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Sample records for poorly water-soluble drug

  1. Transformation of acidic poorly water soluble drugs into ionic liquids.

    PubMed

    Balk, Anja; Wiest, Johannes; Widmer, Toni; Galli, Bruno; Holzgrabe, Ulrike; Meinel, Lorenz

    2015-08-01

    Poor water solubility of active pharmaceutical ingredients (API) is a major challenge in drug development impairing bioavailability and therapeutic benefit. This study is addressing the possibility to tailor pharmaceutical and physical properties of APIs by transforming these into tetrabutylphosphonium (TBP) salts, including the generation of ionic liquids (IL). Therefore, poorly water soluble acidic APIs (Diclofenac, Ibuprofen, Ketoprofen, Naproxen, Sulfadiazine, Sulfamethoxazole, and Tolbutamide) were converted into TBP ILs or low melting salts and compared to the corresponding sodium salts. Free acids and TBP salts were characterized by NMR and IR spectroscopy, DSC and XRPD, DVS and dissolution rate measurements, release profiles, and saturation concentration measurements. TBP salts had lower melting points and glass transition temperatures and dissolution rates were improved up to a factor of 1000 as compared to the corresponding free acid. An increase in dissolution rates was at the expense of increased hygroscopicity. In conclusion, the creation of TBP ionic liquids or solid salts from APIs is a valuable concept addressing dissolution and solubility challenges of poorly water soluble acidic compounds. The data suggested that tailor-made counterions may substantially expand the formulation scientist's armamentarium to meet challenges of poorly water soluble drugs.

  2. 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.

  3. Nanoformulation and encapsulation approaches for poorly water-soluble drug nanoparticles

    NASA Astrophysics Data System (ADS)

    Wais, Ulrike; Jackson, Alexander W.; He, Tao; Zhang, Haifei

    2016-01-01

    During the last few decades the nanomedicine sector has emerged as a feasible and effective solution to the problems faced by the high percentage of poorly water-soluble drugs. Decreasing the size of such drug compounds to the nanoscale can significantly change their physical properties, which lays the foundation for the use of nanomedicine for pharmaceutical applications. Various techniques have been developed to produce poorly water-soluble drug nanoparticles, mainly to address the poor water-soluble issues but also for the efficient and targeted delivery of such drugs. These techniques can be generally categorized into top-down, bottom-up and encapsulation approaches. Among them, the top-down approaches have been the main choice for industrial preparation of drug nanoparticles while other methods are actively investigated by researchers. In this review, we aim to give a comprehensive overview and latest progress of the top-down, bottom-up, and encapsulation methods for the preparation of poorly water-soluble drug nanoparticles and how solvents and additives can be selected for these methods. In addition to the more industrially applied top-down approaches, the review is focused more on bottom-up and encapsulation methods, particularly covering supercritical fluid-related methods, cryogenic techniques, and encapsulation with dendrimers and responsive block copolymers. Some of the approved and mostly used nanodrug formulations on the market are also covered to demonstrate the applications of poorly water-soluble drug nanoparticles. This review is complete with perspectives on the development and challenges of fabrication techniques for more effective nanomedicine.

  4. Nanocrystals for the parenteral delivery of poorly water-soluble drugs

    PubMed Central

    Sun, Bo; Yeo, Yoon

    2012-01-01

    Nanocrystals have drawn increasing interest in pharmaceutical industry because of the ability to improve dissolution of poorly water-soluble drugs. Nanocrystals can be produced by top-down and bottom-up technologies and have been explored for a variety of therapeutic applications. Here we review the methods of nanocrystal production and parenteral applications of nanocrystals. We also discuss remaining challenges in the development of nanocrystal products. PMID:23645994

  5. Polymeric Micelles, a Promising Drug Delivery System to Enhance Bioavailability of Poorly Water-Soluble Drugs

    PubMed Central

    Ling, Peixue; Zhang, Tianmin

    2013-01-01

    Oral administration is the most commonly used and readily accepted form of drug delivery; however, it is find that many drugs are difficult to attain enough bioavailability when administered via this route. Polymeric micelles (PMs) can overcome some limitations of the oral delivery acting as carriers able to enhance drug absorption, by providing (1) protection of the loaded drug from the harsh environment of the GI tract, (2) release of the drug in a controlled manner at target sites, (3) prolongation of the residence time in the gut by mucoadhesion, and (4) inhibition of efflux pumps to improve the drug accumulation. To explain the mechanisms for enhancement of oral bioavailability, we discussed the special stability of PMs, the controlled release properties of pH-sensitive PMs, the prolongation of residence time with mucoadhesive PMs, and the P-gp inhibitors commonly used in PMs, respectively. The primary purpose of this paper is to illustrate the potential of PMs for delivery of poorly water-soluble drugs with bioavailability being well maintained. PMID:23936656

  6. Nanonization of poorly water-soluble drug clobetasone butyrate by using femtosecond laser

    NASA Astrophysics Data System (ADS)

    Pan, Sunqiang; Takebe, Gen; Suzuki, Masumi; Takamoto, Hisayoshi; Ge, Jianhong; Liu, Chong; Hiramatsu, Mitsuo

    2014-02-01

    Nanonization, which involves the formation of the drug with nanometer particle size, is an effective method to improve the dissolution rate and bioavailability of poorly water-soluble drugs. A pulsewidth-tunable femtosecond laser was used to produce nanoparticles of clobetasone butyrate using poloxamer 188 as stabilizing agent. The effects of temperature and pulsewidth on the particle size and concentration were studied for the first time. The particle size and drug concentration dependence on the laser intensity and irradiation time were also investigated. Permeability test releaved that laser nanonization improved the drug permeability across Caco-2 cell monolayer. This laser nanonization method has a great potential to be used for new drug development.

  7. 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

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

    PubMed

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

    2012-11-01

    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.

  9. 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.

  10. 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. PMID:23651401

  11. Improvement in solubility of poor water-soluble drugs by solid dispersion

    PubMed Central

    Sareen, Swati; Mathew, George; Joseph, Lincy

    2012-01-01

    This article is intended to combine recent literature on solid dispersion technology for solubility enhancement with special emphasis on mechanism responsible for the same by solid dispersion, various preparation methods, and evaluation parameters. Solubility behavior is the most challenging aspect for various new chemical entities as 60% of the new potential products possess solubility problems. This is the biggest reason for new drug molecules not reaching to the market or not reaches to full potential. There are various techniques to enhance the drug solubility such as particle size reduction, nanosuspension, use of surfactants, salt formation, solid dispersion, etc. From this article it may be concluded that solid dispersion is an important approach for improvement of bioavailability of poor water-soluble drugs. PMID:23071955

  12. 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. PMID:22923874

  13. Lipid nanoparticles with no surfactant improve oral absorption rate of poorly water-soluble drug.

    PubMed

    Funakoshi, Yuka; Iwao, Yasunori; Noguchi, Shuji; Itai, Shigeru

    2013-07-15

    A pharmacokinetic study was performed in rats to evaluate the oral absorption ratios of nanoparticle suspensions containing the poorly water-soluble compound nifedipine (NI) and two different types of lipids, including hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol. NI-lipid nanoparticle (LN) suspensions with a mean particle size of 48.0 nm and a zeta potential of -57.2 mV were prepared by co-grinding combined with a high-pressure homogenization process. The oral administration of NI-LN suspensions to rats led to a significant increase in the NI plasma concentration, and the area under the curve (AUC) value was found to be 108 min μg mL⁻¹, indicating a 4-fold increase relative to the NI suspensions. A comparison of the pharmacokinetic parameters of the NI-LN suspensions with those of the NI solution prepared using only the surfactant polysorbate 80 revealed that although the AUC and bioavailability (59%) values were almost identical, a rapid absorption rate was still observed in the NI-LN suspensions. These results therefore indicated that lipid nanoparticles prepared using only two types of phospholipid with a mean particle size of less than 50 nm could improve the absorption of the poorly water-soluble drug.

  14. Effect of particle size on the dissolution behaviors of poorly water-soluble drugs.

    PubMed

    Chu, Kyung Rok; Lee, Eunhee; Jeong, Seong Hoon; Park, Eun-Seok

    2012-07-01

    This study examined the effects of the particle size of various poorly water-soluble drugs on their dissolution behavior through physicochemical and mathematical analysis. As model drugs, hydrochlorothiazide, aceclofenac, ibuprofen and a discovery candidate were selected. The materials were crystallized using an evaporation method and milled without transformation behavior of crystal forms. The particles were sieved and divided into four size groups (< 45 μm, 45∼150 μm, 150∼250 μm, and 250∼600 μm). The specific surface area with regard to the particle size was measured using a BET surface area measurement. The specific surface area increased with decreasing particle size of the drug, resulting in an increase in dissolution rate. During the initial period of the dissolution study, significant differences in dissolution rate were observed according to the particle size and specific surface areas. On the other hand, in the later stages, the surface-specific dissolution rate was almost consistent regardless of the particle size. These observations were evaluated mathematically and the results suggested that the dissolution rate of poorly soluble drugs is strongly related to the particle size distribution. Moreover, physicochemical analysis helped explain the effect of particle size on the dissolution profiles. PMID:22864741

  15. Cyclodextrin and Meglumine-Based Microemulsions as a Poorly Water-Soluble Drug Delivery System.

    PubMed

    Aloisio, Carolina; G de Oliveira, Anselmo; Longhi, Marcela

    2016-09-01

    Cyclodextrins (CDs) and meglumine (MEG) are pharmaceutical excipients widely used to improve solubility of poorly water-soluble drugs. The purpose of this work was to study the effect of CDs or MEG on the internal microstructure of soya oil-based O/W microemulsions (MEs) and on the modulation of the solubility and release rate of Class II model hydrophobic drugs, sulfamerazine and indomethacin. The pseudoternary phase diagrams revealed that higher proportions of oil phase, as well as the presence of β-cyclodextrin (ßCD), methyl-ßCD, and MEG, favored the incorporation of the drugs. The conductivity studies, particle size, and zeta potential analysis showed that the O/W ME structure remained unaffected and that the ME presented reduced droplet sizes after the incorporation of the ligands. The drug-component interactions were assessed by proton nuclear magnetic resonance studies. The highest incorporations of sulfamerazine (35.6 mg/mL) and indomethacin (73.1 mg/mL) were obtained with the ME with W = 5%, MEG and W = 1.8% ßCD in a phosphate buffer solution of pH 8, respectively. In addition, the ligands in ME significantly enhanced the released amount of the drugs, probably due to a solubilizing effect that facilitates the drug to penetrate the unstirred water layer adjacent to membranes. PMID:26886337

  16. Cyclodextrin and Meglumine-Based Microemulsions as a Poorly Water-Soluble Drug Delivery System.

    PubMed

    Aloisio, Carolina; G de Oliveira, Anselmo; Longhi, Marcela

    2016-09-01

    Cyclodextrins (CDs) and meglumine (MEG) are pharmaceutical excipients widely used to improve solubility of poorly water-soluble drugs. The purpose of this work was to study the effect of CDs or MEG on the internal microstructure of soya oil-based O/W microemulsions (MEs) and on the modulation of the solubility and release rate of Class II model hydrophobic drugs, sulfamerazine and indomethacin. The pseudoternary phase diagrams revealed that higher proportions of oil phase, as well as the presence of β-cyclodextrin (ßCD), methyl-ßCD, and MEG, favored the incorporation of the drugs. The conductivity studies, particle size, and zeta potential analysis showed that the O/W ME structure remained unaffected and that the ME presented reduced droplet sizes after the incorporation of the ligands. The drug-component interactions were assessed by proton nuclear magnetic resonance studies. The highest incorporations of sulfamerazine (35.6 mg/mL) and indomethacin (73.1 mg/mL) were obtained with the ME with W = 5%, MEG and W = 1.8% ßCD in a phosphate buffer solution of pH 8, respectively. In addition, the ligands in ME significantly enhanced the released amount of the drugs, probably due to a solubilizing effect that facilitates the drug to penetrate the unstirred water layer adjacent to membranes.

  17. Functions of Lipids for Enhancement of Oral Bioavailability of Poorly Water-Soluble Drugs

    PubMed Central

    Nanjwade, Basavaraj K.; Patel, Didhija J.; Udhani, Ritesh A.; Manvi, Fakirappa V.

    2011-01-01

    Lipid-based formulations encompass a diverse group of formulations with very different physical appearance, ranging from simple triglyceride vehicles to more sophisticated formulations such as self-emulsifying drug delivery systems (SEDDS). Lipid-based drug delivery systems may contain a broad range of oils, surfactants, and co-solvents. They represent one of the most popular approaches to overcome the absorption barriers and to improve the bioavailability of poorly water-soluble drugs. Diversity and versatility of pharmaceutical grade lipid excipients and drug formulations as well as their compatibility with liquid, semi-solid and solid dosage forms make lipid systems most complex. Digestion of triglyceride lipids, physicochemical characteristics and solubilisation of lipid digestion products as well as intestinal permeability are some of the variable parameters of such formulations. Furthermore, among the factors affecting the bioavailability of the drug from lipid-based formulations are the digestion of lipid, the mean emulsion droplet diameter, the lipophilicity of the drug and the type of lipids. The solubility of the Active Pharmaceutical Ingredient in the Lipid System, the desorption/sorption isotherm and the digestibility of lipid vehicle are important issues to be considered for formulations of isotropic lipid formulations. This review also describes the fate of lipid formulations in the gut and the factors influencing the bioavailability from lipid-based formulations. Novel formulation systems and currently marketed products conclude this review. PMID:22145101

  18. 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

  19. A kinetic study of a poorly water soluble drug released from pectin microcapsules using diffusion/dissolution model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A new microcapsular system for controlled drug delivery was developed from pectins obtained from various sources, with different molecular weight and degree of esterification. The release kinetics of a poorly water-soluble drug from the pectin microcapsules was investigated in simulated gastrointes...

  20. Current Trends in Self-Emulsifying Drug Delivery Systems (SEDDSs) to Enhance the Bioavailability of Poorly Water-Soluble Drugs.

    PubMed

    Karwal, Rohit; Garg, Tarun; Rath, Goutam; Markandeywar, Tanmay S

    2016-01-01

    The main object of the self-emulsifying drug-delivery system (SEDDS) is oral bioavailability (BA) enhancement of a poorly water-soluble drug. Low aqueous solubility and low oral BA are major concerns for formulation scientists. As many drugs are lipophilic in nature, their lower solubility and dissolution are major drawbacks for their successful formulation into oral dosage forms. More than 60% of drugs have a lipophilic nature and exhibit poor aqueous solubility. Various strategies are reported in the literature to improve the solubility and enhance BA of lipophilic drugs, including the formation of a cyclodextrin complex, solid dispersions, and micronization. SEDDSs are ideally isotropic mixtures of drug, oil, surfactant, and/or cosurfactant. SEDDSs have gained increasing attention for enhancing oral BA and reducing drug dose. SEDDSs also provide an effective and excellent solution to the various issues related to the formulation of hydrophobic drugs that have limited solubility in gastrointestinal fluid. Our major focus of this review is to highlight the importance of SEDDSs in oral BA enhancement of poorly water-soluble drugs. PMID:27279337

  1. Invertible micellar polymer assemblies for delivery of poorly water-soluble drugs.

    PubMed

    Hevus, Ivan; Modgil, Amit; Daniels, Justin; Kohut, Ananiy; Sun, Chengwen; Stafslien, Shane; Voronov, Andriy

    2012-08-13

    Strategically designed amphiphilic invertible polymers (AIPs) are capable of (i) self-assembling into invertible micellar assemblies (IMAs) in response to changes in polarity of environment, polymer concentration, and structure, (ii) accommodating (solubilizing) substances that are otherwise insoluble in water, and (iii) inverting their molecular conformation in response to changes in the polarity of the local environment. The unique ability of AIPs to invert the molecular conformation depending on the polarity of the environment can be a decisive factor in establishing the novel stimuli-responsive mechanism of solubilized drug release that is induced just in response to a change in the polarity of the environment. The IMA capability to solubilize lipophilic drugs and deliver and release the cargo molecules by conformational inversion of polymer macromolecules in response to a change of the polarity of the environment was demonstrated by loading IMA with a phytochemical drug, curcumin. It was demonstrated that four sets of micellar vehicles based on different AIPs were capable of delivering the curcumin from water to an organic medium (1-octanol) by means of unique mechanism: AIP conformational inversion in response to changing polarity from polar to nonpolar. The IMAs are shown to be nontoxic against human cells up to a concentration of 10 mg/L. On the other hand, the curcumin-loaded IMAs are cytotoxic to breast carcinoma cells at this concentration, which confirms the potential of IMA-based vehicles in controlled delivery of poorly water-soluble drug candidates and release by means of this novel stimuli-responsive mechanism.

  2. Template occluded SBA-15: An effective dissolution enhancer for poorly water-soluble drug

    NASA Astrophysics Data System (ADS)

    Tingming, Fu; Liwei, Guo; Kang, Le; Tianyao, Wang; Jin, Lu

    2010-09-01

    The aim of the present work was to improve the dissolution rate of piroxicam by inclusion into template occluded SBA-15. Our strategy involves directly introducing piroxicam into as-prepared SBA-15 occluded with P123 (EO 20PO 70EO 20) by self assembling method in acetonitrile/methylene chloride mixture solution. Ultraviolet spectrometry experiment and thermogravimetric analysis-differential scanning calorimetry (TG-DSC) profiles show that the piroxicam and P123 contents in the inclusion compound are 12 wt% and 28 wt%, respectively. X-ray powder diffraction and DSC analysis reveal that the included piroxicam is arranged in amorphous form. N 2 adsorption-desorption experiment indicates that the piroxicam has been introduced to the mesopores instead of precipitating at the outside of the silica material. The inclusion compound was submitted to in vitro dissolution tests, the results show that the piroxicam dissolve from template occluded inclusion compound more rapidly, than these from the piroxicam crystalline and template removed samples in all tested conditions. Thus a facile method to improve the dissolution rate of poorly water-soluble drug was established, and this discovery opens a new avenue for the utilization of templates used for the synthesis of mesoporous materials.

  3. Lipid-based systems as a promising approach for enhancing the bioavailability of poorly water-soluble drugs.

    PubMed

    Cerpnjak, Katja; Zvonar, Alenka; Gašperlin, Mirjana; Vrečer, Franc

    2013-12-01

    Low oral bioavailability as a consequence of low water solubility of drugs is a growing challenge to the development of new pharmaceutical products. One of the most popular approaches of oral bioavailability and solubility enhancement is the utilization of lipid-based drug delivery systems. Their use in product development is growing due to the versatility of pharmaceutical lipid excipients and drug formulations, and their compatibility with liquid, semi-solid, and solid dosage forms. Lipid formulations, such as self-emulsifying (SEDDS), self-microemulsifying SMEDDS) and self- -nanoemulsifying drug delivery systems (SNEDDS) were explored in many studies as an efficient approach for improving the bioavailability and dissolution rate of poorly water-soluble drugs. One of the greatest advantages of incorporating poorly soluble drugs into such formulations is their spontaneous emulsification and formation of an emulsion, microemulsion or nanoemulsion in aqueous media. This review article focuses on the following topics. First, it presents a classification overview of lipid-based drug delivery systems and mechanisms involved in improving the solubility and bioavailability of poorly water-soluble drugs. Second, the article reviews components of lipid-based drug delivery systems for oral use with their characteristics. Third, it brings a detailed description of SEDDS, SMEDDS and SNEDDS, which are very often misused in literature, with special emphasis on the comparison between microemulsions and nanoemulsions. PMID:24451070

  4. Transformation of poorly water-soluble drugs into lipophilic ionic liquids enhances oral drug exposure from lipid based formulations.

    PubMed

    Sahbaz, Yasemin; Williams, Hywel D; Nguyen, Tri-Hung; Saunders, Jessica; Ford, Leigh; Charman, Susan A; Scammells, Peter J; Porter, Christopher J H

    2015-06-01

    Absorption after oral administration is a requirement for almost all drug products but is a challenge for drugs with intrinsically low water solubility. Here, the weakly basic, poorly water-soluble drugs (PWSDs) itraconazole, cinnarizine, and halofantrine were converted into lipophilic ionic liquids to facilitate incorporation into lipid-based formulations and integration into lipid absorption pathways. Ionic liquids were formed via metathesis reactions of the hydrochloride salt of the PWSDs with a range of lipophilic counterions. The resultant active pharmaceutical ingredient-ionic liquids (API-ILs) were liquids or low melting point solids and either completely miscible or highly soluble in lipid based, self-emulsifying drug delivery systems (SEDDS) comprising mixtures of long or medium chain glycerides, surfactants such as Kolliphor-EL and cosolvents such as ethanol. They also readily incorporated into the colloids formed in intestinal fluids during lipid digestion. Itraconazole docusate or cinnarizine decylsulfate API-ILs were subsequently dissolved in long chain lipid SEDDS at high concentration, administered to rats and in vivo exposure assessed. The data were compared to control formulations based on the same SEDDS formulations containing the same concentrations of drug as the free base, but in this case as a suspension (since the solubility of the free base in the SEDDS was much lower than the API-ILs). For itraconazole, comparison was also made to a physical mixture of itraconazole free base and sodium docusate in the same SEDDS formulation. For both drugs plasma exposure was significantly higher for the API-IL containing formulations (2-fold for cinnarizine and 20-fold for itraconazole), when compared to the suspension formulations (or the physical mixture in the case of itraconazole) at the same dose. The liquid SEDDS formulations, made possible by the use of the API-ILs, also provide advantages in dose uniformity, capsule filling, and stability compared

  5. 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. PMID:26065533

  6. Soluplus-coated colloidal silica nanomatrix system for enhanced supersaturation and oral absorption of poorly water-soluble drugs.

    PubMed

    Kim, Min-Soo

    2013-12-01

    In this study, a Soluplus-coated colloidal silica nanomatrix (SCCSN) formulation for the entrapment of poorly water-soluble drugs was devised. The maximum supersaturation of the drug-loaded nanomatrix was higher than that of a physical mixture as indicated by the results of in vitro kinetic solubility studies. For atorvastatin calcium, dutasteride, and sorafenib tosylate, there were 2.8-, 326-, and 46.4-fold increases in solubility, respectively. For dutasteride, a promising 4.7-fold increase for in vivo oral drug absorption in the entrapped nanomatrix was observed as compared to the free physical mixture, supported by statistical significance testing of pharmacokinetic parameters.

  7. Nanotechnology Based Approaches for Enhancing Oral Bioavailability of Poorly Water Soluble Antihypertensive Drugs

    PubMed Central

    Sharma, Mayank; Sharma, Rajesh; Jain, Dinesh Kumar

    2016-01-01

    Oral administration is the most convenient route among various routes of drug delivery as it offers high patient compliance. However, the poor aqueous solubility and poor enzymatic/metabolic stability of drugs are major limitations in successful oral drug delivery. There are several approaches to improve problems related to hydrophobic drugs. Among various approaches, nanotechnology based drug delivery system has potential to overcome the challenges associated with the oral route of administration. Novel drug delivery systems are available in many areas of medicine. The application of these systems in the treatment of hypertension continues to broaden. The present review focuses on various nanocarriers available in oral drug administration for improving solubility profile, dissolution, and consequently bioavailability of hydrophobic antihypertensive drugs. PMID:27239378

  8. 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.

  9. Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water-soluble drugs.

    PubMed

    Bhakay, Anagha; Merwade, Maneesh; Bilgili, Ecevit; Dave, Rajesh N

    2011-08-01

    Micronization and nanoparticle production of poorly water-soluble drugs was investigated using single wet milling equipment operating in the attritor and stirred media modes. The drug particles in the median size range of 0.2?2??m were prepared by changing the milling mode and operating conditions of a Micros mill with a purpose of elucidating the dynamics of the wet milling process. It was determined that particle breakage due to mechanical stresses and aggregation due to insufficient stabilization are two competing mechanisms which together control the wet milling dynamics of the poorly water-soluble drugs. The study in the attritor mode using four different classes of stabilizers with six drugs indicated that steric stabilization worked better than electrostatic stabilization for the drugs studied. In addition, the existence of different minimum polymer concentrations for the stabilization of microsuspensions and nanosuspensions was indicated. The major role of a non-ionic polymer during the production of fine particles is its stabilization action through steric effects, and no experimental evidence was found to support the so-called Rehbinder effect. Periodic addition of the polymer as opposed to the addition of the polymer at the start of milling process was introduced as a novel processing method. This novel method of polymer addition provided effective stabilization and breakage of drug particles leading to a narrower and finer particle size distribution. Alternatively, it may allow shorter processing time and lower overall power consumption of the milling process for a desired particle size.

  10. Calcium Alginate-Neusilin US2 Nanocomposite Microbeads for Oral Sustained Drug Delivery of Poor Water Soluble Drug Aceclofenac Sodium

    PubMed Central

    Mallappa, Manjanna Kolammanahalli; Kesarla, Rajesh; Banakar, Shivakumar

    2015-01-01

    The aim of the present study was to formulate and investigate the calcium alginate- (CA-) Neusilin US2 nanocomposite microbeads containing preconcentrate of aceclofenac sodium (ACF-Na) liquid microemulsion (L-ME) for enhancement of oral bioavailability. The preconcentrate L-ME is prepared by using Labrafac PG, Labrasol, and Span 80 as oil, surfactant, and cosurfactant, respectively. The solid CA nanocomposite microbeads of L-ME prepared by microemulsification internal gelation technique using sodium alginate (SA) gelling agent, Neusilin US2 as adsorbent, and calcium chloride as crosslinking agent. L-ME has good thermodynamic stability; globule size was found to be 32.4 nm with polydispersity index 0.219 and −6.32 mV zeta potential. No significant interactions of excipients, drug in the formulations observed by FT-IR, DSC and XPRD. The concentration of SA and Neusilin US2 influences the flow properties, mean particle size, mechanical strength, drug entrapment efficiency, and percentage of drug release. All the formulations show minimum drug release in simulated gastric fluid (SGF) pH 1.2 for initial 2 h, maximum drug release in pH 6.8 phosphate buffer solution (PBS) at 6 h, followed by sustaining in simulated intestinal fluid (SIF) of pH 7.4 up to 12 h. The interaction of SA with Neusilin US2 creates a thick thixotropic gel network structure which acts as barrier to control the release of drug in the alkaline pH environment. Neusilin US2 is a novel filler used to convert L-ME into solid nanocomposite microbeads to enhance dissolution rate of poor water soluble drugs sustaining the drug release for prolonged period of time. PMID:25802761

  11. Amino acids as co-amorphous stabilizers for poorly water-soluble drugs--Part 2: molecular interactions.

    PubMed

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

    2013-11-01

    The formation of co-amorphous drug-drug mixtures has proved to be a powerful approach to stabilize the amorphous form and at the same time increase the dissolution of poorly water-soluble drugs. Molecular interactions in these co-amorphous formulations can play a crucial role in stabilization and dissolution enhancement. In this regard, Fourier-transform infrared spectroscopy (FTIR) is a valuable tool to analyze the molecular near range order of the compounds in the co-amorphous mixtures. In this study, several co-amorphous drugs--low molecular weight excipient blends--have been analyzed with FTIR spectroscopy. Molecular interactions of the drugs carbamazepine and indomethacin with the amino acids arginine, phenylalanine, and tryptophan were investigated. The amino acids were chosen from the biological target site of both drugs and prepared as co-amorphous formulations together with the drugs by vibrational ball milling. A detailed analysis of the FTIR spectra of these formulations revealed specific peak shifts in the vibrational modes of functional groups of drug and amino acid, as long as one amino acid from the biological target site was present in the blends. These peak shifts indicate that the drugs formed specific molecular interactions (hydrogen bonding and π-π interactions) with the amino acids. In the drug-amino acid mixtures that contained amino acids which were not present at the biological target site, no such interactions were identified. This study shows the potential of amino acids as small molecular weight excipients in co-amorphous formulations to stabilize the amorphous form of a poorly water-soluble drug through strong and specific molecular interactions with the drug.

