritz, Małgorzata; Moritz, Michał

2016-04-01

Four mesoporous siliceous materials such as SBA-16, SBA-15, PHTS and MCF functionalized with (3-aminopropyl)triethoxysilane were successfully prepared and applied as the carriers for poorly water-soluble drug diflunisal. Several techniques including nitrogen sorption analysis, XRD, TEM, FTIR and thermogravimetric analysis were employed to characterize mesoporous matrices. Adsorption isotherms were analyzed using Langmuir, Freundlich, Temkin and Dubinin-Radushkevich models. In order to find the best-fit isotherm for each model, both linear and nonlinear regressions were carried out. The equilibrium data were best fitted by the Langmuir isotherm model revealing maximum adsorption capacity of 217.4 mg/g for aminopropyl group-modified SBA-15. The negative values of Gibbs free energy change indicated that the adsorption of diflunisal is a spontaneous process. Weibull release model was employed to describe the dissolution profile of diflunisal. At pH 4.5 all prepared mesoporous matrices exhibited the improvement of drug dissolution kinetics as compared to the dissolution rate of pure diflunisal.

How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?

PubMed Central

Watanabe, Kazutoshi; Tanaka, Masahiko; Yuki, Satoshi; Hirai, Manabu; Yamamoto, Yorihiro

2018-01-01

Edaravone is a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS. PMID:29371752

An in-vitro evaluation of silicone elastomer latex for topical drug delivery.

PubMed

Li, L C; Vu, N T

1995-06-01

A silicone elastomer latex was evaluated as a topical drug-delivery system. With the addition of a fumed silica and the removal of water, the latex produced elastomeric solid films. The water vapour permeability of the solid film was found to be a function of the film composition. An increase in silica content and the incorporation of a water-soluble component, PEG 3350, rendered the silicone elastomer-free film even more permeable to water vapour. The release of hydrocortisone from the elastomer film can be described by a matrix-diffusion-controlled mechanism. Drug diffusion is thought to occur through the hydrophobic silicone polymer network and the hydrated hydrophilic silica region in the film matrix. Silicone elastomer film with a higher silica content exhibited a faster drug-release rate. The addition of PEG 3350 to the film further enhanced the drug-release rate.

The preparation by extrusion/spheronization and the properties of pellets containing drugs, microcrystalline cellulose and glyceryl monostearate.

PubMed

Chatchawalsaisin, Jittima; Podczeck, Fridrun; Newton, J Michael

2005-01-01

Pellets have been prepared by extrusion and spheronization containing microcrystalline cellulose (MCC) and four model drugs with decreasing order of solubility, paracetamol (P), diclofenac sodium (D), ibuprofen (IB) and indomethacin (IN) at a 10% level with and without the addition of a range of levels of glyceryl monostearate (GMS). The drugs differed in their response to extrusion in that all formulations containing the drug D had a 'steady state' extrusion profile whereas the other three drugs exhibited 'forced flow' indicating the possibility of water migration during the process of ram extrusion. The presence of GMS did not influence this effect. The drug D also required consistently less water to function than the other three drugs. In spite of these differences in extrusion performance, it was possible to prepare satisfactory pellets from formulations of all the drugs with 0, 30 and 60% GMS combined with 90, 60 or 30% of MCC at a range of water levels. It was also possible to prepare pellets containing the drug D with 70, 80 and 90% GMS, with corresponding quantities of 20, 10 and 0% of MCC. It was also possible to prepare the pellet formulations by dispersing the drugs in molten GMS, grinding and processing this with MCC and water. Such systems retained the processing characteristics of the composition made by the blending of the powder. The presence of GMS in all cases reduced the quantity of water required for the process to function. The steady state or the mean of the range of the forces observed during forced flow, were dependent on the composition and the quantity of water added. The surface of the extrudate appeared smooth and measurements of surface roughness established that the value of the rugosity R(a) for any of the extrudates did not exceed 6 microm. The extrudate diameter was found to increase with the quantity of GMS in the formulation. The pellets produced were all within a relatively narrow size range (three sieve fractions of a root two progression), the median value of which increased with the level of GMS. For the drug D, there was a linear increase of pellet diameter with increase in the extrudate diameter. For the three other drugs this relationship was less certain but nevertheless there was a similar trend for the pellet diameter to increase as the extrudate diameter increased, suggesting the mechanism of the process is the same irrespective of the composition. Considering the value of the shape factor e(R), all the pellets produced from the various formulations were well within acceptable levels for further processing and the only observable trend in the values was that the formulations with the lower water contents were the least round. The porosity of the pellets of the different formulations generally decreased with the increase in water used to prepare the pellets, the extent of this decrease being dependent on the drug and the level of GMS. The in vitro drug release from the pellets was controlled by the solubility of the drug, the lower the value of the solubility, the longer the mean dissolution time (MDT). This was not influenced by the presence of GMS or the method of incorporation of the drug into the formulation.

Microemulsion Transdermal Formulation for Simultaneous Delivery of Valsartan and Nifedipine: Formulation by Design.

PubMed

Sood, Jatin; Sapra, Bharti; Tiwary, Ashok K

2017-08-01

The objective of the study was to optimize the proportion of different components for formulating oil in water microemulsion formulation meant for simultaneous transdermal delivery of two poorly soluble antihypertensive drugs. Surface response methodology of Box-Behnken design was utilized to evaluate the effect of two oils (Captex 500 - x1 and Capmul MCM - x2) and surfactant (Acrysol EL135 - x3) on response y1 (particle size), y2 (solubility of valsartan), and y3 (solubility of nifedipine). The important factors which significantly affected the responses were identified and validated using ANOVA. The model was diagnosed using normal plot of residuals and Box-Cox plot. The design revealed an inverse correlation between particle size and concentration of Capmul MCM and Acrysol EL 135. However, an increase in concentration of Captex 500 led to an increase in particle size of microemulsion. Solubility of valsartan decreased while that of nifedipine increased with increase in concentration of Captex 500. Capmul MCM played a significant role in increasing the solubility of valsartan. The effect of Acrysol EL 135 on solubility of both drugs, although significant, was only marginal as compared to that of Captex 500 and Capmul MCM. The optimized microemulsion was able to provide an enhancement ratio of 27.21 and 63.57-fold for valsartan and nifedipine, respectively, with respect to drug dispersion in aqueous surfactant system when evaluated for permeation studies. The current studies candidly suggest the scope of microemulsion systems for solubilizing as well as promoting the transport of both drugs across rat skin at an enhanced permeation rate.

Biopharmaceutics classification of puerarin and comparison of perfusion approaches in rats.

PubMed

Li, Hewei; Dong, Ling; Liu, Yang; Wang, Guopeng; Wang, Gang; Qiao, Yanjiang

2014-05-15

The present study was conducted to characterize the biopharmaceutics classification system (BCS) category of puerarin in terms of intrinsic dissolution rate (IDR) and rat intestinal permeability and to investigate the poor intestinal absorption probably related to the drug metabolism in the gut wall of rats. Equilibrium solubility of puerarin was determined in various phosphate buffers and water, and IDR was estimated by measuring the dissolution of a non-disintegrating compact. Intestinal permeability (Peff and Pblood) of puerarin was determined using the technology of in situ single-pass intestinal perfusion (SPIP) and intestinal perfusion with venous sampling (IPVS) in fasted rats. Metabolism of puerarin in intestinal tissue was tested by S9 incubation in vitro. The aqueous solubility of puerarin in phosphate buffers and water was good with a maximum solubility of 7.56 mg/mL at pH 7.4. Obtained IDR values of puerarin were in the range of 0.360-1.088 mg/min/cm(2), with maximum and minimum IDR value of pH 7.4 and pH 4.0, respectively. The Peff was 1.252 × 10(-5)cm/s determined by SPIP and the Pblood was 0.068×10(-5)cm/s by IPVS in jejunum at puerarin 80 μg/mL. The metabolism rate of puerarin determined by the intestinal S9 fraction indicated that the gut wall metabolism of puerarin is one cause of poor absorption. According to the proposed classification of drugs and the results obtained from equilibrium solubility, IDR, Peff and Pblood, it is concluded that puerarin could be categorized IV drug of the BCS based on its low solubility and low intestinal permeability values. Copyright © 2014 Elsevier B.V. All rights reserved.

Drug loading into beta-cyclodextrin granules using a supercritical fluid process for improved drug dissolution.

PubMed

Hussein, Khaled; Türk, Michael; Wahl, Martin A

2008-03-03

To improve dissolution properties of drugs, a supercritical fluid (SCF) technique was used to load these drugs into a solid carrier. In this study, granules based on beta-cyclodextrin (betaCD) were applied as a carrier for poor water-soluble drug and loaded with a model drug (ibuprofen) using two different procedures: controlled particle deposition (CPD), SCF process and solution immersion (SI) as a conventional method for comparison. Using the CPD technique, 17.42+/-2.06wt.% (n=3) ibuprofen was loaded into betaCD-granules, in contrast to only 3.8+/-0.15wt.% (n=3) in the SI-product. The drug loading was confirmed as well by reduction of the BET surface area for the CPD-product (1.134+/-0.07m(2)/g) compared to the unloaded-granules (1.533+/-0.031m(2)/g). Such a reduction was not seen in the SI-product (1.407+/-0.048m(2)/g). The appearance of an endothermic melting peak at 77 degrees C and X-ray patterns representing ibuprofen in drug-loaded granules can be attributed to the amount of ibuprofen loaded in its crystalline form. A significant increase in drug dissolution was achieved by either drug-loading procedures compared to the unprocessed ibuprofen. In this study, the CPD technique, a supercritical fluid process avoiding the use of toxic or organic solvents was successfully applied to load drug into solid carriers, thereby improving the water-solubility of the drug.

Using Environment-Sensitive Fluorescent Probes to Characterize Liquid-Liquid Phase Separation in Supersaturated Solutions of Poorly Water Soluble Compounds.

PubMed

Raina, Shweta A; Alonzo, David E; Zhang, Geoff G Z; Gao, Yi; Taylor, Lynne S

2015-11-01

Highly supersaturated aqueous solutions of poorly soluble compounds can undergo liquid-liquid phase separation (LLPS) when the concentration exceeds the "amorphous solubility". This phenomenon has been widely observed during high throughput screening of new molecular entities as well as during the dissolution of amorphous solid dispersions. In this study, we have evaluated the use of environment-sensitive fluorescence probes to investigate the formation and properties of the non-crystalline drug-rich aggregates formed in aqueous solutions as a result of LLPS. Six different environment-sensitive fluorophores were employed to study LLPS in highly supersaturated solutions of several model compounds, all dihydropyridine derivatives. Each fluoroprobe exhibited a large hypsochromic shift with decreasing environment polarity. Upon drug aggregate formation, the probes partitioned into the drug-rich phase and exhibited changes in emission wavelength and intensity consistent with sensing a lower polarity environment. The LLPS onset concentrations determined using the fluorescence measurements were in good agreement with light scattering measurements as well as theoretically estimated amorphous solubility values. Environment-sensitive fluorescence probes are useful to help understand the phase behavior of highly supersaturated aqueous solutions, which in turn is important in the context of developing enabling formulations for poorly soluble compounds.

A novel solubility-modulated granules through porosity osmotic pump for controlled carvedilol delivery.

PubMed

Song, Qun-Li; Li, Ping; Li, Yu-Min

2012-01-01

A method for the preparation of porosity osmotic pump granules was obtained by modulating carvedilol solubility with tartaric acid. Controlled porosity of the membrane was accomplished by the use of pore-forming agent in the coating. In this study, carvedilol was chosen as a model drug with an aim to develop a zero-order release system; tartaric acid was used as the solubility promoter; NaCl was used as the osmotic agent; cellulose acetate (CA) was used as the materials of semipermeable membrane; and PEG-400 was used as the pore-forming agent in the semipermeable membrane. The influence of different factors or levels on the in vitro release was studied. In order to simulate the gastrointestinal tract environments, two kinds of pH media (pH 1.5 and 6.8) on drug release were studied in this research, respectively. This porosity osmotic pump was optimized by single factor design experiments, and it was found to deliver carvedilol at a zero-order rate within 12 h and controlled release for 24 h. We drew a conclusion that the solubility-modulated porosity osmotic pump system is simple to prepare and might be used for the preparation of osmotic pump system of other poorly water-soluble drugs with alkaline or acid groups.

Novel furosemide cocrystals and selection of high solubility drug forms.

PubMed

Goud, N Rajesh; Gangavaram, Swarupa; Suresh, Kuthuru; Pal, Sharmistha; Manjunatha, Sulur G; Nambiar, Sudhir; Nangia, Ashwini

2012-02-01

Furosemide was screened in cocrystallization experiments with pharmaceutically acceptable coformer molecules to discover cocrystals of improved physicochemical properties, that is high solubility and good stability. Eight novel equimolar cocrystals of furosemide were obtained by liquid-assisted grinding with (i) caffeine, (ii) urea, (iii) p-aminobenzoic acid, (iv) acetamide, (v) nicotinamide, (vi) isonicotinamide, (vii) adenine, and (viii) cytosine. The product crystalline phases were characterized by powder x-ray diffraction, differential scanning calorimetry, infrared, Raman, near IR, and (13) C solid-state NMR spectroscopy. Furosemide-caffeine was characterized as a neutral cocrystal and furosemide-cytosine an ionic salt by single crystal x-ray diffraction. The stability of furosemide-caffeine, furosemide-adenine, and furosemide-cytosine was comparable to the reference drug in 10% ethanol-water slurry; there was no evidence of dissociation of the cocrystal to furosemide for up to 48 h. The other five cocrystals transformed to furosemide within 24 h. The solubility order for the stable forms is furosemide-cytosine > furosemide-adenine > furosemide-caffeine, and their solubilities are approximately 11-, 7-, and 6-fold higher than furosemide. The dissolution rates of furosemide cocrystals were about two times faster than the pure drug. Three novel furosemide compounds of higher solubility and good phase stability were identified in a solid form screen. Copyright © 2011 Wiley Periodicals, Inc.

Product development studies of amino acid conjugate of Aceclofenac.

PubMed

Singh, Ajay Pal; Ramadan, Wafa Mossa; Dahiya, Rajiv; Sarpal, A S; Pathak, Kamla

2009-04-01

The prodrugs designed by classical approach increase lipophilicity of the drug, which decreases the water solubility thus decreasing the concentration gradient, which controls drug absorption. To overcome the limitations of traditional prodrug approach, water soluble prodrugs can be designed by adding selected amino acid to the drug moiety that are the substrates for the enzyme located at the intestinal brush border thus overcoming pharmaceutical problem without compromising bioavailability. ACaa (Amino acid conjugate of Aceclofenac) was synthesized by conjugation with l-phenylalanine by conventional coupling method using N, N-dicyclohexylcarbodiimide and ACaa was characterized by melting point, TLC, photomicrograph, UV, FT-IR, FT-NMR, MS-FAB, XRD and DSC. As a part of product development study ACaa was subjected to studies like In-vivo in albino rats and in-vitro like ACaa reversion to AC (Aceclofenac) in aqueous buffers of pH 1.21, 2.38. 3.10, 6.22 and 7.41, at a constant concentration (0.05M), ionic strength (micro = 0.5) and at a temperature of 37 degrees C +/- 0.5 degrees C, ACaa showed negligible reversion (2.15 %) up to 24 hrs study at acidic pH thus suggesting stability in acidic environment of stomach, the rate of reversion increased as pH of medium increased. pH- partition profile, pH- solubility profile and micromeritic studies were also carried out in comparison to pure drug. The solubility and lipophilicity of ACaa exhibited higher values at all pH range when compared to AC. The micromeritic properties also evaluated in terms of particle shape and size, IQCS and kurtosis. Resulting IQCS value approached zero thus suggesting reducing in the degree of skewness.

Water soluble biocompatible vesicles based on polysaccharides and oligosaccharides inclusion complexes for carotenoid delivery.

PubMed

Polyakov, Nikolay E; Kispert, Lowell D

2015-09-05

Since carotenoids are highly hydrophobic, air- and light-sensitive hydrocarbon compounds, developing methods for increasing their bioavailability and stability towards irradiation and reactive oxygen species is an important goal. Application of inclusion complexes of "host-guest" type with polysaccharides and oligosaccharides such as arabinogalactan, cyclodextrins and glycyrrhizin minimizes the disadvantages of carotenoids when these compounds are used in food processing (colors and antioxidant capacity) as well as for production of therapeutic formulations. Cyclodextrin complexes which have been used demonstrated enhanced storage stability but suffered from poor solubility. Polysaccharide and oligosaccharide based inclusion complexes play an important role in pharmacology by providing increased solubility and stability of lipophilic drugs. In addition they are used as drug delivery systems to increase absorption rate and bioavailability of the drugs. In this review we summarize the existing data on preparation methods, analysis, and chemical reactivity of carotenoids in inclusion complexes with cyclodextrin, arabinogalactan and glycyrrhizin. It was demonstrated that incorporation of carotenoids into the "host" macromolecule results in significant changes in their physical and chemical properties. In particular, polysaccharide complexes show enhanced photostability of carotenoids in water solutions. A significant decrease in the reactivity towards metal ions and reactive oxygen species in solution was also detected. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multicomponent amorphous nanofibers electrospun from hot aqueous solutions of a poorly soluble drug.

PubMed

Yu, Deng-Guang; Gao, Li-Dong; White, Kenneth; Branford-White, Christopher; Lu, Wei-Yue; Zhu, Li-Min

2010-11-01

To design and fabricate multicomponent amorphous electrospun nanofibers for synergistically improving the dissolution rate and permeation profiles of poorly water-soluble drugs. Nanofibers were designed to be composed of a poorly water soluble drug, helicid, a hydrophilic polymer polyvinylpyrrolidone as filament-forming matrix, sodium dodecyl sulfate as transmembrane enhancer and mannitol as taste masking agent, and were prepared from hot aqueous co-dissolving solutions of them. An elevated temperature electrospinning process was developed to fabricate the composite nanofibers, which were characterized using FESEM, DSC, XRD, ATR-FTIR, in vitro dissolution and permeation tests. The composite nanofibers were homogeneous with smooth surfaces and uniform structure, and the components were combined together in an amorphous state because of the favorable interactions such as hydrogen bonding, electrostatic interaction and hydrophobic interactions among them. In vitro dissolution and permeation tests demonstrated that the composite nanofibers had a dissolution rate over 26-fold faster than that of crude helicid particles and a 10-fold higher permeation rate across sublingual mucosa. A new type of amorphous material in the form of nanofibers was prepared from hot aqueous solutions of multiple ingredients using an electrospinning process. The amorphous nanofibers were able to improve the dissolution rate and permeation rate of helicid.

Preparation, characterization and in vitro evaluation of microemulsion of raloxifene hydrochloride.

PubMed

Golmohammadzadeh, Shiva; Farhadian, Nafiseh; Biriaee, Amir; Dehghani, Faranak; Khameneh, Bahman

2017-10-01

Raloxifene hydrochloride (RLX) is a selective estrogen receptor modulator which is orally used for treatment of osteoporosis and prevention of breast cancer. The drug has low aqueous solubility and bioavailability. The aim of the present study is to formulate and characterize oil-in-water microemulsion systems for oral delivery of RLX. To enhance the drug aqueous solubility, microemulsion based on sesame oil was prepared. Sesame oil and Tween 80 were selected as the drug solvent oil and surfactant, respectively. In the first and second formulations, Edible glycerin and Span 80 were applied as co-surfactant, respectively. Pseudo-ternary phase diagrams showed that the best surfactant/co-surfactant ratios in the first and second formulations were 4:1 and 9:1, respectively. The particle size of all free drug-loaded and drug loaded samples were in the range of 31.25 ± 0.3 nm and 60.9 ± 0.1 nm, respectively. Electrical conductivity coefficient and refractive index of all microemulsion samples confirmed the formation of oil-in-water type of microemulsion. In vitro drug release profile showed that after 24 hours, 46% and 63% of the drug released through the first formulation in 0.1% (w/v) Tween 80 in distilled water as a release medium and phosphate buffer solution (PBS) at pH = 5.5, respectively. These values were changed to 57% and 98% for the second formulation. Results confirmed that the proposed microemulsion system containing RLX could improve and control the drug release profile in comparison to conventional dosage form.

Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D

PubMed Central

Ke, Zhongcheng; Hou, Xuefeng; Jia, Xiao-bin

2016-01-01

Background The main purpose of this research was to design a self-nanoemulsifying drug delivery system (SNEDDS) for improving the bioavailability of cyclovirobuxine D as a poorly water-soluble drug. Materials and methods Solubility trials, emulsifying studies, and pseudo-ternary phase diagrams were used to screen the SNEDDS formulations. The optimized drug-loaded SNEDDS was prepared at a mass ratio of 3:24:38:38 for cyclovirobuxine D, oleic acid, Solutol SH15, and propylene glycol, respectively. The optimized formulation was characterized in terms of physicochemical and pharmacokinetic parameters compared with marketed cyclovirobuxine D tablets. Results The optimized cyclovirobuxine-D-loaded SNEDDS was spontaneously dispersed to form a nanoemulsion with a globule size of 64.80±3.58 nm, which exhibited significant improvement of drug solubility, rapid absorption rate, and enhanced area under the curve, together with increased permeation and decreased efflux. Fortunately, there was a nonsignificant cytotoxic effect toward Caco-2 cells. The relative bioavailability of SNEDDS was 200.22% in comparison with market tablets, in rabbits. Conclusion SNEDDS could be a potential candidate for an oral dosage form of cyclovirobuxine D with improved bioavailability. PMID:27418807

Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis.

PubMed

Murdande, Sharad B; Pikal, Michael J; Shanker, Ravi M; Bogner, Robin H

2010-03-01

In recent years there has been growing interest in advancing amorphous pharmaceuticals as an approach for achieving adequate solubility. Due to difficulties in the experimental measurement of solubility, a reliable estimate of the solubility enhancement ratio of an amorphous form of a drug relative to its crystalline counterpart would be highly useful. We have developed a rigorous thermodynamic approach to estimate enhancement in solubility that can be achieved by conversion of a crystalline form to the amorphous form. We rigorously treat the three factors that contribute to differences in solubility between amorphous and crystalline forms. First, we calculate the free energy difference between amorphous and crystalline forms from thermal properties measured by modulated differential scanning calorimetry (MDSC). Secondly, since an amorphous solute can absorb significant amounts of water, which reduces its activity and solubility, a correction is made using water sorption isotherm data and the Gibbs-Duhem equation. Next, a correction is made for differences in the degree of ionization due to differences in solubilities of the two forms. Utilizing this approach the theoretically estimated solubility enhancement ratio of 7.0 for indomethacin (amorphous/gamma-crystal) was found to be in close agreement with the experimentally determined ratio of 4.9. 2009 Wiley-Liss, Inc. and the American Pharmacists Association

Drug-nutrient interaction.

PubMed

Matsui, M S; Rozovski, S J

1982-01-01

The effect of certain drugs on nutrient metabolism is discussed. Antituberculotic drugs such as INH and cycloserine interfere with vitamin B6 metabolism and may produce a secondary niacin deficiency. Oral contraceptives interfere with the metabolism of folic acid and ascorbic acid, and in cases of deficient nutrition, they also seem to interfere with riboflavin. Anticonvulsants can act as folate antagonists and precipitate folic acid deficiency. Therefore, in some cases, supplementation with folate has been recommended simultaneously with anticonvulsant therapy. Cholestyramine therapy has been associated with malabsorption of vitamins; several reports suggest that cholestyramine affects absorption of the fat-soluble vitamins K and D and, in addition, may alter water-soluble vitamins, including folic acid. The study of the interaction of drugs and nutrients is an area that deserves a greater attention in the future, especially in groups where nutrient deficiencies may be prevalent.

Molecularly designed water soluble, intelligent, nanosize polymeric carriers.

PubMed

Pişkin, Erhan

2004-06-11

Intelligent polymers, also referred as "stimuli-responsive polymers" undergo strong property changes (in shape, surface characteristics, solubility, etc.) when only small changes in their environment (changes in temperature, pH, ionic strength light, electrical and magnetic field, etc.). They have been used in several novel applications, drug delivery systems, tissue engineering scaffolds, bioseparation, biomimetic actuators, etc. The most popular member of these type of polymers is poly(N-isopropylacrylamide) (poly(NIPA)) which exhibits temperature-sensitive character, in which the polymer chains change from water-soluble coils to water-insoluble globules in aqueous solution as temperature increases above the lower critical solution temperature (LCST) of the polymer. Copolymerization of NIPA with acrylic acid (AAc) allows the synthesis of both pH and temperature-responsive copolymers. This paper summarizes some of our related studies in which NIPA and its copolymers were synthesized and used as intelligent carriers in diverse applications.

Feasibility of Using Gluconolactone, Trehalose and Hydroxy-Propyl Gamma Cyclodextrin to Enhance Bendroflumethiazide Dissolution Using Lyophilisation and Physical Mixing Techniques.

PubMed

Saleh, Ashraf; McGarry, Kenneth; Chaw, Cheng Shu; Elkordy, Amal Ali

2018-02-01

Hydrophobic drugs are facing a major challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been used to improve dissolution rate and/or solubility of bendroflumethiazide as a model hydrophobic drug. In this study, two main methods (physical mixing and lyophilisation) were used with gluconolactone, hydroxyl propyl γ-ccyclodextrin, and trehalose to explore this challenge. Bendroflumethiazide, practically insoluble in water, was mixed with one of the three excipients gluconolactone, hydroxyl propyl γ-cyclodextrin, and trehalose in three different ratios 1:1, 1:2, 1:5. To the best of our knowledge, the dissolution of the drug has not been previously enhanced by using either these methods or any of the used excipients. Samples containing drug and each of the excipients were characterized via dissolution testing, Fourier Transform infra-red spectroscopy, differential scanning calorimetry, and scanning electron microscopy. The used methods showed a significant enhancement in dug dissolution rate; physical mixing significantly, p < 0.05, increased the percentage of the drug released with time; for example, bendroflumethiazide dissolution in distilled water was improved from less than 20% to 99.79% within 90 min for physically mixed drug-cyclodextrin 1:5. The lyophilisation process was enhanced and the drug dissolution rate and the highest drug dissolution was achieved for (drug-gluconolactone 1:1) with 98.98% drug release within 90 min. the physical mixing and freeze drying processes significantly increased the percentage of drug release with time.

Waterborne Electrospinning of Poly(N-isopropylacrylamide) by Control of Environmental Parameters.

PubMed

Schoolaert, Ella; Ryckx, Paulien; Geltmeyer, Jozefien; Maji, Samarendra; Van Steenberge, Paul H M; D'hooge, Dagmar R; Hoogenboom, Richard; De Clerck, Karen

2017-07-19

With increasing toxicity and environmental concerns, electrospinning from water, i.e., waterborne electrospinning, is crucial to further exploit the resulting nanofiber potential. Most water-soluble polymers have the inherent limitation of resulting in water-soluble nanofibers, and a tedious chemical cross-linking step is required to reach stable nanofibers. An interesting alternative route is the use of thermoresponsive polymers, such as poly(N-isopropylacrylamide) (PNIPAM), as they are water-soluble beneath their lower critical solution temperature (LCST) allowing low-temperature electrospinning while the obtained nanofibers are water-stable above the LCST. Moreover, PNIPAM nanofibers show major potential to many application fields, including biomedicine, as they combine the well-known on-off switching behavior of PNIPAM, thanks to its LCST, with the unique properties of nanofibers. In the present work, based on dedicated turbidity and rheological measurements, optimal combinations of polymer concentration, environmental temperature, and relative humidity are identified allowing, for the first time, the production of continuous, bead-free PNIPAM nanofibers electrospun from water. More specifically, PNIPAM gelation was found to occur well below its LCST at higher polymer concentrations leading to a temperature regime where the viscosity significantly increases without compromising the polymer solubility. This opens up the ecological, water-based production of uniform PNIPAM nanofibers that are stable in water at temperatures above PNIPAM's LCST, making them suitable for various applications, including drug delivery and switchable cell culture substrates.

Investigation of novel supersaturating drug delivery systems of chlorthalidone: The use of polymer-surfactant complex as an effective carrier in solid dispersions.

PubMed

França, Maria Terezinha; Nicolay Pereira, Rafael; Klüppel Riekes, Manoela; Munari Oliveira Pinto, Juliana; Stulzer, Hellen Karine

2018-01-01

Supersaturating drug delivery systems (SDDS), as solid dispersions (SDs), stand out among strategies to enhance bioavailability of poorly soluble drugs. After oral administration, their dissolution in gastrointestinal fluids often leads to supersaturation, which drives to a rapid and sustained absorption. Polymers and surfactants play important roles in SDs through inhibiting precipitation caused by transitions from amorphous into crystalline form, in supersaturated solutions, and also through improving SDs physical stability. Novel chlorthalidone SDs, a BCS IV drug, were developed using polymeric and non-polymeric carriers, specially a polymer-surfactant complex. SDs drug releases were evaluated using sink and non-sink conditions in water and biorelevant medium. Their physical stability was also monitored under different storage conditions. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL), sodium lauryl sulfate (SLS) and a combination of both showed promising results in apparent solubility studies, and therefore they were selected to compose the spray dried SDs. Dissolution studies demonstrated the SOL-SLS complex potential for providing chlorthalidone fast release (>80% in 15min), producing and maintaining in vitro supersaturation. This formulation comprising high drug loading (75%) reached a high supersaturation degree under non-sink condition (up to 6-fold the equilibrium solubility) once maintained for 6h in biorelevant medium. In addition, this SD presented better physical stability when compared to the chlorthalidone neat amorphous. The SOL-SLS complex impacts positively on chlorthalidone release and physical stability, highlighting its potential as carrier in SDDS of a poorly soluble drug. Copyright © 2017. Published by Elsevier B.V.

Unintended and in situ amorphisation of pharmaceuticals.

PubMed

Priemel, P A; Grohganz, H; Rades, T

2016-05-01

Amorphisation of poorly water-soluble drugs is one approach that can be applied to improve their solubility and thus their bioavailability. Amorphisation is a process that usually requires deliberate external energy input. However, amorphisation can happen both unintentionally, as in process-induced amorphisation during manufacturing, or in situ during dissolution, vaporisation, or lipolysis. The systems in which unintended and in situ amorphisation has been observed normally contain a drug and a carrier. Common carriers include polymers and mesoporous silica particles. However, the precise mechanisms by which in situ amorphisation occurs are often not fully understood. In situ amorphisation can be exploited and performed before administration of the drug or possibly even within the gastrointestinal tract, as can be inferred from in situ amorphisation observed during in vitro lipolysis. The use of in situ amorphisation can thus confer the advantages of the amorphous form, such as higher apparent solubility and faster dissolution rate, without the disadvantage of its physical instability. Copyright © 2015 Elsevier B.V. All rights reserved.