  12. Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system.

    PubMed

    Kataoka, Makoto; Yano, Koji; Hamatsu, Yoriko; Masaoka, Yoshie; Sakuma, Shinji; Yamashita, Shinji

    2013-11-01

    This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33-36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use.

  13. Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system.

    PubMed

    Kataoka, Makoto; Yano, Koji; Hamatsu, Yoriko; Masaoka, Yoshie; Sakuma, Shinji; Yamashita, Shinji

    2013-11-01

    This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33-36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use. PMID:23811221

  14. A new self-microemulsifying mouth dissolving film to improve the oral bioavailability of poorly water soluble drugs.

    PubMed

    Xiao, Lu; Yi, Tao; Liu, Ying

    2013-09-01

    A new self-microemulsifying mouth dissolving film (SMMDF) for poorly water-soluble drugs such as indomethacin was developed by incorporating self-microemulsifying components with solid carriers mainly containing microcrystalline cellulose, low-substituted hydroxypropyl cellulose and hypromellose. The uniformity of dosage units of the preparation was acceptable according to the criteria of Chinese Pharmacopoeia 2010. The SMMDF was disintegrated within 20 s after immersion into water, released completely at 5 min in the dissolution medium and achieved microemulsion particle size of 28.81 ± 3.26 nm, which was similar to that of liquid self- microemulsifying drug delivery system (SMEDDS). Solid state characterization of the SMMDF was performed by SEM, DSC and X-ray powder diffraction. Results demonstrated that indomethacin in the SMMDF was in the amorphous state, which might be due to self-microemulsifying ingredients. Pharmacokinetic parameters in rats including T(max), C(max), AUC were similar between the SMMDF and liquid SMEDDS. AUC and C(max) from the SMMDF were significantly higher than those from the common mouth dissolving film or the conventional tablet, and Tmax from SMMDF group was also significantly decreased. These findings suggest that the SMMDF is a new promising dosage form, showing notable characteristics of convenience, quick onset of action and enhanced oral bioavailability of poorly water-soluble drugs.

  15. pH-Sensitive micelles self-assembled from amphiphilic copolymer brush for delivery of poorly water-soluble drugs.

    PubMed

    Yang, You Qiang; Zheng, Ling Shan; Guo, Xin Dong; Qian, Yu; Zhang, Li Juan

    2011-01-10

    A novel pH-sensitive amphiphilic copolymer brush poly(methyl methacrylate-co-methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether monomethacrylate) [P(MMA-co-MAA)-b-PPEGMA] was defined and synthesized by atom transfer radical polymerization (ATRP) technique. The molecular structures and characteristics of this copolymer and its precursors were confirmed by (1)H NMR, FT-IR, and GPC. The CMC of P(MMA-co-MAA)-b-PPEGMA in aqueous medium was determined to be 1-4 mg/L. This copolymer could self-assemble into micelles in aqueous solution with an average size of 120-250 nm determined by DLS. The morphologies of the micelles were found to be spherical by SEM and TEM. Ibuprofen (IBU), a poorly water-soluble drug, was selected as the model drug and wrapped into the core of micelles via dialysis method. Drug entrapment efficiency reached to 90%. The in vitro release behavior of IBU from these micelles was pH-dependent. The cumulative release percent of IBU was less than 20% of the initial drug content in simulated gastric fluid (SGF, pH 1.2) over 12 h, but 90% was released in simulated intestinal fluid (SIF, pH 7.4) within 6 h. The release profiles showed that the P(MMA-co-MAA)-b-PPEGMA micelles could inhibit the premature burst drug release under the intestinal conditions. All the results indicate that the P(MMA-co-MAA)-b-PPEGMA micelle may be a potential oral drug delivery carrier for poorly water-soluble drugs. PMID:21121600

  16. Application of spray-drying and electrospraying/electospinning for poorly water-soluble drugs: a particle engineering approach.

    PubMed

    Bohr, Adam; Boetker, Johan P; Rades, Thomas; Rantanen, Jukka; Yang, Mingshi

    2014-01-01

    Solid dispersions have been widely studied as an attractive formulation strategy for the increasingly prevalent poorly water-soluble drug compounds, including herbal medicines, often leading to improvements in drug dissolution rate and bioavailability. However, several challenges are encountered with solid dispersions, for instance regarding their physical stability, and the full potential of these formulations has yet to be reached. Solid dispersions have mainly been used to produce immediate release systems using water-soluble polymers but an extended release system may provide equal or better performance due to enhancement in the pharmacokinetics and low variability in plasma concentration. Progress in processing technologies and particle engineering provides new opportunities to prepare particle-based solid dispersions with control of physical characteristics and tailored drug release kinetics. Spray-drying and electrospraying are both technologies that allow production and continuous manufacturing of particle-based amorphous solid dispersions in a single step process and electrospinning further allows the production of fiber based systems. This review presents the use of spray drying and electrospraying/electrospinning as techniques for preparing particle-based solid dispersions, describes the particle formation processes via numerical and experimental models and discusses particle engineering using these techniques. Examples are given on the applications of these techniques for preparing solid dispersions and the challenges associated with the techniques such as stability, preparation of final dosage form and scale-up are also discussed.

  17. The Precipitation Behavior of Poorly Water-Soluble Drugs with an Emphasis on the Digestion of Lipid Based Formulations.

    PubMed

    Khan, Jamal; Rades, Thomas; Boyd, Ben

    2016-03-01

    An increasing number of newly discovered drugs are poorly water-soluble and the use of natural and synthetic lipids to improve the oral bioavailability of these drugs by utilizing the digestion pathway in-vivo has proved an effective formulation strategy. The mechanisms responsible for lipid digestion and drug solubilisation during gastrointestinal transit have been explored in detail, but the implications of drug precipitation beyond the potential adverse effect on bioavailability have received attention only in recent years. Specifically, these implications are that different solid forms of drug on precipitation may affect the total amount of drug absorbed in-vivo through their different physico-chemical properties, and the possibility that the dynamic environment of the small intestine may afford re-dissolution of precipitated drug if present in a high-energy form. This review describes the events that lead to drug precipitation during the dispersion and digestion of lipid based formulations, common methods used to inhibit precipitation, as well as conventional and newly emerging characterization techniques for studying the solid state form of the precipitated drug. Moreover, selected case studies are discussed where drug precipitation has ensued from the digestion of lipid based formulations, as well as the apparent link between drug ionisability and altered solid forms on precipitation, culminating in a discussion about the importance of the solid form on precipitation with relevance to the total drug absorbed.

  18. 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

  19. Nanostructured liquid crystalline particles provide long duration sustained-release effect for a poorly water soluble drug after oral administration.

    PubMed

    Nguyen, Tri-Hung; Hanley, Tracey; Porter, Christopher J H; Boyd, Ben J

    2011-07-30

    This study is the first to demonstrate the ability of nanostructured liquid crystal particles to sustain the absorption of a poorly water soluble drug after oral administration. Cubic (V(2)) liquid crystalline nanostructured particles (cubosomes) formed from phytantriol (PHY) were shown to sustain the absorption of cinnarizine (CZ) beyond 48h after oral administration to rats. Plasma concentrations were sustained within the range of 21.5±1.5ng/mL from 12 to 48h. In stark contrast, cubosomes prepared using glyceryl monooleate (GMO) did not sustain the absorption of CZ and drug concentrations fell below quantifiable levels after 24h. Sustained absorption of CZ from PHY cubosomes lead to a significant enhancement (p<0.05) in oral bioavailability (F%=21%) compared to a CZ suspension (9%) and oleic acid emulsion (12%). Analysis of the nanostructured particles in simulated gastric and intestinal fluids using small angle x-ray scattering (SAXS) revealed that the V(2)Pn3m nanostructure of PHY cubosomes was maintained for extended periods of time, in contrast to GMO cubosomes where the V(2)Im3m nanostructure was lost within 18h after exposure, suggesting that degradation of the LC nanostructure may limit sustained drug release. In addition, PHY cubosomes were shown to be extensively retained in the stomach (>24h) leading to the conclusion that in the case of non-digestible PHY cubosomes, the stomach may act as a non-sink reservoir that facilitates the slow release of poorly water soluble drugs, highlighting the potential use of non-digestible LC nanostructured particles as novel sustained oral drug delivery systems.

  20. 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.

  1. A continuous and highly effective static mixing process for antisolvent precipitation of nanoparticles of poorly water-soluble drugs.

    PubMed

    Dong, Yuancai; Ng, Wai Kiong; Hu, Jun; Shen, Shoucang; Tan, Reginald B H

    2010-02-15

    Rapid and homogeneous mixing of the solvent and antisolvent is critical to achieve submicron drug particles by antisolvent precipitation technique. This work aims to develop a continuous and highly effective static mixing process for antisolvent precipitation of nanoparticles of poorly water-soluble drugs with spironolactone as a model drug. Continuous antisolvent production of drug nanoparticles was carried out with a SMV DN25 static mixer comprising 6-18 mixing elements. The total flow rate ranged from 1.0 to 3.0 L/min while the flow rate ratio of solvent to antisolvent was maintained at 1:9. It is found that only 6 mixing elements were sufficient to precipitate the particles in the submicron range. Increasing the number of elements would further reduce the precipitated particle size. Increasing flow rate from 1.0 to 3.0 L/min did not further reduce the particle size, while higher drug concentrations led to particle size increase. XRD and SEM results demonstrated that the freshly precipitated drug nanoparticles are in the amorphous state, which would, in presence of the mixture of solvent and antisolvent, change to crystalline form in short time. The lyophilized spironolactone nanoparticles with lactose as lyoprotectant possessed good redispersibility and showed 6.6 and 3.3 times faster dissolution rate than that of lyophilized raw drug formulation in 5 and 10 min, respectively. The developed static mixing process exhibits high potential for continuous and large-scale antisolvent precipitation of submicron drug particles. PMID:19922777

  2. Development and Characterization of a Biocompatible Soybean Oil-Based Microemulsion for the Delivery of Poorly Water-Soluble Drugs.

    PubMed

    Aloisio, Carolina; Longhi, Marcela R; De Oliveira, Anselmo Gomes

    2015-10-01

    The aim of this work was the development and characterization of a biocompatible microemulsion (ME) containing soybean oil (O), phosphatidylcholine/sodium oleate/Eumulgin®HRE40 as the surfactant mixture (S) and water or buffer solution as the aqueous phase (W), for oral delivery of the poorly water-soluble drugs sulfamerazine (SMR) and indomethacin (INM). A wide range of combinations to obtain clear oil-in-water (o/w) ME was observed from pseudo-ternary phase diagrams, which was greater after the incorporation of both drugs, suggesting that they acted as stabilizers. Drug partition studies indicated a lower affinity of the drugs for the oil domain when they were ionized and with increased temperature, explained by the fact that both drugs were introduced inside the oil domain, determined by nuclear magnetic resonance. High concentrations of SMR and INM were able to be incorporated (22.0 and 62.3 mg/mL, respectively). The ME obtained presented an average droplet size of 100 nm and a negative surface charge. A significant increase in the release of SMR was observed with the ME with the highest percentage of O, because of the solubilizing properties of the ME. Also, a small retention effect was observed for INM, which may be explained by the differences in the partitioning properties of the drugs. PMID:26149419

  3. 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.

  4. Novel polyvinylpyrrolidones to improve delivery of poorly water-soluble drugs: from design to synthesis and evaluation.

    PubMed

    Niemczyk, Anna I; Williams, Adrian C; Rawlinson-Malone, Clare F; Hayes, Wayne; Greenland, Barnaby W; Chappell, David; Khutoryanskaya, Olga; Timmins, Peter

    2012-08-01

    Polyvinylpyrrolidone is widely used in tablet formulations with the linear form acting as a wetting agent and disintegrant, whereas the cross-linked form is a superdisintegrant. We have previously reported that simply mixing the commercial cross-linked polymer with ibuprofen disrupted drug crystallinity with consequent improvements in drug dissolution behavior. In this study, we have designed and synthesized novel cross-linking agents containing a range of oligoether moieties that have then been polymerized with vinylpyrrolidone to generate a suite of novel excipients with enhanced hydrogen-bonding capabilities. The polymers have a porous surface and swell in the most common solvents and in water, properties that suggest their value as disintegrants. The polymers were evaluated in simple physical mixtures with ibuprofen as a model poorly water-soluble drug. The results show that the novel PVPs induce the drug to become "X-ray amorphous", which increased dissolution to a greater extent than that seen with commercial cross-linked PVP. The polymers stabilize the amorphous drug with no evidence for recrystallization seen after 20 weeks of storage. PMID:22738427

  5. Preparation and pharmacokinetics evaluation of oral self-emulsifying system for poorly water-soluble drug Lornoxicam.

    PubMed

    Li, Fei; Song, Shuangshuang; Guo, Yingxin; Zhao, Qianqian; Zhang, Xuemei; Pan, Weisan; Yang, Xinggang

    2015-01-01

    The present work was performed aiming to develop a new solid self-emulsifying system (SMEDDS) for poorly water-soluble drug Lornoxicam and evaluate the bioavailability in Wister rats by oral gavage. Liquid SMEDDS of Lornoxicam was formulated with Labrafil M 1944 CS as oil phase, Kolliphor HS 15 as a surfactant and Transcutol HP as a cosurfactant after screening various vehicles. The microemulsion system selected from the phase diagram and optimized by central composite design (CCD) response surface method was transformed into solid-SMEDDS (S-SMEDDS) by lyophilization using sucrose as cryoprotectant. The formulations were further characterized by the particle size, poly dispersity index (PDI), self-emulsifying time, zeta potential, transmission electron microscope (TEM), differential scanning calorimeter (DSC), in vitro drug release and in vivo pharmacokinetics. Results of DSC studies confirmed that the drug was incorporated in the S-SMEDDS. The in vitro drug release from Lornoxicam SMEDDS was found to be greatly higher in comparison with that from the commercial tablets. It was indicated that SMEDDS might be effective in reducing the effect of pH variability of Lornoxicam and improving the release performance of Lornoxicam. HPLC system was applied to study the concentration of Lornoxicam in the plasma of the Wister rats after oral administration of Lornoxicam SMEDDS and Lornoxicam commercial tablets. The pharmacokinetics parameters of the rats were C(max) 1065.91 ± 224.90 and 1855.22 ± 748.25 ngmL(-1), T(max) were 2.5 ± 0.4 h and 1.8 ± 0.5 h, and AUC(0∼t) were 5316.35 ± 323.62 and 7758.07 ± 241.57 ngmL(-1) h, respectively. Calculated by AUC(0∼∞), the relative bioavailability of Lornoxicam S-SMEDDS was 151.69 ± 15.32%. It suggested that this S-SMEDDS could be used as a successful oral solid dosage form to improve the solubility and bioavailability of poorly water-soluble drug Lornoxicam as well.

  6. Recent advances in delivery systems and therapeutics of cinnarizine: a poorly water soluble drug with absorption window in stomach.

    PubMed

    Raghuvanshi, Smita; 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

  7. 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

  8. 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.

  9. 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. PMID:26608620

  10. Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: formulation and process considerations.

    PubMed

    Paudel, Amrit; Worku, Zelalem Ayenew; Meeus, Joke; Guns, Sandra; Van den Mooter, Guy

    2013-08-30

    Spray drying is an efficient technology for solid dispersion manufacturing since it allows extreme rapid solvent evaporation leading to fast transformation of an API-carrier solution to solid API-carrier particles. Solvent evaporation kinetics certainly contribute to formation of amorphous solid dispersions, but also other factors like the interplay between the API, carrier and solvent, the solution state of the API, formulation parameters (e.g. feed concentration or solvent type) and process parameters (e.g. drying gas flow rate or solution spray rate) will influence the final physical structure of the obtained solid dispersion particles. This review presents an overview of the interplay between manufacturing process, formulation parameters, physical structure, and performance of the solid dispersions with respect to stability and drug release characteristics.

  11. 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.

  12. Development of self-nanoemulsifying drug delivery systems for the enhancement of solubility and oral bioavailability of fenofibrate, a poorly water-soluble drug

    PubMed Central

    Mohsin, Kazi; Alamri, Rayan; Ahmad, Ajaz; Raish, Mohammad; Alanazi, Fars K; Hussain, Muhammad Delwar

    2016-01-01

    Background Self-nanoemulsifying drug delivery systems (SNEDDS) have become a popular formulation option as nanocarriers for poorly water-soluble drugs. The objective of this study was to investigate the factor that can influence the design of successful lipid formulation classification system (LFCS) Type III SNEDDS formulation and improve the oral bioavailability (BA) of fenofibrate. Materials and methods LFCS Type III SNEDDS were designed using various oils, water-soluble surfactants, and/or cosolvents (in considering the polarity of the lipids) for the model anticholesterol drug, fenofibrate. The developed SNEDDS were assessed visually and by measurement of the droplet size. Equilibrium solubility of fenofibrate in the SNEDDS was conducted to find out the maximum drug loading. Dynamic dispersion studies were carried out (1/100 dilution) in water to investigate how much drug stays in solution after aqueous dispersion of the formulation. The BA of SNEDDS formulation was evaluated in the rat. Results The results from the characterization and solubility studies showed that formulations containing mixed glycerides were highly efficient SNEDDS as they had higher solubility of the drug and produced nanosized droplets. The dispersion studies confirmed that SNEDDS (containing polar mixed glycerides) can retain >98% drug in solution for >24 hours in aqueous media. The in vivo pharmacokinetics parameters of SNEDDS formulation in comparison with pure drug showed significant increase in Cmax and AUC0–t, ~78% and 67%, respectively. The oral BA of fenofibrate from SNEDDS in rats was ~1.7-fold enhanced as compared with the BA from pure drug. Conclusion Fenofibrate-loaded LFCS Type III SNEDDS formulations could be a potential oral pharmaceutical product for administering the poorly water-soluble drug, fenofibrate, with an enhanced oral BA. PMID:27366063

  13. Enhancement of the dissolution rate and gastrointestinal absorption of pranlukast as a model poorly water-soluble drug by grinding with gelatin.

    PubMed

    Chono, Sumio; Takeda, Eri; Seki, Toshinobu; Morimoto, Kazuhiro

    2008-01-22

    The effect of grinding with gelatin on the dissolution behavior and gastrointestinal absorption of a poorly water-soluble drug was evaluated using the antiasthmatic agent, pranlukast, as a model poorly water-soluble drug. A ground pranlukast-gelatin mixture was prepared by grinding equal quantities of pranlukast and gelatin. In the dissolution testing, the dissolution rate of pranlukast in the suspension of the ground pranlukast-gelatin mixture under conditions of pH 3.0, 5.0 and 7.0 was markedly faster than that in the suspension of pranlukast. According to powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC) analysis, the enhanced dissolution rate of pranlukast produced by grinding with gelatin was caused by changing the crystalline state of pranlukast into an amorphous state. In an animal experiment, the bioavailability of pranlukast following oral administration of the ground pranlukast-gelatin mixture to rats was threefold greater than that following administration of pranlukast. In the in vitro permeation experiment, the amount of permeated pranlukast through Caco-2 cell monolayers after application of the ground pranlukast-gelatin mixture was greater than that after application of pranlukast. These results suggest that the enhancement of the gastrointestinal absorption of pranlukast by grinding with gelatin is due to enhancement of the dissolution rate. Grinding a poorly water-soluble drug with gelatin is a useful method of enhancing its gastrointestinal absorption.

  14. Human Lipocalin-Type Prostaglandin D Synthase-Based Drug Delivery System for Poorly Water-Soluble Anti-Cancer Drug SN-38.

    PubMed

    Nakatsuji, Masatoshi; Inoue, Haruka; Kohno, Masaki; Saito, Mayu; Tsuge, Syogo; Shimizu, Shota; Ishida, Atsuko; Ishibashi, Osamu; Inui, Takashi

    2015-01-01

    Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily, which is composed of secretory transporter proteins, and binds a wide variety of small hydrophobic molecules. Using this function, we have reported the feasibility of using L-PGDS as a novel drug delivery vehicle for poorly water-soluble drugs. In this study, we show the development of a drug delivery system using L-PGDS, one that enables the direct clinical use of 7-ethyl-10-hydroxy-camptothecin (SN-38), a poorly water-soluble anti-cancer drug. In the presence of 2 mM L-PGDS, the concentration of SN-38 in PBS increased 1,130-fold as compared with that in PBS. Calorimetric experiments revealed that L-PGDS bound SN-38 at a molecular ratio of 1:3 with a dissociation constant value of 60 μM. The results of an in vitro growth inhibition assay revealed that the SN-38/L-PGDS complexes showed high anti-tumor activity against 3 human cancer cell lines, i.e., Colo201, MDA-MB-231, and PC-3 with a potency similar to that of SN-38 used alone. The intravenous administration of SN-38/L-PGDS complexes to mice bearing Colo201 tumors showed a pronounced anti-tumor effect. Intestinal mucositis, which is one of the side effects of this drug, was not observed in mice administered SN-38/L-PGDS complexes. Taken together, L-PGDS enables the direct usage of SN-38 with reduced side effects.

  15. 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.

  16. Design of self-dispersible dry nanosuspension through wet milling and spray freeze-drying for poorly water-soluble drugs.

    PubMed

    Niwa, Toshiyuki; Danjo, Kazumi

    2013-11-20

    The purpose of the present research is to establish a novel nanosizing technique starting from wet nano-milling, named "dry nanosuspension" technique for poorly water-soluble drugs. The spray freeze-drying (SFD) method was applied instead of the spray-drying one previously developed. Drug particles were milled in the aqueous solution of dispersing agents using an oscillating beads-milling apparatus. The milled nanosuspension was sprayed to the surface of liquid nitrogen, and the resultant iced droplets were freeze-dried to obtain the powdery product. The loading ratio of a dispersing agent was investigated to enhance its redispersing property. Dry nanosuspension, which could be spontaneously dispersed into original nanosuspension in water, was obtained by SFD process. It was assumed that self dispersion property would be attributed to its structure with porous network, in which the primary milled drug crystals were embedded. Such unique structure contributed greatly to immediate release behaviors of the drug in gastrointestinal buffered media. These pharmaceutical properties were enhanced by increasing the ratio of the dispersing agent to the drug and the solid content in suspension to be sprayed. The present technique via wet milling and spray freeze-drying processes would be a novel dissolution-enhanced technology for poorly water-soluble drugs.

  17. [Preparation of two poor water soluble drugs - nanoporous ZnO solid dispersions and the mechanism of drug dissolution improvement].

    PubMed

    Gao, Bei; Sun, Chang-shan; Zhi, Zhuang-zhi; Wang, Yan; Chang, Di; Wang, Si-ling; Jiang, Tong-ying

    2011-11-01

    Nanoporous ZnO was used as a carrier to prepare drug solid dispersion, the mechanism of which to improve the drug dissolution was also studied. Nanoporous ZnO, obtained through chemical deposition method, was used as a carrier to prepare indomethacin and cilostazol solid dispersions by melt-quenching method, separately. The results of scanning electron microscope, surface area analyzer, fourier transform infra-red spectroscopy, differential scanning calorimeter and X-ray diffraction showed that drugs were implanted into nanopores of ZnO by physical adsorption effect and highly dispersed into nanopores of ZnO in amorphous form, moreover, these nanopores strongly inhibited amorphous recrystallization in the condition of 45 degrees C and 75% RH. In addition, the results of the dissolution tested in vitro exhibited that the accumulated dissolutions of indomethacin and cilostazol solid dispersions achieved about 90% within 5 min and approximately 80% within 30 min. It was indicated in this study that the mechanism of drug dissolution improvement was associated with the effects of nanoporous ZnO carrier on increasing drug dispersion, controlling drug in nanopores as amorphous form and inhibiting amorphous recrystallization. PMID:22260037

  18. In situ molecular elucidation of drug supersaturation achieved by nano-sizing and amorphization of poorly water-soluble drug.

    PubMed

    Ueda, Keisuke; Higashi, Kenjirou; Yamamoto, Keiji; Moribe, Kunikazu

    2015-09-18

    Quantitative evaluation of drug supersaturation and nanoparticle formation was conducted using in situ evaluation techniques, including nuclear magnetic resonance (NMR) spectroscopy. We prepared a ternary complex of carbamazepine (CBZ) with hydroxypropyl methylcellulose (HPMC) and sodium dodecyl sulfate (SDS) to improve the drug concentration. Different preparation methods, including grinding and spray drying, were performed to prepare the ternary component products, ground mixture (GM) and spray-dried sample (SD), respectively. Although CBZ was completely amorphized in the ternary SD, CBZ was partially amorphized with the remaining CBZ crystals in the ternary GM. Aqueous dispersion of the ternary GM formed nanoparticles of around 150 nm, originating from the CBZ crystals in the ternary GM. In contrast, the ternary SD formed transparent solutions without a precipitate. The molecular-level evaluation using NMR measurements revealed that approximately half a dose of CBZ in the ternary GM dispersion was present as nanoparticles; however, CBZ in the ternary SD was completely dissolved in the aqueous solution. The characteristic difference between the solid states, followed by different preparation methods, induced different solution characteristics in the ternary GM and SD. The permeation study, using a dialysis membrane, showed that the CBZ concentration dissolved in the bulk water phase rapidly reduced in the ternary SD dispersion compared to the ternary GM dispersion; this demonstrated the advantage of ternary GM dispersion in the maintenance of CBZ supersaturation. Long-term maintenance of a supersaturated state of CBZ observed in the ternary GM dispersion rather than in the ternary SD dispersion was achieved by the inhibition of CBZ crystallization owing to the existence of CBZ nanoparticles in the ternary GM dispersion. Nanoparticle formation, combined with drug amorphization, could be a promising approach to improve drug concentrations. The detailed elucidation

  19. Fast drying of biocompatible polymer films loaded with poorly water-soluble drug nano-particles via low temperature forced convection.

    PubMed

    Susarla, Ramana; Sievens-Figueroa, Lucas; Bhakay, Anagha; Shen, Yueyang; Jerez-Rozo, Jackeline I; Engen, William; Khusid, Boris; Bilgili, Ecevit; Romañach, Rodolfo J; Morris, Kenneth R; Michniak-Kohn, Bozena; Davé, Rajesh N

    2013-10-15

    Fast drying of nano-drug particle laden strip-films formed using water-soluble biocompatible polymers via forced convection is investigated in order to form films having uniform drug distribution and fast dissolution. Films were produced by casting and drying a mixture of poorly water soluble griseofulvin (GF) nanosuspensions produced via media milling with aqueous hydroxypropyl methylcellulose (HPMC E15LV) solutions containing glycerin as a plasticizer. The effects of convective drying parameters, temperature and air velocity, and film-precursor viscosity on film properties were investigated. Two major drying regimes, a constant rate period as a function of the drying conditions, followed by a single slower falling rate period, were observed. Films dried in an hour or less without any irreversible aggregation of GF nanoparticles with low residual water content. Near-infrared chemical imaging (NIR-CI) and the content uniformity analysis indicated a better drug particle distribution when higher viscosity film-precursors were used. Powder X-ray diffraction showed that the GF in the films retained crystallinity and the polymorphic form. USP IV dissolution tests showed immediate release (~20 min) of GF. Overall, the films fabricated from polymer-based suspensions at higher viscosity dried at different conditions exhibited similar mechanical properties, improved drug content uniformity, and achieved fast drug dissolution.