Impact of Dendrimers on Solubility of Hydrophobic Drug Molecules

PubMed Central

Choudhary, Sonam; Gupta, Lokesh; Rani, Sarita; Dave, Kaushalkumar; Gupta, Umesh

2017-01-01

Adequate aqueous solubility has been one of the desired properties while selecting drug molecules and other bio-actives for product development. Often solubility of a drug determines its pharmaceutical and therapeutic performance. Majority of newly synthesized drug molecules fail or are rejected during the early phases of drug discovery and development due to their limited solubility. Sufficient permeability, aqueous solubility and physicochemical stability of the drug are important for achieving adequate bioavailability and therapeutic outcome. A number of different approaches including co-solvency, micellar solubilization, micronization, pH adjustment, chemical modification, and solid dispersion have been explored toward improving the solubility of various poorly aqueous-soluble drugs. Dendrimers, a new class of polymers, possess great potential for drug solubility improvement, by virtue of their unique properties. These hyper-branched, mono-dispersed molecules have the distinct ability to bind the drug molecules on periphery as well as to encapsulate these molecules within the dendritic structure. There are numerous reported studies which have successfully used dendrimers to enhance the solubilization of poorly soluble drugs. These promising outcomes have encouraged the researchers to design, synthesize, and evaluate various dendritic polymers for their use in drug delivery and product development. This review will discuss the aspects and role of dendrimers in the solubility enhancement of poorly soluble drugs. The review will also highlight the important and relevant properties of dendrimers which contribute toward drug solubilization. Finally, hydrophobic drugs which have been explored for dendrimer assisted solubilization, and the current marketing status of dendrimers will be discussed. PMID:28559844

MACROMOLECULAR THERAPEUTICS

PubMed Central

Yang, Jiyuan; Kopeček, Jindřich

2014-01-01

This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines – (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. PMID:24747162

Physicochemical characterization of atorvastatin calcium/ezetimibe amorphous nano-solid dispersions prepared by electrospraying method.

PubMed

Jahangiri, Azin; Barzegar-Jalali, Mohammad; Javadzadeh, Yousef; Hamishehkar, Hamed; Adibkia, Khosro

2017-09-01

In the present study, electrospraying was applied as a novel method for the fabrication of amorphous nano-solid dispersions (N-SDs) of atorvastatin calcium (ATV), ezetimibe (EZT), and ATV/EZT combination as poorly water-soluble drugs. N-SDs were prepared using polyvinylpyrrolidone K30 as an amorphous carrier in 1:1 and 1:5 drug to polymer ratios and the total solid (including drug and polymer) concentrations of 10 and 20% (w/v). The prepared formulations were further investigated for their morphological, physicochemical, and dissolution properties. Scanning electron microscopy studies indicated that the morphology and diameter of the electrosprayed samples (ESs) were influenced by the solution concentration and drug:polymer ratio, so that an increase in the solution concentration resulted in fiber formation while an increase in the polymer ratio led to enhancement of the particle diameter. Differential scanning calorimetry and X-ray powder diffraction studies together with in vitro dissolution test revealed that the ESs were present in an amorphous form with improved dissolution properties. Infrared spectroscopic studies showed hydrogen-bonding interaction between the drug and polymer in ESs. Since the electrospraying method benefits from the both amorphization and nanosizing effect, this novel approach seems to be an efficient method for the fabrication of N-SDs of poorly water-soluble drugs.

Floating elementary osmotic pump tablet (FEOPT) for controlled delivery of diethylcarbamazine citrate: a water-soluble drug.

PubMed

Khan, Zulfequar Ahamad; Tripathi, Rahul; Mishra, Brahmeshwar

2011-12-01

The present work investigates the feasibility of the design of a novel floating elementary osmotic pump tablet (FEOPT) to prolong the gastric residence of a highly water-soluble drug. Diethylcarbamazine citrate (DEC) was chosen as a model drug. The FEOPT consisted of an osmotic core (DEC, mannitol, and hydrophilic polymers) coated with a semipermeable layer (cellulose acetate) and a gas-generating gelling layer (sodium bicarbonate, hydrophilic polymers) followed by a polymeric film (Eudragit RL 30D). The effect of formulation variables such as concentration of polymers, types of diluent, and coat thickness of semipermeable membrane was evaluated in terms of physical parameters, floating lag time, duration of floatation, and in vitro drug release. The Fourier transform infrared and X-ray diffraction analysis were carried out to study the physicochemical changes in the drug excipients powder blend. The integrity of the orifice and polymeric film layer was confirmed from scanning electron microscopy image. All the developed FEOPT showed floating lag time of less than 8 min and floating duration of 24 h. A zero-order drug release could be attained for DEC. The formulations were found to be stable up to 3 months of stability testing at 40°C/75% relative humidity.

Preparation and characterization of PEGylated chitosan nanocapsules as a carrier for pharmaceutical application

NASA Astrophysics Data System (ADS)

Najafabadi, Alireza Hassani; Abdouss, Majid; Faghihi, Shahab

2014-03-01

A new method to conjugate methoxy polyethylene glycol (mPEG) to C6 position of chitosan under the mild condition is introduced that improves the biocompatibility and water solubility of chitosan. Harsh deprotecting step and several purification cycles are two major disadvantages of the current methods for preparing PEGylated chitosan. In this study, the amine groups at C2 position of chitosan are protected using SDS followed by grafting the PEG. The protecting group of chitosan is simply removed by dialyzing against Tris solution. The chemical structure of the prepared polymer is characterized by FTIR and 1H NMR spectroscopy. Fourier transformed-infrared (FT-IR) and 1H NMR spectra confirmed that the mPEG is successfully grafted to C6 position of chitosan. Prepared methoxy polyethylene glycol (mPEG) is then employed to prepare the nanocapsules for the encapsulation of poor water-soluble drug, propofol. The TEM, AFM, and DLS techniques are used to characterize the prepared nanocapsules size and morphology. The results show a size of about 80 nm with spherical shape for nanocapsules. In vitro drug release is carried out to evaluate the potential of nanocarriers for the intravenous delivery of drugs. The profile of release from formulated nanocapsules is similar to those of commercial lipid emulsion (CLE). In vivo animal sleep-recovery test on rats shows a close similarity between the time of unconsciousness and recovery of righting reflex between nanoparticles and CLE. This study provides an efficient, novel, and easy method for preparing a carrier system that requires less intensive reaction conditions, fewer reaction steps, and less purification steps. In addition, the nanocapsules introduced here could be a promising nano carrier for the delivery of poor water-soluble drugs.

Treating SCA1 Mice with Water-Soluble Compounds to Non-Specifically Boost Mitochondrial Function.

PubMed

Ferro, Austin; Carbone, Emily; Marzouk, Evan; Siegel, Asher; Nguyen, Donna; Polley, Kailen; Hartman, Jessilyn; Frederick, Kimberley; Ives, Stephen; Lagalwar, Sarita

2017-01-22

Mitochondrial dysfunction plays a significant role in the aging process and in neurodegenerative diseases including several hereditary spinocerebellar ataxias and other movement disorders marked by progressive degeneration of the cerebellum. The goal of this protocol is to assess mitochondrial dysfunction in Spinocerebellar ataxia type 1 (SCA1) and assess the efficacy of pharmacological targeting of metabolic respiration via the water-soluble compound succinic acid to slow disease progression. This approach is applicable to other cerebellar diseases and can be adapted to a host of water-soluble therapies. Ex vivo analysis of mitochondrial respiration is used to detect and quantify disease-related changes in mitochondrial function. With genetic evidence (unpublished data) and proteomic evidence of mitochondrial dysfunction in the SCA1 mouse model, we evaluate the efficacy of treatment with the water-soluble metabolic booster succinic acid by dissolving this compound directly into the home cage drinking water. The ability of the drug to pass the blood brain barrier can be deduced using high performance liquid chromatography (HPLC). The efficacy of these compounds can then be tested using multiple behavioral paradigms including the accelerating rotarod, balance beam test and footprint analysis. Cytoarchitectural integrity of the cerebellum can be assessed using immunofluorescence assays that detect Purkinje cell nuclei and Purkinje cell dendrites and soma. These methods are robust techniques for determining mitochondrial dysfunction and the efficacy of treatment with water-soluble compounds in cerebellar neurodegenerative disease.

Structural, functional and pH sensitive release characteristics of water-soluble polysaccharide from the seeds of Albizia lebbeck L.

PubMed

Kumar Varma, Chekuri Ashok; Jayaram Kumar, K

2017-11-01

Plant polysaccharides, generally regarded as safe (GRAS), are gaining importance as excipients in drug delivery. Therefore, the current paper presents the studies on structural, functional and drug release study of water soluble polysaccharide (ALPS) from seeds of Albizia lebbeck L. High swelling, water holding capacity, foam stability and lower moisture content suggests its use as additive in food preparations. The apparent molecular weight of polysaccharide was found to be 1.98×10 2 kDa. Monosaccharide composition analysis indicated that ALPS consists of mannose (4.06%), rhamnose (22.79%), glucose (38.9%), galactose (17.84%) and xylose (16.42%). Micromeritic properties revealed that the polysaccharide possess potential for pharmaceutical applications. From the surface charge analysis, ALPS was found to be non-ionic polysaccharide. Morphological study reveals the polysaccharide with irregular particle shape and rough surface. Fourier transformed infrared spectroscopy (FTIR) study confirms the carbohydrate nature of polysaccharide. From the thermogravimetric analysis (TGA) data, the second mass loss (243-340°C) attributed to polysaccharide degradation. The drug release profile reveals the use of polysaccharide for the preparation of pH sensitive pharmaceutical dosage forms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acyclic Cucurbit[n]uril-type Molecular Containers: Influence of Aromatic Walls on their Function as Solubilizing Excipients for Insoluble Drugs

PubMed Central

2015-01-01

We studied the influence of the aromatic sidewalls on the ability of acyclic CB[n]-type molecular containers (1a–1e) to act as solubilizing agents for 19 insoluble drugs including the developmental anticancer agent PBS-1086. All five containers exhibit good water solubility and weak self-association (Ks ≤ 624 M–1). We constructed phase solubility diagrams to extract Krel and Ka values for the container·drug complexes. The acyclic CB[n]-type containers generally display significantly higher Ka values than HP-β-CD toward drugs. Containers 1a–1e bind the steroidal ring system and aromatic moieties of insoluble drugs. Compound 1b displays highest affinity toward most of the drugs studied. Containers 1a and 1b are broadly applicable and can be used to formulate a wider variety of insoluble drugs than was previously possible with cyclodextrin technology. For drugs that are solubilized by both HP-β-CD and 1a–1e, lower concentrations of 1a–1e are required to achieve identical [drug]. PMID:25369565

Acyclic cucurbit[n]uril-type molecular containers: influence of aromatic walls on their function as solubilizing excipients for insoluble drugs.

PubMed

Zhang, Ben; Isaacs, Lyle

2014-11-26

We studied the influence of the aromatic sidewalls on the ability of acyclic CB[n]-type molecular containers (1a-1e) to act as solubilizing agents for 19 insoluble drugs including the developmental anticancer agent PBS-1086. All five containers exhibit good water solubility and weak self-association (Ks ≤ 624 M(-1)). We constructed phase solubility diagrams to extract Krel and Ka values for the container·drug complexes. The acyclic CB[n]-type containers generally display significantly higher Ka values than HP-β-CD toward drugs. Containers 1a-1e bind the steroidal ring system and aromatic moieties of insoluble drugs. Compound 1b displays highest affinity toward most of the drugs studied. Containers 1a and 1b are broadly applicable and can be used to formulate a wider variety of insoluble drugs than was previously possible with cyclodextrin technology. For drugs that are solubilized by both HP-β-CD and 1a-1e, lower concentrations of 1a-1e are required to achieve identical [drug].

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement.

PubMed

Rezhdo, Oljora; Speciner, Lauren; Carrier, Rebecca

2016-10-28

The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid in the understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented. Copyright © 2016 Elsevier B.V. All rights reserved.

Self-microemulsifying smaller molecular volume oil (Capmul MCM) using non-ionic surfactants: a delivery system for poorly water-soluble drug.

PubMed

Bandivadeka, Mithun Mohanraor; Pancholi, Shyam Sundar; Kaul-Ghanekar, Ruchika; Choudhari, Amit; Koppikar, Soumya

2012-07-01

The main purpose of this work is to formulate self-microemulsifying drug delivery system (SMEDDS) using smaller molecular oil with Atorvastatin calcium as a model drug. Solubility of the selected drug was accessed in oils and surfactants. Percent transmittance (%T) test study was performed to identify the efficient self-microemulsifying formulations. Those formulations which showed higher value for %T were evaluated for droplet size, polydispersity index, ζ potential, refractive index and cloud point measurement. Effect of drug loading on droplet size, increasing dilution in different media, thermodynamic stability and in vitro dissolution was performed to observe the performance of the selected formulation. Further cytotoxicity and permeation enhancement studies were carried out on Caco2 cell lines. Of all the oils accessed for drug solubility, Capmul MCM showed higher solubility capacity for Atorvastatin calcium. Capmul MCM was better microemulsified using combination of Tween 20 and Labrasol surfactant. Droplet size was as low as 86.93 nm with polydispersity index and ζ potential at 0.195 ± 0.011 and -7.27 ± 3.11 mV respectively. The selected undiluted formulation showed refractive index values ranging from 1.40 to 1.47 indicating the isotropicity of the formulation. The selected formulation was robust to dilution in different media and thermodynamically stable. Dissolution profile was enhanced for the selected drug as compared to marketed formulation with t85% and DE values at 10 min and 80.15 respectively. Also cytotoxicity measurement showed minimum effect with good permeation enhancing capacity. Thus our study demonstrates the use of smaller molecular oil (Capmul MCM) for developing self-microemulsifying drug delivery system for better in vitro and in vivo performance.

Glass-Transition Temperature of the β-Relaxation as the Major Predictive Parameter for Recrystallization of Neat Amorphous Drugs.

PubMed

Kissi, Eric Ofosu; Grohganz, Holger; Löbmann, Korbinian; Ruggiero, Michael T; Zeitler, J Axel; Rades, Thomas

2018-03-15

Recrystallization of amorphous drugs is currently limiting the simple approach to improve solubility and bioavailability of poorly water-soluble drugs by amorphization of a crystalline form of the drug. In view of this, molecular mobility, α-relaxation and β-relaxation processes with the associated transition temperatures T gα and T gβ , was investigated using dynamic mechanical analysis (DMA). The correlation between the transition temperatures and the onset of recrystallization for nine amorphous drugs, stored under dry conditions at a temperature of 296 K, was determined. From the results obtained, T gα does not correlate with the onset of recrystallization under the experimental storage conditions. However, a clear correlation between T gβ and the onset of recrystallization was observed. It is shown that at storage temperature below T gβ , amorphous nifedipine retains its amorphous form. On the basis of the correlation, an empirical correlation is proposed for predicting the onset of recrystallization for drugs stored at 0% RH and 296 K.

Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility.

PubMed

Enright, Elaine F; Joyce, Susan A; Gahan, Cormac G M; Griffin, Brendan T

2017-04-03

In recent years, the gut microbiome has gained increasing appreciation as a determinant of the health status of the human host. Bile salts that are secreted into the intestine may be biotransformed by enzymes produced by the gut bacteria. To date, bile acid research at the host-microbe interface has primarily been directed toward effects on host metabolism. The aim of this work was to investigate the effect of changes in gut microbial bile acid metabolism on the solubilization capacity of bile salt micelles and consequently intraluminal drug solubility. First, the impact of bile acid metabolism, mediated in vivo by the microbial enzymes bile salt hydrolase (BSH) and 7α-dehydroxylase, on drug solubility was assessed by comparing the solubilization capacity of (a) conjugated vs deconjugated and (b) primary vs secondary bile salts. A series of poorly water-soluble drugs (PWSDs) were selected as model solutes on the basis of an increased tendency to associate with bile micelles. Subsequently, PWSD solubility and dissolution was evaluated in conventional biorelevant simulated intestinal fluid containing host-derived bile acids, as well as in media modified to contain microbial bile acid metabolites. The findings suggest that deconjugation of the bile acid steroidal core, as dictated by BSH activity, influences micellar solubilization capacity for some PWSDs; however, these differences appear to be relatively minor. In contrast, the extent of bile acid hydroxylation, regulated by microbial 7α-dehydroxylase, was found to significantly affect the solubilization capacity of bile salt micelles for all nine drugs studied (p < 0.05). Subsequent investigations in biorelevant media containing either the trihydroxy bile salt sodium taurocholate (TCA) or the dihydroxy bile salt sodium taurodeoxycholate (TDCA) revealed altered drug solubility and dissolution. Observed differences in biorelevant media appeared to be both drug- and amphiphile (bile salt/lecithin) concentration-dependent. Our studies herein indicate that bile acid modifications occurring at the host-microbe interface could lead to alterations in the capacity of intestinal bile salt micelles to solubilize drugs, providing impetus to consider the gut microbiota in the drug absorption process. In the clinical setting, disruption of the gut microbial ecosystem, through disease or antibiotic treatment, could transform the bile acid pool with potential implications for drug absorption and bioavailability.

Developing an in situ nanosuspension: a novel approach towards the efficient administration of poorly soluble drugs at the anterior eye.

PubMed

Luschmann, Christoph; Tessmar, Joerg; Schoeberl, Simon; Strauss, Olaf; Framme, Carsten; Luschmann, Karl; Goepferich, Achim

2013-11-20

With about 50-60 million cases in the US alone, dry eye disease represents a severe health care problem. Cyclosporin A (CsA) would be a potent candidate for a causal therapy. However, CsA is not sufficiently water soluble to be administrated via simple eye drops. We developed an in situ nanosuspension (INS) as a novel approach towards the administration of CsA to the cornea. It precipitates upon contact with the tear fluid and creates CsA nanoparticles that enter the cornea and release the drug by dissolution. We selected two liquid poly(ethylene glycols) (PEG) that dissolve CsA and create nanoparticles by precipitation of CsA upon water contact. Aqueous solutions of PEG and Solutol, a non-ionic surfactant, were well tolerated by primary human epithelial cells in vitro. To determine the critical water content needed for a precipitation, the solubility of CsA was investigated in quaternary systems of drug, solvent, surfactant and water. The best INS formulation showed a particle size of 505 ± 5 nm, a polydispersity index (PdI) of 0.23 ± 0.03 and a neutral zeta potential of -0.07 ± 0.05 mV. After single administration to porcine eyes in vitro, 3165 ± 597 ng(CsA)/g(cornea) were detected in corneal tissue, while the levels of Restasis a commercial formulation were, with 545 ± 137 ng(CsA)/g(cornea), significantly lower (P<0.01). These results demonstrate that an INS is a promising, novel approach towards the causal treatment of inflammatory diseases at the anterior eye. Copyright © 2013 Elsevier B.V. All rights reserved.

Intestinal absorption of water-soluble vitamins in health and disease.

PubMed

Said, Hamid M

2011-08-01

Our knowledge of the mechanisms and regulation of intestinal absorption of water-soluble vitamins under normal physiological conditions, and of the factors/conditions that affect and interfere with theses processes has been significantly expanded in recent years as a result of the availability of a host of valuable molecular/cellular tools. Although structurally and functionally unrelated, the water-soluble vitamins share the feature of being essential for normal cellular functions, growth and development, and that their deficiency leads to a variety of clinical abnormalities that range from anaemia to growth retardation and neurological disorders. Humans cannot synthesize water-soluble vitamins (with the exception of some endogenous synthesis of niacin) and must obtain these micronutrients from exogenous sources. Thus body homoeostasis of these micronutrients depends on their normal absorption in the intestine. Interference with absorption, which occurs in a variety of conditions (e.g. congenital defects in the digestive or absorptive system, intestinal disease/resection, drug interaction and chronic alcohol use), leads to the development of deficiency (and sub-optimal status) and results in clinical abnormalities. It is well established now that intestinal absorption of the water-soluble vitamins ascorbate, biotin, folate, niacin, pantothenic acid, pyridoxine, riboflavin and thiamin is via specific carrier-mediated processes. These processes are regulated by a variety of factors and conditions, and the regulation involves transcriptional and/or post-transcriptional mechanisms. Also well recognized now is the fact that the large intestine possesses specific and efficient uptake systems to absorb a number of water-soluble vitamins that are synthesized by the normal microflora. This source may contribute to total body vitamin nutrition, and especially towards the cellular nutrition and health of the local colonocytes. The present review aims to outline our current understanding of the mechanisms involved in intestinal absorption of water-soluble vitamins, their regulation, the cell biology of the carriers involved and the factors that negatively affect these absorptive events. © The Authors Journal compilation © 2011 Biochemical Society

Exploiting the biosynthetic machinery of Streptomyces pilosus to engineer a water-soluble zirconium(iv) chelator.

PubMed

Richardson-Sanchez, Tomas; Tieu, William; Gotsbacher, Michael P; Telfer, Thomas J; Codd, Rachel

2017-07-21

The water solubility of a natural product-inspired octadentate hydroxamic acid chelator designed to coordinate Zr(iv)-89 has been improved by using a combined microbiological-chemical approach to engineer four ether oxygen atoms into the main-chain region of a methylene-containing analogue. First, an analogue of the trimeric hydroxamic acid desferrioxamine B (DFOB) that contained three main-chain ether oxygen atoms (DFOB-O 3 ) was generated from cultures of the native DFOB-producer Streptomyces pilosus supplemented with oxybis(ethanamine) (OBEA), which competed against the native 1,5-diaminopentane (DP) substrate during DFOB assembly. This precursor-directed biosynthesis (PDB) approach generated a suite of DFOB analogues containing one (DFOB-O 1 ), two (DFOB-O 2 ) or three (DFOB-O 3 ) ether oxygen atoms, with the latter produced as the major species. Log P measurements showed DFOB-O 3 was about 45 times more water soluble than DFOB. Second, a peptide coupling chain-extension reaction between DFOB-O 3 and the synthetic ether-containing endo-hydroxamic acid monomer 4-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-4-oxobutanoic acid (PBH-O 1 ) gave the water soluble tetrameric hydroxamic acid DFOB-O 3 -PBH-O 1 as an isostere of sparingly water soluble DFOB-PBH. The complex between DFOB-O 3 -PBH-O 1 and nat Zr(iv), examined as a surrogate measure of the radiolabelling procedure, analysed by LC-MS as the protonated adduct ([M + H] + , m/z obs = 855.2; m/z calc = 855.3), with supporting HRMS data. The use of a microbiological system to generate a water-soluble analogue of a natural product for downstream semi-synthetic chemistry is an attractive pathway for developing new drugs and imaging agents. The improved water solubility of DFOB-O 3 -PBH-O 1 could facilitate the synthesis and purification of downstream products, as part of the ongoing development of ligands optimised for Zr(iv)-89 immunological PET imaging.

Intestinal absorption of water-soluble vitamins in health and disease

PubMed Central

Said, Hamid M.

2014-01-01

Our knowledge of the mechanisms and regulation of intestinal absorption of water-soluble vitamins under normal physiological conditions, and of the factors/conditions that affect and interfere with theses processes has been significantly expanded in recent years as a result of the availability of a host of valuable molecular/cellular tools. Although structurally and functionally unrelated, the water-soluble vitamins share the feature of being essential for normal cellular functions, growth and development, and that their deficiency leads to a variety of clinical abnormalities that range from anaemia to growth retardation and neurological disorders. Humans cannot synthesize water-soluble vitamins (with the exception of some endogenous synthesis of niacin) and must obtain these micronutrients from exogenous sources. Thus body homoeostasis of these micronutrients depends on their normal absorption in the intestine. Interference with absorption, which occurs in a variety of conditions (e.g. congenital defects in the digestive or absorptive system, intestinal disease/resection, drug interaction and chronic alcohol use), leads to the development of deficiency (and sub-optimal status) and results in clinical abnormalities. It is well established now that intestinal absorption of the water-soluble vitamins ascorbate, biotin, folate, niacin, pantothenic acid, pyridoxine, riboflavin and thiamin is via specific carrier-mediated processes. These processes are regulated by a variety of factors and conditions, and the regulation involves transcriptional and/or post-transcriptional mechanisms. Also well recognized now is the fact that the large intestine possesses specific and efficient uptake systems to absorb a number of water-soluble vitamins that are synthesized by the normal microflora. This source may contribute to total body vitamin nutrition, and especially towards the cellular nutrition and health of the local colonocytes. The present review aims to outline our current understanding of the mechanisms involved in intestinal absorption of water-soluble vitamins, their regulation, the cell biology of the carriers involved and the factors that negatively affect these absorptive events. PMID:21749321

Development of nanostructured lipid carrier for dacarbazine delivery

NASA Astrophysics Data System (ADS)

Almousallam, Musallam; Moia, Claudia; Zhu, Huijun

2015-09-01

Dacarbazine (Dac) is one of the most commonly used chemotherapy drugs for treating various cancers. However, its poor water solubility, short half-life in blood circulation, low response rate and high side effect limit its application. This study aimed to improve the drug solubility and prolong drug release by developing nanostructured lipid carriers (NLCs) for Dac delivery. The NLC and Dac-encapsulated NLC were synthesized with precirol ATO 5 and isopropyl myristate as lipids, tocopheryl polyethylene glycol succinate, soybean lecithin and Kolliphor P 188 as co-surfactants. The NLCs with controlled size were achieved using high shear dispersion following solidification of oil-in-water emulsion. For Dac encapsulation, the smallest NLC with 155 ± 10 nm in size, 0.2 ± 0.01 polydispersion index and -43.4 ± 2 mV zeta potential was selected. The resultant DLC-Dac possessed size, polydispersion index and zeta potential of 190 ± 10, 0.2 ± 0.01, and -43.5 ± 1.2, respectively. The drug encapsulation efficiency and drug loading were 98.5 % and 14 %, respectively. In vitro drug release study showed a biphasic pattern, with 50 % released in the first 2 h, and the remaining released sustainably for up to 30 h. This is the first report on the development of NLC for Dac delivery, implying that NLC could be a new potential candidate as drug carrier to improve the therapeutic profile of Dac.

Macromolecular therapeutics.

PubMed

Yang, Jiyuan; Kopeček, Jindřich

2014-09-28

This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. Copyright © 2014 Elsevier B.V. All rights reserved.

Enhancement of carvedilol solubility by solid dispersion technique using cyclodextrins, water soluble polymers and hydroxyl acid.

PubMed

Yuvaraja, K; Khanam, Jasmina

2014-08-05

Aim of the present work is to enhance aqueous solubility of carvedilol (CV) by solid dispersion technique using wide variety of carriers such as: β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD), tartaric acid (TA), polyvinyl pyrrolidone K-30 (PVP K-30) and poloxamer-407 (PLX-407). Various products of 'CV-solid dispersion' had been studied extensively in various pH conditions to check enhancement of solubility and dissolution characteristics of carvedilol. Any physical change upon interaction between CV and carriers was confirmed by instrumental analysis: XRD, DSC, FTIR and SEM. Negative change of Gibb's free energy and complexation constants (Kc, 75-240M(-1), for cyclodextrins and 1111-20,365M(-1), for PVP K-30 and PLX-407) were the evidence of stable nature of the binding between CV and carriers. 'Solubility enhancement factor' of ionized-CV was found high enough (340 times) with HPβCD in presence of TA. TA increases the binding efficiency of cyclodextrin and changing the pH of microenvironment in dissolution medium. In addition, ionization process was used to increase the apparent intrinsic solubility of drug. In vitro, dissolution time of CV was remarkably reduced in the solid dispersion system compared to that of pure drug. This may be attributed to increased wettability, dispersing ability and transformation of crystalline state of drug to amorphous one. Copyright © 2014 Elsevier B.V. All rights reserved.

Polymorphisms of the KCNQ1 gene are associated with the therapeutic responses of sulfonylureas in Chinese patients with type 2 diabetes.

PubMed

Li, Qing; Tang, Ting-Ting; Jiang, Feng; Zhang, Rong; Chen, Miao; Yin, Jun; Bao, Yu-Qian; Cheng, Xiang; Hu, Cheng; Jia, Wei-Ping

2017-01-01

KCNQ1 channel is a member of the voltage-gated potassium channel KQT-like subfamily. The KCNQ1 gene has recently been identified as a susceptibility locus for type 2 diabetes mellitus (T2DM). In the present study, we examined the effects of KCNQ1 variants on the therapeutic response to modified-release gliclazide (gliclazide MR) treatment in Chinese patients newly diagnosed with T2DM. A total of 100 newly diagnosed T2DM patients without a history of any anti-diabetic medications were treated with gliclazide MR for 16 weeks, but 91 patients completed the entire study. The anthropometric parameters were determined at baseline and at the final visit, while clinical laboratory tests were performed at baseline and on weeks 2, 4, 6, 12, 16. Two SNPs, rs2237892 and rs2237895, in the region of the KCNQ1 gene were genotyped in all the participants. All calculations and statistical analyses were conducted using SPSS. The rs2237892 TT homozygotes exhibited significantly higher 2-h glucose levels at baseline (P<0.05) and a lower cumulative attainment rate of the target 2-h glucose level (P log-rank =0.020) than the C allele carriers. Patients with greater numbers of rs2237892 T alleles exhibited larger augmentations (Δ) in the 2-h glucose levels (P=0.027); and patients with the rs2237892 TT genotype exhibited a higher Δ homeostasis model assessment of β-cell function (HOMA-β) than CC and CT genotype carriers (P=0.021 and P=0.043, respectively). Moreover, the rs2237895 C allele was associated with a greater decrement in Δ glycated hemoglobin (HbA1c) (P=0.024); and patients with the CC genotype exhibited greater variance than those with the AA and AC genotypes (P=0.005 and 0.021, respectively). Compared with the C allele, the odds ratio for treatment success among carriers of the rs2237892 T allele was 2.533 (P=0.007); and the rs2237895 C allele was associated with a 2.360-fold decrease in HbA1c compared with the A allele (P=0.009). KCNQ1 polymorphisms are associated with gliclazide MR efficacy in Chinese patients with type 2 diabetes.

Kinetics and mechanism of release from glyceryl monostearate-based implants: evaluation of release in a gel simulating in vivo implantation.

PubMed

Allababidi, S; Shah, J C

1998-06-01

The overall objective of the study was to design an implantable delivery system based on glyceryl monostearate (GMS) for the site-specific delivery of antibiotics for the prevention of surgical wound infection. To design the implant, a release method had to be developed that simulate the in vivo implantation conditions to be able to predict the release characteristics from the implants when they are actually used in vivo. Also, identifying the release kinetics and mechanism and evaluating the factors that influence the release of drugs from the GMS-based matrix were necessary to allow further design of implants that could yield a desired release rate. The release of cefazolin was monitored from GMS matrixes implanted into agar gel, simulating subcutaneous tissues with respect to viscosity and water content. The gel method resulted in observation of spatial and temporal concentration profiles in the immediate vicinity of the implants, indicating the benefits of local drug delivery; however, there was no significant difference between the cumulative release profiles by the gel method or the vial release method. The release of cefazolin from the GMS-based matrix with the vial method followed Higuchi's square root of time kinetics. The release rate was found to be directly proportional to cefazolin load (A) and the surface area (SA) of the matrix as expressed by the following equation: = 0.24ASA. On the basis of this equation, one can design a variety of GMS matrixes that would result in a desired release rate or release duration. This also indicated that cefazolin release followed the release kinetics of a freely soluble drug from an insoluble matrix and hence it is a diffusion-controlled process. The effect of drug solubility on the release kinetics was determined by comparing the release kinetics of the poorly water soluble ciprofloxacin (0.16 mg/mL) to that of the highly water soluble cefazolin (325 mg/mL). The release duration of ciprofloxacin (80 h) was longer than that of cefazolin (25 h) from identical GMS matrixes. Although ciprofloxacin release was initially controlled by the matrix, agitation accelerated disintegration of the matrix and release due to its poor solubility, and ciprofloxacin release appeared to be a dissolution-controlled process following zero-order release kinetics.