  20. 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.

  1. 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. PMID:27402100

  2. Development and characterization of solid dispersion-microsphere controlled release system for poorly water-soluble drug.

    PubMed

    Malipeddi, Venkata Ramana; Dua, Kamal; Awasthi, Rajendra

    2016-10-01

    The present study aimed to improve solubility and prolong the release duration of a poorly soluble drug using a combination of two different types of formulations (solid dispersion and microspheres). The solid dispersions were prepared by fusion method using urea and mannitol as hydrophilic carriers. Microspheres were prepared by solvent evaporation method using Eudragit L-100 (EL100) and Eudragit RS PO (ERS) as rate-controlling polymers. Flurbiprofen (FBP)-urea (1:2) solid dispersion and microspheres of FBP-EL-100-ERS (1:0.25:0.75) were used for the development of controlled release formulation by mixing them in different proportions. The FBP-containing formulations were evaluated for percentage yield, drug content, morphology, in vitro release, and in vivo anti-inflammatory activity. The best selected formulation was further evaluated for the controlled and improved effects. SEM photomicrograph confirmed the spherical shape of microspheres and with particle size in the range of 73.5-85.4 μm. In vitro release of FBP from controlled release formulations indicated that the formulation containing solid dispersion:microspheres (1:0.5) yielded prolonged effect up to 10 h. The release kinetics followed zero-order, and the mechanism of drug release was found to be diffusion rate controlled. This formulation had shown better inhibition of edema of rat paw up to 16 h and identified as a suitable product for controlled delivery of FBP. In conclusion, the concept of using a binary mixture of solid dispersion and microspheres can be used for other drugs that exhibit a poor solubility in stomach pH and a faster release in intestinal pH.

  3. Development and characterization of solid dispersion-microsphere controlled release system for poorly water-soluble drug.

    PubMed

    Malipeddi, Venkata Ramana; Dua, Kamal; Awasthi, Rajendra

    2016-10-01

    The present study aimed to improve solubility and prolong the release duration of a poorly soluble drug using a combination of two different types of formulations (solid dispersion and microspheres). The solid dispersions were prepared by fusion method using urea and mannitol as hydrophilic carriers. Microspheres were prepared by solvent evaporation method using Eudragit L-100 (EL100) and Eudragit RS PO (ERS) as rate-controlling polymers. Flurbiprofen (FBP)-urea (1:2) solid dispersion and microspheres of FBP-EL-100-ERS (1:0.25:0.75) were used for the development of controlled release formulation by mixing them in different proportions. The FBP-containing formulations were evaluated for percentage yield, drug content, morphology, in vitro release, and in vivo anti-inflammatory activity. The best selected formulation was further evaluated for the controlled and improved effects. SEM photomicrograph confirmed the spherical shape of microspheres and with particle size in the range of 73.5-85.4 μm. In vitro release of FBP from controlled release formulations indicated that the formulation containing solid dispersion:microspheres (1:0.5) yielded prolonged effect up to 10 h. The release kinetics followed zero-order, and the mechanism of drug release was found to be diffusion rate controlled. This formulation had shown better inhibition of edema of rat paw up to 16 h and identified as a suitable product for controlled delivery of FBP. In conclusion, the concept of using a binary mixture of solid dispersion and microspheres can be used for other drugs that exhibit a poor solubility in stomach pH and a faster release in intestinal pH. PMID:27343081

  4. Novel in situ self-assembly nanoparticles for formulating a poorly water-soluble drug in oral solid granules, improving stability, palatability, and bioavailability

    PubMed Central

    Guo, Shujie; Pham, Kevin; Li, Diana; Penzak, Scott R; Dong, Xiaowei

    2016-01-01

    Purpose The purpose of this study was to develop a novel lipid-based nanotechnology to formulate poorly water-soluble drugs in oral solid granules to improve stability, palatability, and bioavailability. Materials and methods In one method, we prepared ritonavir (RTV) nanoparticles (NPs) by a microemulsion-precursor method and then converted the RTV NPs to solid granules by wet granulation to produce RTV NP-containing granules. In the other innovative method, we did not use water in the formulation preparation, and discovered novel in situ self-assembly nanoparticles (ISNPs). We prepared RTV ISNP granules that did not initially contain NPs, but spontaneously produced RTV ISNPs when the granules were introduced to water with gentle agitation. We fully characterized these RTV nanoformulations. We also used rats to test the bioavailability of RTV ISNP granules. Finally, an Astree electronic tongue was used to assess the taste of the RTV ISNP granules. Results RTV NP-containing granules only had about 1% drug loading of RTV in the solid granules. In contrast, RTV ISNP granules achieved over 16% drug loading and were stable at room temperature over 24 weeks. RTV ISNPs had particle size between 160 nm and 300 nm with narrow size distribution. RTV ISNPs were stable in simulated gastric fluid for 2 hours and in simulated intestinal fluid for another 6 hours. The data from the electronic tongue showed that the RTV ISNP granules were similar in taste to blank ISNP granules, but were much different from RTV solution. RTV ISNP granules increased RTV bioavailability over 2.5-fold compared to RTV solution. Conclusion We successfully discovered and developed novel ISNPs to manufacture RTV ISNP granules that were reconstitutable, stable, and palatable, and improved RTV bioavailability. The novel ISNP nanotechnology is a platform to manufacture oral solid dosage forms for poorly water-soluble drugs, especially for pediatric formulation development. PMID:27103803

  5. A novel oral delivery system consisting in "drug-in cyclodextrin-in nanostructured lipid carriers" for poorly water-soluble drug: vinpocetine.

    PubMed

    Lin, Congcong; Chen, Fen; Ye, Tiantian; Zhang, Lina; Zhang, Wenji; Liu, Dandan; Xiong, Wei; Yang, Xinggang; Pan, Weisan

    2014-04-25

    The purpose of this study was to develop a new delivery system based on drug cyclodextrin (CD) complexation and loading into nanostructured lipid carriers (NLC) to improve the oral bioavailability of vinpocetine (VP). Three different CDs and three different methods to obtain solid vinpocetine-cyclodextrin-tartaric acid complexes (VP-CD-TA) were contrasted. The co-evaporation vinpocetine-β-cyclodextrin-tartaric acid loaded NLC (VP-β-CD-TA COE-loaded NLC) was obtained by emulsification ultrasonic dispersion method. VP-β-CD-TA COE-loaded NLC was suitably characterized for particle size, polydispersity index, zeta potential, entrapment efficiency and the morphology. The crystallization of drug in VP-CD-TA and NLC was investigated by differential scanning calorimetry (DSC). The in vitro release study was carried out at pH 1.2, pH 6.8 and pH 7.4 medium. New Zealand rabbits were applied to investigate the pharmacokinetic behavior in vivo. The VP-β-CD-TA COE-loaded NLC presented a superior physicochemical property and selected to further study. In the in vitro release study, VP-β-CD-TA COE-loaded NLC exhibited a higher dissolution rate in the pH 6.8 and pH 7.4 medium than VP suspension and VP-NLC. The relative bioavailability of VP-β-CD-TA COE-loaded NLC was 592% compared with VP suspension and 92% higher than VP-NLC. In conclusion, the new formulation significantly improved bioavailability of VP for oral delivery, demonstrated a perspective way for oral delivery of poorly water-soluble drugs.

  6. Impact of polymer conformation on the crystal growth inhibition of a poorly water-soluble drug in aqueous solution.

    PubMed

    Schram, Caitlin J; Beaudoin, Stephen P; Taylor, Lynne S

    2015-01-01

    Poor aqueous solubility is a major hindrance to oral delivery of many emerging drugs. Supersaturated drug solutions can improve passive absorption across the gastrointestinal tract membrane as long as crystallization can be inhibited, enhancing the delivery of such poorly soluble therapeutics. Polymers can inhibit crystallization and prolong supersaturation; therefore, it is desirable to understand the attributes which render a polymer effective. In this study, the conformation of a polymer adsorbed to a crystal surface and its impact on crystal growth inhibition were investigated. The crystal growth rate of a poorly soluble pharmaceutical compound, felodipine, was measured in the presence of hydroxypropyl methylcellulose acetate succinate (HPMCAS) at two different pH conditions: pH 3 and pH 6.8. HPMCAS was found to be a less effective growth rate inhibitor at pH 3, below its pKa. It was expected that the ionization state of HPMCAS would most likely influence its conformation at the solid-liquid interface. Further investigation with atomic force microscopy (AFM) revealed significant differences in the conformation of HPMCAS adsorbed to felodipine at the two pH conditions. At pH 3, HPMCAS formed coiled globules on the surface, whereas at pH 6.8, HPMCAS adsorbed more uniformly. Thus, it appeared that the reduced effectiveness of HPMCAS at pH 3 was directly related to its conformation. The globule formation leaves many felodipine growth sites open and available for growth units to attach, rendering the polymer less effective as a growth rate inhibitor.

  7. The effect of administered dose of lipid-based formulations on the in vitro and in vivo performance of cinnarizine as a model poorly water-soluble drug.

    PubMed

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

    2013-02-01

    The influence of varying the amount of lipid co-administered with the drug on drug solubilisation and absorption is poorly understood. In the current study, the effect of lipid dose on the in vitro drug distribution is compared with the in vivo absorption of cinnarizine (CZ) when formulated using long-chain triacylglyceride (LCT) and medium-chain triacylglycerides (MCT). At a fixed drug-lipid ratio, in the closed in vitro model, the drug concentrations in the aqueous phase increased and decreased for MCT and LCT, respectively, with increasing lipid dose. However, in vivo, the oral bioavailability (F%) of CZ was independent of the quantity of lipid administered for both MCT and LCT, but was higher for LCT (32.1 ± 2.3%) than for MCT (16.6 ± 2.3%). Increasing the quantity of lipid relative to the dose of CZ resulted in an increase in the oral F% when the lipid mass was increased from 125 to 250 mg, but was no greater at 500 mg lipid dose. The results confirm the limitations of the in vitro model but positively indicate that the use of the rat as a pre-clinical model for studying the bioavailability of poorly water-soluble drugs is not compromised by the mass of formulation administered. PMID:23242691

  8. Influence of particle design on oral absorption of poorly water-soluble drug in a silica particle-supercritical fluid system.

    PubMed

    Miura, Hiroshi; Kanebako, Makoto; Shirai, Hiroyuki; Nakao, Hiroshi; Inagi, Toshio; Terada, Katsuhide

    2011-01-01

    The physicochemical characteristics and oral absorption of a poorly water-soluble drug, K-832, adsorbed onto porous silica (Sylysia 350), were compared with those of K-832 adsorbed onto non-porous silica (Aerosil 200). K-832 and silica were treated with supercritical CO(2) (scCO(2)) to produce K-832-Sylysia 350 and K-832-Aerosil 200 formulations. Scanning electron microscopy, polarizing microscopy, powder X-ray diffraction, and differential scanning calorimetry results suggested that K-832 mainly existed in an amorphous state in both formulations. The specific surface area of both formulations was much larger than that of pure K-832 crystals. The dissolution rate of K-832 from both formulations was considerably greater than that from corresponding physical mixtures due to rapid wetting of the hydrophilic carrier surfaces and amorphous state, the dissolution from the K-832-Sylysia 350 formulation being the fastest. In vivo absorption tests on the two formulations indicated no significant differences in their peak concentration (C(max)) and the area under their plasma concentration-time curve (AUC), while the concentrations of K-832 in the K-832-Sylysia 350 formulation were significantly higher than those in the K-832-Aerosil 200 formulation 1 h and 1.5 h after administration of these formulations (p<0.05). This could be attributed to the different dispersion states of K-832 in the formulations due to their different three-dimensional structures (porous and non-porous). In physical stability tests, the amorphous drugs in both formulations were stable at room temperature for at least 14 months. Thus, the absorption of poorly water-soluble drugs could be greatly improved by adsorption onto porous silica using scCO(2).

  9. Supersaturation, nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs.

    PubMed

    Sarode, Ashish L; Wang, Peng; Obara, Sakae; Worthen, David R

    2014-04-01

    The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit® EPO and AQOAT® AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat® 603 and Kollidon® VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat® 603>Eudragit® L-100-55>AQOAT® AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation.

  10. A lipid-based liquid crystalline matrix that provides sustained release and enhanced oral bioavailability for a model poorly water soluble drug in rats.

    PubMed

    Boyd, Ben J; Khoo, Shui-Mei; Whittaker, Darryl V; Davey, Greg; Porter, Christopher J H

    2007-08-01

    Liquid crystalline phases that are stable in excess water, formed using lipids such as glyceryl monooleate (GMO) and oleyl glycerate (OG), are known to provide a sustained release matrix for poorly water soluble drugs in vitro, yet there has been no report of the use of these materials to impart oral sustained release behaviour in vivo. In the first part of this study, in vitro lipolysis experiments were used to compare the digestibility of GMO with a second structurally related lipid, oleyl glycerate, which was found to be less susceptible to hydrolysis by pancreatic lipase than GMO. Subsequent oral bioavailability studies were conducted in rats, in which a model poorly water soluble drug, cinnarizine (CIN), was administered orally as an aqueous suspension, or as a solution in GMO or OG. In the first bioavailability study, plasma samples were taken over a 30 h period and CIN concentrations determined by HPLC. Plasma CIN concentrations after administration in the GMO formulation were only sustained for a few hours after administration while for the OG formulation, the plasma concentration of cinnarizine was at its highest level 30 h after dosing, and appeared to be increasing. A second study in which CIN was again administered in OG, and plasma samples taken for 120 h, revealed a Tmax for CIN in rats of 36 h and a relative oral bioavailability of 344% when compared to the GMO formulation (117%) and the aqueous suspension formulation (assigned a nominal bioavailability of 100%). The results indicate that lipids that form liquid crystalline structures in excess water, may have application as an oral sustained release delivery system, providing they are not digested rapidly on administration.

  11. The effects of surfactants on the solubility and dissolution profiles of a poorly water-soluble basic drug, carvedilol.

    PubMed

    Incecayir, T

    2015-12-01

    This study investigated the most suitable surfactant medium for the dissolution testing of a poorly soluble basic drug, namely, carvedilol reflecting the in vivo behavior. Sodium lauryl sulfate (SLS), hexadecyltrimethylammonium bromide (CTAB) and polysorbate 80 were used as anionic, cationic and nonionic surfactants, respectively. Saturation solubilities of carvedilol were determined in the presence of SLS, CTAB and polysorbate 80 (0.5, 1 and 2% (w/v)) at pH 1.2 and 6.8. Dissolution behaviors of the commercial tablets were studied using USP apparatus II in pH 1.2, 4.5 and 6.8 buffers and pH 6.8 dissolution media with 0.5% (w/v) SLS, polysorbate 80 and CTAB. Polysorbate 80 enhanced the solubility of carvedilol irrespective of pH, while SLS and CTAB exhibited larger solubilization effect than polysorbate 80 depending on pH and the ionic nature of the surfactant. Based on in vitro dissolution profile similarity, pH 6.8 dissolution medium with 0.5% (w/v) polysorbate 80 was found to be the most biorelevant medium, which probably reflects the bioequivalence of test products to the reference product of carvedilol.

  12. 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.

  13. Quantification of swelling and erosion in the controlled release of a poorly water-soluble drug using synchrotron X-ray computed microtomography.

    PubMed

    Yin, Xianzhen; Li, Haiyan; Guo, Zhen; Wu, Li; Chen, Fangwei; de Matas, Marcel; Shao, Qun; Xiao, Tiqiao; York, Peter; He, You; Zhang, Jiwen

    2013-10-01

    The hydration layer plays a key role in the controlled drug release of gel-forming matrix tablets. For poorly water-soluble drugs, matrix erosion is considered as the rate limiting step for drug release. However, few investigations have reported on the quantification of the relative importance of swelling and erosion in the release of poorly soluble drugs, and three-dimensional (3D) structures of the hydration layer are poorly understood. Here, we employed synchrotron radiation X-ray computed microtomography with 9-μm resolution to investigate the hydration dynamics and to quantify the relative importance of swelling and erosion on felodipine release by a statistical model. The 3D structures of the hydration layer were revealed by the reconstructed 3D rendering of tablets. Twenty-three structural parameters related to the volume, the surface area (SA), and the specific surface area (SSA) for the hydration layer and the tablet core were calculated. Three dominating parameters, including SA and SSA of the hydration layer (SA hydration layer and SSA hydration layer ) and SA of the glassy core (SA glassy core ), were identified to establish the statistical model. The significance order of independent variables was SA hydration layer > SSA hydration layer > SA glassy core , which quantitatively indicated that the release of felodipine was dominated by a combination of erosion and swelling. The 3D reconstruction and structural parameter calculation methods in our study, which are not available from conventional methods, are efficient tools to quantify the relative importance of swelling and erosion in the controlled release of poorly soluble drugs from a structural point of view.

  14. Preparation of a Novel Form of Gelatin With a Three-Dimensional Ordered Macroporous Structure to Regulate the Release of Poorly Water-Soluble Drugs.

    PubMed

    Xu, Jie; Zhao, Zongzhe; Hao, Yanna; Zhao, Ying; Qiu, Yang; Jiang, Jie; Yu, Tong; Ji, Peng; Liu, Ying; Wu, Chao

    2016-09-01

    In this study, a novel three-dimensional ordered macroporous gelatin (3DOMG) was fabricated as a carrier for increasing the solubility of poorly water-soluble drugs, offering sustained release and a high oral bioavailability. Polymethyl methacrylate nanospheres (257 nm) were used as a colloidal plastic framework to synthesize 3DOMG. Fenofibrate (FNB) was selected as a model drug and loaded onto 3DOMG by the adsorption equilibrium method. Detailed characterization showed that the FNB absorbed onto 3DOMG was in a microcrystalline state. A fluorescence experiment and the prepared drug microcrystal network gave further information on the physical state of the drug. A degradation experiment proved that 3DOMG was readily biodegradable. In vitro release testing showed that 3DOMG increased the dissolution rate of FNB and produced a sustained release. An in vivo pharmacokinetic study confirmed that 3DOMG improved the oral bioavailability compared with that of commercial sustained-release capsules. These findings confirm that 3DOMG can be regarded as a promising carrier for an oral drug delivery system. PMID:26906173

  15. 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. PMID:27012901

  16. 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.

  17. Development of micro-fibrous solid dispersions of poorly water-soluble drugs in sucrose using temperature-controlled centrifugal spinning

    PubMed Central

    Marano, Stefania; Barker, Susan Anne; Raimi-Abraham, Bahijja Tolulope; Missaghi, Shahrzad; Rajabi-Siahboomi, Ali; Craig, Duncan Q.M.

    2016-01-01

    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. PMID:27012901

  18. Design and synthesis of pH-sensitive polymeric micelles for oral delivery of poorly water-soluble drugs.

    PubMed

    Yang, Xiaolan; Fan, Rongrong; Wang, Wenlong; Wang, Jiexin; Le, Yuan

    2016-09-01

    pH-sensitive polymer poly (polylactide-co-methacrylic acid)-b-poly (acrylic acid) was synthesized using atom transfer radical polymerization and ring-opening polymerization and characterized by gel permeation chromatography and (1)H NMR. The polymers can self-assemble to form micelles in aqueous medium, which respond rapidly to pH change within the gastrointestinal relevant pH range. Critical micelle concentrations and pH response behavior of the polymeric micelle were investigated. Water-insoluble drug nifedipine was loaded and the drug-loading content can be controlled by tuning the composition of the polymers. The in vitro release studies indicate pH sensitivity enabled rapid drug release at the environment of simulated intestinal fluid (pH 7.36), the cumulative released amount of NFD reached more than 80% within 24 h, while only 35% in the simulated gastric fluid (pH 1.35). All the results showed that the pH-sensitive P(PLAMA-co-MAA)-b-PAA micelle may be a prospective candidate as oral drug delivery carrier for hydrophobic drugs with controlled release behavior. PMID:27342342

  19. Design and synthesis of pH-sensitive polymeric micelles for oral delivery of poorly water-soluble drugs.

    PubMed

    Yang, Xiaolan; Fan, Rongrong; Wang, Wenlong; Wang, Jiexin; Le, Yuan

    2016-09-01

    pH-sensitive polymer poly (polylactide-co-methacrylic acid)-b-poly (acrylic acid) was synthesized using atom transfer radical polymerization and ring-opening polymerization and characterized by gel permeation chromatography and (1)H NMR. The polymers can self-assemble to form micelles in aqueous medium, which respond rapidly to pH change within the gastrointestinal relevant pH range. Critical micelle concentrations and pH response behavior of the polymeric micelle were investigated. Water-insoluble drug nifedipine was loaded and the drug-loading content can be controlled by tuning the composition of the polymers. The in vitro release studies indicate pH sensitivity enabled rapid drug release at the environment of simulated intestinal fluid (pH 7.36), the cumulative released amount of NFD reached more than 80% within 24 h, while only 35% in the simulated gastric fluid (pH 1.35). All the results showed that the pH-sensitive P(PLAMA-co-MAA)-b-PAA micelle may be a prospective candidate as oral drug delivery carrier for hydrophobic drugs with controlled release behavior.

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

    PubMed

    Mohsin, Kazi

    2012-06-01

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

  1. Development of a novel ultra cryo-milling technique for a poorly water-soluble drug using dry ice beads and liquid nitrogen.

    PubMed

    Sugimoto, Shohei; Niwa, Toshiyuki; Nakanishi, Yasuo; Danjo, Kazumi

    2012-04-15

    A novel ultra cryo-milling micronization technique has been established using dry ice beads and liquid nitrogen (LN2). Drug particles were co-suspended with dry ice beads in LN2 and ground by stirring. Dry ice beads were prepared by storing dry ice pellets in LN2. A poorly water-soluble drug, phenytoin, was micronized more efficiently using either dry ice beads or zirconia beads compared to jet milling. Dry ice beads retained their granular shape without pulverizing and sublimating in LN2 as the milling operation progressed. Longer milling times produced smaller-sized phenytoin particles. The agitation speed for milling was optimized. Analysis of the glass transition temperature revealed that phenytoin particles co-ground with polyvinylpyrrolidone (PVP) by dry ice milling were crystalline, whereas a planetary ball-milled mixtures process with zirconia beads contained the amorphous form. The dissolution rate of phenytoin milled with PVP using dry ice beads or zirconia beads was significantly improved compared to jet-milled phenytoin or the physical mixture. Dry ice beads together with LN2 were spontaneously sublimated at ambient condition after milling. Thus, the yield was significantly improved by dry ice beads compared to zirconia beads since the loss arisen from adhering to the surface of dry ice beads could be completely avoided, resulting in about 85-90% of recovery. In addition, compounds milled using dry ice beads are free from abraded contaminating material originating from the beads and internal vessel wall. PMID:22266538

  2. A new strategy for enhancing the oral bioavailability of drugs with poor water-solubility and low liposolubility based on phospholipid complex and supersaturated SEDDS.

    PubMed

    Zhou, Hui; Wan, Jiangling; Wu, Lei; Yi, Tao; Liu, Wei; Xu, Huibi; Yang, Xiangliang

    2013-01-01

    A novel supersaturated self-emulsifying drug delivery system (Super-SEDDS) loaded with scutellarin-phospholipid complex (SPC) was developed. The system aimed to address the limitations presented by conventional SEDDS as delivery carriers for drugs with poor water-solubility, low liposolubility and high dose. As an intermediate, SPC was first prepared based on the response surface design. The presence of amorphous scutellarin was demonstrated through differential scanning calorimetry (DSC) and X-ray diffraction (XRD), while enhanced liposolubility was confirmed through comparison with scutellarin powder via an octanol/water distribution test. On the basis of the solubility study and ternary phase diagram, Super-SEDDS containing SPC of up to 200% equilibrium solubility (Seq) was designed, which composed of ethyl oleate, Cremophor RH40 and Transcutol HP with a ratio of 60:25:15 (w/w%). The subsequent in vitro lipolysis study and ex vivo intestinal absorption test indicated that Super-SEDDS enhanced the cumulative dissolution from 70% to 100% and improved the intestinal absorption from 0.04 to 0.12 µg/cm(2) compared with scutellarin powder. Furthermore, an in vivo study demonstrated that Super-SEDDS achieved the AUC0-t of scutellarin up to approximate 1.7-fold as scutellarin powder. It was also proved superior to SPC and the conventional SEDDS. Super-SEDDS showed great potential for expanding the usage of SEDDS and could act as an alternative to conventional SEDDS.

  3. 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. PMID:26456294

  4. Development of a novel ultra cryo-milling technique for a poorly water-soluble drug using dry ice beads and liquid nitrogen.

    PubMed

    Sugimoto, Shohei; Niwa, Toshiyuki; Nakanishi, Yasuo; Danjo, Kazumi

    2012-04-15

    A novel ultra cryo-milling micronization technique has been established using dry ice beads and liquid nitrogen (LN2). Drug particles were co-suspended with dry ice beads in LN2 and ground by stirring. Dry ice beads were prepared by storing dry ice pellets in LN2. A poorly water-soluble drug, phenytoin, was micronized more efficiently using either dry ice beads or zirconia beads compared to jet milling. Dry ice beads retained their granular shape without pulverizing and sublimating in LN2 as the milling operation progressed. Longer milling times produced smaller-sized phenytoin particles. The agitation speed for milling was optimized. Analysis of the glass transition temperature revealed that phenytoin particles co-ground with polyvinylpyrrolidone (PVP) by dry ice milling were crystalline, whereas a planetary ball-milled mixtures process with zirconia beads contained the amorphous form. The dissolution rate of phenytoin milled with PVP using dry ice beads or zirconia beads was significantly improved compared to jet-milled phenytoin or the physical mixture. Dry ice beads together with LN2 were spontaneously sublimated at ambient condition after milling. Thus, the yield was significantly improved by dry ice beads compared to zirconia beads since the loss arisen from adhering to the surface of dry ice beads could be completely avoided, resulting in about 85-90% of recovery. In addition, compounds milled using dry ice beads are free from abraded contaminating material originating from the beads and internal vessel wall.

  5. Novel lipid-based formulations enhancing the in vitro dissolution and permeability characteristics of a poorly water-soluble model drug, piroxicam.