Formulation Strategies to Improve the Bioavailability of Poorly Absorbed Drugs with Special Emphasis on Self-Emulsifying Systems

PubMed Central

Gupta, Shweta; Kesarla, Rajesh

2013-01-01

Poorly water-soluble drug candidates are becoming more prevalent. It has been estimated that approximately 60–70% of the drug molecules are insufficiently soluble in aqueous media and/or have very low permeability to allow for their adequate and reproducible absorption from the gastrointestinal tract (GIT) following oral administration. Formulation scientists have to adopt various strategies to enhance their absorption. Lipidic formulations are found to be a promising approach to combat the challenges. In this review article, potential advantages and drawbacks of various conventional techniques and the newer approaches specifically the self-emulsifying systems are discussed. Various components of the self-emulsifying systems and their selection criteria are critically reviewed. The attempts of various scientists to transform the liquid self-emulsifying drug delivery systems (SEDDS) to solid-SEDDS by adsorption, spray drying, lyophilization, melt granulation, extrusion, and so forth to formulate various dosage forms like self emulsifying capsules, tablets, controlled release pellets, beads, microspheres, nanoparticles, suppositories, implants, and so forth have also been included. Formulation of SEDDS is a potential strategy to deliver new drug molecules with enhanced bioavailability mostly exhibiting poor aqueous solubility. The self-emulsifying system offers various advantages over other drug delivery systems having potential to solve various problems associated with drugs of all the classes of biopharmaceutical classification system (BCS). PMID:24459591

Coherent anti-Stokes Raman scattering microscopy driving the future of loaded mesoporous silica imaging.

PubMed

Fussell, Andrew L; Mah, Pei Ting; Offerhaus, Herman; Niemi, Sanna-Mari; Salonen, Jarno; Santos, Hélder A; Strachan, Clare

2014-11-01

This study reports the use of variants of coherent anti-Stokes Raman scattering (CARS) microscopy as a novel method for improved physicochemical characterization of drug-loaded silica particles. Ordered mesoporous silica is a biomaterial that can be loaded to carry a number of biochemicals, including poorly water-soluble drugs, by allowing the incorporation of drug into nanometer-sized pores. In this work, the loading of two poorly water-soluble model drugs, itraconazole and griseofulvin, in MCM-41 silica microparticles is characterized qualitatively, using the novel approach of CARS microscopy, which has advantages over other analytical approaches used to date and is non-destructive, rapid, label free, confocal and has chemical and physical specificity. The study investigated the effect of two solvent-based loading methods, namely immersion and rotary evaporation, and microparticle size on the three-dimensional (3-D) distribution of the two loaded drugs. Additionally, hyperspectral CARS microscopy was used to confirm the amorphous nature of the loaded drugs. Z-stacked CARS microscopy suggested that the drug, but not the loading method or particle size range, affected 3-D drug distribution. Hyperspectral CARS confirmed that the drug loaded in the MCM-41 silica microparticles was in an amorphous form. The results show that CARS microscopy and hyperspectral CARS microscopy can be used to provide further insights into the structural nature of loaded mesoporous silica microparticles as biomaterials. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Biowaiver extension potential and IVIVC for BCS Class II drugs by formulation design: Case study for cyclosporine self-microemulsifying formulation.

PubMed

Yang, Su-Geun

2010-11-01

The objective of this work was to suggest the biowaiver potential of biopharmaceutical classification system (BCS) Class II drugs in self-microemulsifying drug delivery systems (SMEDDS) which are known to increase the solubility, dissolution and oral absorption of water-insoluble drugs. Cyclosporine was selected as a representative BCS Class II drug. New generic candidate of cyclosporine SMEDDS (test) was applied for the study with brand SMEDDS (reference I) and cyclosporine self-emulsifying drug delivery systems (SEDDS, reference II). Solubility and dissolution of cyclosporine from SMEDDS were critically enhanced, which were the similar behaviors with BCS class I drug. The test showed the identical dissolution rate and the equivalent bioavailability (0.34, 0.42 and 0.68 of p values for AUC₀(→)₂₄(h), C(max) and T(max), respectively) with the reference I. Based on the results, level A in vitro-in vivo correlation (IVIVC) was established from these two SMEDDS formulations. This study serves as a good example for speculating the biowaiver extension potential of BCS Class II drugs specifically in solubilizing formulation such as SMEDDS.

Exploitation of 3D face-centered cubic mesoporous silica as a carrier for a poorly water soluble drug: influence of pore size on release rate.

PubMed

Zhu, Wenquan; Wan, Long; Zhang, Chen; Gao, Yikun; Zheng, Xin; Jiang, Tongying; Wang, Siling

2014-01-01

The purposes of the present work were to explore the potential application of 3D face-centered cubic mesoporous silica (FMS) with pore size of 16.0nm as a delivery system for poorly soluble drugs and investigate the effect of pore size on the dissolution rate. FMS with different pore sizes (16.0, 6.9 and 3.7nm) was successfully synthesized by using Pluronic block co-polymer F127 as a template and adjusting the reaction temperatures. Celecoxib (CEL), which is a BCS class II drug, was used as a model drug and loaded into FMS with different pore sizes by the solvent deposition method at a drug-silica ratio of 1:4. Characterization using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transformation infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), nitrogen adsorption, X-ray diffraction (XRD), and differential scanning calorimetry (DSC) was used to systematically investigate the drug loading process. The results obtained showed that CEL was in a non-crystalline state after incorporation of CEL into the pores of FMS-15 with pore size of 16.0nm. In vitro dissolution was carried out to demonstrate the effects of FMS with different pore sizes on the release of CEL. The results obtained indicated that the dissolution rate of CEL from FMS-15 was significantly enhanced compared with pure CEL. This could be explained by supposing that CEL encountered less diffusion resistance and its crystallinity decreased due to the large pore size of 16.0nm and the nanopore channels of FMS-15. Moreover, drug loading and pore size both play an important role in enhancing the dissolution properties for the poorly water-soluble drugs. As the pore size between 3.7 and 16.0nm increased, the dissolution rate of CEL from FMS gradually increased. © 2013.

Soy polysaccharide as a novel superdisintegrant in sildenafil citrate sublingual tablets: preparation, characterization, and in vivo evaluation

PubMed Central

Hosny, Khaled Mohamed; Mosli, Hisham Ahmed; Hassan, Ali Habiballah

2015-01-01

Sildenafil citrate (SC), a drug used to treat erectile dysfunction, is available in tablet form but has three major problems. First, the drug displays inadequate aqueous solubility, which delays the onset of its action. Second, the drug undergoes extensive first-pass metabolism, resulting in a low (40%) bioavailability. Third, the gastrointestinal effects of SC include dyspepsia and a burning sensation. The aim of this research was to prepare SC as a sublingual tablet utilizing soy polysaccharide as novel superdisintegrant to mitigate the abovementioned problems. The solubility of SC in various hydrophilic carrier solutions was estimated in order to prepare the drug as a coprecipitate. Sublingual tablets were prepared and evaluated for hardness, friability, drug content, wetting time, water absorption ratio, in vitro dispersion time, dissolution rate, and stability study. The pharmacokinetic study of the tablets was carried out on healthy volunteers. The results indicated that the co-precipitation of SC with polyvinylpyrollidone K30 enhanced the solubility of SC by more than eight folds. The tablet contained 8% soy polysaccharide as a superdisintegrant and provided a wetting time of 25 seconds, and in vitro dispersion times of 55 seconds. The drug release was found to be 95.6%. The prepared SC sublingual tablet also exhibited a rapid onset of action, and its bioavailability was enhanced 1.68-fold compared with that of the marketed tablets. It can be concluded that SC sublingual tablet is a promising formulation that results in higher solubility, faster dispersion and onset of action, higher release rate, and higher systemic bioavailability. PMID:25624751

Ocular delivery systems for poorly soluble drugs: an in-vivo evaluation.

PubMed

Luschmann, C; Herrmann, W; Strauss, O; Luschmann, K; Goepferich, A

2013-10-15

For highly potent but poorly water-soluble drugs like cyclosporine A, the development of aqueous formulations providing an increase of corneal drug tissue levels, and thus of bioavailability, to increase patient compliance is still a challenge. Therefore, we designed two water-based liquid application systems, an in-situ nanosuspension (INS) and a micellar solution (MS), and tested both formulations in vivo at the rabbit cornea for tolerability and the tissue uptake of CsA. The evaluation of the biological tolerability by periodical eye examination during 180 min and quantification in a defined grading system revealed that the INS evoked minimal to no irritations whereas the MS was perfectly tolerated. After the observation period, the rabbits were sacrificed and the corneal tissue levels of CsA were analyzed. The INS and the MS both showed high levels of 1683±430 ngCsA/gcornea and 826±163 ngCsA/gcornea, respectively, and exceeded drug tissue levels reported for Restasis(®) (350 ngCsA/gcornea) and cationic emulsions (750 ngCsA/gcornea). These results marked our INS and MS as outstanding novel approaches for the treatment of inflammatory corneal diseases. Copyright © 2013 Elsevier B.V. All rights reserved.

Rapid fabrication method of a microneedle mold with controllable needle height and width.

PubMed

Lin, Yen-Heng; Lee, I-Chi; Hsu, Wei-Chieh; Hsu, Ching-Hong; Chang, Kai-Ping; Gao, Shao-Syuan

2016-10-01

The main issue of transdermal drug delivery is that macromolecular drugs cannot diffuse through the stratum corneum of skin. Many studies have pursued micro-sized needles encapsulated with drugs to overcome this problem, as these needles can pierce the stratum corneum and allow drugs to enter the circulatory system of the human body. However, most microneedle fabrication processes are time-consuming and require expensive equipment. In this study, we demonstrate a rapid method for fabricating a microneedle mold using drawing lithography and a UV-cured resin. The mold was filled with a water-soluble material, polyvinylpyrrolidone (PVP), which was then demolded to produce a water-soluble microneedle array. The results of an in vitro skin insertion test using PVP microneedles and pig ear skin demonstrated the feasibility of the microneedle mold. In addition, by controlling the viscosity of the UV-cured resin through various heat treatments, microneedles with different heights and aspect ratios were produced. Compared with other methods, this technology significantly simplifies and accelerates the mold fabrication process. In addition, the required equipment is relatively simple and inexpensive. Through this technology, we can rapidly fabricate microneedle molds with controllable dimensions for various applications.

Water-Soluble Vitamin E-Tocopheryl Phosphate.

PubMed

Zingg, Jean-Marc

The hydrophobicity of vitamin E poses transport and metabolic challenges to regulate its bioavailability and to prevent its accumulation in lipid-rich tissues such as adipose tissue, brain, and liver. Water-soluble precursors of vitamin E (α-tocopherol, αT), such as its esters with acetate (αTA), succinate (αTS), or phosphate (αTP), have increased solubility in water and stability against reaction with free radicals, but they are rapidly converted during their uptake into the lipid-soluble vitamin E. Therefore, the bioavailability of these precursors as intact molecules is low; nevertheless, at least for αTS and αTP, the recent research has revealed unique regulatory effects on signal transduction and gene expression and the modulation of cellular events ranging from proliferation, survival/apoptosis, lipid uptake and metabolism, phagocytosis, long term potentiation, cell migration, telomere maintenance, and angiogenesis. Moreover, water-soluble derivatives of vitamin E including some based on αTP are increasingly used as components of nanocarriers for enhanced and targeted delivery of drugs and other molecules (vitamins, including αT and αTP itself, vitamin D3, carnosine, caffeine, docosahexaenoic acid (DHA), insulin) and cofactors such as coenzyme Q10. In this review, the chemical characteristics, transport, metabolic pathways, and molecular mechanisms of action of αTP in cells and tissues are summarized and put into perspective with its possible role in the prevention of a number of diseases. © 2018 Elsevier Inc. All rights reserved.

The development of a stable, coated pellet formulation of a water-sensitive drug, a case study: development of a stable core formulation.

PubMed

Fitzpatrick, Shaun; Taylor, Scott; Booth, Steven W; Newton, Michael J

2006-01-01

A development program has been carried out to provide a stable extrusion/spheronisation pellet formulation for a highly water-soluble drug, sitagliptin, which undergoes a change in physical form on processing and is subject to hydrolytic decomposition. A conventional extrusion/spheronization formulation resulted in significant degradation of the drug. The inclusion of glyceryl monostearate into the formulation was found to reduce the water levels required to such a level that there was no significant degradation of the drug during processing to form pellets. The use of a ram extruder to screen formulations with small quantities minimizes the need for the drug in the formulation-screening process, and the results from this method of extrusion were found to be translatable to the use of a screen extruder, which allowed scale-up of the process.

A Molecular-Level View of the Physical Stability of Amorphous Solid Dispersions

NASA Astrophysics Data System (ADS)

Yuan, Xiaoda

Many pharmaceutical compounds being developed in recent years are poorly soluble in water. This has led to insufficient oral bioavailability of many compounds in vitro. The amorphous formulation is one of the promising techniques to increase the oral bioavailability of these poorly water-soluble compounds. However, an amorphous drug substance is inherently unstable because it is a high energy form. In order to increase the physical stability, the amorphous drug is often formulated with a suitable polymer to form an amorphous solid dispersion. Previous research has suggested that the formation of an intimately mixed drug-polymer mixture contributes to the stabilization of the amorphous drug compound. The goal of this research is to better understand the role of miscibility, molecular interactions and mobility on the physical stability of amorphous solid dispersions. Methods were developed to detect different degrees of miscibility on nanometer scale and to quantify the extent of hydrogen-bonding interactions between the drug and the polymer. Miscibility, hydrogen-bonding interactions and molecular mobility were correlated with physical stability during a six-month period using three model systems. Overall, this research provides molecular-level insights into many factors that govern the physical stability of amorphous solid dispersions which can lead to a more effective design of stable amorphous formulations.

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

PubMed

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

2006-03-01

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

Preparation of finasteride capsules-loaded drug nanoparticles: formulation, optimization, in vitro, and pharmacokinetic evaluation

PubMed Central

Ahmed, Tarek A

2016-01-01

In this study, optimized freeze-dried finasteride nanoparticles (NPs) were prepared from drug nanosuspension formulation that was developed using the bottom–up technique. The effects of four formulation and processing variables that affect the particle size and solubility enhancement of the NPs were explored using the response surface optimization design. The optimized formulation was morphologically characterized using transmission electron microscopy (TEM). Physicochemical interaction among the studied components was investigated. Crystalline change was investigated using X-ray powder diffraction (XRPD). Crystal growth of the freeze-dried NPs was compared to the corresponding aqueous drug nanosuspension. Freeze-dried NPs formulation was subsequently loaded into hard gelatin capsules that were examined for in vitro dissolution and pharmacokinetic behavior. Results revealed that in most of the studied variables, some of the quadratic and interaction effects had a significant effect on the studied responses. TEM image illustrated homogeneity and shape of the prepared NPs. No interaction among components was noticed. XRPD confirmed crystalline state change in the optimized NPs. An enhancement in the dissolution rate of more than 2.5 times from capsules filled with optimum drug NPs, when compared to capsules filled with pure drug, was obtained. Crystal growth, due to Ostwald ripening phenomenon and positive Gibbs free energy, was reduced following lyophilization of the nanosuspension formulation. Pharmacokinetic parameters from drug NPs were superior to that of pure drug and drug microparticles. In conclusion, freeze-dried NPs based on drug nanosuspension formulation is a successful technique in enhancing stability, solubility, and in vitro dissolution of poorly water-soluble drugs with possible impact on the drug bioavailability. PMID:26893559

Water-soluble benzodiazepine prodrug/enzyme combinations for intranasal rescue therapies.