    PubMed

    Prabhu, Sunil; Ortega, Maru; Ma, Chan

    2005-09-14

    Lipid-based delivery systems are becoming increasingly popular as carriers of drugs due to their ability to overcome barriers to oral absorption. The purpose of this study was to prepare novel lipid-based formulations of a model drug, piroxicam (PXCM), a poorly water-soluble non-steroidal anti-inflammatory drug (NSAID) using 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) phospholipid alone, and in combination with polyethylene glycol (PEG 4600). Lipid-based drug delivery systems were prepared using conventional methods of preparation and the following aspects were evaluated (1) in vitro dissolution behavior, (2) absorption via Caco-2 cell monolayers and (3) stability of formulations over a 12-month period. In addition, physical characterization studies using differential scanning calorimetry (DSC) were also performed. Formulations of PXCM were prepared using DMPC in the following combinations (A) 1:1 and (B) 2:1 and a mixture of DMPC and PEG 4600 (C) 2:1:1, respectively. Dissolution studies conducted in phosphate buffered saline (PBS, pH 7.4, 37+/-0.5 degrees C) using the USP type II (paddle) dissolution apparatus showed an increase in dissolution rate and extent of the PXCM from all solid dispersion formulations when compared to the control. As such, the rate of drug release was observed to be fastest with formulation (C) showing the greatest increase of over two-fold compared to the control. Release of PXCM from formulations (A) and (B) was intermediate with the latter showing superior dissolution behavior despite containing lower amounts of the carrier lipid than the former. This observation indicates a possible existence of threshold levels for phospholipids carriers beyond which dissolution could be adversely affected. DSC studies further confirmed the dissolution behavior of these formulations demonstrating different levels of amorphous to crystalline nature. Results of HPLC analysis from Caco-2 cell culture studies showed increase in transport of

  6. Preparation and characterisation of Kolliphor® P 188 and P 237 solid dispersion oral tablets containing the poorly water soluble drug disulfiram.

    PubMed

    Ramadhani, Nisrina; Shabir, Mehwish; McConville, Christopher

    2014-11-20

    The oral route of administration is the most common and preferred route of drug delivery due to its ease of administration, cost-effectiveness and flexibility in design. However, limited aqueous solubility of the active pharmaceutical ingredient can result in poor bioavailability, which is a major issue for the pharmaceutical industry. Increasing numbers of new drugs are falling into class II of the Biopharmaceutical Classification System (BCS), where they have a low solubility and high tissue permeability, meaning that bioavailability is solubility dependent. Here we demonstrate the development and characterisation of solid dispersion oral tablets, containing the poorly water-soluble drug disulfiram, prepared using both the hot melt and solvent evaporation methods and manufactured from two different polymers, Kolliphor(®) P 188 and P 237, specifically designed for the manufacture of solid dispersions. This paper demonstrates that the disulfiram solid dispersions tablets have an enhanced release rate of disulfiram compared to the control tablets. The Kolliphor(®) P 188 polymer control tablets released approximately 48.8% of their disulfiram content over 8h, with the solvent evaporated tablets releasing approximately 65.8%, while the 60 and 80 °C hot melt tablets released approximately 73.2 and 100% of their disulfiram content respectively. A similar trend was seen with Kolliphor(®) P 237 as the control tablets released approximately 50.5% of their disulfiram content over 8h, while the solvent evaporated tablets released approximately 79.5% and the 60 and 80 °C hot melt tablets released 100.2 and 100.3% respectively. Depending on what method and polymer is used to manufacture the solid dispersions the disulfiram is either maintained completely or partially in its amorphous state and it is this which enhances its solubility and release rate from the tablets. The disulfiram in the Kolliphor(®) P 188 solvent evaporated and 60 °C hot melt tablets retained 50

  7. A comparative study on the effects of amphiphilic and hydrophilic polymers on the release profiles of a poorly water-soluble drug.

    PubMed

    Irwan, Anastasia W; Berania, Jacqueline E; Liu, Xueming

    2016-03-01

    This paper reports the use of two crystalline polymers, an amphiphilic Pluronic® F-127 (PF-127) and a hydrophilic poly(ethylene glycol) (PEG6000) as drug delivery carriers for improving the drug release of a poorly water-soluble drug, fenofibrate (FEN), via micelle formation and formation of a solid dispersion (SD). In 10% PF-127 (aq.), FEN showed an equilibrium solubility of ca. 0.6 mg/mL, due to micelle formation. In contrast, in 10% PEG6000 (aq.), FEN only exhibited an equilibrium solubility of 0.0037 mg/mL. FEN-loaded micelles in PF-127 were prepared by direct dissolution and membrane dialysis. Both methods only yielded a highest drug loading (DL) of 0.5%. SDs of FEN in PF-127 and PEG6000, at DLs of 5-80%, were prepared by solvent evaporation. In-vitro dissolution testing showed that both micelles and SDs significantly improved FEN's release rate. The SDs of FEN in PF-127 showed significantly faster release than crystalline FEN, when the DL was as high as 50%, whereas SDs of PEG6000 showed similar enhancement in the release rate when the DL was not more than 20%. The DSC thermograms of SDs of PF-127 exhibited a single phase transition peak at ca. 55-57 °C when the DL was not more than 50%, whereas those in PEG6000 exhibited a similar peak at ca. 61-63 °C when the DL was not more than 35%. When the DL exceeded 50% for SDs of PF-127 and 35% for SDs of PEG6000, DSC thermograms showed two melting peaks for the carrier polymer and FEN, respectively. FT-IR studies revealed that PF-127 has a stronger hydrophobic-hydrophobic interaction with FEN than PEG6000. It is likely that both dispersion and micelle formation contributed to the stronger effect of PF-127 on enhancing the release rate of FEN in its SDs.

  8. 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

    2016-01-01

    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.

  9. Glyceryl monooleate/poloxamer 407 cubic nanoparticles as oral drug delivery systems: I. In vitro evaluation and enhanced oral bioavailability of the poorly water-soluble drug simvastatin.

    PubMed

    Lai, Jie; Chen, Jianming; Lu, Yi; Sun, Jing; Hu, Fuqiang; Yin, Zongning; Wu, Wei

    2009-01-01

    Glyceryl monooleate (GMO)/poloxamer 407 cubic nanoparticles were investigated as potential oral drug delivery systems to enhance the bioavailability of the water-insoluble model drug simvastatin. The simvastatin-loaded cubic nanoparticles were prepared through fragmentation of the GMO/poloxamer 407 bulk cubic-phase gel using high-pressure homogenization. The internal structure of the cubic nanoparticles was identified by cryo-transmission electron microscopy. The mean diameter of the cubic nanoparticles varied within the range of 100-150 nm, and both GMO/poloxamer 407 ratio and theoretical drug loading had no significant effect on particle size and distribution. Almost complete entrapment with efficiency over 98% was achieved due to the high affinity of simvastatin to the hydrophobic regions of the cubic phase. Release of simvastatin from the cubic nanoparticles was limited both in 0.1 M hydrochloride solution containing 0.2% sodium lauryl sulfate and fasted-state simulated intestinal fluid with a total release of <3.0% at 10 h. Pharmacokinetic profiles in beagle dogs showed sustained plasma levels of simvastatin for cubic nanoparticles over 12 h. The relative oral bioavailability of simvastatin cubic nanoparticles calculated on the basis of area under the curve was 241% compared to simvastatin crystal powder. The enhancement of simvastatin bioavailability was possibly attributable to facilitated absorption by lipids in the formulation rather than improved release.

  10. Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid Naringenin: design, characterization, in vitro and in vivo evaluation.

    PubMed

    Khan, Abdul Wadood; Kotta, Sabna; Ansari, Shahid Husain; Sharma, Rakesh Kumar; Ali, Javed

    2015-01-01

    Naringenin (NRG), predominant flavanone in grapefruits, possesses anti-inflammatory, anti-carcinogenic, hepato-protective and anti-lipid peroxidation effects. Slow dissolution after oral ingestion due to its poor solubility in water, as well as low bioavailability following oral administration, restricts its therapeutic application. The study is an attempt to improve the solubility and bioavailability of NRG by employing self-nanoemulsifying drug delivery technique. Preliminary screening was carried out to select oil, surfactant and co-surfactant, based on solubilization and emulsification efficiency of the components. Pseudo ternary phase diagrams were constructed to identify the area of nanoemulsification. The developed self-nanoemulsifying drug delivery systems (SNEDDS) were evaluated in term of goluble size, globule size distribution, zeta potential, and surface morphology of nanoemulsions so obtained. The TEM analysis proves that nanoemulsion shows a droplet size less than 50 nm. Freeze thaw cycling and centrifugation studies were carried out to confirm the stability of the developed SNEDDS. In vitro drug release from SNEDDS was significantly higher (p < 0.005) than pure drug. Furthermore, area under the drug concentration time-curve (AUC(0-24)) of NRG from SNEDDS formulation revealed a significant increase (p < 0.005) in NRG absorption compared to NRG alone. The increase in drug release and bioavailability as compared to drug suspension from SNEDDS formulation may be attributed to the nanosized droplets and enhanced solubility of NRG in the SNEDDS.

  11. Glycyrrhetinic acid-poly(ethylene glycol)-glycyrrhetinic acid tri-block conjugates based self-assembled micelles for hepatic targeted delivery of poorly water soluble drug.

    PubMed

    Wu, Fengbo; Xu, Ting; Liu, Chi; Chen, Can; Song, Xiangrong; Zheng, Yu; He, Gu

    2013-01-01

    The triblock 18β-glycyrrhetinic acid-poly(ethylene glycol)18β-glycyrrhetinic acid conjugates (GA-PEG-GA) based self-assembled micelles were synthesized and characterized by FTIR, NMR, transmission electron microscopy, and particle size analysis. The GA-PEG-GA conjugates having the critical micelle concentration of 6 × 10(-5) M were used to form nanosized micelles, with mean diameters of 159.21 ± 2.2 nm, and then paclitaxel (PTX) was incorporated into GA-PEG-GA micelles by self-assembly method. The physicochemical properties of the PTX loaded GA-PEG-GA micelles were evaluated including in vitro cellular uptake, cytotoxicity, drug release profile, and in vivo tissue distribution. The results demonstrate that the GA-PEG-GA micelles had low cytotoxicity and good ability of selectively delivering drug to hepatic cells in vitro and in vivo by the targeting moiety glycyrrhetinic acid. In conclusion, the GA-PEG-GA conjugates have potential medical applications for targeted delivery of poor soluble drug delivery.

  12. Trends in the precipitation and crystallization behavior of supersaturated aqueous solutions of poorly water-soluble drugs assessed using synchrotron radiation.

    PubMed

    Raina, Shweta A; Eerdenbrugh, Bernard Van; Alonzo, David E; Mo, Huaping; Zhang, Geoff G Z; Gao, Yi; Taylor, Lynne S

    2015-06-01

    Amorphous materials are high-energy solids that can potentially enhance the bioavailability of poorly soluble compounds. A major impediment to their widespread use as a formulation platform is the tendency of amorphous materials to crystallize. The aim of this study was to evaluate the relative crystallization tendency of six structural analogues belonging to the dihydropyridine class, in an aqueous environment in the absence and presence of polymers, using wide-angle X-ray scattering synchrotron radiation and polarized light microscopy. The crystallization behavior of precipitates generated from supersaturated solutions of the active pharmaceutical ingredients was found to be highly variable ranging from immediate to several hours in the absence of polymers. Polymers with intermediate hydrophilicity/hydrophobicity were found to substantially delay crystallization, whereas strongly hydrophilic or hydrophobic polymers were largely ineffective. Nuclear magnetic resonance spectroscopy experiments supported the supposition that polymers need to have affinity for both the drug-rich precipitate and the aqueous phase in order to be effective crystallization inhibitors. This study highlights the variability in the crystallization tendency of different compounds and provides insight into the mechanism of inhibition by polymeric additives.

  13. Nanosizing of poorly water soluble compounds using rotation/revolution mixer.

    PubMed

    Takatsuka, Takayuki; Endo, Tomoko; Jianguo, Yao; Yuminoki, Kayo; Hashimoto, Naofumi

    2009-10-01

    In this study, nanoparticles of various poorly water soluble compounds were prepared by wet milling that was carried out using a rotation/revolution mixer and zirconia balls. To be compared with Beads mill, rotation/revolution mixer has superior in very quick process (5 min) and needs very few amounts of zirconia balls (2.4 g) for pulverizing drugs to nanometer range. Phenytoin, indomethacin, nifedipine, danazol, and naproxen were selected as the standard poorly water soluble compounds. Various parameters of the rotation/revolution mixer were studied to decide the optimal pulverization conditions for the production of nanoparticles of the abovementioned compounds. The rotation/revolution speed, shape of the mixing vessel, amount of zirconia balls, and volume of the vehicle (methylcellulose solution) mainly affected the pulverization of the compounds. Using the mixer, phenytoin could be pulverized to nanoparticles within a few minutes. The particle size was confirmed by using a scanning electron microscope and a particle size analyzer. The crystallinity of the pulverized phenytoin particles was confirmed by X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). It was observed that the pulverized phenytoin particles retained their crystallinity, and amorphous phenytoin was not detected. Particles of other poorly water soluble compounds were also reduced to the nanometer range by using this method. PMID:19801859

  14. Nanosizing of poorly water soluble compounds using rotation/revolution mixer.

    PubMed

    Takatsuka, Takayuki; Endo, Tomoko; Jianguo, Yao; Yuminoki, Kayo; Hashimoto, Naofumi

    2009-10-01

    In this study, nanoparticles of various poorly water soluble compounds were prepared by wet milling that was carried out using a rotation/revolution mixer and zirconia balls. To be compared with Beads mill, rotation/revolution mixer has superior in very quick process (5 min) and needs very few amounts of zirconia balls (2.4 g) for pulverizing drugs to nanometer range. Phenytoin, indomethacin, nifedipine, danazol, and naproxen were selected as the standard poorly water soluble compounds. Various parameters of the rotation/revolution mixer were studied to decide the optimal pulverization conditions for the production of nanoparticles of the abovementioned compounds. The rotation/revolution speed, shape of the mixing vessel, amount of zirconia balls, and volume of the vehicle (methylcellulose solution) mainly affected the pulverization of the compounds. Using the mixer, phenytoin could be pulverized to nanoparticles within a few minutes. The particle size was confirmed by using a scanning electron microscope and a particle size analyzer. The crystallinity of the pulverized phenytoin particles was confirmed by X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). It was observed that the pulverized phenytoin particles retained their crystallinity, and amorphous phenytoin was not detected. Particles of other poorly water soluble compounds were also reduced to the nanometer range by using this method.

  15. 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

    2016-06-01

    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

  16. 'Stealth' lipid-based formulations: poly(ethylene glycol)-mediated digestion inhibition improves oral bioavailability of a model poorly water soluble drug.

    PubMed

    Feeney, Orlagh M; Williams, Hywel D; Pouton, Colin W; Porter, Christopher J H

    2014-10-28

    For over 20years, stealth drug delivery has been synonymous with nanoparticulate formulations and intravenous dosing. The putative determinants of stealth in these applications are the molecular weight and packing density of a hydrophilic polymer (commonly poly(ethylene glycol) (PEG)) that forms a steric barrier at the surface of the nanoparticle. The current study examined the potential translation of the concepts learned from stealth technology after intravenous administration to oral drug delivery and specifically, to enhance drug exposure after administration of oral lipid-based formulations (LBFs) containing medium-chain triglycerides (MCT). MCT LBFs are rapidly digested in the gastrointestinal tract, typically resulting in losses in solubilisation capacity, supersaturation and drug precipitation. Here, non-ionic surfactants containing stealth PEG headgroups were incorporated into MCT LBFs in an attempt to attenuate digestion, reduce precipitation risk and enhance drug exposure. Stealth capabilities were assessed by measuring the degree of digestion inhibition that resulted from steric hindrance of enzyme access to the oil-water interface. Drug-loaded LBFs were assessed for maintenance of solubilising capacity during in vitro digestion and evaluated in vivo in rats. The data suggest that the structural determinants of stealth LBFs mirror those of parenteral formulations, i.e., the key factors are the molecular weight of the PEG in the surfactant headgroup and the packing density of the PEG chains at the interface. Interestingly, the data also show that the presence of labile ester bonds within a PEGylated surfactant also impact on the stealth properties of LBFs, with digestible surfactants requiring a PEG Mw of ~1800g/mol and non-digestible ether-based surfactants ~800g/mol to shield the lipidic cargo. In vitro evaluation of drug solubilisation during digestion showed stealth LBFs maintained drug solubilisation at or above 80% of drug load and reduced

  17. 'Stealth' lipid-based formulations: poly(ethylene glycol)-mediated digestion inhibition improves oral bioavailability of a model poorly water soluble drug.

    PubMed

    Feeney, Orlagh M; Williams, Hywel D; Pouton, Colin W; Porter, Christopher J H

    2014-10-28

    For over 20years, stealth drug delivery has been synonymous with nanoparticulate formulations and intravenous dosing. The putative determinants of stealth in these applications are the molecular weight and packing density of a hydrophilic polymer (commonly poly(ethylene glycol) (PEG)) that forms a steric barrier at the surface of the nanoparticle. The current study examined the potential translation of the concepts learned from stealth technology after intravenous administration to oral drug delivery and specifically, to enhance drug exposure after administration of oral lipid-based formulations (LBFs) containing medium-chain triglycerides (MCT). MCT LBFs are rapidly digested in the gastrointestinal tract, typically resulting in losses in solubilisation capacity, supersaturation and drug precipitation. Here, non-ionic surfactants containing stealth PEG headgroups were incorporated into MCT LBFs in an attempt to attenuate digestion, reduce precipitation risk and enhance drug exposure. Stealth capabilities were assessed by measuring the degree of digestion inhibition that resulted from steric hindrance of enzyme access to the oil-water interface. Drug-loaded LBFs were assessed for maintenance of solubilising capacity during in vitro digestion and evaluated in vivo in rats. The data suggest that the structural determinants of stealth LBFs mirror those of parenteral formulations, i.e., the key factors are the molecular weight of the PEG in the surfactant headgroup and the packing density of the PEG chains at the interface. Interestingly, the data also show that the presence of labile ester bonds within a PEGylated surfactant also impact on the stealth properties of LBFs, with digestible surfactants requiring a PEG Mw of ~1800g/mol and non-digestible ether-based surfactants ~800g/mol to shield the lipidic cargo. In vitro evaluation of drug solubilisation during digestion showed stealth LBFs maintained drug solubilisation at or above 80% of drug load and reduced

  18. Solid self-nanoemulsifying drug delivery system (SNEDDS) for enhanced oral bioavailability of poorly water-soluble tacrolimus: physicochemical characterisation and pharmacokinetics.

    PubMed

    Seo, Youn Gee; Kim, Dong Wuk; Yousaf, Abid Mehmood; Park, Jong Hyuck; Chang, Pahn-Shick; Baek, Hyung Hee; Lim, Soo-Jeong; Kim, Jong Oh; Yong, Chul Soon; Choi, Han-Gon

    2015-01-01

    To develop a novel self-nanoemulsifying drug delivery system (solid SNEDDS) with better oral bioavailability of tacrolimus, the solid SNEDDS was obtained by spray-drying the solutions containing the liquid SNEDDS and colloidal silica. Its reconstitution properties were determined and correlated to solid state characterisation of the powder. Moreover, the dissolution and pharmacokinetics in rats was done in comparison to the commercial product. Among the liquid SNEDDS formulations tested, the liquid SNEDDS comprised of Capryol PGMC, Transcutol HP and Labrasol (10:15:75, v/v/v) presented the highest dissolution rate. In the solid SNEDDS, this liquid SNEDDS was absorbed in the pores and attached onto the surface of the colloidal silica. Drug was present in the amorphous state in it. The solid SNEDDS with 5% w/v tacrolimus produced the nanoemulsions and improved the oral bioavailability of tacrolimus in rats. Therefore, this solid SNEDDS would be a potential candidate for enhancing the oral bioavailability of tacrolimus.

  19. Food protein-stabilized nanoemulsions as potential delivery systems for poorly water-soluble drugs: preparation, in vitro characterization, and pharmacokinetics in rats

    PubMed Central

    He, Wei; Tan, Yanan; Tian, Zhiqiang; Chen, Lingyun; Hu, Fuqiang; Wu, Wei

    2011-01-01

    Nanoemulsions stabilized by traditional emulsifiers raise toxicological concerns for long-term treatment. The present work investigates the potential of food proteins as safer stabilizers for nanoemulsions to deliver hydrophobic drugs. Nanoemulsions stabilized by food proteins (soybean protein isolate, whey protein isolate, β-lactoglobulin) were prepared by high-pressure homogenization. The toxicity of the nanoemulsions was tested in Caco-2 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide viability assay. In vivo absorption in rats was also evaluated. Food protein-stabilized nanoemulsions, with small particle size and good size distribution, exhibited better stability and biocompatibility compared with nanoemulsions stabilized by traditional emulsifiers. Moreover, β-lactoglobulin had a better emulsifying capacity and biocompatibility than the other two food proteins. The pancreatic degradation of the proteins accelerated drug release. It is concluded that an oil/water nanoemulsion system with good biocompatibility can be prepared by using food proteins as emulsifiers, allowing better and more rapid absorption of lipophilic drugs. PMID:21468355

  20. Combining in vitro and in silico methods for better prediction of surfactant effects on the absorption of poorly water soluble drugs-a fenofibrate case example.

    PubMed

    Berthelsen, Ragna; Sjögren, Erik; Jacobsen, Jette; Kristensen, Jakob; Holm, René; Abrahamsson, Bertil; Müllertz, Anette

    2014-10-01

    The aim of this study was to develop a sensitive and discriminative in vitro-in silico model able to simulate the in vivo performance of three fenofibrate immediate release formulations containing different surfactants. In addition, the study was designed to investigate the effect of dissolution volume when predicting the oral bioavailability of the formulations. In vitro dissolution studies were carried out using the USP apparatus 2 or a mini paddle assembly, containing 1000 mL or 100mL fasted state biorelevant medium, respectively. In silico simulations of small intestinal absorption were performed using the GI-Sim absorption model. All simulation runs were performed twice adopting either a total small intestinal volume of 533 mL or 105 mL, in order to examine the implication of free luminal water volumes for the in silico predictions. For the tested formulations, the use of a small biorelevant dissolution volume was critical for in vitro-in silico prediction of drug absorption. Good predictions, demonstrating rank order in vivo-in vitro-in silico correlations for Cmax, were obtained with in silico predictions utilizing a 105 mL estimate for the human intestinal water content combined with solubility and dissolution data performed in a mini paddle apparatus with 100mL fasted state simulated media.

  1. 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

  2. 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.

  3. Solid Lipid Nanoparticles of a Water Soluble Drug, Ciprofloxacin Hydrochloride

    PubMed Central

    Shah, M.; Agrawal, Y. K.; Garala, K.; Ramkishan, A.

    2012-01-01

    The aim of this study was to understand and investigate the relationship between experimental factors and their responses in the preparation of ciprofloxacin hydrochloride based solid lipid nanoparticles. A quadratic relationship was studied by developing central composite rotatable design. Amount of lipid and drug, stirring speed and stirring time were selected as experimental factors while particle size, zeta potential and drug entrapment were used as responses. Prior to the experimental design, a qualitative prescreening study was performed to check the effect of various solid lipids and their combinations. Results showed that changing the amount of lipid, stirring speed and stirring time had a noticeable influence on the entrapment efficiencies and particle size of the prepared solid lipid nanoparticles. The particle size of a solid lipid nanoparticle was in the range of 159-246 nm and drug encapsulation efficiencies were marginally improved by choosing a binary mixture of physically incompatible solid lipids. Release of ciprofloxacin hydrochloride from solid lipid nanoparticle was considerably slow, and it shows Higuchi matrix model as the best fitted model. Study of solid lipid nanoparticle suggested that the lipid based carrier system could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release for water soluble actives. PMID:23716872

  4. Formulation and particle size reduction improve bioavailability of poorly water-soluble compounds with antimalarial activity.

    PubMed

    Wang, Hongxing; Li, Qigui; Reyes, Sean; Zhang, Jing; Xie, Lisa; Melendez, Victor; Hickman, Mark; Kozar, Michael P

    2013-01-01

    Decoquinate (DQ) is highly effective at killing malaria parasites in vitro; however, it is extremely insoluble in water. In this study, solid dispersion method was used for DQ formulation which created a suitable physical form of DQ in aqueous phase for particle manipulation. Among many polymers and surfactants tested, polyvinylpyrrolidone 10, a polymer, and L- α -phosphatidylcholine or polysorbate, two surfactants, were chosen as DQ formulation components. The formulation particles were reduced to a mean size between 200 to 400 nm, which was stable in aqueous medium for at least three weeks. Pharmacokinetic (PK) studies showed that compared to DQ microparticle suspension, a nanoparticle formulation orally dosed to mice showed a 14.47-fold increase in area under the curve (AUC) of DQ plasma concentration and a 4.53-fold increase in AUC of DQ liver distribution. WR 299666, a poorly water-soluble compound with antimalarial activity, was also tested and successfully made into nanoparticle formulation without undergoing solid dispersion procedure. We concluded that nanoparticles generated by using appropriate formulation components and sufficient particle size reduction significantly increased the bioavailability of DQ and could potentially turn this antimalarial agent to a therapeutic drug.

  5. Silica gel as a particulate carrier of poorly water-soluble substances in aquatic toxicity testing.

    PubMed

    Breitholtz, Magnus; Ricklund, Niklas; Bengtsson, Bengt-Erik; Persson, N Johan

    2007-05-31

    Aquatic toxicity tests were originally developed for water-soluble substances. However, many substances are hydrophobic and thus poorly water-soluble, resulting in at least two major implications. Firstly, toxicity may not be reached within the range of water solubility of the tested compound(s), which may result in the formation of solids or droplets of the tested substance and consequently an uneven exposure. Secondly, because of multi-phase distribution of the tested substance it may be complicated to keep exposure concentrations constant. To overcome such problems, we have introduced silica gel as a particulate carrier in a toxicity test with the benthic copepod Nitocra spinipes. The main objective of the current study was to evaluate whether a controlled exposure could be achieved with the help of silica gel for testing single poorly water-soluble substances. A secondary objective was to evaluate whether an equilibrium mass balance model could predict internal concentrations that were consistent with the toxicity data and measured internal concentrations of two model hydrophobic substances, i.e., the polybrominated diphenyl ethers BDE-47 and BDE-99. Larval N. spinipes were exposed for 6 days to BDE-47 and BDE-99, respectively, in the silica gel test system and, for comparative reasons, in a similar and more traditional semi-static water test system. Via single initial amounts of the model substances administered on the silica gel, effects on both larval development and mortality resulted in higher and more concentration-related toxicity than in the water test system. We conclude that the silica gel test system enables a more controlled exposure of poorly water-soluble substances than the traditional water test system since the concentration-response relationship becomes distinct and there is no carrier solvent present during testing. Also, the single amount of added substance given in the silica gel test system limits the artefacts (e.g., increased chemical

  6. 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

    2015-12-01

    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.

  7. 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

    2015-12-01

    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. PMID:26523928

  8. 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.

  9. Denatured globular protein and bile salt-coated nanoparticles for poorly water-soluble drugs: Penetration across the intestinal epithelial barrier into the circulation system and enhanced oral bioavailability.

    PubMed

    He, Wei; Yang, Ke; Fan, Lifang; Lv, Yaqi; Jin, Zhu; Zhu, Shumin; Qin, Chao; Wang, Yiao; Yin, Lifang

    2015-11-10

    Oral drug delivery is the most preferred route for patients; however, the low solubility of drugs and the resultant poor absorption compromise the benefits of oral administration. On the other hand, for years, the overwhelmingly accepted mechanism for enhanced oral absorption using lipid nanocarriers was based on the process of lipid digestion and drug solubilization in the small intestine. Few reports indicated that other bypass pathways are involved in drug absorption in the gastrointestinal tract (GIT) for oral delivery of nanocarriers. Herein, we report a new nanoemulsion system with a denatured globular protein with a diameter of 30 nm, soybean protein isolates (SPI), and bile salt as emulsifiers, aiming to enhance the absorption of insoluble drugs and explore other pathways for absorption. A BCS class II drug, fenofibrate (FB), was used as the model drug. The SPI and bile salt-coated Ns with a diameter of approximately 150 nm were prepared via a high-pressure homogenizing procedure. Interestingly, the present Ns could be converted to solid dosage form using fluid-bed coating technology, maintaining a nanoscale size. Most importantly, in a model of in situ rat intestinal perfusion, Ns could penetrate across the intestinal epithelial barrier into the systemic circulation and then obtain biodistribution into other tissues. In addition, Ns significantly improved FB oral absorption, exhibited as a greater than 2- and 2.5-fold increase in Cmax and AUC0-t, respectively, compared to the suspension formulation. Overall, the present Ns are promising nanocarriers for the oral delivery of insoluble drugs, and the penetration of intact Ns across the GIT barrier into systemic circulation may be a new strategy for improved drug absorption with the use of nanocarriers.

  10. In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol.

    PubMed

    Jinno, Jun-ichi; Kamada, Naoki; Miyake, Masateru; Yamada, Keigo; Mukai, Tadashi; Odomi, Masaaki; Toguchi, Hajime; Liversidge, Gary G; Higaki, Kazutaka; Kimura, Toshikiro

    2008-08-25

    The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. Irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively.

  11. Understanding improved dissolution of indomethacin through the use of cohesive poorly water-soluble aluminium hydroxide: effects of concentration and particle size distribution.

    PubMed

    Tay, Tracy; Allahham, Ayman; Morton, David A V; Stewart, Peter J

    2011-10-01

    The objective of this study was to explore the effects of concentration and particle size distribution of an added poorly water-soluble inorganic salt, aluminium hydroxide, on the dissolution of a poorly water-soluble drug, indomethacin (IMC), from lactose interactive mixtures. Dissolution was studied using the United States Pharmacopeia paddle method in buffer pH 5.0 and the data most aptly fitted a bi-exponential dissolution model which represented dissolution occurring from dispersed and agglomerated particles. The dispersion of IMC mixtures was measured in dissolution media under non-sink conditions by laser diffraction. The dissolution of IMC increased as a function of the concentration of aluminium hydroxide (5-20%) added to the mixtures. Increasing the proportion of larger particles of the cohesive aluminium hydroxide increased the dissolution rate of IMC. The enhanced dissolution was attributed to increases in both the dissolution rate constant and initial concentration of dispersed particles. Mechanistically, the aluminium hydroxide was found to facilitate the detachment of IMC particles from the carrier surface, forming a complex interactive mixture that more readily deagglomerated than the cohesive drug agglomerates. The outcomes of this work would therefore allow more careful control and selection of the excipient specifications in producing solid dosage formulations with improved dissolution of poorly water-soluble drugs.

  12. Cryomilling-induced solid dispersion of poor glass forming/poorly water-soluble mefenamic acid with polyvinylpyrrolidone K12.

    PubMed

    Kang, Naewon; Lee, Jangmi; Choi, Ji Na; Mao, Chen; Lee, Eun Hee

    2015-06-01

    The effect of mechanical impact on the polymorphic transformation of mefenamic acid (MFA) and the formation of a solid dispersion of mefenamic acid, a poor glass forming/poorly-water soluble compound, with polyvinylpyrrolidone (PVP) K12 was investigated. The implication of solid dispersion formation on solubility enhancement of MFA, prepared by cryomilling, was investigated. Solid state characterization was conducted using powder X-ray diffraction (PXRD) and Fourier-transform infrared (FTIR) spectroscopy combined with crystal structure analysis. Apparent solubility of the mixtures in pH 7.4 buffer was measured. A calculation to compare the powder patterns and FTIR spectra of solid dispersions with the corresponding physical mixtures was conducted. Solid state characterization showed that (1) MFA I transformed to MFA II when pure MFA I was cryogenically milled (CM); and (2) MFA forms a solid dispersion when MFA was cryogenically milled with PVP K12. FTIR spectral analysis showed that hydrogen bonding facilitated by mechanical impact played a major role in forming solid dispersions. The apparent solubility of MFA was significantly improved by making a solid dispersion with PVP K12 via cryomilling. This study highlights the importance of cryomilling with a good hydrogen bond forming excipient as a technique to prepare solid dispersion, especially when a compound shows a poor glass forming ability and therefore, is not easy to form amorphous forms by conventional method.

  13. Evaluating the ready biodegradability of two poorly water-soluble substances: comparative approach of bioavailability improvement methods (BIMs).

    PubMed

    Sweetlove, Cyril; Chenèble, Jean-Charles; Barthel, Yves; Boualam, Marc; L'Haridon, Jacques; Thouand, Gérald

    2016-09-01

    Difficulties encountered in estimating the biodegradation of poorly water-soluble substances are often linked to their limited bioavailability to microorganisms. Many original bioavailability improvement methods (BIMs) have been described, but no global approach was proposed for a standardized comparison of these. The latter would be a valuable tool as part of a wider strategy for evaluating poorly water-soluble substances. The purpose of this study was to define an evaluation strategy following the assessment of different BIMs adapted to poorly water-soluble substances with ready biodegradability tests. The study was performed with two poorly water-soluble chemicals-a solid, anthraquinone, and a liquid, isodecyl neopentanoate-and five BIMs were compared to the direct addition method (reference method), i.e., (i) ultrasonic dispersion, (ii) adsorption onto silica gel, (iii) dispersion using an emulsifier, (iv) dispersion with silicone oil, and (v) dispersion with emulsifier and silicone oil. A two-phase evaluation strategy of solid and liquid chemicals was developed involving the selection of the most relevant BIMs for enhancing the biodegradability of tested substances. A description is given of a BIM classification ratio (R BIM), which enables a comparison to be made between the different test chemical sample preparation methods used in the various tests. Thereby, using this comparison, the BIMs giving rise to the greatest biodegradability were ultrasonic dispersion and dispersion with silicone oil or with silicone oil and emulsifier for the tested solid chemical, adsorption onto silica gel, and ultrasonic dispersion for the liquid one. PMID:27234835

  14. Impact of FaSSIF on the solubility and dissolution-/permeation rate of a poorly water-soluble compound.

    PubMed

    Frank, Kerstin J; Westedt, Ulrich; Rosenblatt, Karin M; Hölig, Peter; Rosenberg, Jörg; Mägerlein, Markus; Brandl, Martin; Fricker, Gert

    2012-08-30

    The poorly water-soluble drug ABT-102, a potent TRPV1 (transient receptor potential cation channel subfamily V member 1) antagonist, was investigated in terms of its solubility and dissolution-permeation rate across Caco-2 cell monolayers in the presence and absence of fasted state simulated intestinal fluid (FaSSIF). ABT-102 showed a more than 30-fold higher apparent solubility in FaSSIF, compared to Hank's balanced salt solution (HBSS). On the other hand, the amount of truly dissolved API in the suspension, as assessed by inverse dialysis, was found hardly influenced by FaSSIF. Neither the drug nor FaSSIF adversely affected cell viability or integrity of the Caco-2 monolayer. P-gp-inhibition experiments confirmed that the drug was not a substrate of the export pump. The flux of ABT-102 across the Caco-2 barrier was found virtually the same in FaSSIF and in buffer, i.e. in vitro overall dissolution-/permeation rate of ABT-102 from suspensions appears not affected by its enhanced apparent solubility due to association with TC/PC-micelles. PMID:22579958

  15. The use of inert carriers in regulatory biodegradation tests of low density poorly water-soluble substances.

    PubMed

    Handley, J W; Mead, C; Rausina, G A; Waid, L J; Gee, J C; Herron, S J

    2002-08-01

    Many poorly water-soluble compounds fail regulatory ready biodegradation tests as the method of test material preparation limits the bioavailability of the chemical. The recognised method for delivery of poorly soluble materials into biodegradability tests consists of coating test material inside the test vessel or onto inert substrates (i.e., glass cover slide, boiling beads, filter paper, or Teflon stir bar) that are placed inside the vessels. Volatile solvents are often used to augment this process. Although these substrates work fairly well for delivering many poorly soluble materials into biodegradability tests, they have not been effective in keeping low density, poorly water-soluble substances in the test medium. Soon after medium is added to the test vessels, these chemicals break loose from the substrates and float on the surface where they have limited contact with micro-organisms in the test medium. Hence, there is a reduced potential for measuring substantial biodegradability in the test. This paper describes the work undertaken to establish a standard method of adding low density, poorly water-soluble substances into test vessels of biodegradability studies to ensure these materials remain in contact with micro-organisms in the test medium. The substances are prepared for testing by adsorption onto silica gel followed by dispersion into the culture medium. This method of delivery may provide greater intra- and inter-laboratory consistency in biodegradability test results for low density, poorly water-soluble substances and it may more closely mimic the probable transport and fate of these substances in the environment.

  16. Fatty acid and water-soluble polymer-based controlled release drug delivery system.

    PubMed

    Desai, Divyakant; Kothari, Sanjeev; Chen, Wei; Wang, Jennifer; Huang, Ming; Sharma, Laxmikant

    2011-05-01

    Sustained release capsule formulations based on three components, drug, water-soluble polymer, and water-insoluble fatty acid, were developed. Theophylline, acetaminophen, and glipizide, representing a wide spectrum of aqueous solubility, were used as model drugs. Povidone and hydroxypropyl cellulose were selected as water-soluble polymers. Stearic acid and lauric acid were selected as water-insoluble fatty acids. Fatty acid, polymer, and drug mixture was filled into size #0 gelatin capsules and heated for 2 h at 50 °C. The drug particles were trapped into molten fatty acid and released at a controlled rate through pores created by the water-soluble polymer when capsules were exposed to an aqueous dissolution medium. Manipulation of the formulation components enabled release rates of glipizide and theophylline capsules to be similar to commercial Glucotrol XL tablets and Theo-24 capsules, respectively. The capsules also exhibited satisfactory dissolution stability after exposure to 30 °C/60% relative humidity (RH) in open Petri dishes and to 40 °C/75% RH in closed high-density polyethylene bottles. A computational fluid dynamic-based model was developed to quantitatively describe the drug transport in the capsule matrix and the drug release process. The simulation results showed a diffusion-controlled release mechanism from these capsules.

  17. 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

  18. Hybrid aerogel preparations as drug delivery matrices for low water-solubility drugs.

    PubMed

    Veres, Peter; López-Periago, Ana M; Lázár, István; Saurina, Javier; Domingo, Concepción

    2015-12-30

    A comprehensive study of 14 hybrid aerogels of different composition with applications in drug delivery has been carried out. The overall objective was to modulate the release behavior of drug-impregnated aerogels, from an almost instantaneous release to a semi-retarded delivery prolonged during several hours, through internal surface functionalization. The designed hybrid aerogels were composed of silica and gelatin and functionalized with either phenyl, long (16) hydrocarbon chain or methyl moiety. As model systems, three class II active agents (pKa<5.5), ibuprofen, ketoprofen and triflusal, were chosen to impregnate the aerogels. The work relied on the use of supercritical fluid technology for both the synthesis and functionalization of the hybrid aerogels, as well as for the impregnation with an active agent using supercritical CO2 as a solvent. For the impregnated aerogels, in vitro release profiles were recorded under gastric and intestinal pH-conditions using HPLC techniques. The release behavior observed for the three studied drugs was explained considering the measured dissolution profiles of the crystalline drugs, the aerogel composition and its functionalization. Such features are considered of great interest to tailor the bioavailability of drugs with low water solubility.

  19. 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. PMID:24797563

  20. Nano-pulverization of poorly water soluble compounds with low melting points by a rotation/revolution pulverizer.

    PubMed

    Yuminoki, K; Takeda, M; Kitamura, K; Numata, S; Kimura, K; Takatsuka, T; Hashimoto, N

    2012-08-01

    We report a method for pulverizing poorly water soluble compounds with low melting points to nanoparticles without producing an amorphous phase using a rotation/revolution pulverizer. Fenofibrate, flurbiprofen, and probucol were used as crystalline model compounds. They were suspended in a methylcellulose aqueous solution and pulverized with zirconia balls by the rotation/revolution pulverizer. Beeswax, an amorphous compound, was also examined to investigate whether nano-pulverization of a compound with a low melting point was possible. Beeswax was suspended in ethyl alcohol cooled with liquid nitrogen and pulverized with zirconia balls by the rotation/revolution pulverizer. By optimizing the pulverization parameters, nanoparticles (D50 < 0.15 microm) of the crystalline compounds were obtained with narrow particle size distributions at a rotation/revolution speed of 1000 rpm and a rotation/revolution ratio of 1.0 when the vessel was 0 degrees C. Amorphous fenofibrate and flurbiprofen were not detected by differential scanning calorimetry or powder X-ray diffraction, whereas small amounts of amorphous probucol were detected. Beeswax was pulverized to nanoparticles (D50 = 0.14 microm) with ethyl alcohol cooled with liquid nitrogen. Fine nanoparticles of these poorly water soluble compounds with low melting points were obtained by controlling the rotation/revolution speed and reducing the vessel temperature.

  1. Dissolution-enhancing mechanism of alkalizers in poloxamer-based solid dispersions and physical mixtures containing poorly water-soluble valsartan.

    PubMed

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

    2011-01-01

    The purpose of this study was to investigate the effects of alkalizers in dissolution rate and crystal structure of valsartan (VAL) in Poloxamer 407 (POX)-based solid dispersions (SD). VAL, a poorly-water soluble drug was selected as a model drug because of its low solubility at low pH. The POX-based SDs containing alkalizers (Na₂CO₃, MgO, meglumine and arginine) were prepared by melting method. The dissolution tests were performed using the United States Pharmacopeia (USP) paddle II method in enzyme-free simulated gastric fluid (pH 1.2) for 2 h. Microenvironmental pH (pH(M)) was examined potentiometrically by using a surface pH electrode. Dissolution rate of SD incorporating Na₂CO₃ was drastically increased. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) data indicated that crystalline structure of VAL in SD was transformed to amorphous form by the addition of alkalizers but could not explain the differences in the dissolution rates. The molecular interaction between VAL and Na₂CO₃ was observed in the Fourier transform infrared spectroscopy (FT-IR) spectra by the shift of C=O band from 1732 to 1719 cm⁻¹ and the disappearance of carbonyl group at 1598 cm⁻¹. Furthermore, Na₂CO₃ efficiently modulated pH(M) by providing a favorable microenvironment for drug dissolution. A combination of SD method and use of alkalizer is a promising approach to modulate release rate of poorly water-soluble and ionizable drug with an aid of changes of drug crystallinity, molecular interaction and pH(M).

  2. Water soluble drug releasing soft contact lens in response to pH of tears

    NASA Astrophysics Data System (ADS)

    Kim, G.; Noh, H.

    2016-06-01

    Human tear characteristics including pH and compositions can vary significantly depending on physical and environmental factors. Contact lenses directly contact with human tears can be swelled or de-swelled depending on the pH of the solution due to the nature of the hydrogel. For examples, anionic hydrogels, when the solution's pH is low, is shrunken due to the electric attraction force within the hydrogel network; the opposite phenomenon appears when the solution is basic. The purpose of this study was to evaluate the extent of water soluble drug, hydroxyl propyl methyl cellulose, released from contact lens according to the pH of the artificial tears. Artificial tears are prepared by mixing lysozyme, albumin, sodium chloride, potassium chloride, and calcium chloride following physiological concentrations. Hydrogel contact lens was thermally polymerized using HEMA, EGDMA, and AIBN. The prepared hydrogel lens was immersed in drug for 3 hours and the eluted drug mass was measured as a function of the time. As a result, the drug was released from the lens for 12 hours in all the pH of artificial tears. At the lower pH of artificial tears (pH 5.8), the total amount of dye emitted from the lens was increased than the total amount of dye emitted at the basic tear (pH 8.4). Also, initial burst at acidic tears was increased within 1 hour. Release pattern of water-soluble drug from hydrogel lens turned out to be different depending on the pH of the artificial tears. When designing drug releasing contact lens, physiological pH of tears should be considered.

  3. Improvement of solubility and dissolution rate of poorly water-soluble salicylic acid by a spray-drying technique.

    PubMed

    Kawashima, Y; Saito, M; Takenaka, H

    1975-01-01

    Spray drying techniques have been applied to improve the solubility and dissolution rate of poorly water-soluble salicylic acid. Spray drying of the acid dispersed in acacia solutions resulted in as much as a 50% improvement in the solubility of the product. Solubility improvement was closely related not only to the concentration of acacia but also the amount of amorphous material in the spray-dried products. The heat of solution was inversely related to these parameters. The dissolution rate of spray-dried product was almost instantaneous being about 60 times faster than that of the original powder. A great improvement in the wettability of the spray-dried material seemed to be mainly responsible for the increase of dissolution rate.

  4. Removal of acidic or basic α-amino acids in water by poorly water soluble scandium complexes.

    PubMed

    Hayashi, Nobuyuki; Jin, Shigeki; Ujihara, Tomomi

    2012-11-01

    To recognize α-amino acids with highly polar side chains in water, poorly water soluble scandium complexes with both Lewis acidic and basic portions were synthesized as artificial receptors. A suspension of some of these receptor molecules in an α-amino acid solution could remove acidic and basic α-amino acids from the solution. The compound most efficient at preferentially removing basic α-amino acids (arginine, histidine, and lysine) was the receptor with 7,7'-[1,3-phenylenebis(carbonylimino)]bis(2-naphthalenesulfonate) as the ligand. The neutral α-amino acids were barely removed by these receptors. Removal experiments using a mixed amino acid solution generally gave results similar to those obtained using solutions containing a single amino acid. The results demonstrated that the scandium complex receptors were useful for binding acidic and basic α-amino acids. PMID:23050492

  5. Removal of acidic or basic α-amino acids in water by poorly water soluble scandium complexes.

    PubMed

    Hayashi, Nobuyuki; Jin, Shigeki; Ujihara, Tomomi

    2012-11-01

    To recognize α-amino acids with highly polar side chains in water, poorly water soluble scandium complexes with both Lewis acidic and basic portions were synthesized as artificial receptors. A suspension of some of these receptor molecules in an α-amino acid solution could remove acidic and basic α-amino acids from the solution. The compound most efficient at preferentially removing basic α-amino acids (arginine, histidine, and lysine) was the receptor with 7,7'-[1,3-phenylenebis(carbonylimino)]bis(2-naphthalenesulfonate) as the ligand. The neutral α-amino acids were barely removed by these receptors. Removal experiments using a mixed amino acid solution generally gave results similar to those obtained using solutions containing a single amino acid. The results demonstrated that the scandium complex receptors were useful for binding acidic and basic α-amino acids.

  6. Effect of solubilizing excipients on permeation of poorly water-soluble compounds across Caco-2 cell monolayers.

    PubMed

    Saha, P; Kou, J H

    2000-11-01

    The purpose of this study was to evaluate the effects of solubilizing excipients on Caco-2 transport parameters of poorly water-soluble NCEs (new chemical entities), and determine their permeability class under the BCS guidance (Biopharmaceutics Classification System). The effect of solubilizing excipients on soluble donor concentration of Sch 56592, Sch-X and Sch-Y was estimated. The transport of reference compounds and NCEs was studied across Caco-2 monolayers in absence or presence of solubilizing agents. The Caco-2 permeability of reference compounds showed good correlation with their extent of human oral absorption data. Sch 56592, Sch-X and Sch-Y exhibited high baseline Caco-2 permeability (>10(-5) cm/s). Povidone (1%) improved soluble donor concentration and flux of Sch 56592 by 40%. Other solubilizing excipients predominantly improved Sch 56592 soluble donor concentration, with either no change or a decrease in flux. With Sch-X, 1% povidone, pluronic F68, gelucir 44/14, and 3:2 propylene glycol/Tween-80 markedly improved soluble donor concentration, while increasing Sch-X flux by 40-65%. The soluble donor concentration of Sch-Y was also enhanced by excipients; however, only 1% pluronic F68 and PEG 300 increased Sch-Y flux by 35-50%. Sch 56592, Sch-X and Sch-Y are low solubility-high permeability compounds under the BCS guidance. For such poorly water-soluble NCEs, solubilizing excipients should be carefully screened based on their effects on solubility profiles and membrane transport.

  7. Lipospheres and pro-nano lipospheres for delivery of poorly water soluble compounds.

    PubMed

    Elgart, Anna; Cherniakov, Irina; Aldouby, Yanir; Domb, Abraham J; Hoffman, Amnon

    2012-05-01

    Lipospheres are a drug encapsulation system composed of water dispersible solid microparticles of particle size between 0.01 and 100 μm in diameter with a solid hydrophobic lipid core stabilized by a layer of phospholipid molecules embedded in their surface. The bioactive compound is dissolved or dispersed in the solid lipid matrix of the internal core. Since lipospheres were introduced in the beginning of the 1990s, they have been used for the delivery of multiple types of drugs by various routes of administration. Later, a self-assembling pro-nano lipospheres (PNL) encapsulation system was developed for oral drug delivery. Lipospheres have several advantages over other delivery systems, such as better physical stability, low cost of ingredients, ease of preparation and scale-up, high dispersibility in an aqueous medium, high entrapment of hydrophobic drugs, controlled particle size, and extended release of entrapped drug after administration, from a few hours to several days. This review article focuses on updated information on several aspects of lipospheres and PNL, including preparation techniques, physicochemical properties and in vitro evaluation methods. Additionally, it covers lipospheres and PNL utilization for oral, ocular, and parenteral delivery, with special attention to unique considerations and aspects for each route of administration.

  8. Intestinal solubility and absorption of poorly water soluble compounds: predictions, challenges and solutions.

    PubMed

    Fagerberg, Jonas H; Bergström, Christel A S

    2015-01-01

    We have explored for which type of compounds biorelevant dissolution profiling in simulated intestinal fluids would accurately predict solubility in human intestinal fluid. In total, 460 solubility values in simulated and aspirated human intestinal fluid for 78 drugs were compiled and analyzed. Significant solubilization in the colloidal structures was obtained in fasted and fed state fluids for drug compounds with a logD(oct)>3. Highly lipophilic compounds with high melting points (Tm > 200 °C) could also be significantly solubilized, but typically such compounds had solubility values in the lower µg/ml range also in the presence of the colloidal structures. On the basis of our analysis, compounds with a logD(oct)>3 should be explored in biorelevant dissolution media to better predict in vivo performance after oral dosing.

  9. Scaling up nano-milling of poorly water soluble compounds using a rotation/revolution pulverizer.

    PubMed

    Yuminoki, K; Tachibana, S; Nishimura, Y; Mori, H; Takatsuka, T; Hashimoto, N

    2016-02-01

    We previously reported that a rotation/revolution pulverizer (NP-100) could mill a small amount of a drug (0.1 g) into nanoparticles in several minutes. In this investigation, scale up from the milligram to the kilogram scale of the nano-milling process by the rotation/revolution pulverizer was studied. Phenytoin was used as a model drug with low solubility in water. After confirming the improvement of the phenytoin bioavailability by milling to nanoparticles using NP-100, scaling parameters were evaluated using NP-100 and the middle scale model of NP-100 (ARV-3000T). A theoretical equation for the specific collisional energy was adapted for wet milling; this suggested that the relative centrifugal acceleration of revolution (revolution G) and the drug concentration in the suspension were the two most important parameters. The results obtained using NP-100 and ARV-3000T correlated well when these two parameters were identical. These results were applied to the large scale model of NP-100 (ARV-10KT), where 2 kg (1 kg x 2) of phenytoin nanoparticles were obtained in 60 min. The results from PXRD and DSC indicated that the milled phenytoin by ARV-3000T and ARV-10KT maintained its crystallinity. These results suggest nano-milling using a rotation/revolution pulverizer will be widely applicable to the development of nano-medicine.

  10. 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

  11. Improved oral bioavailability of poorly water-soluble glimepiride by utilizing microemulsion technique.

    PubMed

    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

  12. SNEDDS Containing Poorly Water Soluble Cinnarizine; Development and in Vitro Characterization of Dispersion, Digestion and Solubilization.

    PubMed

    Larsen, Anne T; Ogbonna, Anayo; Abu-Rmaileh, Ragheb; Abrahamsson, Bertil; Ostergaard, Jesper; Müllertz, Anette

    2012-01-01

    Self-Nanoemulsifying Drug Delivery Systems (SNEDDSs) were developed using well-defined excipients with the objective of mimicking digested SNEDDSs without the use of enzymes and in vitro lipolysis models and thereby enabling studies of the morphology and size of nanoemulsions as well as digested nanoemulsions by Cryo-TEM imaging and Dynamic Light Scattering. Four SNEDDSs (I-IV) were developed. Going from SNEDDS I to IV lipid content and solubility of the model drug cinnarizine decreased, which was also the case for dispersion time and droplet size. Droplet size of all SNEDDS was evaluated at 1% (w/w) dispersion under different conditions. Cinnarizine incorporation increased the droplet size of SNEDDSs I and II whereas for SNEDDSs III and IV no difference was observed. At low pH cinnarizine had no effect on droplet size, probably due to increased aqueous solubility and partitioning into the aqueous phase. Dispersion of the SNEDDSs in Simulated Intestinal Media (SIM) containing bile salts and phospholipids resulted in a decrease in droplet size for all SNEDDS, as compared to dispersion in buffer. Increasing the bile salt/phospholipid content in the SIM decreased the droplet sizes further. Mimicked digested SNEDDS with highest lipid content (I and II) formed smaller nanoemulsion droplet sizes upon dispersion in SIM, whereas droplet size from III and IV were virtually unchanged by digestion. Increasing the bile acid/phosphatidylcholine content in the SIM generally decreased droplet size, due to the solubilizing power of the endogenous surfactants. Digestion of SNEDDSs II resulted in formation of vesicles or micelles in fasted and fed state SIM, respectively. The developed and characterized SNEDDS provide for a better knowledge of the colloid phases generated during digestion of SNEDDS and therefore will enable studies that may yield a more detailed understanding of SNEDDS performance. PMID:24300374

  13. SNEDDS Containing Poorly Water Soluble Cinnarizine; Development and in Vitro Characterization of Dispersion, Digestion and Solubilization

    PubMed Central

    Larsen, Anne T.; Ogbonna, Anayo; Abu-Rmaileh, Ragheb; Abrahamsson, Bertil; Østergaard, Jesper; Müllertz, Anette

    2012-01-01

    Self-Nanoemulsifying Drug Delivery Systems (SNEDDSs) were developed using well-defined excipients with the objective of mimicking digested SNEDDSs without the use of enzymes and in vitro lipolysis models and thereby enabling studies of the morphology and size of nanoemulsions as well as digested nanoemulsions by Cryo-TEM imaging and Dynamic Light Scattering. Four SNEDDSs (I-IV) were developed. Going from SNEDDS I to IV lipid content and solubility of the model drug cinnarizine decreased, which was also the case for dispersion time and droplet size. Droplet size of all SNEDDS was evaluated at 1% (w/w) dispersion under different conditions. Cinnarizine incorporation increased the droplet size of SNEDDSs I and II whereas for SNEDDSs III and IV no difference was observed. At low pH cinnarizine had no effect on droplet size, probably due to increased aqueous solubility and partitioning into the aqueous phase. Dispersion of the SNEDDSs in Simulated Intestinal Media (SIM) containing bile salts and phospholipids resulted in a decrease in droplet size for all SNEDDS, as compared to dispersion in buffer. Increasing the bile salt/phospholipid content in the SIM decreased the droplet sizes further. Mimicked digested SNEDDS with highest lipid content (I and II) formed smaller nanoemulsion droplet sizes upon dispersion in SIM, whereas droplet size from III and IV were virtually unchanged by digestion. Increasing the bile acid/phosphatidylcholine content in the SIM generally decreased droplet size, due to the solubilizing power of the endogenous surfactants. Digestion of SNEDDSs II resulted in formation of vesicles or micelles in fasted and fed state SIM, respectively. The developed and characterized SNEDDS provide for a better knowledge of the colloid phases generated during digestion of SNEDDS and therefore will enable studies that may yield a more detailed understanding of SNEDDS performance. PMID:24300374

  14. Statistical optimization of controlled release microspheres containing cetirizine hydrochloride as a model for water soluble drugs.