PubMed

Siegel, Ronald A; Kapoor, Mamta; Cheryala, Narsihmulu; Georg, Gunda I; Cloyd, James C

2015-08-01

Benzodiazepines (BZDs), including diazepam (DZP) and midazolam (MDZ), are drugs of choice for rapid treatment of seizure emergencies. Current approved use of these drugs involves administration via either intravenous or rectal routes. The former requires trained medical personnel, while the latter is socially unacceptable for many patients and caregivers. In recent years, efforts have been made to formulate BZDs for nasal administration. Because of the low solubility of these molecules, organic vehicles have been used to solubilize the drugs in the nasal products under development. However, organic solvents are irritating, potentially resulting in injury to nasal tissue. Here we report preliminary studies supporting a strategy in which water-soluble BZD prodrugs and a suitable converting enzyme are coadministered in an aqueous vehicle. Diazepam and midazolam prodrugs were synthesized and were readily converted to their active forms by a protease from Aspergillus oryzae. Using a permeation assay based on monolayers of Madin-Darby canine kidney II-wild type cells, we found that enzymatically produced BZDs could be maintained at high degrees of supersaturation, enabling faster transport across the membrane than can be achieved using saturated solutions. This strategy not only obviates the need for organic solvents, but it also suggests more rapid absorption and earlier peak concentrations than can be otherwise achieved. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015 Elsevier Inc. All rights reserved.

Polymer-coated nanoparticles: Carrier platforms for hydrophobic water- and air-sensitive metallo-organic compounds.

PubMed

Valdeperez, Daniel; Wang, Tianqiang; Eußner, Jens P; Weinert, Bastian; Hao, Jianyuan; Parak, Wolfgang J; Dehnen, Stefanie; Pelaz, Beatriz

2017-03-01

Many of the relevant compounds for anticancer therapy are metal-based compounds (metallodrugs), being platinum-based drugs such as cisplatin, carboplatin (Paraplatin ® ), and oxaliplatin (Eloxatin ® ) the most widely used. Despite this, their application is limited by issues such as cell-acquired platinum resistance and manifold side effects following systemic delivery. Thus, the development of new metal-based compounds is highly needed. The catalytic properties of a variety of metal-based compounds are nowadays very well known, which opens new opportunities to take advantage of them inside living cells or organisms. However, many of these compounds are hydrophobic and thus not soluble in aqueous solution, as they lack stability against water or oxygen presence. Thus, versatile platforms capable of enhancing the features of these compounds in aqueous solutions are of importance in the development of new drugs. Surface engineered nanoparticles may render metallodrugs with good colloidal stability in water and in complex media containing high salt concentration and/or proteins. Herein, polymer coated nanoparticles are proposed as a platform to link insoluble and water/oxygen sensitive drugs. The linkage of insoluble and oxygen sensitive tin clusters to nanoparticles is presented, aiming to enhance both, the solubility and the stability of these compounds in water, which may be an alternative approach in the development of metal-based drugs. The formation of the cluster-nanoparticle system was confirmed via inductively coupled plasma mass spectrometry experiments. The catalytic activity and the stability of the cluster in water were studied through the reduction of methylene blue. Results demonstrate that in fact the tin clusters could be transferred into aqueous solution and retained their catalytic activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Site specific solubility improvement using solid dispersions of HPMC-AS/HPC SSL--mixtures.

PubMed

Zecevic, Damir Elmar; Meier, Robin; Daniels, Rolf; Wagner, Karl-Gerhard

2014-07-01

Many upcoming drug candidates are pH-dependent poorly soluble weak bases in the pH range of the gastrointestinal tract. This often leads to a high in vivo variability and bioavailability issues. Aiming to overcome these limitations, the design of solid dispersions for site specific dissolution improvement or maintenance of a potent supersaturation over the entire gastro-intestinal pH-range, is proposed to assure a reliable drug therapy. Solid dispersions containing different ratios of Dipyridamole (DPD) or Griseofulvin (GRI) and the enteric polymer hydroxypropylmethylcellulose-acetate succinate (HPMC-AS) and the water soluble low-viscosity hydroxypropylcellulose (HPC-SSL) were prepared by hot melt extrusion (HME). The solid dispersions were evaluated for their solid state, dissolution characteristics applying a three pH-step dissolution method following an acidic to neutral pH transition and stability. The use of HPMC-AS in binary mixtures with DPD and GRI facilitated increased solubility and supersaturation at pH-controlled release of the preserved amorphous state of the dispersed drug, which even inverted the pH-dependent solubility profile of the weakly basic model drug (Dipyridamole). I.e. a potent site specific delivery system was created. With ternary solid dispersions of API, HPMC-AS and HPC-SSL, tailored release profiles with superior supersaturation over the applied pH-range could be obtained. At the same time, binary and ternary mixtures showed favorable stability properties at a temperature difference between glass transition temperature and the applied storage temperature of down to 16°C. Copyright © 2014 Elsevier B.V. All rights reserved.

Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system.

PubMed

Zhang, Zhenhai; Cui, Changchang; Wei, Fang; Lv, Huixia

2017-08-01

The aim of this study was to develop a novel mix micelles system composing of two biocompatible copolymers of Soluplus ® and Pluronic F127 to improve the solubility, oral bioavailability of insoluble drug apigenin (AP) as model drug. The AP-loaded mixed micelles (AP-M) were prepared by ethanol thin-film hydration method. The formed optimal formulation of AP-M were provided with small size (178.5 nm) and spherical shape at ratio of 4:1 (Soluplus ® :Pluronic F127), as well as increasing solubility of to 5.61 mg/mL in water which was about 3442-fold compared to that of free AP. The entrapment efficiency and drug loading of AP-M were 95.72 and 5.32%, respectively, and a sustained release of AP-M was obtained as in vitro release study indicated. Transcellular transport study showed that the cell uptake of AP was increased in Caco-2 cell transport models. The oral bioavailability of AP-M was 4.03-fold of free AP in SD rats, indicating the mixed micelles of Soluplus ® and Pluronic F127 is an industrially feasible drug delivery system to promote insoluble drug oral absorption in the gastrointestinal tract.

Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs.

PubMed

Raina, Shweta A; Zhang, Geoff G Z; Alonzo, David E; Wu, Jianwei; Zhu, Donghua; Catron, Nathaniel D; Gao, Yi; Taylor, Lynne S

2014-09-01

Amorphous solid dispersions (ASDs) give rise to supersaturated solutions (solution concentration greater than equilibrium crystalline solubility). We have recently found that supersaturating dosage forms can exhibit the phenomenon of liquid-liquid phase separation (LLPS). Thus, the high supersaturation generated by dissolving ASDs can lead to a two-phase system wherein one phase is an initially nanodimensioned and drug-rich phase and the other is a drug-lean continuous aqueous phase. Herein, the membrane transport of supersaturated solutions, at concentrations above and below the LLPS concentration has been evaluated using a side-by-side diffusion cell. Measurements of solution concentration with time in the receiver cell yield the flux, which reflects the solute thermodynamic activity in the donor cell. As the nominal concentration of solute in the donor cell increases, a linear increase in flux was observed up to the concentration where LLPS occurred. Thereafter, the flux remained essentially constant. Both nifedipine and felodipine solutions exhibit such behavior as long as crystallization is absent. This suggests that there is an upper limit in passive membrane transport that is dictated by the LLPS concentration. These results have several important implications for drug delivery, especially for poorly soluble compounds requiring enabling formulation technologies. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

[Quality comparison of Hirudo before and after processed by French chalk].

PubMed

Zhang, Yong-Tai

2008-04-01

To evaluate the effects of processing methods of Hirudo. Both water and alcohol extracts of Hirudo were studied according to Chinese Pharmacopeia (Edition 2005). The content of hypoxanthine in Hirudo was measured by high performance liquid chromatography (HPLC) and Hirudin was determined by thrombin. The contents of water, water soluble extraction, ethanol soluble extraction and hirudin in crude Hirudo are higher than those in processed Hirudo. But the contents of hypoxanthine in processed Hirudo is higher than in crude Hirudo. Hirudo fried by French chalk can decrease the active components with high intensive drug property, accordingly the toxicity of Hirudo was decreased. As a result, the effects of Hirudo as invigorate the circulation of blood and stimulate the menstrual flow were abated.

Readily prepared biodegradable nanoparticles to formulate poorly water soluble drugs improving their pharmacological properties: The example of trabectedin.

PubMed

Capasso Palmiero, Umberto; Morosi, Lavinia; Bello, Ezia; Ponzo, Marianna; Frapolli, Roberta; Matteo, Cristina; Ferrari, Mariella; Zucchetti, Massimo; Minoli, Lucia; De Maglie, Marcella; Romanelli, Pierpaolo; Morbidelli, Massimo; D'Incalci, Maurizio; Moscatelli, Davide

2018-04-28

The improvement of the pharmacological profile of lipophilic drug formulations is one of the main successes achieved using nanoparticles (NPs) in medicine. However, the complex synthesis procedure and numerous post-processing steps hamper the cost-effective use of these formulations. In this work, an approach which requires only a syringe to produce self-assembling biodegradable and biocompatible poly(caprolactone)-based NPs is developed. The effective synthesis of monodisperse NPs has been made possible by the optimization of the block-copolymer synthesized via a combination of ring opening polymerization and reversible addition-fragmentation chain transfer polymerization. These NPs can be used to formulate lipophilic drugs that are barely soluble in water, such as trabectedin, a potent anticancer therapeutic. Its biodistribution and antitumor activity have been compared with the commercially available formulation Yondelis®. The results indicate that this trabectedin NP formulation performs with the same antitumor activity as Yondelis®, but does not have the drawback of severe local vascular toxicity in the injection site. Copyright © 2018 Elsevier B.V. All rights reserved.

Y-shaped biotin-conjugated poly (ethylene glycol)-poly (epsilon-caprolactone) copolymer for the targeted delivery of curcumin.

PubMed

Zhu, Wenxia; Song, Zhimei; Wei, Peng; Meng, Ning; Teng, Fangfang; Yang, Fengying; Liu, Na; Feng, Runliang

2015-04-01

In order to improve curcumin's low water-solubility and selective delivery to cancer, we reported ligand-mediated micelles based on a Y-shaped biotin-poly (ethylene glycol)-poly (epsilon-caprolactone)2 (biotin-PEG-PCL2) copolymer. Its structure was characterized by (1)H NMR. The blank and drug-loaded micelles obtained by way of thin-film hydration were characterized by dynamic light scattering, X-ray diffraction, infrared spectroscopy and hemolytic test. Curcumin was loaded into micelles with a high encapsulating efficiency (93.83%). Curcumin's water-solubility was enhanced 170,400 times higher than free curcumin. Biotin-PEG-PCL2 micelles showed slower drug release in vitro than H2N-PEG-PCL2 micelles. In vitro cellular uptake and cytotoxicity tests showed that higher dosage of curcumin might overcome the effect of slow release on cytotoxicities because of its higher uptake induced by biotin, resulting in higher anticancer activities against MDA-MB-436 cells. In brief, Y-shaped biotin-PEG-PCL2 is a promising delivery carrier for anticancer drug. Copyright © 2014 Elsevier Inc. All rights reserved.

Microbial cyclic β-(1→3),(1→6)-glucans as potential drug carriers: Interaction studies between cyclic β-glucans isolated from Bradyrhizobium japonicum and betulinic acid.

PubMed

Kambhampati, Naga Sai Visweswar; Kar, Swayamsiddha; Pinnepalli, Sai Siva Kumar; Chelli, Janardhana; Doble, Mukesh

2018-10-05

Betulinic acid (BA), a pentacyclic triterpenoid, is a very promising therapeutic drug with varied medicinal properties but it has low water solubility and consequentially low bioavailability. Cyclic β-(1→3),(1→6)-glucans (CBG), microbial cyclooligosaccharides produced by Bradyrhizobium japonicum ATCC 10324 having a cavity structure and good solubility in water have been tested for their ability to encapsulate betulinic acid and drug-binding interactions of CBG and BA were studied. First, in silico approach was employed to study the scope of any interaction between the CBG and BA. Then, the cyclic glucan-betulinic acid complexes were prepared in three compositions of 1:1, 1:2 and 1:3 CBG:BA. The complexes were analysed using UV-VIS spectroscopy, IR spectroscopy, powder XRD, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) to confirm the computational results and consequently the encapsulation efficiency was found to be 9.53%. Copyright © 2017. Published by Elsevier B.V.

Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles

NASA Astrophysics Data System (ADS)

Dian, Linghui; Yu, Enjiang; Chen, Xiaona; Wen, Xinguo; Zhang, Zhengzan; Qin, Lingzhen; Wang, Qingqing; Li, Ge; Wu, Chuanbin

2014-12-01

To improve its poor aqueous solubility and stability, the potential chemotherapeutic drug quercetin was encapsulated in soluplus polymeric micelles by a modified film dispersion method. With the encapsulation efficiency over 90%, the quercetin-loaded polymeric micelles (Qu-PMs) with drug loading of 6.7% had a narrow size distribution around mean size of 79.00 ± 2.24 nm, suggesting the complete dispersibility of quercetin in water. X-ray diffraction (XRD) patterns illustrated that quercetin was in amorphous or molecular form within PMs. Fourier transform infrared spectroscopy (FTIR) indicated that quercetin formed intermolecular hydrogen bonding with carriers. An in vitro dialysis test showed the Qu-PMs possessed significant sustained-release property, and the formulation was stable for at least 6 months under accelerated conditions. The pharmacokinetic study in beagle dogs showed that absorption of quercetin after oral administration of Qu-PMs was improved significantly, with a half-life 2.19-fold longer and a relative oral bioavailability of 286% as compared to free quercetin. Therefore, these novel soluplus polymeric micelles can be applied to encapsulate various poorly water-soluble drugs towards a development of more applicable therapeutic formulations.

Native and β-cyclodextrin-enclosed curcumin: entrapment within liposomes and their in vitro cytotoxicity in lung and colon cancer.

PubMed

Rahman, Shafiur; Cao, Siyu; Steadman, Kathryn J; Wei, Ming; Parekh, Harendra S

2012-01-01

With a view to improving the solubility and delivery characteristics of poorly water-soluble drugs, we prepared β-cyclodextrin-curcumin (βCD-C) inclusion complexes (hydrophilic curcumin) and entrapped both native curcumin (hydrophobic) and the complexes separately into liposomes; these were then assessed for in vitro cytotoxicity in lung and colon cancer cell lines. Optimization of curcumin entrapment within βCD was achieved, with the resultant βCD-C complexes prepared by methanol reflux. Inclusion complexes were confirmed using UV spectroscopy, Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction. The water solubility of βCD-C complexes improved markedly (c.f. native curcumin) and successful entrapment of complexes into liposomes, prepared using a thin-film hydration approach, was also achieved. All the liposomal formulations were characterized for curcumin and βCD-C complex entrapment efficiency, particle size, polydispersity and stability at 2-8°C. Curcumin, βCD-C complex and their optimized liposomal formulations were evaluated for anticancer activity in lung (A-459) and colon (SW-620) cancer cell lines. All curcumin-containing formulations tested were effective in inhibiting cell proliferation, as determined via an MTT assay. The median effective dose (EC(50)) for all curcumin formulations was found to be in the low µM range for both lung and colon cancer cell lines tested. Our results confirm that βCD inclusion complexes of poorly water soluble drugs, such as curcumin can be entrapped within biocompatible vesicles such as liposomes, and this does not preclude their anticancer activity.

A minitablet formulation made from electrospun nanofibers.