    PubMed

    El-Say, Khalid M; El-Helw, Abdel-Rahim M; Ahmed, Osama A A; Hosny, Khaled M; Ahmed, Tarek A; Kharshoum, Rasha M; Fahmy, Usama A; Alsawahli, Majed

    2015-01-01

    The purpose was to improve the encapsulation efficiency of cetirizine hydrochloride (CTZ) microspheres as a model for water soluble drugs and control its release by applying response surface methodology. A 3(3) Box-Behnken design was used to determine the effect of drug/polymer ratio (X1), surfactant concentration (X2) and stirring speed (X3), on the mean particle size (Y1), percentage encapsulation efficiency (Y2) and cumulative percent drug released for 12 h (Y3). Emulsion solvent evaporation (ESE) technique was applied utilizing Eudragit RS100 as coating polymer and span 80 as surfactant. All formulations were evaluated for micromeritic properties and morphologically characterized by scanning electron microscopy (SEM). The relative bioavailability of the optimized microspheres was compared with CTZ marketed product after oral administration on healthy human volunteers using a double blind, randomized, cross-over design. The results revealed that the mean particle sizes of the microspheres ranged from 62 to 348 µm and the efficiency of entrapment ranged from 36.3% to 70.1%. The optimized CTZ microspheres exhibited a slow and controlled release over 12 h. The pharmacokinetic data of optimized CTZ microspheres showed prolonged tmax, decreased Cmax and AUC0-∞ value of 3309 ± 211 ng h/ml indicating improved relative bioavailability by 169.4% compared with marketed tablets.

  15. Antimicrobial Action of Water-Soluble β-Chitosan against Clinical Multi-Drug Resistant Bacteria

    PubMed Central

    Park, Seong-Cheol; Nam, Joung-Pyo; Kim, Jun-Ho; Kim, Young-Min; Nah, Jae-Woon; Jang, Mi-Kyeong

    2015-01-01

    Recently, the number of patients infected by drug-resistant pathogenic microbes has increased remarkably worldwide, and a number of studies have reported new antibiotics from natural sources. Among them, chitosan, with a high molecular weight and α-conformation, exhibits potent antimicrobial activity, but useful applications as an antibiotic are limited by its cytotoxicity and insolubility at physiological pH. In the present study, the antibacterial activity of low molecular weight water-soluble (LMWS) α-chitosan (α1k, α5k, and α10k with molecular masses of 1, 5, and 10 kDa, respectively) and β-chitosan (β1k, β5k, and β10k) was compared using a range of pathogenic bacteria containing drug-resistant bacteria isolated from patients at different pH. Interestingly, β5k and β10k exhibited potent antibacterial activity, even at pH 7.4, whereas only α10k was effective at pH 7.4. The active target of β-chitosan is the bacterial membrane, where the leakage of calcein is induced in artificial PE/PG vesicles, bacterial mimetic membrane. Moreover, scanning electron microscopy showed that they caused significant morphological changes on the bacterial surfaces. An in vivo study utilizing a bacteria-infected mouse model found that LMWS β-chitosan could be used as a candidate in anti-infective or wound healing therapeutic applications. PMID:25867474

  16. Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery.

    PubMed

    Liu, Zhuang; Sun, Xiaoming; Nakayama-Ratchford, Nozomi; Dai, Hongjie

    2007-08-01

    We show that large surface areas exist for supramolecular chemistry on single-walled carbon nanotubes (SWNTs) prefunctionalized noncovalently or covalently by common surfactant or acid-oxidation routes. Water-soluble SWNTs with poly(ethylene glycol) (PEG) functionalization via these routes allow for surprisingly high degrees of pi-stacking of aromatic molecules, including a cancer drug (doxorubicin) with ultrahigh loading capacity, a widely used fluorescence molecule (fluorescein), and combinations of molecules. Binding of molecules to nanotubes and their release can be controlled by varying the pH. The strength of pi-stacking of aromatic molecules is dependent on nanotube diameter, leading to a method for controlling the release rate of molecules from SWNTs by using nanotube materials with suitable diameter. This work introduces the concept of "functionalization partitioning" of SWNTs, i.e., imparting multiple chemical species, such as PEG, drugs, and fluorescent tags, with different functionalities onto the surface of the same nanotube. Such chemical partitioning should open up new opportunities in chemical, biological, and medical applications of novel nanomaterials.

  17. Improving Co-Amorphous Drug Formulations by the Addition of the Highly Water Soluble Amino Acid, Proline

    PubMed Central

    Jensen, Katrine Tarp; Löbmann, Korbinian; Rades, Thomas; Grohganz, Holger

    2014-01-01

    Co-amorphous drug amino acid mixtures were previously shown to be a promising approach to create physically stable amorphous systems with the improved dissolution properties of poorly water-soluble drugs. The aim of this work was to expand the co-amorphous drug amino acid mixture approach by combining the model drug, naproxen (NAP), with an amino acid to physically stabilize the co-amorphous system (tryptophan, TRP, or arginine, ARG) and a second highly soluble amino acid (proline, PRO) for an additional improvement of the dissolution rate. Co-amorphous drug-amino acid blends were prepared by ball milling and investigated for solid state characteristics, stability and the dissolution rate enhancement of NAP. All co-amorphous mixtures were stable at room temperature and 40 °C for a minimum of 84 days. PRO acted as a stabilizer for the co-amorphous system, including NAP–TRP, through enhancing the molecular interactions in the form of hydrogen bonds between all three components in the mixture. A salt formation between the acidic drug, NAP, and the basic amino acid, ARG, was found in co-amorphous NAP–ARG. In comparison to crystalline NAP, binary NAP–TRP and NAP–ARG, it could be shown that the highly soluble amino acid, PRO, improved the dissolution rate of NAP from the ternary co-amorphous systems in combination with either TRP or ARG. In conclusion, both the solubility of the amino acid and potential interactions between the molecules are critical parameters to consider in the development of co-amorphous formulations. PMID:25025400

  18. Effect of liquid crystals with cyclodextrin on the bioavailability of a poorly water-soluble compound, diosgenin, after its oral administration to rats.

    PubMed

    Okawara, Masaki; Hashimoto, Fumie; Todo, Hiroaki; Sugibayashi, Kenji; Tokudome, Yoshihiro

    2014-09-10

    Diosgenin, found in wild yam (Dioscorea villosa), has been shown to ameliorate diabetes and hyperlipidemia, increase cell proliferation in a human 3D skin model, and inhibits melanin production in B16 melanoma cells. It is also an active element in cosmeceutical and dietary supplements. Although the bioavailability of diosgenin is low due to its poor solubility and intestinal permeability, it was subsequently improved using a β-cyclodextrin (β-CD) inclusion complex. Recently liquid crystals (LCs) were shown to enhance the bioavailability of poorly water-soluble drugs. The purpose in the present study was to prepare diosgenin LCs and investigate the interaction between LC and β-CD in order to improve its bioavailability of diosgenin. Crystallinity and particle diameters of LCs in water were determined by small angle X-ray scattering (SAXS) and Zetasizer. Pharmacokinetic parameters were calculated using the plasma content of diosgenin after its oral administration to Wistar rats. Regarding the formation of glyceryl monooleate (GMO) and phytantriol (PHY) LC, SAXS patterns showed the hexagonal and cubic phases, respectively. Bioavailability was significantly enhanced after oral administration of LCs prepared by GMO than after diosgenin alone. The bioavailability was further improved with the combination of LC and β-CD than LC and water.

  19. Fundamental aspects of solid dispersion technology for poorly soluble drugs.

    PubMed

    Huang, Yanbin; Dai, Wei-Guo

    2014-02-01

    The solid dispersion has become an established solubilization technology for poorly water soluble drugs. Since a solid dispersion is basically a drug-polymer two-component system, the drug-polymer interaction is the determining factor in its design and performance. In this review, we summarize our current understanding of solid dispersions both in the solid state and in dissolution, emphasizing the fundamental aspects of this important technology.

  20. Detailed study of precipitation of a poorly water soluble test compound using methodologies as in activity and solubility screening - mixing and automation effects.

    PubMed

    Gillespie, Cheska; Kennedy, Alan R; Edwards, Darren; Dowden, Lee; Daublain, Pierre; Halling, Peter

    2013-09-01

    Storage of pharmaceutical discovery compounds dissolved in dimethylsulfoxide (DMSO) is commonplace within industry. Often, the DMSO stock solution is added to an aqueous system (e.g. in bioassay or kinetic solubility testing)- since most test compounds are hydrophobic, precipitation could occur. Little is known about the factors affecting this precipitation process at the low (µM) concentrations used in screening analyses. Here, a poorly water soluble test compound (tolnaftate) was used to compare manual and automated pipetting, and explore the effect of mixing variables on precipitation. The amount of drug present in the supernatant after precipitation and centrifugation of the samples was quantified. An unusual result was obtained in three different laboratories: results of experiments performed initially were statistically significantly higher than those performed after a few days in the same lab. No significant differences were found between automated and manual pipetting, including in variability. Vortex mixing was found to give significantly lower supernatant amounts compared to milder mixing types. The mixing employed affects the particle growth of the precipitate. These findings are of relevance to discovery stage bioassay and kinetic solubility analyses.

  1. 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

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

    PubMed Central

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

    2015-01-01

    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

  3. Aqueous coating dispersion (pseudolatex) of zein improves formulation of sustained-release tablets containing very water-soluble drug.

    PubMed

    Li, X N; Guo, H X; Heinamaki, J

    2010-05-01

    Zein is an alcohol soluble protein of corn origin that exhibits hydrophobic properties. Pseudolatexes are colloidal dispersions containing spherical solid or semisolid particles less than 1 microm in diameter and can be prepared from any existing thermoplastic water-insoluble polymer. The novel plasticized film-coating pseudolatex of zein was studied in formulation of sustained-release tablets containing very water-soluble drug. Film formation of plasticized aqueous dispersion was compared with film forming properties of plasticized organic solvent system (ethanol) of zein. The water vapor permeability (WVP), water uptake and erosion, and moisture sorption were evaluated with free films. The tablets containing metoprolol tartrate as a model drug were used in pan-coating experiments. Aqueous film coatings plasticized with PEG 400 exhibited very low water uptake. No significant difference in WVP, moisture sorption and erosion were found between aqueous films and organic solvent-based films of zein plasticized with PEG 400. The atomic force microscopy (AFM) images on microstructure of films showed that colloidal particle size of zein in the aqueous films was smaller than that observed in the solvent-based films. In addition, the aqueous-based films were more compact and smoother than the respective solvent-based films. The aqueous zein-coated tablets containing very water-soluble drug (metoprolol tartrate) exhibited clear sustained-release dissolution profiles in vitro, while the respective solvent-based film-coated tablets showed much faster drug release. Furthermore, aqueous zein-coated tablets had lower water absorption at high humidity conditions. In conclusion, the plasticized aqueous dispersion (pseudolatex) of zein can be used for moisture resistant film coating of sustained-release tablets containing very water-soluble drug. PMID:20129615

  4. Molecular-Level Understanding of the Encapsulation and Dissolution of Poorly Water-Soluble Ibuprofen by Functionalized Organic Nanotubes Using Solid-State NMR Spectroscopy.

    PubMed

    Liu, Nan; Higashi, Kenjirou; Kikuchi, Junko; Ando, Shigeru; Kameta, Naohiro; Ding, Wuxiao; Masuda, Mitsutoshi; Shimizu, Toshimi; Ueda, Keisuke; Yamamoto, Keiji; Moribe, Kunikazu

    2016-05-19

    A comprehensive study of the encapsulation and dissolution of the poorly water-soluble drug ibuprofen (IBU) using two types of organic nanotubes (ONT-1 and ONT-2) was conducted. ONT-1 and ONT-2 had similar inner and outer diameters, but these surfaces were functionalized with different groups. IBU was encapsulated by each ONT via solvent evaporation. The amount of IBU in the ONTs was 9.1 and 29.2 wt % for ONT-1 and ONT-2, respectively. Dissolution of IBU from ONT-1 was very rapid, while from ONT-2 it was slower after the initial burst release. One-dimensional (1D) (1)H, (13)C, and two-dimensional (2D) (1)H-(13)C solid-state NMR measurements using fast magic-angle spinning (MAS) at a rate of 40 kHz revealed the molecular state of the encapsulated IBU in each ONT. Extremely mobile IBU was observed inside the hollow nanosapce of both ONT-1 and ONT-2 using (13)C MAS NMR with a single pulse (SP) method. Interestingly, (13)C cross-polarization (CP) MAS NMR demonstrated that IBU also existed on the outer surface of both ONTs. The encapsulation ratios of IBU inside the hollow nanospaces versus on the outer surfaces were calculated by waveform separation to be approximately 1:1 for ONT-1 and 2:1 for ONT-2. Changes in (13)C chemical shifts showed the intermolecular interactions between the carboxyl group of IBU and the amino group on the ONT-2 inner surface. The cationic ONT-2 could form the stronger electrostatic interactions with IBU in the hollow nanosapce than anionic ONT-1. On the other hand, 2D (1)H-(13)C NMR indicated that the hydroxyl groups of the glucose unit on the outer surface of the ONTs interacted with the carboxyl group of IBU in both ONT-1 and ONT-2. The changes in peak shape and chemical shift of the ONT glucose group after IBU encapsulation were larger in ONT-2 than in ONT-1, indicating a stronger interaction between IBU and the outer surface of ONT-2. The smaller amount of IBU encapsulation and rapid IBU dissolution from ONT-1 could be due to the weak

  5. 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.

  6. Nanosuspension formulations of poorly water-soluble compounds for intravenous administration in exploratory toxicity studies: in vitro and in vivo evaluation.

    PubMed

    Fujimura, Hisako; Komasaka, Takao; Tomari, Taizo; Kitano, Yasunori; Takekawa, Kouji

    2016-10-01

    This study was conducted to investigate the use of a nanosuspension for intravenous injection into dogs to increase exposure without toxic additives for preclinical studies in the discovery stage. Nanosuspensions were prepared with a mixer mill and zirconia beads with a vehicle of 2% (w/v) poloxamer 338, which was confirmed to lead to no histamine release in dogs. Sterilized nanosuspensions of poorly water-soluble compounds, cilostazol (Cil), spironolactone (Spi) and probucol (Pro), at 10 mg ml(-1) were obtained by milling for 30 min, followed by autoclaving for 20 min at 121 °C and milling for 30 min (mill-autoclave-mill method). The particle sizes (d50) of Cil, Spi and Pro were 0.554, 0.484 and 0.377 µm, respectively, and the percentages of the nominal concentration were 79.1%, 99.6% and 75.4%, respectively. In chromatographic data, no extra peaks were observed. The particle size of Cil was 0.564 µm after storage for 16 days at 2-8 °C. Cil in nanosuspension, but not in microsuspension, rapidly dissolved in dog plasma. Cil nanosuspension at 0.4 mg kg(-1) and Cil saline solution at 0.03 mg kg(-1) , around the saturation solubility, were intravenously administered to dogs. Nanosuspension increased exposure. The versatility of the mill-autoclave-mill method was checked for 15 compounds, and the particle size of 12 compounds was in the nano range. The nanosuspension optimized in this study may be useful for intravenous toxicological and pharmacological studies in the early stage of drug development. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26849104

  7. Fundamental aspects of solid dispersion technology for poorly soluble drugs

    PubMed Central

    Huang, Yanbin; Dai, Wei-Guo

    2013-01-01

    The solid dispersion has become an established solubilization technology for poorly water soluble drugs. Since a solid dispersion is basically a drug–polymer two-component system, the drug–polymer interaction is the determining factor in its design and performance. In this review, we summarize our current understanding of solid dispersions both in the solid state and in dissolution, emphasizing the fundamental aspects of this important technology. PMID:26579360

  8. Water-soluble photoluminescent fullerene capped mesoporous silica for pH-responsive drug delivery and bioimaging

    NASA Astrophysics Data System (ADS)

    Tan, Lei; Wu, Tao; Tang, Zhao-Wen; Xiao, Jian-Yun; Zhuo, Ren-Xi; Shi, Bin; Liu, Chuan-Jun

    2016-08-01

    In this paper, a biocompatible and water-soluble fluorescent fullerene (C60-TEG-COOH) coated mesoporous silica nanoparticle (MSN) was successfully fabricated for pH-sensitive drug release and fluorescent cell imaging. The MSN was first reacted with 3-aminopropyltriethoxysilane to obtain an amino-modified MSN, and then the water-soluble C60 with a carboxyl group was used to cover the surface of the MSN through electrostatic interaction with the amino group in PBS solution (pH = 7.4). The release of doxorubicin hydrochloride (DOX) could be triggered under a mild acidic environment (lysosome, pH = 5.0) due to the protonation of C60-TEG-COO‑, which induced the dissociation of the C60-TEG-COOH modified MSN (MSN@C60). Furthermore, the uptake of nanoparticles by cells could be tracked because of the green fluorescent property of the C60-modified MSN. In an in vitro study, the prepared materials showed excellent biocompatibility and the DOX-loaded nanocarrier exhibited efficient anticancer ability. This work offered a simple method for designing a simultaneous pH-responsive drug delivery and bioimaging system.

  9. Water-soluble photoluminescent fullerene capped mesoporous silica for pH-responsive drug delivery and bioimaging

    NASA Astrophysics Data System (ADS)

    Tan, Lei; Wu, Tao; Tang, Zhao-Wen; Xiao, Jian-Yun; Zhuo, Ren-Xi; Shi, Bin; Liu, Chuan-Jun

    2016-08-01

    In this paper, a biocompatible and water-soluble fluorescent fullerene (C60-TEG-COOH) coated mesoporous silica nanoparticle (MSN) was successfully fabricated for pH-sensitive drug release and fluorescent cell imaging. The MSN was first reacted with 3-aminopropyltriethoxysilane to obtain an amino-modified MSN, and then the water-soluble C60 with a carboxyl group was used to cover the surface of the MSN through electrostatic interaction with the amino group in PBS solution (pH = 7.4). The release of doxorubicin hydrochloride (DOX) could be triggered under a mild acidic environment (lysosome, pH = 5.0) due to the protonation of C60-TEG-COO-, which induced the dissociation of the C60-TEG-COOH modified MSN (MSN@C60). Furthermore, the uptake of nanoparticles by cells could be tracked because of the green fluorescent property of the C60-modified MSN. In an in vitro study, the prepared materials showed excellent biocompatibility and the DOX-loaded nanocarrier exhibited efficient anticancer ability. This work offered a simple method for designing a simultaneous pH-responsive drug delivery and bioimaging system.

  10. 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

  11. Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base.

    PubMed

    Hecq, J; Deleers, M; Fanara, D; Vranckx, H; Boulanger, P; Le Lamer, S; Amighi, K

    2006-11-01

    Ucb-35440-3 is a new drug entity under investigation at UCB S.A. Due to its physicochemical characteristics, the drug, a poorly water-soluble weak base, shows poor solubility and dissolution characteristics. In rat, the low oral bioavailability (F < 10%) is largely due to poor absorption. In order to enhance the solubility and dissolution characteristics, formulation of ucb-35440-3 as nanocrystals has been achieved in this study. Nanoparticles were prepared using high pressure homogenization and were characterized in terms of size and morphology. In vitro dissolution characteristics were investigated and compared to the un-milled drug in order to verify the theoretical hypothesis on the benefit of increased surface area. In vivo pharmacokinetic evaluation of ucb-35440-3 nanoparticles was also carried out on rats. Crystalline state evaluation before and following particle size reduction was conducted through polarized light microscopy and PXRD to denote any possible transformation to an amorphous state during the homogenization process. Drug chemical stability was also assessed following homogenization. The dissolution rate increased significantly at pH 3.0, 5.0 and 6.5 for ucb-35440-3 nanoparticles. However, the pharmacokinetic profile obtained yielded lower systemic exposure than the un-milled compound (in fed state), this although being thought to be the consequence of the drug and formulation characteristics.

  12. Supramolecular Drug Delivery Systems Based on Water-Soluble Pillar[n]arenes.

    PubMed

    Wu, Xuan; Gao, Lei; Hu, Xiao-Yu; Wang, Leyong

    2016-06-01

    Supramolecular drug delivery systems (SDDSs), including various kinds of nanostructures that are assembled by reversible noncovalent interactions, have attracted considerable attention as ideal drug carriers owing to their fascinating ability to undergo dynamic switching of structure, morphology, and function in response to various external stimuli, which provides a flexible and robust platform for designing and developing functional and smart supramolecular nano-drug carriers. Pillar[n]arenes represent a new generation of macrocyclic hosts, which have unique structures and excellent properties in host-guest chemistry. This account describes recent progress in our group to develop pillararene-based stimuli-responsive supramolecular nanostructures constructed by reversible host-guest interactions for controllable anticancer drug delivery. The potential applications of these supramolecular drug carriers in cancer treatment and the fundamental questions facing SDDSs are also discussed.

  13. Release of Water Soluble Drugs from Dynamically Swelling POLY(2-HYDROXYETHYL Methacrylate - CO - Methacrylic Acid) Hydrogels.

    NASA Astrophysics Data System (ADS)

    Kou, Jim Hwai-Cher

    In this study, ionizable copolymers of HEMA and methacrylic acid (MA) are investigated for their potential use in developing pH dependent oral delivery systems. Because of the MA units, these gels swell extensively at high pH. Since solute diffusion in the hydrophilic polymers depends highly on the water content of the matrix, it is anticipated that the release rate will be modulated by this pH induced swelling. From a practical point of view, the advantage of the present system is that one can minimize drug loss in the stomach and achieve a programmed release in intestine. This approach is expected to improve delivery of acid labile drugs or drugs that cause severe gastrointestinal side effects. This work mainly focuses on the basic understanding of the mechanism involved in drug release from the poly(HEMA -co- MA) gels, especially under dynamic swelling conditions. Equilibrium swelling is first characterized since water content is the major determinant of transport properties in these gels. Phenylpropanolamine (PPA) is chosen as the model drug for the release study and its diffusion characteristics in the gel matrix determined. The data obtained show that the PPA diffusivity follows the free volume theory of Yasuda, which explains the accelerating effect of swelling on drug release. A mathematical model based on a diffusion mechanism has been developed to describe PPA release from the swelling gels. Based on this model, several significant conclusions can be drawn. First, the release rate can be modulated by the aspect ratio of the cylindrical geometry, and this has a practical implication in dosage form design. Second, the release rate can be lowered quite considerably if the dimensional increase due to swelling is significant. Consequently, it is the balance between the drug diffusivity increase and the gel dimensional growth that determines the release rate from the swelling matrix. Third, quasi-steady release kinetics, which are characteristic of swelling

  14. Diffusion of water-soluble sorptive drugs in HEMA/MAA hydrogels.

    PubMed

    Liu, D E; Dursch, T J; Taylor, N O; Chan, S Y; Bregante, D T; Radke, C J

    2016-10-10

    We measure and, for the first time, theoretically predict four prototypical aqueous-drug diffusion coefficients in five soft-contact-lens material hydrogels where solute-specific adsorption is pronounced. Two-photon fluorescence confocal microscopy and UV/Vis-absorption spectrophotometry assess transient solute concentration profiles and concentration histories, respectively. Diffusion coefficients are obtained for acetazolamide, riboflavin, sodium fluorescein, and theophylline in 2-hydroxyethyl methacrylate/methacrylic acid (HEMA/MAA) copolymer hydrogels as functions of composition, equilibrium water content (30-90%), and aqueous pH (2 and 7.4). At pH2, MAA chains are nonionic, whereas at pH7.4, MAA chains are anionic (pKa≈5.2). All studied prototypical drugs specifically interact with HEMA and nonionic MAA (at pH2) moieties. Conversely, none of the prototypical drugs adsorb specifically to anionic MAA (at pH7.4) chains. As expected, diffusivities of adsorbing solutes are significantly diminished by specific interactions with hydrogel strands. Despite similar solute size, relative diffusion coefficients in the hydrogels span several orders of magnitude because of varying degrees of solute interactions with hydrogel-polymer chains. To provide a theoretical framework for the new diffusion data, we apply an effective-medium model extended for solute-specific interactions with hydrogel copolymer strands. Sorptive-diffusion kinetics is successfully described by local equilibrium and Henry's law. All necessary parameters are determined independently. Predicted diffusivities are in good agreement with experiment. PMID:27565214

  15. 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. PMID:26686139

  16. 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.

  17. 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

  18. Water soluble polymer films for intravascular drug delivery of antithrombotic biomolecules.

    PubMed

    Scott, Rebecca A; Park, Kinam; Panitch, Alyssa

    2013-05-01

    Over the past 10 years, the number of percutaneous coronary intervention (PCI) procedures performed in the United States has increased by 33%; however, restenosis, which inhibits complete functional recovery of the vessel wall, remains a complication of this procedure. To traverse the complications associated with PCI, the investigation of therapeutic delivery has become an integral topic in modern research. One such therapeutic, a mimic of the proteoglycan decorin, termed DS-SILY, can mask exposed collagen and thereby effectively decrease platelet activation, has recently been developed by our lab. Drawing inspiration from coating technologies developed by the pharmaceutical industry, a fast-dissolving polymer film has been developed to deliver active therapeutic agents from a balloon catheter during PCI. This research investigates the release of DS-SILY from fast-dissolving polymer films composed of poly(vinyl alcohol) (PVA) and poly(ethylene glycol) (PEG). Thin, uniform polymer films were produced via spin coating technique. The dissolution speed of the polymer films was found to be dependent on the concentration of polymer solution, where at least 65% of the films were shown to dissolve into nanometer sized polymer fragments within 2 min. DS-SILY, up to 6.26 μg/cm(2), was loaded into the films and functional release of the mimic was demonstrated by its successful binding to collagen upon release. Furthermore, DS-SILY released from films resulted in increased platelet inhibition. These results indicate that use of fast-dissolving polymer films allow for the successful release of biomolecules and further investigation of their use for localized drug delivery during PCI procedures is warranted. PMID:23262161

  19. Analyses of the Binding between Water Soluble C60 Derivatives and Potential Drug Targets through a Molecular Docking Approach

    PubMed Central

    Liu, Junjun; Zhang, Houjin

    2016-01-01

    Fullerene C60, a unique sphere-shaped molecule consisting of carbon, has been proved to have inhibitory effects on many diseases. However, the applications of C60 in medicine have been severely hindered by its complete insolubility in water and low solubility in almost all organic solvents. In this study, the water-soluble C60 derivatives and the C60 binding protein’s structures were collected from the literature. The selected proteins fall into several groups, including acetylcholinesterase, glutamate racemase, inosine monophosphate dehydrogenase, lumazine synthase, human estrogen receptor alpha, dihydrofolate reductase and N-myristoyltransferase. The C60 derivatives were docked into the binding sites in the proteins. The binding affinities of the C60 derivatives were calculated. The bindings between proteins and their known inhibitors or native ligands were also characterized in the same way. The results show that C60 derivatives form good interactions with the binding sites of different protein targets. In many cases, the binding affinities of C60 derivatives are better than those of known inhibitors and native ligands. This study demonstrates the interaction patterns of C60 derivatives and their binding partners, which will have good impact on the fullerene-based drug discovery. PMID:26829126

  20. Design, synthesis, fabrication and in vitro evalution of mucoadhesive 5-amino-2-mercaptobenzimidazole chitosan as low water soluble drug carriers.

    PubMed

    Kongsong, Mullika; Songsurang, Kultida; Sangvanich, Polkit; Siralertmukul, Krisana; Muangsin, Nongnuj

    2014-11-01

    Mucoadhesive thiolated chitosan suitable as a carrier for low water soluble drugs was designed and synthesized by conjugating 5-amino-2-mercaptobenzimidazole (MBI) using methylacrylate (MA) as the linking agent. A 14.4% degree of substitution of MA, as determined by (1)H NMR analysis, and 11.86±0.01μmol thiol groups/g of polymer, as determined by Ellman's method, was obtained. The MBI-MA-chitosan had an 11-fold stronger mucoadhesive property compared to unmodified chitosan at pH 1.2, as determined by the periodic acid: Schiff colorimetric method. Chitosan, MA-chitosan and MBI-MA-chitosan were fabricated as well-formed microspheres using electrospray ionization, including an entrapment efficiency of simvastatin (SV) of over 80% for the MBI-MA-chitosan. The mucoadhesiveness of the SV-loaded MBI-MA-CS microspheres was still higher than that for SV-loaded chitosan at pH 1.2 and 6.4. The SV-loaded MBI-MA-CS microspheres revealed a reduced burst effect and an increased release rate (more than fivefold higher than pure SV) of SV over 12h.

  1. Practical method for preparing nanosuspension formulations for toxicology studies in the discovery stage: formulation optimization and in vitro/in vivo evaluation of nanosized poorly water-soluble compounds.

    PubMed

    Komasaka, Takao; Fujimura, Hisako; Tagawa, Toshiaki; Sugiyama, Akio; Kitano, Yasunori

    2014-01-01

    The present study aimed to develop a practical method for preparing nanosuspension formulations of poorly water-soluble compounds for enhancing oral absorption in toxicology studies in the discovery stage. To obtain a suitable nanosuspension formulation for the intended purpose, formulations were optimized with a focus on the following characteristics: i) containing a high drug concentration, ii) consisting of commonly used excipient types in proper quantities for toxicology studies, iii) having long-term stability, and iv) having versatility for use with diverse compounds. Test compounds were milled with various excipients by wet media milling methods using a mixer mill (10 mg/batch) and a rotation/revolution mixer (0.5 g/batch). As a result, 100 mg/mL nanosuspensions of all 11 test compounds could be prepared with an optimized dispersing agent, 0.5% hydroxypropyl methylcellulose (HPMC) (3 cP)-0.5% Tween 80. Notably, it was found that the molecular weight of HPMC influenced not only particle size but also the stability of nanosuspensions and they were stable for 4 weeks at 5°C. The nanosuspensions increased in vitro dissolution rates and provided 3.9 and 3.0 times higher Cmax and 4.4 and 1.6 times higher area under the concentration-time curve from 0-24 h (AUC0-24 h) in rats (oral dose of 300 mg/kg) for cilostazol and danazol, respectively. In conclusion, applying a wet media milling method with the combination of HPMC of a small molecular weight and Tween 80 as a dispersing agent, nanosuspensions can be practically prepared and conveniently utilized for enhancing the oral absorption of poorly water-soluble compounds in toxicology studies in the discovery stage.

  2. Peculiar mechanism of solubilization of a sparingly water soluble drug into polymeric micelles. Kinetic and equilibrium studies.

    PubMed

    Turco Liveri, Maria Liria; Licciardi, Mariano; Sciascia, Luciana; Giammona, Gaetano; Cavallaro, Gennara

    2012-04-26

    Complementary kinetic and equilibrium studies on the solubilization process of the sparingly water soluble tamoxifen (TAM) drug in polymeric aqueous solutions have been performed by using the spectrophotometric method. In particular, the amphiphilic copolymers obtained by derivatization of polymeric chain of poly(N-2-hydroxyethyl)-dl-aspartamide, PHEA, with poly(ethylene glycol)s, PEG (2000 or 5000 Da), and/or hexadecylamine chain, C16, namely PHEA-PEG2000-C16, PHEA-PEG5000-C16, PHEA-C16, have been employed. Preliminary to the kinetic and equilibrium data quantitative treatment, the molar absorption coefficient of TAM in polymeric micelle aqueous solution has been determined. By these studies the solubization sites of TAM into the polymeric micelles have been determined and the solubilization mechanism has been elucidated through a nonconventional approach by considering the TAM partitioned between three pseudophases, i.e., the aqueous pseudophase, the hydrophilic corona, and the hydrophobic core. The simultaneous solution of the rate laws associated with each step of the proposed mechanism allowed the calculation of the rate constants associated with the involved processes, the values of which are independent of both the copolymer concentration and nature, with the exception of the rate of the TAM transfer from the corona to the core. This has been attributed to the steric barrier, represented by the corona, which hampers the solubilization into the core. The binding constant values of the TAM to the hydrophilic corona of the polymeric micelles, calculated through the quantitative analysis of the equilibrium data, depend on the thickness of the hydrophilic headgroup, while those of the hydrophobic core are almost independent of the copolymer type. Further confirmation to the proposed solubilization mechanism has been provided by performing the kinetic and equilibrium measurements in the presence of PHEA-PEG2000 and PHEA-PEG5000 copolymers.

  3. Ultrasound influence on the solubility of solid dispersions prepared for a poorly soluble drug.

    PubMed

    Pereira, Simone Vieira; Colombo, Fábio Belotti; de Freitas, Luis Alexandre Pedro

    2016-03-01

    Solid dispersions have been successfully used to enhance the solubility of several poorly water soluble drugs. Solid dispersions are produced by melting hydrophilic carriers and mixing in the poorly water soluble drug. Supersaturation is obtained by quickly cooling the mixture until it solidifies, thereby entrapping the drug. The effects of using ultrasound to homogenize the molten carrier and drug mixture were studied. In particular, the increase in drug solubility for the resulting solid dispersions was analyzed. Piroxicam, which has very low water solubility, was used as a model drug. A full factorial design was used to analyze how sonication parameters affected the solubility and in vitro release of the drug. The results show that the use of ultrasound can significantly increase the solubility and dissolution rate of the piroxicam solid dispersion. Pure piroxicam presented a solubility of 13.3 μg/mL. A maximum fourfold increase in solubility, reaching 53.8 μg/mL, was observed for a solid dispersion sonicated at 19 kHz for 10 min and 475 W. The in vitro dissolution rate test showed the sonicated solid dispersion reached a maximum rate of 18%/min, a sixfold increase over the piroxicam rate of 2.9%/min. Further solid state characterization by thermal, X-ray diffraction and Fourier transform infrared analyses also showed that the sonication process, in the described conditions, did not adversely alter the drug or significantly change its polymorphic form. Ultrasound is therefore an interesting technique to homogenize drug/carrier mixtures with the objective of increasing the solubility of drugs with poor water solubility. PMID:26548840

  4. Ultrasound influence on the solubility of solid dispersions prepared for a poorly soluble drug.

    PubMed

    Pereira, Simone Vieira; Colombo, Fábio Belotti; de Freitas, Luis Alexandre Pedro

    2016-03-01

    Solid dispersions have been successfully used to enhance the solubility of several poorly water soluble drugs. Solid dispersions are produced by melting hydrophilic carriers and mixing in the poorly water soluble drug. Supersaturation is obtained by quickly cooling the mixture until it solidifies, thereby entrapping the drug. The effects of using ultrasound to homogenize the molten carrier and drug mixture were studied. In particular, the increase in drug solubility for the resulting solid dispersions was analyzed. Piroxicam, which has very low water solubility, was used as a model drug. A full factorial design was used to analyze how sonication parameters affected the solubility and in vitro release of the drug. The results show that the use of ultrasound can significantly increase the solubility and dissolution rate of the piroxicam solid dispersion. Pure piroxicam presented a solubility of 13.3 μg/mL. A maximum fourfold increase in solubility, reaching 53.8 μg/mL, was observed for a solid dispersion sonicated at 19 kHz for 10 min and 475 W. The in vitro dissolution rate test showed the sonicated solid dispersion reached a maximum rate of 18%/min, a sixfold increase over the piroxicam rate of 2.9%/min. Further solid state characterization by thermal, X-ray diffraction and Fourier transform infrared analyses also showed that the sonication process, in the described conditions, did not adversely alter the drug or significantly change its polymorphic form. Ultrasound is therefore an interesting technique to homogenize drug/carrier mixtures with the objective of increasing the solubility of drugs with poor water solubility.

  5. High-efficiency loading and controlled release of highly water-soluble drug, pravastatin sodium by use of cross-linked β-cyclodextrin

    PubMed Central

    Kumar, Yatendra; Philip, Betty; Pathak, Kamla

    2011-01-01

    Aim: The aim of the project was to develop cross-linked b-cyclodextrin (CL β-CD) microparticles for controlled delivery of a highly water-soluble drug. Materials and Methods: CL β-CD microparticles were prepared by emulsification phase separation technique using epichlorohydrin as a cross-linking reagent. The developed microparticles were compared with β-CD for their pharmacotechnical properties. A highly water-soluble model drug, pravastatin sodium (PS) was loaded within these hydrophobic microparticles by active drug loading method using nonionic surfactant Tween 80 as the loading facilitator. Results: Maximal drug fixation (216.8 mg/g beads) was observed in pH 4 at 20°C. In vitro release studies of PS-loaded CL β-CD microparticles in simulated gastric fluid and simulated intestinal fluid resulted in modified dissolution profiles. Modeling of release profiles confirmed controlled release (r2 = 0.9910) of PS from the cross-linked system. Conclusion: Controlled release CL β-CD microparticles PS that have the potential to enhance its therapeutic properties by offering the advantage of less frequent dosing and decreased fluctuations in the blood levels during the dosing interval were successfully developed. PMID:23071914

  6. 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.

  7. 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.

  8. 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. PMID:27048207

  9. 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. PMID:25460850

  10. Support Tools in Formulation Development for Poorly Soluble Drugs.

    PubMed

    Fridgeirsdottir, Gudrun A; Harris, Robert; Fischer, Peter M; Roberts, Clive J

    2016-08-01

    The need for solubility enhancement through formulation is a well-known but still problematic issue because of the numbers of poorly water-soluble drugs in development. There are several possible routes that can be taken to increase the bioavailability of drugs intended for immediate-release oral formulation. The best formulation strategy for any given drug will depend on numerous factors, including required dose, shelf life, manufacturability, and the properties of the active pharmaceutical ingredient (API). Choosing an optimal formulation and manufacturing route for a new API is therefore not a straightforward process. Currently, there are several approaches that are used in the pharmaceutical industry to select the best formulation strategy. These differ in complexity and efficiency, but most try to predict which route will best suit the API based on selected molecular parameters such as molecular weight, lipophilicity (logP), and solubility. These methods range from using no tools, trial and error methods through a variety of complex tools from small in vitro or in vivo experiments or high throughput screening, guidance maps, and decision trees to the most complex methods based on computational modelling tools. This review aims to list available support tools and explain how they are used. PMID:27368122

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

    NASA Astrophysics Data System (ADS)

    Li, Yongqiang

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

  12. Dual photo- and pH-responsive supramolecular nanocarriers based on water-soluble pillar[6]arene and different azobenzene derivatives for intracellular anticancer drug delivery.

    PubMed

    Hu, Xiao-Yu; Jia, Keke; Cao, Yu; Li, Yan; Qin, Shan; Zhou, Fan; Lin, Chen; Zhang, Dongmei; Wang, Leyong

    2015-01-12

    Two novel types of supramolecular nanocarriers fabricated by the amphiphilic host-guest inclusion complex formed from water-soluble pillar[6]arene (WP6) and azobenzene derivatives G1 or G2 have been developed, in which G1 is structurally similar to G2 but has an extra phenoxy group in its hydrophobic region. Supramolecular micelles can be initially formed by WP6 with G1, which gradually transform into layered structures with liquid-crystalline properties, whereas stable supramolecular vesicles are obtained from WP6 and G2, which exhibit dual photo- and pH-responsiveness. Notably, the resulting WP6⊃G2 vesicles can efficiently encapsulate anticancer drug mitoxantrone (MTZ) to achieve MTZ-loaded vesicles, which maintain good stability in a simulated normal physiological environment, whereas in an acid environment similar to that of tumor cells or with external UV irradiation, the encapsulated drug is promptly released. More importantly, cytotoxicity assay indicates that such vesicles have good biocompatibility and the MTZ-loaded vesicles exhibit comparable anticancer activity to free MTZ, especially with additional UV stimulus, whereas its cytotoxicity for normal cells was remarkably reduced. Flow cytometric analysis further confirms that the cancer cell death caused by MTZ-loaded vesicles is associated with apoptosis. Therefore, the dual pH- and UV-responsive supramolecular vesicles are a potential platform for controlled release and targeted anticancer drug delivery.

  13. 'Genipin' - the natural water soluble cross-linking agent and its importance in the modified drug delivery systems: an overview.

    PubMed

    Manickam, Balamurugan; Sreedharan, Rajesh; Elumalai, Manogaran

    2014-01-01

    One of the popular approaches in controlling drug delivery from the polymeric carriers is suitably achieved by the inclusion of crosslinking agents into the formulations at different concentrations. Nevertheless, addition of the chemical crosslinkers such as glutaraldehyde, formaldehyde etc, used in the drug delivery systems causes very serious cytotoxic reactions. These chemical crosslinking agents did not offer any significant advantageous effects when compared to the natural crosslinking agents for instance genipin, which is quite less toxic, biocompatible and offers very stable crosslinked products. Based on the earlier reports the safety of this particular natural crosslinker is very well established, since it has been widely used as a Chinese traditional medicine for long-time, isolated from fruits of the plant Gardenia jasminoides Ellis. This concise article largely portrayed the value of this unique natural crosslinker, utilized in controlling the drug delivery from the various formulations. PMID:24041312

  14. Water-soluble vitamins.

    PubMed

    Konings, Erik J M

    2006-01-01

    Simultaneous Determination of Vitamins.--Klejdus et al. described a simultaneous determination of 10 water- and 10 fat-soluble vitamins in pharmaceutical preparations by liquid chromatography-diode-array detection (LC-DAD). A combined isocratic and linear gradient allowed separation of vitamins in 3 distinct groups: polar, low-polar, and nonpolar. The method was applied to pharmaceutical preparations, fortified powdered drinks, and food samples, for which results were in good agreement with values claimed. Heudi et al. described a separation of 9 water-soluble vitamins by LC-UV. The method was applied for the quantification of vitamins in polyvitaminated premixes used for the fortification of infant nutrition products. The repeatability of the method was evaluated at different concentration levels and coefficients of variation were <6.5%. The concentrations of vitamins found in premixes with the method were comparable to the values declared. A disadvantage of the methods mentioned above is that sample composition has to be known in advance. According to European legislation, for example, foods might be fortified with riboflavin phosphate or thiamin phosphate, vitamers which are not included in the simultaneous separations described. Vitamin B2.--Viñas et al. elaborated an LC analysis of riboflavin vitamers in foods. Vitamin B2 can be found in nature as the free riboflavin, but in most biological materials it occurs predominantly in the form of 2 coenzymes, flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD). Several methods usually involve the conversion of these coenzymes into free riboflavin before quantification of total riboflavin. According to the authors, there is growing interest to know flavin composition of foods. The described method separates the individual vitamers isocratically. Accuracy of the method is tested with 2 certified reference materials (CRMs). Vitamin B5.-Methods for the determination of vitamin B5 in foods are limited

  15. Water soluble nanoporous nanoparticle for in vivo targeted drug delivery and controlled release in B cells tumor context

    NASA Astrophysics Data System (ADS)

    de Angelis, F.; Pujia, A.; Falcone, C.; Iaccino, E.; Palmieri, C.; Liberale, C.; Mecarini, F.; Candeloro, P.; Luberto, L.; de Laurentiis, A.; Das, G.; Scala, G.; di Fabrizio, E.

    2010-10-01

    Multitasking nanoparticles are gaining great attention for smart drug delivery systems. The exploration of the nano-scale opens new concrete opportunities for revealing new properties and undiscovered cell-particle interactions. Here we present a biodegradable nanoporous silicon nanoparticle that can be successfully employed for in vivo targeted drug delivery and sustained release. The bare nanoporous nanocarriers can be accurately designed and fabricated with an effective control of porosity, surface chemistry and particle size, up to a few nm. The proposed nanoparticles exhibit several remarkable features including high payload, biodegradability, no toxicity, and multiple loading in water without the need of additional chemical reagents at room temperature. The targeting strategy is based on phage display technology that was successfully used to discover cell surface binding peptide for murine B lymphoma A20 cell line. The peptide used in combination with the nanoporous nanoparticles allows an efficient in vivo targeting, a sustained release and a sensible therapeutic effect.Multitasking nanoparticles are gaining great attention for smart drug delivery systems. The exploration of the nano-scale opens new concrete opportunities for revealing new properties and undiscovered cell-particle interactions. Here we present a biodegradable nanoporous silicon nanoparticle that can be successfully employed for in vivo targeted drug delivery and sustained release. The bare nanoporous nanocarriers can be accurately designed and fabricated with an effective control of porosity, surface chemistry and particle size, up to a few nm. The proposed nanoparticles exhibit several remarkable features including high payload, biodegradability, no toxicity, and multiple loading in water without the need of additional chemical reagents at room temperature. The targeting strategy is based on phage display technology that was successfully used to discover cell surface binding peptide for

  16. Water soluble laser dyes

    DOEpatents

    Hammond, Peter R.; Feeman, James F.; Field, George F.

    1998-01-01

    Novel water soluble dyes of the formula I are provided ##STR1## wherein R.sup.1 and R.sup.4 are alkyl of 1 to 4 carbon atoms or hydrogen; or R.sup.1 -R.sup.2 or R.sup.2 -R.sup.4 form part of aliphatic heterocyclic rings; R.sup.2 is hydrogen or joined with R.sup.1 or R.sup.4 as described above; R.sup.3 is --(CH.sub.2).sub.m --SO.sub.3.sup.-, where m is 1 to 6; X is N, CH or ##STR2## where Y is 2 --SO.sub.3.sup.- ; Z is 3, 4, 5 or 6 --SO.sub.3.sup.-. The novel dyes are particularly useful as the active media in water solution dye lasers.

  17. Water soluble laser dyes

    DOEpatents

    Hammond, P.R.; Feeman, J.F.; Field, G.F.

    1998-08-11

    Novel water soluble dyes of the formula 1 are provided by the formula described in the paper wherein R{sup 1} and R{sup 4} are alkyl of 1 to 4 carbon atoms or hydrogen; or R{sup 1}--R{sup 2} or R{sup 2}--R{sup 4} form part of aliphatic heterocyclic rings; R{sup 2} is hydrogen or joined with R{sup 1} or R{sup 4} as described above; R{sup 3} is --(CH{sub 2}){sub m}--SO{sub 3}{sup {minus}}, where m is 1 to 6; X is N, CH or formula 2 given in paper where Y is 2 --SO{sub 3}{sup {minus}} ; Z is 3, 4, 5 or 6 --SO{sub 3}{sup {minus}}. The novel dyes are particularly useful as the active media in water solution dye lasers.

  18. Physical state of poorly water soluble therapeutic molecules loaded into SBA-15 ordered mesoporous silica carriers: a case study with itraconazole and ibuprofen.

    PubMed

    Mellaerts, Randy; Jammaer, Jasper A G; Van Speybroeck, Michiel; Chen, Hong; Van Humbeeck, Jan; Augustijns, Patrick; Van den Mooter, Guy; Martens, Johan A

    2008-08-19

    The ordered mesoporous silica material SBA-15 was loaded with the model drugs itraconazole and ibuprofen using three different procedures: (i) adsorption from solution, (ii) incipient wetness impregnation, and (iii) heating of a mixture of drug and SBA-15 powder. The location of the drug molecules in the SBA-15 particles and molecular interactions were investigated using nitrogen adsorption, TGA, DSC, DRS UV-vis, and XPS. The in vitro release of hydrophobic model drugs was evaluated in an aqueous environment simulating gastric fluid. The effectiveness of the loading method was found to be strongly compound dependent. Incipient wetness impregnation using a concentrated itraconazole solution in dichloromethane followed by solvent evaporation was most efficient for dispersing itraconazole in SBA-15. The itraconazole molecules were located on the mesopore walls and inside micropores of the mesopore walls. When SBA-15 was loaded by slurrying it in a diluted itraconazole solution from which the solvent was evaporated, the itraconazole molecules ended up in the mesopores that they plugged locally. At a loading of 30 wt %, itraconazole exhibited intermolecular interactions inside the mesopores revealed by UV spectroscopy and endothermic events traced with DSC. The physical mixing of itraconazole and SBA-15 powder followed by heating above the itraconazole melting temperature resulted in formulations in which glassy itraconazole particles were deposited externally on the SBA-15 particles. Loading with ibuprofen was successful with each of the three loading procedures. Ibuprofen preferably is positioned inside the micropores. In vitro release experiments showed fast release kinetics provided the drug molecules were evenly deposited over the mesoporous surface. PMID:18630936

  19. Chemoenzymatic syntheses of water-soluble lipid I fluorescent probes

    PubMed Central

    Mitachi, Katsuhiko; Siricilla, Shajila; Klaic, Lada; Clemons, William M.; Kurosu, Michio

    2015-01-01

    Peptidoglycan (PG) is unique to bacteria, and thus, the enzymes responsible for its biosynthesis are promising antibacterial drug targets. The membrane-embedded enzymes in PG remain significant challenges in studying their mechanisms due to the fact that preparations of suitable enzymatic substrates require time-consuming biological transformations or chemical synthesis. Lipid I (prenyl diphosphoryl-MurNAc-pentapeptide) is an important PG biosynthesis intermediate to study the central enzymes, translocase I (MraY/MurX) and MurG. Lipid I isolated from nature contains the C50-or C55-prenyl unit that shows extremely poor water-solubility that renders studies of translocase I and MurG enzymes difficult. We have studied biological transformation of water soluble lipid I fluorescent probes using bacterial membrane fractions and purified MraY enzymes. In our investigation of the minimum structural requirements of the prenyl phosphates in MraY-catalyzed lipid I synthesis, we found that (2Z,6E)-farnesyl phosphate (C15-phosphate) can be recognized by E. coli MraY to generate the water-soluble lipid I fluorescent probes in high-yield. Under the optimized conditions, the same reaction was performed by using the purified MraY from Hydrogenivirga spp. to afford the lipid I analog with high-yield in a short reaction time. PMID:26190869

  20. Drug release from film-coated chlorpheniramine maleate nonpareil beads: effect of water-soluble polymer, coating level, and soluble core material.

    PubMed

    Tang, L; Schwartz, J B; Porter, S C; Schnaare, R L; Wigent, R J

    2000-01-01

    The purpose of this research was to use a new drug release model to study the effects of formulation parameters on drug release from a film-coated chlorpheniramine (CPM) nonpareil system. The film-coated CPM nonpareils were prepared by using a fluid bed apparatus. A hydroxylpropylmethylcellulose (HPMC) solution was blended with an aqueous ethylcellulose dispersion (Surelease) to adjust the permeability of the film. The apparent permeability of samples was obtained from dissolution data using a previously reported drug release equation. The apparent permeability was plotted versus the film coating level or the HPMC concentration in the film. When the natural logarithm of the apparent permeability versus coating level was graphed, a biphasic plot was observed in the group without HPMC in the film, showing the occurrence of a critical coating level. It was suggested that a mechanically formed porous film (due to an incomplete coating) could change to a nonporous film after the bead was completely coated. However, in the group that contained 12% HPMC in the film, the critical coating level was not observed. A porous film, formed by the leaching out of the water-soluble polymer, would not change to a nonporous film even after the bead is completely coated. Through a mathematical derivation, the decrease of apparent permeability versus coating level was related to the reduction of the total hole area. The apparent permeability was found to increase with the HPMC concentration. After a critical concentration was reached, the further addition of HPMC into the film caused a rapid increase in apparent permeability. The critical HPMC concentration was related to a minimum domain formation concentration (MDFC). A rapid increase of the drug release was observed when the dissolution profile of a sample made from a regular sugar nonpareil core (soluble) was compared with the sample made from a precoated nonpareil core (insoluble), which suggests that the drug release can be

  1. 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

  2. Synthesis, characterization and antimicrobial activity of water-soluble silver(i) complexes of metronidazole drug and selected counter-ions.

    PubMed

    Kalinowska-Lis, Urszula; Felczak, Aleksandra; Chęcińska, Lilianna; Zawadzka, Katarzyna; Patyna, Emilia; Lisowska, Katarzyna; Ochocki, Justyn

    2015-05-01

    A series of water-soluble silver(i) complexes of the type [Ag(MTZ)2X] [MTZ = 1-(2-hydroxyethyl)-2-methyl-5-nitro-1H-imidazole (metronidazole drug); X = NO3(-), ClO4(-), CF3COO(-), BF4(-) and CH3SO3(-)] was synthesised by the reactions of various Ag(i) salts with metronidazole (MTZ). All the complexes were characterized by ESI-MS spectrometry, solution NMR ((1)H and (13)C) and IR spectroscopy, and elemental analysis. Further evidence for the formation and molecular structure of all the complexes was provided by X-ray single-crystal crystallography. The different counter ions affect the crystal packing of the complexes and thus have an impact on the final geometries. The antimicrobial activities of the complexes against two Gram-positive strains: Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, three Gram-negative strains: Pseudomonas aeruginosa ATCC 15442, Escherichia coli ATCC 25922, Proteus hauseri ATCC 13315 and yeast Candida albicans ATCC 10231 were evaluated and compared with antibacterial and antifungal properties of appropriate silver salts, metronidazole and silver sulfadiazine drugs. The newly synthesized compounds exhibited significant antibacterial activity against Gram-positive bacteria, better than the referenced silver sulfadiazine. The best active silver(i)-metronidazole complex contains a methanesulphonate counter-ion. Moreover, the complex inhibited the growth of yeast Candida albicans at a concentration 3-fold lower than that required for silver sulfadiazine. In addition, the complexes containing a tetrafluoroborate and a perchlorate as counter-ions were characterized as effective antibacterial agents against the tested Gram-negative bacteria.