PubMed

Poller, Bettina; Strachan, Clare; Broadbent, Roland; Walker, Greg F

2017-05-01

The purpose of this study was to evaluate electrospun drug loaded nanofibers as a new matrix for minitablets. Prednisone, a poorly water-soluble drug, was loaded into povidone (polyvinylpyrrolidone, PVP) nanofibers using the process of electrospinning. The drug-loaded nanofiber mat was compressed into minitablets with a 2mm diameter and a height of 2.63±0.04mm. SEM analysis of the minitablet identified a nano-web structure with a nanofiber diameter in the range of 400-500nm. The minitablets met the requirements of the US Pharmacopeia with respect to content uniformity and friability. DSC and XRPD analysis of the minitablet indicated that the drug-polymer mixture was a one-phase amorphous system. XRPD analysis of the drug loaded nanofiber mat after 10-months of storage at ambient temperature showed no evidence of recrystallization of the drug. Solubility and dissolution properties of the drug formulated into a nanofiber mat and minitablet were evaluated. These results show that electrospun nanofibers may provide a useful matrix for the further development of minitablets. Copyright © 2017 Elsevier B.V. All rights reserved.

Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids.

PubMed

Remenar, Julius F; Morissette, Sherry L; Peterson, Matthew L; Moulton, Brian; MacPhee, J Michael; Guzmán, Héctor R; Almarsson, Orn

2003-07-16

Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.

Recent advances in non-ionic surfactant vesicles (niosomes): self-assembly, fabrication, characterization, drug delivery applications and limitations.

PubMed

Abdelkader, Hamdy; Alani, Adam W G; Alany, Raid G

2014-03-01

Non-ionic surfactant vesicles, simply known as niosomes are synthetic vesicles with potential technological applications. Niosomes have the same potential advantages of phospholipid vesicles (liposomes) of being able to accommodate both water soluble and lipid soluble drug molecules control their release and as such serve as versatile drug delivery devices of numerous applications. Additionally, niosomes can be considered as more economically, chemically, and occasionally physically stable alternatives to liposomes. Niosomes can be fabricated using simple methods of preparations and from widely used surfactants in pharmaceutical technology. Many reports have discussed niosomes in terms of physicochemical properties and their applications as drug delivery systems. In this report, a brief and simplified summary of different theories of self-assembly will be given. Furthermore manufacturing methods, physical characterization techniques, bilayer membrane additives, unconventional niosomes (discomes, proniosomes, elastic and polyhedral niosomes), their recent applications as drug delivery systems, limitations and directions for future research will be discussed.

Polymeric micelles: nanocarriers for cancer-targeted drug delivery.

PubMed

Zhang, Yifei; Huang, Yixian; Li, Song

2014-08-01

Polymeric micelles represent an effective delivery system for poorly water-soluble anticancer drugs. With small size (10-100 nm) and hydrophilic shell of PEG, polymeric micelles exhibit prolonged circulation time in the blood and enhanced tumor accumulation. In this review, the importance of rational design was highlighted by summarizing the recent progress on the development of micellar formulations. Emphasis is placed on the new strategies to enhance the drug/carrier interaction for improved drug-loading capacity. In addition, the micelle-forming drug-polymer conjugates are also discussed which have both drug-loading function and antitumor activity.

Polymeric nanoparticles for increased oral bioavailability and rapid absorption using celecoxib as a model of a low-solubility, high-permeability drug.

PubMed

Morgen, Michael; Bloom, Corey; Beyerinck, Ron; Bello, Akintunde; Song, Wei; Wilkinson, Karen; Steenwyk, Rick; Shamblin, Sheri

2012-02-01

To demonstrate drug/polymer nanoparticles can increase the rate and extent of oral absorption of a low-solubility, high-permeability drug. Amorphous drug/polymer nanoparticles containing celecoxib were prepared using ethyl cellulose and either sodium caseinate or bile salt. Nanoparticles were characterized using dynamic light scattering, transmission and scanning electron microscopy, and differential scanning calorimetry. Drug release and resuspension studies were performed using high-performance liquid chromatography. Pharmacokinetic studies were performed in dogs and humans. A physical model is presented describing the nanoparticle state of matter and release performance. Nanoparticles dosed orally in aqueous suspensions provided higher systemic exposure and faster attainment of peak plasma concentrations than commercial capsules, with median time to maximum drug concentration (Tmax) of 0.75 h in humans for nanoparticles vs. 3 h for commercial capsules. Nanoparticles released celecoxib rapidly and provided higher dissolved-drug concentrations than micronized crystalline drug. Nanoparticle suspensions are stable for several days and can be spray-dried to form dry powders that resuspend in water. Drug/polymer nanoparticles are well suited for providing rapid oral absorption and increased bioavailability of BCS Class II drugs.

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

PubMed

Carrière, Frédéric

2016-06-01

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

Maintenance of supersaturation I: indomethacin crystal growth kinetic modeling using an online second-derivative ultraviolet spectroscopic method.

PubMed

Patel, Dhaval D; Joguparthi, Vijay; Wang, Zeren; Anderson, Bradley D

2011-07-01

Formulations that produce supersaturated solutions after their oral administration have received increased attention as a means to improve bioavailability of poorly water-soluble drugs. Although it is widely recognized that excipients can prolong supersaturation, the mechanisms by which these beneficial effects are realized are generally unknown. Difficulties in separately measuring the kinetics of nucleation and crystal growth have limited progress in understanding the mechanisms by which excipients contribute to the supersaturation maintenance. This paper describes the crystal growth kinetic modeling of indomethacin, a poorly water-soluble drug, from supersaturated aqueous suspensions using a newly developed, online second-derivative ultraviolet spectroscopic method. The apparent indomethacin equilibrium solubility after crystal growth at a high degree of supersaturation (S=6) was approximately 55% higher than the indomethacin equilibrium solubility determined prior to growth, which was attributed to the deposition of a higher energy indomethacin form on the seed crystals. The indomethacin crystal growth kinetics (S=6) was of first order. By comparing the mass transfer coefficients from indomethacin dissolution and crystal growth, it was shown that the indomethacin crystal growth kinetics at S=6 was bulk diffusion controlled. The change in indomethacin seed crystal size distribution before and after crystal growth was determined and modeled using a mass-balance relationship. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

Glucose-Responsive Supramolecular Vesicles Based on Water-Soluble Pillar[5]arene and Pyridylboronic Acid Derivatives for Controlled Insulin Delivery.

PubMed

Gao, Lei; Wang, Tingting; Jia, Keke; Wu, Xuan; Yao, Chenhao; Shao, Wei; Zhang, Dongmei; Hu, Xiao-Yu; Wang, Leyong

2017-05-11

The stimuli-responsive behavior of supramolecular nanocarriers is crucial for their potential applications as smart drug delivery systems. We hereby constructed a glucose-responsive supramolecular drug delivery system based on the host-guest interaction between a water-soluble pillar[5]arene (WP5) and a pyridylboronic acid derivative (G) for insulin delivery and controlled release under physiological conditions. The approach represents the ideal treatment of diabetes mellitus. The drug loading and in vitro drug release experiments demonstrated that large molecular weight insulin could be encapsulated into the vesicles with high loading efficiency, which, to our knowledge, is the first example of small-size supramolecular vesicles with excellent encapsulation capacity of a large protein molecule. Moreover, FITC-labeled insulin was used to evaluate the release behavior of insulin, and it was demonstrated that high glucose concentration could facilitate the quick release of insulin, suggesting a smart drug delivery system for potential application in controlled insulin release only under hyperglycemic conditions. Finally, we demonstrated that these supramolecular nanocarriers have good cytocompatibility, which is essential for their further biomedical applications. The present study provides a novel strategy for the construction of glucose-responsive smart supramolecular drug delivery systems, which has potential applications for the treatment of diabetes mellitus. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Discovery of cryptophycin-1 and BCN-183577: examples of strategies and problems in the detection of antitumor activity in mice.

PubMed

Corbett, T H; Valeriote, F A; Demchik, L; Lowichik, N; Polin, L; Panchapor, C; Pugh, S; White, K; Kushner, J; Rake, J; Wentland, M; Golakoti, T; Hetzel, C; Ogino, J; Patterson, G; Moore, R

1997-01-01

Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected i.v.

Immunomodulating activities of soluble synthetic polymer-bound drugs.

PubMed

Ríhová, Blanka

2002-09-13

The introduction of a synthetic material into the body always affects different body systems, including the defense system. Synthetic polymers are usually thymus-independent antigens with only a limited ability to elicit antibody formation or to induce a cellular immune response against them. However, there are many other ways that they influence or can be used to influence the immune system of the host. Low-immunogenic water-soluble synthetic polymers sometimes exhibit significant immunomodulating activity, mainly concerning the activation/suppression of NK cells, LAK cells and macrophages. Some of them, such as poly(ethylene glycol) and poly[N-(2-hydroxypropyl)methacrylamide], can be used as effective protein carriers, as they are able to reduce the immunogenicity of conjugated proteins and/or to reduce non-specific uptake of liposome/nanoparticle-entrapped drugs and other therapeutic agents. Recently, the development of vaccine delivery systems prepared from biodegradable and biocompatible water-soluble synthetic polymers, microspheres, liposomes and/or nanoparticles has received considerable attention, as they can be tailored to meet the specific physical, chemical, and immunogenic requirements of a particular antigen and some of them can also act as adjuvants. Copyright 2002 Elsevier Science B.V.

'Pro et contra' ionic liquid drugs - Challenges and opportunities for pharmaceutical translation.

PubMed

Balk, Anja; Holzgrabe, Ulrike; Meinel, Lorenz

2015-08-01

Ionic liquids (ILs) are organic salts with a melting point below 100°C. Active pharmaceutical ingredients (APIs) are transformed into ILs by combining them with typically large yet charged counterions. ILs hold promise to build a large design space for relevant pharmaceutical parameters, particularly for poorly water soluble drugs. It is for this wide design space that ILs may be the entry into the fascinating vision of modifying physico-chemical properties without the need to structurally modify the active pharmaceutical ingredient itself. This extremely intriguing pharmaceutical option is critically discussed including its potential and limitations. The review is starting off with an introduction to the metathesis and characterization of ILs, and leads over to examples for pharmaceutical application, including enhancement of dissolution rate and kinetic solubility and hygroscopicity adaptation, respectively. Tuning biopharmaceutics and toxicology by proper IL design is another focus. The review connects the interrelated chemical, physical, pharmaceutical, and toxicological outcome of API-ILs, serving as guidance for the formulation scientist who aims at expanding ones armamentarium for poorly water soluble APIs while avoiding structural modification, thereof. Copyright © 2015 Elsevier B.V. All rights reserved.

New ethanol and propylene glycol free gel formulations containing a minoxidil-methyl-β-cyclodextrin complex as promising tools for alopecia treatment.

PubMed

Lopedota, Angela; Cutrignelli, Annalisa; Denora, Nunzio; Laquintana, Valentino; Lopalco, Antonio; Selva, Stefano; Ragni, Lorella; Tongiani, Serena; Franco, Massimo

2015-05-01

New topical totally aqueous formulations that improve the low water solubility of minoxidil and realize an adequate permeability of drug in the skin are proposed. These formulations are lacking in propylene glycol and alcohol that are the principal irritant ingredients present in minoxidil commercial solutions. In order to enhance poor water solubility of minoxidil randomly methyl-β-cyclodextrin was used, and four hydrogels such as, calcium alginate, sodium alginate, carbopol 934 and hydroxyethylcellulose were utilized to ensure a prolonged time of contact with the scalp. The inclusion complex minoxidil/methyl-β-cyclodextrin with a molar ratio 1:1 was obtained by freeze drying and evaluated by NMR, FT-IR and DSC analysis. An apparent stability constant of formed inclusion complex was calculated by phase solubility diagram and its value was 400 M(-1). The solid inclusion complex was used to prepare gel formulations with similar dose to minoxidil commercial solution. The gels were evaluated for various technological parameters including rheological behavior, in vitro drug release and ex vivo permeation through pig skin. The best performance was observed for the calcium alginate formulation.

Polymeric anticancer drugs with pH-controlled activation.

PubMed

Ulbrich, Karel; Subr, Vladimír

2004-04-23

Use of macromolecular water-soluble carriers of anti-cancer drugs represents a promising approach to cancer therapy. Release of drugs from the carrier system is a prerequisite for therapeutic activity of most macromolecular anti-cancer conjugates. Incorporation of acid-sensitive spacers between the drug and carrier enables release of an active drug from the carrier in a tumor tissue, either in slightly acidic extracellular fluids or, after endocytosis, in endosomes or lysosomes of cancer cells. This paper reviews advances in development and study of properties of various acid-sensitive macromolecular drug delivery systems, starting from simple polymer-drug conjugates to ending with site-specific antibody-targeted polymer-drug conjugates.

Preparation and characterization of fast dissolving pullulan films containing BCS class II drug nanoparticles for bioavailability enhancement.

PubMed

Krull, Scott M; Ma, Zhelun; Li, Meng; Davé, Rajesh N; Bilgili, Ecevit

2016-01-01

The aim of this study is to assess pullulan as a novel steric stabilizer during the wet-stirred media milling (WSMM) of griseofulvin, a model poorly water-soluble drug, and as a film-former in the preparation of strip films via casting-drying the wet-milled drug suspensions for dissolution and bioavailability enhancement. To this end, pullulan films, with xanthan gum (XG) as thickening agent and glycerin as plasticizer, were loaded with griseofulvin nanoparticles prepared by WSMM using pullulan in combination with sodium dodecyl sulfate (SDS) as an ionic stabilizer. The effects of drug loading and milling time on the particle size and suspension stability were investigated, as well as XG concentration and casting thickness on film properties and dissolution rate. The nanosuspensions prepared with pullulan-SDS combination were relatively stable over 7 days; hence, this combination was used for the film preparation. All pullulan-based strip films exhibited excellent content uniformity (most <3% RSD) despite containing only 0.3-1.3 mg drug, which was ensured by the use of precursor suspensions with >5000 cP viscosity. USP IV dissolution tests revealed fast/immediate drug release (t80 < 30 min) from films <120 μm thick. Thinner films, films with lower XG loading, or smaller drug particles led to faster drug dissolution, while drug loading had no discernible effect. Overall, these results suggest that pullulan may serve as an acceptable stabilizer for media milling in combination with surfactant as well as a fast-dissolving film former for the fast release of poorly water-soluble drug nanoparticles.

Influence of lidocaine forms (salt vs. freebase) on properties of drug-eudragit® L100-55 extrudates prepared by reactive melt extrusion.

PubMed

Liu, Xu; Ma, Xiangyu; Kun, Eucharist; Guo, Xiaodi; Yu, Zhongxue; Zhang, Feng

2018-06-05

This study examines the preparation of sustained-release lidocaine polyelectrolyte complex using reactive melt extrusion. Eudragit L100-55 was selected as the ionic polymer. The influence of drug forms (freebase vs. hydrochloride salt) on lidocaine-Eudragit L100-55 interactions, physical stability, and dissolution properties of extrudates was investigated. It was confirmed by DSC, FT-IR and Raman spectroscopy that polyelectrolyte could only form via the acid-base reaction between Eudragit L100-55 and lidocaine freebase. Due to this ionic interaction, the lidocaine extrudate was physically more stable than the lidocaine hydrochloride extrudate during the storage under stressed condition. Drug release from lidocaine extrudate was a function of drug solubility, polymer solubility, drug-polymer interaction, and drug-induced microenvironment pH. At 30% drug loading, extrudate exhibited sustained release in aqueous media at pH 1.2 and 4.5. Due to the alkaline microenvironment pH induced by dissolved lidocaine, Eudragit L100-55 was solubilized and sustained-release was not achieved in water and aqueous media at pH 5.5. In comparison, lidocaine hydrochloride induced an acidic microenvironment. Drug release of lidocaine hydrochloride extrudate was similar at pH 1.2, 4.5, 5.5 and water with drug being released over 10 h. The release of lidocaine hydrochloride from the extrudates in these media was primarily controlled by microenvironment pH. It is concluded that different forms of lidocaine resulted in different drug-polymer interactions and distinctive physicochemical properties of extrudates. Copyright © 2018. Published by Elsevier B.V.

Synergistic Skin Penetration Enhancer and Nanoemulsion Formulations Promote the Human Epidermal Permeation of Caffeine and Naproxen.

PubMed

Abd, Eman; Namjoshi, Sarika; Mohammed, Yousuf H; Roberts, Michael S; Grice, Jeffrey E

2016-01-01

We examined the extent of skin permeation enhancement of the hydrophilic drug caffeine and lipophilic drug naproxen applied in nanoemulsions incorporating skin penetration enhancers. Infinite doses of fully characterized oil-in-water nanoemulsions containing the skin penetration enhancers oleic acid or eucalyptol as oil phases and caffeine (3%) or naproxen (2%) were applied to human epidermal membranes in Franz diffusion cells, along with aqueous control solutions. Caffeine and naproxen fluxes were determined over 8 h. Solute solubility in the formulations and in the stratum corneum (SC), as well as the uptake of product components into the SC were measured. The nanoemulsions significantly enhanced the skin penetration of caffeine and naproxen, compared to aqueous control solutions. Caffeine maximum flux enhancement was associated with a synergistic increase in both caffeine SC solubility and skin diffusivity, whereas a formulation-increased solubility in the SC was the dominant determinant for increased naproxen fluxes. Enhancements in SC solubility were related to the uptake of the formulation excipients containing the active compounds into the SC. Enhanced skin penetration in these systems is largely driven by uptake of formulation excipients containing the active compounds into the SC with impacts on SC solubility and diffusivity.

Nanoparticle-in-microparticle oral drug delivery system of a clinically relevant darunavir/ritonavir antiretroviral combination.

PubMed

Augustine, Robin; Ashkenazi, Dana Levin; Arzi, Roni Sverdlov; Zlobin, Vita; Shofti, Rona; Sosnik, Alejandro

2018-05-01

Nanonizationhas been extensively investigated to increase theoral bioavailability of hydrophobicdrugsin general andantiretrovirals(ARVs)used inthe therapy of the human immunodeficiency virus (HIV) infection in particular. Weanticipatedthatin the caseofprotease inhibitors, a family of pH-dependent ARVsthatdisplay high aqueous solubility undertheacidconditionsof thestomach andextremely low solubilityunder the neutral ones ofthe small intestine, this strategy might failowing to an uncontrolled dissolution-re-precipitation process that will take place along the gastrointestinal tract.To tackle thisbiopharmaceutical challenge, in this work, wedesigned, produced and fully characterized a novelNanoparticle-in-MicroparticleDelivery System(NiMDS)comprised of pure nanoparticlesofthefirst-line protease inhibitor darunavir(DRV) and itsboosting agentritonavir (RIT) encapsulated within film-coated microparticles.For this, a clinically relevant combination of pure DRV and RIT nanoparticles wassynthesized by a sequential nanoprecipitation/solvent diffusion and evaporation method employing sodium alginateas viscosity stabilizer. Then, pure nanoparticles were encapsulated within calcium alginate/chitosanmicroparticlesthat were film-coated with a series ofpoly(methacrylate) copolymers with differential solubility in the gastrointestinal tract. This coating ensured full stability under gastric-like pH and sustained drug release under intestinal one. PharmacokineticstudiesconductedinalbinoSpragueDawleyratsshowed that DRV/RIT-loadedNiMDSs containing 17% w/w drug loading based on dry weight significantlyincreasedthe oral bioavailabilityof DRVby 2.3-foldwith respect to both theunprocessedandthenanonized DRV/RIT combinations that showed statistically similar performance. Moreover, they highlighted the limited advantage of only drugnanonizationto improve the oral pharmacokinetics of protease inhibitors and the potential of our novel delivery approach to improve the oral pharmacokinetics of nanonized poorly water-soluble drugs displaying pH-dependent solubility. Protease inhibitors (PIs) are gold-standard drugs in many ARV cocktails. Darunavir (DRV) is the latest approved PI and it is included in the 20th WHO Model List of Essential Medicines. PIs poorly-water soluble at intestinal pH and more soluble under gastric conditions. Drug nanonization represents one of the most common nanotechnology strategies to increase dissolution rate of hydrophobic drugs and thus, their oral bioavailability. For instance, pure drug nanosuspensions became the most clinically relevant nanoformulation. However, according to the physicochemical properties of PIs, nanonization does not appear as a very beneficial strategy due to the fast dissolution rate anticipated under the acid conditions of the stomach and their uncontrolled recrystallization and precipitation in the small intestine that might result in the formation of particles of unpredictable size and structure (e.g., crystallinity and polymorphism) and consequently, unknown dissolution rate and bioavailability. In this work, we developed a sequential nanoprecipitation method for the production of pure nanoparticles of DRV and its boosting agent ritonavir in a clinically relevant 8:1 wt ratio using alginate as viscosity stabilizer and used this nanosuspension to produce a novel kind of nanoparticle-in-microparticle delivery system that was fully characterized and the pharmacokinetics assessed in rats. The most significant points of the current manuscript are. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Assessment of solubilization characteristics of different surfactants for carvedilol phosphate as a function of pH.

PubMed

Chakraborty, Subhashis; Shukla, Dali; Jain, Achint; Mishra, Brahmeshwar; Singh, Sanjay

2009-07-15

The effect of surfactants on the solubility of a new phosphate salt of carvedilol was investigated at different biorelevent pH to evaluate their solubilization capacity. Solutions of different classes of surfactants viz., anionic-sodium dodecyl sulfate (SDS) and sodium taurocholate (STC), cationic-cetyltrimethylammonium bromide (CTAB) and non-ionic-Tween 80 (T80) were prepared in the concentration range of 5-35 mmol dm(-3) in buffer solutions of pH 1.2, 3.0, 4.5, 5.8, 6.8 and 7.2. The solubility data were used to calculate the solubilization characteristics viz. molar solubilization capacity, water micelle partition coefficient, free energy of solubilization and binding constant. Solubility enhancement in basic pH was in following order: CTAB>T80>SDS>STC. CTAB and T80 showed remarkable solubility enhancement in acidic pH as well. Among the anionic surfactants, solubility in acidic medium was retarded except at pH 1.2 in case of SDS. Cationic and non-ionic surfactants were found to be suitable for enhancing the solubility of CP which can be employed for maintaining the in vitro sink condition in the basic dissolution medium. While anionic surfactants showed solubility retardant behavior which may be exploited in increasing the drug entrapment efficiency of a colloidal drug delivery system formulated by emulsification technique.

Scale-up of water-based spider silk film casting using a film applicator.

PubMed

Agostini, Elisa; Winter, Gerhard; Engert, Julia

2017-10-30

Spider silk proteins for applications in drug delivery have attracted an increased interest during the past years. Some possible future medical applications for this biocompatible and biodegradable material are scaffolds for tissue engineering, implantable drug delivery systems and coatings for implants. Recently, we reported on the preparation of water-based spider silk films for drug delivery applications. In the current study, we describe the development of a manufacturing technique for casting larger spider silk films from aqueous solution employing a film applicator. Films were characterized in terms of morphology, water solubility, protein secondary structure, thermal stability, and mechanical properties. Different post-treatments were evaluated (phosphate ions, ethanol, steam sterilization and water vapor) to increase the content of β-sheets thereby achieving water insolubility of the films. Finally, the mechanical properties of the spider silk films were improved by incorporating 2-pyrrolidone as plasticizer. Copyright © 2017 Elsevier B.V. All rights reserved.

A novel method for determining the solubility of small molecules in aqueous media and polymer solvent systems using solution calorimetry.

PubMed

Fadda, Hala M; Chen, Xin; Aburub, Aktham; Mishra, Dinesh; Pinal, Rodolfo

2014-07-01

To explore the application of solution calorimetry for measuring drug solubility in experimentally challenging situations while providing additional information on the physical properties of the solute material. A semi-adiabatic solution calorimeter was used to measure the heat of dissolution of prednisolone and chlorpropamide in aqueous solvents and of griseofulvin and ritonavir in viscous solutions containing polyvinylpyrrolidone and N-ethylpyrrolidone. Dissolution end point was clearly ascertained when heat generation stopped. The heat of solution was a linear function of dissolved mass for all drugs (<10% RSD, except for chlorpropamide). Heats of solution of 9.8 ± 0.8, 28.8 ± 0.6, 45.7 ± 1.6 and 159.8 ± 20.1 J/g were obtained for griseofulvin, ritonavir, prednisolone and chlorpropamide, respectively. Saturation was identifiable by a plateau in the heat signal and the crossing of the two linear segments corresponds to the solubility limit. The solubilities of prednisolone and chlopropamide in water by the calorimetric method were 0.23 and 0.158 mg/mL, respectively, in agreement with the shake-flask/HPLC-UV determined values of 0.212 ± 0.013 and 0.169 ± 0.015 mg/mL, respectively. For the higher solubility and high viscosity systems of griseofulvin and ritonavir in NEP/PVP mixtures, respectively, solubility values of 65 and 594 mg/g, respectively, were obtained. Solution calorimetry offers a reliable method for measuring drug solubility in organic and aqueous solvents. The approach is complementary to the traditional shake-flask method, providing information on the solid properties of the solute. For highly viscous solutions, the calorimetric approach is advantageous.

In vitro and in vivo evaluation of self-nanoemulsifying drug delivery systems of cilostazol for oral and parenteral administration.

PubMed

Mahmoud, Dina B; Shukr, Marwa H; Bendas, Ehab R

2014-12-10

The current investigation was aimed to improve the solubility of poorly soluble drug, cilostazol (CLZ). Self-nanoemulsifying drug delivery system (SNEDDS) composed of oil, surfactant and co-surfactant for both oral and parenteral administration of CLZ was formulated. The components for SNEDDS were identified by solubility studies, and pseudo-ternary phase diagrams were plotted to identify the efficient self-emulsification regions. The optimum formula, composed of Capryol 90 as an oil phase, Cremophor EL as a surfactant, and Transcutol HP as a co-surfactant in a ratio of 19.8:30.5:49.7 by weight, was able to solubilize CLZ 2000 times higher than its solubility in water. This formula was able to form grade "A" nanoemulsion when diluted with water, resulted in emulsification time of 50±1.1 s, particle size of 14.3 nm, PDI of 0.5 and % transmittance was 97.40%±0.65. It showed excellent in vitro dissolution of 93.1% and 81.5% after 5 min in 0.3% sodium lauryl sulphate solution and phosphate buffer pH 6.4, respectively when compared with the marketed tablet formulation and drug suspension as the tablets showed only 44.3% and 9.9% while CLZ suspension showed 33.9% and 8.8% in 0.3% sodium lauryl sulphate solution and phosphate buffer pH 6.4, respectively. It was found to be robust to dilution, thermodynamically stable with low viscosity values of 14.20±0.35 cP. In vivo study revealed significant increase in bioavailability of CLZ in rabbits to 3.94 fold compared with the marketed tablet formulation after oral administration. This formula could be sterilized by autoclaving and did not cause significant hemolysis to human blood which indicates its safety for intravenous administration with a 1.12 fold increase in bioavailability compared with its oral administration. Our study illustrated the potential use of SNEDDS of poorly soluble CLZ orally, and its successful administration of parenterally when required in acute cases of myocardial and cerebral infarction. Copyright © 2014 Elsevier B.V. All rights reserved.

Preparation and characterization of cyanocobalamin (vit B12) microemulsion properties and structure for topical and transdermal application.

PubMed

Salimi, Anayatollah; Sharif Makhmal Zadeh, Behzad; Moghimipour, Eskandar

2013-07-01

The objective of this study was to design a topical microemulsion of Vit B12 and to study the correlation between internal structure and physicochemical properties of the microemulsions. Microemulsions are thermodynamically stable mixtures of water, oil, surfactants and usually cosurfactants with several advantages for topical and transdermal drug delivery. The formulation of microemulsions for pharmaceutical use requires a clear understanding of the properties and microstructures of the microemulsions. In this study, phase behavior and microstructure of traditional and novel microemulsions of Vit B12 have been investigated by Small-angle X-ray (SAXS), differential scanning calorimetery (DSC) and measuring density, particle size, conductivity and surface tension. WO and bicontinuous microemulsion with different microstructures were found in novel and traditional formulations. In this study, amount of water, surfactant concentration, oil/ surfactant ratio and physicochemical properties of cosurfactants influenced the microstructures. In both formulations, water behavior was affected by the concentration of the surfactant. Water Solubilization capacity and enthalpy of exothermic peak of interfacial and free water of traditional formulations were more than novel ones. This means that the affinity of water to interfacial film is dependent on the surfactant properties.   This study showed that both microemulsions provided good solubility of Vit B12 with a wide range of internal structure. Low water solubilization capacity is a common property of microemulsions that can affect drug release and permeability through the skin.  Based on Vit B12 properties, specially, intermediate oil and water solubility, better drug partitioning into the skin may be obtained by traditional formulations with wide range of structure and high amount of free and bounded water.    

Synthesis, Surface Parameters, and Biodegradability of Water-soluble Surfactants for Various Applications.

PubMed

El-Sayed, Refat; Alotaibi, Hawazin H; Elhady, Heba A

2018-01-01

The synthesis of water-soluble heterocyclic compounds was verified on the basis of nonionic surfactants for use as surface-active agents. Surface characteristics such as surface and interfacial tensions, cloud point, wetting time, emulsion stability, foaming height and foaming stability were measured for these surface factors in aqueous solutions. In addition, the critical micelle concentration (CMC), the surface pressure at CMC (π cmc ), the effectiveness of surface tension reduction (pC 20 ), the maximum surface concentration (Γ ma. ) and the minimum area/molecule at the aqueous solution/air interface (A min ) were calculated. Moreover, the biodegradability for these nonionic surfactants has been investigated. Furthermore, the antimicrobial evaluation has been evaluated with some surfactants that have demonstrated a potent cytotoxicity as antibacterial, antifungal and anticancer. These surfactants have a good water solubility, low toxicity, environmentally friendly environment, high foam, good emulsifier and easy production that will be used them in various fields such as medical drugs, insecticides, detergents, emulsifiers, cosmetics, inks clothing, leather industry and oil recovery.

Structural data and immunomodulatory properties of a water-soluble heteroglycan extracted from the mycelium of an Italian isolate of Ganoderma lucidum.

PubMed

Carrieri, Raffaele; Manco, Rosanna; Sapio, Daniela; Iannaccone, Marco; Fulgione, Andrea; Papaianni, Marina; de Falco, Bruna; Grauso, Laura; Tarantino, Paola; Ianniello, Flora; Lanzotti, Virginia; Lahoz, Ernesto; Capparelli, Rosanna

2017-09-01

Mushrooms produce a wide range of bioactive polysaccharides, different from each other in chemical structure and biological effects. In the last years, the idea to develop functional foods or drugs containing fungal polysaccharides is attracting great attention. Fruiting bodies of Basidiomycetes Ganoderma lucidum are commonly used in Oriental medicine to treat several disorders. G. lucidum polysaccharides - mainly β-glucans and heteroglycans - have numerous biological properties such as antitumour and immunomodulatory activities. This report shows, by gene expression analyses and bioenergetic assays, immunomodulatory properties and capacity to improve glucose metabolism of a water-soluble heteroglycan extracted from mycelium of an Italian isolate of G. lucidum. The findings suggest the use of the heteroglycan as probiotic or ingredient in functional foods, being easy to produce and disperse in a food matrix thanks to its water-solubility. Heteroglycan could exert protective effects in pro-inflammatory conditions and benefits for people characterised by suppressed immune response.