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

    PubMed

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

    2008-08-01

    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.

  4. 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. PMID:27098211

  5. In vivo absorption comparison of nanotechnology-based silybin tablets with its water-soluble derivative.

    PubMed

    Xu, Di; Ni, Rui; Sun, Wei; Li, Luk Chiu; Mao, Shirui

    2015-04-01

    In this study, the in vivo oral absorption of a nanocrystal tablet formulation of a BCS II poorly water-soluble drug was compared with that of its water-soluble salt form. Silybin is used as the model drug, and its nanosuspension was prepared by high-pressure homogenization. Effect of process and formulation parameters on properties of the nansuspensions was investigated. Dried powder of the nanosuspension was prepared by spray drying and used for preparing tablets. A pharmacokinetic study was performed in Beagle dogs to compare the absorption for tablets of silybin nanocrystals and silybin meglumine. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was determined. X-ray powder diffraction results indicated that silybin existed in a crystalline state after homogenization. In vivo absorption study in rats showed that the peroral absorption of silybin was enhanced remarkably by decreasing particle size. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was comparable with that of the commercially available tablet of the water-soluble salt form of silybin. In conclusion, it is possible to increase the bioavailability of poorly soluble drugs by preparing its water-soluble derivative.

  6. water-soluble fluorocarbon coating

    NASA Technical Reports Server (NTRS)

    Nanelli, P.

    1979-01-01

    Water-soluble fluorocarbon proves durable nonpolluting coating for variety of substrates. Coatings can be used on metals, masonry, textiles, paper, and glass, and have superior hardness and flexibility, strong resistance to chemicals fire, and weather.

  7. 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. PMID:22833866

  8. 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.

  9. In-vitro permeability of the human nail and of a keratin membrane from bovine hooves: influence of the partition coefficient octanol/water and the water solubility of drugs on their permeability and maximum flux.

    PubMed

    Mertin, D; Lippold, B C

    1997-01-01

    Penetration of homologous nicotinic acid esters through the human nail and a keratin membrane from bovine hooves was investigated by modified Franz diffusion cells in-vitro to study the transport mechanism. The partition coefficient octanol/water PCOct/W of the esters was over the range 7 to > 51,000. The permeability coefficient P of the nail plate as well as the hoof membrane did not increase with increasing partition coefficient or lipophilicity of the penetrating substance. This indicates that both barriers behave like hydrophilic gel membranes rather than lipophilic partition membranes as in the case of the stratum corneum. Penetration studies with the model compounds paracetamol and phenacetin showed that the maximum flux was first a function of the drug solubility in water or in the swollen keratin matrix. Dissociation hindered the diffusion of benzoic acid and pyridine through the hoof membrane. Since keratin, a protein with an isoelectric point of about 5, is also charged, this reduction can be attributed to an exclusion of the dissociating substance due to the Donnan equilibrium. Nevertheless, the simultaneous enhancement of the water solubility makes a distinct increase of the maximum flux possible. In order to screen drugs for potential topical application to the nail plate, attention has to be paid mainly to the water solubility of the compound. The bovine hoof membrane may serve as an appropriate model for the nail.

  10. Novel Water-Soluble Mucoadhesive Carbosilane Dendrimers for Ocular Administration.

    PubMed

    Bravo-Osuna, I; Vicario-de-la-Torre, M; Andrés-Guerrero, V; Sánchez-Nieves, J; Guzmán-Navarro, M; de la Mata, F J; Gómez, R; de Las Heras, B; Argüeso, P; Ponchel, G; Herrero-Vanrell, R; Molina-Martínez, I T

    2016-09-01

    The purpose of this research was to determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (generations 1-3) as mucoadhesive polymers in eyedrop formulations. Cationic carbosilane dendrimers decorated with ammonium -NH3(+) groups were prepared by hydrosylilation of Boc-protected allylamine and followed by deprotection with HCl. Anionic carbosilane dendrimers with terminal carboxylate groups were also employed in this study. In vitro and in vivo tolerance studies were performed in human ocular epithelial cell lines and rabbit eyes respectively. The interaction of dendrimers with transmembrane ocular mucins was evaluated with a surface biosensor. As proof of concept, the hypotensive effect of a carbosilane dendrimer eyedrop formulation containing acetazolamide (ACZ), a poorly water-soluble drug with limited ocular penetration, was tested after instillation in normotensive rabbits. The methodology used to synthesize cationic dendrimers avoids the difficulty of obtaining neutral -NH2 dendrimers that require harsher reaction conditions and also present high aggregation tendency. Tolerance studies demonstrated that both prototypes of water-soluble anionic and cationic carbosilane dendrimers were well tolerated in a range of concentrations between 5 and 10 μM. Permanent interactions between cationic carbosilane dendrimers and ocular mucins were observed using biosensor assays, predominantly for the generation-three (G3) dendrimer. An eyedrop formulation containing G3 cationic carbosilane dendrimers (5 μM) and ACZ (0.07%) (289.4 mOsm; 5.6 pH; 41.7 mN/m) induced a rapid (onset time 1 h) and extended (up to 7 h) hypotensive effect, and led to a significant increment in the efficacy determined by AUC0(8h) and maximal intraocular pressure reduction. This work takes advantage of the high-affinity interaction between cationic carbosilane dendrimers and ocular transmembrane mucins, as well as the tensioactive behavior observed for these

  11. Process and formulation variables in the preparation of wax microparticles by a melt dispersion technique. II. W/O/W multiple emulsion technique for water-soluble drugs.

    PubMed

    Bodmeier, R; Wang, J; Bhagwatwar, H

    1992-01-01

    Pseudoephedrine HCl-carnauba wax microparticles were prepared by a multiple emulsion-melt dispersion technique. A heated aqueous drug solution was emulsified into the wax melt (W/O emulsion), followed by emulsification of this primary emulsion into a heated external aqueous phase (W/O/W emulsion). The drug-containing microparticles were formed after cooling and congealing of the wax phase. The encapsulation efficiencies were above 80 per cent and actual drug loadings close to 50 per cent were achieved. The surface of the microparticles had submicron pores and drug crystals were visible on cross-sections. The drug loading depended on the rate of cooling and the volume of the internal aqueous phase but was insensitive to the volume of the continuous phase. The drug release was much faster when compared to the release from polymeric microspheres. PMID:1613649

  12. Process and formulation variables in the preparation of wax microparticles by a melt dispersion technique. II. W/O/W multiple emulsion technique for water-soluble drugs.

    PubMed

    Bodmeier, R; Wang, J; Bhagwatwar, H

    1992-01-01

    Pseudoephedrine HCl-carnauba wax microparticles were prepared by a multiple emulsion-melt dispersion technique. A heated aqueous drug solution was emulsified into the wax melt (W/O emulsion), followed by emulsification of this primary emulsion into a heated external aqueous phase (W/O/W emulsion). The drug-containing microparticles were formed after cooling and congealing of the wax phase. The encapsulation efficiencies were above 80 per cent and actual drug loadings close to 50 per cent were achieved. The surface of the microparticles had submicron pores and drug crystals were visible on cross-sections. The drug loading depended on the rate of cooling and the volume of the internal aqueous phase but was insensitive to the volume of the continuous phase. The drug release was much faster when compared to the release from polymeric microspheres.

  13. Controlled release of a sparingly water-soluble anticancer drug through pH-responsive functionalized gold-nanoparticle-decorated liposomes.

    PubMed

    Adhikari, Chandan; Das, Anupam; Chakraborty, Anjan

    2015-03-16

    The binding and detachment of carboxyl-modified gold nanoparticles from liposomes is used for controlled drug delivery. This study reveals that the binding and detachment of nanoparticles from liposomes depends on the degree of hydration of the liposomes. Liposomes with a lower hydration level undergo stronger electrostatic interactions with negatively charged gold nanoparticles, thus leading to a slower detachment of the carboxyl-modified gold nanoparticles under gastric conditions. Therefore, under gastric conditions, gold-nanoparticle-decorated dipalmitoylphosphatidylcholine (DPPC) liposomes exhibit an at least ten-times-slower drug release compared to gold-nanoparticle-decorated 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes, although both liposomes in the bare state fail to pursue controlled release. Our study also reveals that one can modulate the drug-release rate by simply varying the concentration of nanoparticles. This study highlights a novel strategy for the controlled release of drug molecules from liposomes.

  14. Model drug as pore former for controlled release of water-soluble metoprolol succinate from ethylcellulose-coated pellets without lag phase: opportunities and challenges.

    PubMed

    Wang, Yuli; Dai, Jingjing; Chang, Xinyi; Yang, Meiyan; Shen, Ruifang; Shan, Li; Qian, Yong; Gao, Chunsheng

    2015-02-01

    The objective of the present study was to evaluate the feasibility of using model drug metoprolol succinate (MS) as a pore former to modify the initial lag phase (i.e., a slow or non-release phase in the first 1-2 h) associated with the drug release from coated pellets. MS-layered cores with high drug-layering efficiency (97% w/w) were first prepared by spraying a highly concentrated drug aqueous solution (60% w/w, 70°C) on non-pareils without using other binders. The presence of MS in ethylcellulose (EC) coating solution significantly improved the coating process by reducing pellets sticking, which often occurs during organic coating. There may be a maximum physical compatibility of MS with EC, and the physical state of the drug in the functional coating layer of EC/MS (80:20) was simultaneously crystalline and non-crystalline (amorphous or solid molecule solution). The lag phase associated with hydroxypropylcellulose (HPC) as a pore former was not observed when MS was used as a pore former. The drug release from EC/MS-coated pellets was pH independent, inversely proportional to the coating levels, and directly related to the pore former levels. The functional coating layer with MS as a pore former was not completely stabilized without curing. Curing at 60°C for 1 day could substantially improve the stability of EC/MS-coated pellets. The physical state of the drug in the free film of EC/MS (85:15) changed partially from amorphous to crystal when cured at 60°C for 1 day, which should be attributed to the incompatibility of the drug with EC.

  15. Model drug as pore former for controlled release of water-soluble metoprolol succinate from ethylcellulose-coated pellets without lag phase: opportunities and challenges.

    PubMed

    Wang, Yuli; Dai, Jingjing; Chang, Xinyi; Yang, Meiyan; Shen, Ruifang; Shan, Li; Qian, Yong; Gao, Chunsheng

    2015-02-01

    The objective of the present study was to evaluate the feasibility of using model drug metoprolol succinate (MS) as a pore former to modify the initial lag phase (i.e., a slow or non-release phase in the first 1-2 h) associated with the drug release from coated pellets. MS-layered cores with high drug-layering efficiency (97% w/w) were first prepared by spraying a highly concentrated drug aqueous solution (60% w/w, 70°C) on non-pareils without using other binders. The presence of MS in ethylcellulose (EC) coating solution significantly improved the coating process by reducing pellets sticking, which often occurs during organic coating. There may be a maximum physical compatibility of MS with EC, and the physical state of the drug in the functional coating layer of EC/MS (80:20) was simultaneously crystalline and non-crystalline (amorphous or solid molecule solution). The lag phase associated with hydroxypropylcellulose (HPC) as a pore former was not observed when MS was used as a pore former. The drug release from EC/MS-coated pellets was pH independent, inversely proportional to the coating levels, and directly related to the pore former levels. The functional coating layer with MS as a pore former was not completely stabilized without curing. Curing at 60°C for 1 day could substantially improve the stability of EC/MS-coated pellets. The physical state of the drug in the free film of EC/MS (85:15) changed partially from amorphous to crystal when cured at 60°C for 1 day, which should be attributed to the incompatibility of the drug with EC. PMID:25163432

  16. A SPION-eicosane protective coating for water soluble capsules: Evidence for on-demand drug release triggered by magnetic hyperthermia

    PubMed Central

    Che Rose, Laili; Bear, Joseph C.; McNaughter, Paul D.; Southern, Paul; Piggott, R. Ben; Parkin, Ivan P.; Qi, Sheng; Mayes, Andrew G.

    2016-01-01

    An orally-administered system for targeted, on-demand drug delivery to the gastrointestinal (GI) tract is highly desirable due to the high instances of diseases of that organ system and harsh mechanical and physical conditions any such system has to endure. To that end, we present an iron oxide nanoparticle/wax composite capsule coating using magnetic hyperthermia as a release trigger. The coating is synthesised using a simple dip-coating process from pharmaceutically approved materials using a gelatin drug capsule as a template. We show that the coating is impervious to chemical conditions within the GI tract and is completely melted within two minutes when exposed to an RF magnetic field under biologically-relevant conditions. The overall simplicity of action, durability and non-toxic and inexpensive nature of our system demonstrated herein are key for successful drug delivery systems. PMID:26842884

  17. A SPION-eicosane protective coating for water soluble capsules: Evidence for on-demand drug release triggered by magnetic hyperthermia

    NASA Astrophysics Data System (ADS)

    Che Rose, Laili; Bear, Joseph C.; McNaughter, Paul D.; Southern, Paul; Piggott, R. Ben; Parkin, Ivan P.; Qi, Sheng; Mayes, Andrew G.

    2016-02-01

    An orally-administered system for targeted, on-demand drug delivery to the gastrointestinal (GI) tract is highly desirable due to the high instances of diseases of that organ system and harsh mechanical and physical conditions any such system has to endure. To that end, we present an iron oxide nanoparticle/wax composite capsule coating using magnetic hyperthermia as a release trigger. The coating is synthesised using a simple dip-coating process from pharmaceutically approved materials using a gelatin drug capsule as a template. We show that the coating is impervious to chemical conditions within the GI tract and is completely melted within two minutes when exposed to an RF magnetic field under biologically-relevant conditions. The overall simplicity of action, durability and non-toxic and inexpensive nature of our system demonstrated herein are key for successful drug delivery systems.

  18. One-step synthesis of small-sized and water-soluble NaREF4 upconversion nanoparticles for in vitro cell imaging and drug delivery.

    PubMed

    Yang, Dongmei; Dai, Yunlu; Ma, Pingan; Kang, Xiaojiao; Cheng, Ziyong; Li, Chunxia; Lin, Jun

    2013-02-18

    Small (2-28 nm) NaREF(4) (rare earth (RE)=Nd-Lu, Y) nanoparticles (NPs) were prepared by an oil/water two-phase approach. Meanwhile, hydrophilic NPs can be obtained through a successful phase-transition process by introducing the amphiphilic surfactant sodium dodecylsulfate (SDS) into the same reaction system. Hollow-structured NaREF(4) (RE=Y, Yb, Lu) NPs can be fabricated in situ by electron-beam lithography on solid NPs. The MTT assay indicates that these hydrophilic NPs with hollow structures exhibit good biocompatibility. The as-prepared hollow-structured NPs can be used as anti-cancer drug carriers for drug storage/release investigations. Doxorubicin hydrochloride (DOX) was taken as model drug. The release of DOX from hollow α-NaLuF(4):20% Yb(3+), 2% Er(3+) exhibits a pH-sensitive release patterns. Confocal microscopy observations indicate that the NPs can be taken up by HeLa cells and show obvious anti-cancer efficacy. Furthermore, α-NaLuF(4):20% Yb(3+), 2% Er(3+) NPs show bright-red emission under IR excitation, making both the excitation and emission light fall within the "optical window" of biological tissues. The application of α-NaLuF(4):20% Yb(3+), 2% Er(3+) in the luminescence imaging of cells was also investigated, which shows a bright-red emission without background noise.

  19. In-vitro Relationship between Protein-binding and Free Drug Concentrations of a Water-soluble Selective Beta-adrenoreceptor Antagonist (Atenolol) and Its Interaction with Arsenic

    PubMed Central

    Awal, M.A.; Subhan, N.; Mostofa, M.

    2009-01-01

    The degree of binding of a drug to plasma proteins has a marked effect on its distribution, elimination, and pharmacological effect since only the unbound fraction is available for distribution into extra-vascular space. The protein-binding of atenolol was measured by equilibrium dialysis in the bovine serum albumin (BSA). Free atenolol concentration was increased due to addition of arsenic which reduced the binding of the compounds to BSA. During concurrent administration, arsenic displaced atenolol from its high-affinity binding Site I, and free concentration of atenolol increased from 4.286±0.629% and 5.953±0.605% to 82.153±1.924% and 85.486±1.158% in absence and presence of Site I probe respectively. Thus, it can be suggested that arsenic displaced atenolol from its binding site resulting in an increase of the free atenolol concentration in plasma. PMID:19248645

  20. 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

  1. Application of drug nanocrystal technologies on oral drug delivery of poorly soluble drugs.

    PubMed

    Gao, Lei; Liu, Guiyang; Ma, Jianli; Wang, Xiaoqing; Zhou, Liang; Li, Xiang; Wang, Fang

    2013-02-01

    The limited solubility and dissolution rate exhibited by poorly soluble drugs is major challenges in the pharmaceutical process. Following oral administration, the poorly soluble drugs generally show a low and erratic bioavailability which may lead to therapeutic failure. Pure drug nanocrystals, generated by "bottom up" or "top down" technologies, facilitate a significant improvement on dissolution behavior of poorly soluble drugs due to their enormous surface area, which in turn lead to substantial improvement in oral absorption. This is the most distinguished achievement of drug nanocrystals among their performances in various administration routes, reflected by the fact that most of the marketed products based on the nanocrystals technology are for oral application. After detailed investigations on various technologies associated with production of drug nanocrystals and their in vitro physicochemical properties, during the last decade more attentions have been paid into their in vivo behaviors. This review mainly describes the in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics. The technologies and evaluation associated with the solidification process of the drug nanocrystals suspensions were also discussed in detail.

  2. Design, synthesis and in vitro evaluation of novel water-soluble prodrugs of buparvaquone.

    PubMed

    Mäntylä, Antti; Rautio, Jarkko; Nevalainen, Tapio; Keski-Rahkonen, Pekka; Vepsälainen, Jouko; Järvinen, Tomi

    2004-10-01

    Novel water-soluble phosphate prodrugs (2b-5b) of buparvaquone-oxime (1a) and buparvaquone-O-methyloxime (1b) were synthesized and evaluated in vitro as potential oral prodrugs against leishmaniasis. Buparvaquone-oxime (1a), and most probably also buparvaquone-O-methyloxime (1b), released the parent buparvaquone via a cytochrome P450-catalysed reaction. The prodrugs 2b-5b showed significantly higher aqueous solubilities (>4 mg/ml) than buparvaquone (< or = 0.03 microg/ml) over a pH range of 3.0-7.4. The prodrugs 2b, 3b and 5b rapidly released (t1/2 = 7 min) the corresponding oximes of buparvaquone (1a and 1b), and prodrug 4b at a moderate rate (t1/2 = 22.5 min) in alkaline phosphatase solution in vitro. Prodrug 3b was the most chemically stable in the aqueous solutions over a pH range of 3.0-7.4 (t1/2 > 8 days). Although buparvaquone-oxime (1a) has been shown to undergo a cytochrome P450-catalysed oxidation in liver microsomes to the parent buparvaquone and behave as a novel bioreversible prodrug, its usefulness is limited in oral drug delivery due to its poor aqueous solubility, like buparvaquone itself. Further phosphorylation of an oxime form of buparvaquone significantly increased water solubility, and this novel approach is therefore useful to improve physicochemical properties of drugs containing a ketone functional group.

  3. Supersaturation of poorly soluble drugs induced by mesoporous magnesium carbonate.

    PubMed

    Zhang, Peng; Zardán Gómez de la Torre, Teresa; Welch, Ken; Bergström, Christel; Strømme, Maria

    2016-10-10

    This work investigates whether the solubility of poorly soluble compounds can be improved by using mesoporous magnesium carbonate (MMC) as the drug delivery system. A solvent evaporation method was used to load structurally diverse model drugs (celecoxib, cinnarizine and griseofulvin) into the pores of MMC. The drug-loaded carrier system was then characterized in terms of porosity, crystallinity, and release profiles by a variety of experimental techniques, including X-ray diffraction, nitrogen adsorption analysis, differential scanning calorimetry, infrared spectroscopy, UV absorption spectroscopy, and thermogravimetric analysis. All three drugs were in a non-crystalline state after loading into the pores of MMC. The concentrations of the drugs in solution over time (a measure of the release rates from loaded MMC) were higher than the corresponding concentrations (dissolution rates) of equal amounts of the crystalline drugs. The release rates were five (celecoxib), three (cinnarizine) and two times (griseofulvin) higher than the dissolution rates of their crystalline counterparts. Supersaturation release profiles were also observed; the areas under the concentration-time curves (0-240min) were 25- (celecoxib), 5- (cinnarizine) and 2-fold (griseofulvin) greater than those of the crystalline drugs. Hence, MMC shows promise as a general drug delivery vehicle for increasing the bioavailability of compounds with dissolution rate- or solubility-limited absorption. PMID:27590126

  4. Progress in the study of drug nanocrystals.

    PubMed

    Shi, Jing; Guo, Fei; Zheng, Aiping; Zhang, Xiaoyan; Sun, Jianxu

    2015-12-01

    The poor water solubility of many candidate drugs remains a major obstacle to their development and clinical use, especially for oral drug delivery. Nanocrystal technology can improve the solubility and dissolution rates of many poorly water-soluble drugs very effectively, significantly improving their oral bioavailability and decreasing the food effect. For this reason, this technology is becoming a key area of drug delivery research. This review presents much of the recent progress in nanocrystal drug pharmaceuticals, including the characteristics, composition, preparation technology, and clinical applications of these drugs. Finally, the effect of nanocrystal technology on insoluble drugs is quantified and described. PMID:26817271

  5. Access to orphan drugs despite poor quality of clinical evidence

    PubMed Central

    Dupont, Alain G; Van Wilder, Philippe B

    2011-01-01

    AIM We analysed the Belgian reimbursement decisions of orphan drugs as compared with those of innovative drugs for more common but equally severe diseases, with special emphasis on the quality of clinical evidence. METHODS Using the National Health Insurance Agency administrative database, we evaluated all submitted orphan drug files between 2002 and 2007. A quality analysis of the clinical evidence in the orphan reimbursement files was performed. The evaluation reports of the French ‘Haute Autorité de Santé’, including the five-point scale parameter ‘Service Médical Rendu (SMR), were examined to compare disease severity. Chi-squared tests (at P < 0.05 significance level) were used to compare the outcome of the reimbursement decisions between orphan and non-orphan innovative medicines. RESULTS Twenty-five files of orphan drugs and 117 files of non-orphan drugs were evaluated. Twenty-two of 25 (88%) submissions of orphan drugs were granted reimbursement as opposed to 74 of the 117 (63%) non-orphan innovative medicines (P = 0.02). Only 52% of the 25 orphan drug files included a randomized controlled trial as opposed to 84% in a random control sample of 25 non-orphan innovative submissions (P < 0.01). The duration of drug exposure was in most cases far too short in relation to the natural history of the disease. CONCLUSIONS Orphan drug designation predicts reimbursement despite poor quality of clinical evidence. The evidence gap at market authorization should be reduced by post-marketing programmes, in which the centralized regulatory and the local reimbursement authorities collaborate in an efficient way across the European Union member states. PMID:21395641

  6. Synthesis of a highly water-soluble acacetin prodrug for treating experimental atrial fibrillation in beagle dogs

    PubMed Central

    Liu, Hui; Wang, Ya-Jing; Yang, Lei; Zhou, Mei; Jin, Man-Wen; Xiao, Guo-Sheng; Wang, Yan; Sun, Hai-Ying; Li, Gui-Rong

    2016-01-01

    We previously reported that duodenal administration of the natural flavone acacetin can effectively prevent the induction of experimental atrial fibrillation (AF) in canines; however, it may not be used intravenously to terminate AF due to its poor water-solubility. The present study was to design a water-soluble prodrug of acacetin and investigate its anti-AF effect in beagle dogs. Acacetin prodrug was synthesized by a three-step procedure. Aqueous solubility, bioconversion and anti-AF efficacy of acacetin prodrug were determined with different methodologies. Our results demonstrated that the synthesized phosphate sodium salt of acacetin prodrug had a remarkable increase of aqueous solubility in H2O and clinically acceptable solution (5% glucose or 0.9% NaCl). The acacetin prodrug was effectively converted into acacetin in ex vivo rat plasma and liver microsome, and in vivo beagle dogs. Intravenous infusion of acacetin prodrug (3, 6 and 12 mg/kg) terminated experimental AF without increasing ECG QTc interval in beagle dogs. The intravenous LD50 of acacetin prodrug was 721 mg/kg in mice. Our preclinical study indicates that the synthesized acacetin prodrug is highly water-soluble and safe; it effectively terminates experimental AF in beagle dogs and therefore may be a promising drug candidate for clinical trial to treat patients with acute AF. PMID:27160397

  7. Water-soluble polymers and compositions thereof

    DOEpatents

    Smith, Barbara F.; Robison, Thomas W.; Gohdes, Joel W.

    2002-01-01

    Water-soluble polymers including functionalization from the group of amino groups, carboxylic acid groups, phosphonic acid groups, phosphonic ester groups, acylpyrazolone groups, hydroxamic acid groups, aza crown ether groups, oxy crown ethers groups, guanidinium groups, amide groups, ester groups, aminodicarboxylic groups, permethylated polvinylpyridine groups, permethylated amine groups, mercaptosuccinic acid groups, alkyl thiol groups, and N-alkylthiourea groups are disclosed.

  8. Water-soluble polymers and compositions thereof

    DOEpatents

    Smith, Barbara F.; Robison, Thomas W.; Gohdes, Joel W.

    1999-01-01

    Water-soluble polymers including functionalization from the group of amino groups, carboxylic acid groups, phosphonic acid groups, phosphonic ester groups, acylpyrazolone groups, hydroxamic acid groups, aza crown ether groups, oxy crown ethers groups, guanidinium groups, amide groups, ester groups, aminodicarboxylic groups, permethylated polyvinylpyridine groups, permethylated amine groups, mercaptosuccinic acid groups, alkyl thiol groups, and N-alkylthiourea groups are disclosed.

  9. Water-soluble polymers and compositions thereof

    DOEpatents

    Smith, B.F.; Robison, T.W.; Gohdes, J.W.

    1999-04-06

    Water-soluble polymers including functionalization from the group of amino groups, carboxylic acid groups, phosphonic acid groups, phosphonic ester groups, acylpyrazolone groups, hydroxamic acid groups, aza crown ether groups, oxy crown ethers groups, guanidinium groups, amide groups, ester groups, aminodicarboxylic groups, permethylated polyvinylpyridine groups, permethylated amine groups, mercaptosuccinic acid groups, alkyl thiol groups, and N-alkylthiourea groups are disclosed.

  10. Pharmacosomes: An Emerging Novel Vesicular Drug Delivery System for Poorly Soluble Synthetic and Herbal Drugs

    PubMed Central

    2013-01-01

    In the arena of solubility enhancement, several problems are encountered. A novel approach based on lipid drug delivery system has evolved, pharmacosomes. Pharmacosomes are colloidal, nanometric size micelles, vesicles or may be in the form of hexagonal assembly of colloidal drug dispersions attached covalently to the phospholipid. They act as befitting carrier for delivery of drugs quite precisely owing to their unique properties like small size, amphiphilicity, active drug loading, high entrapment efficiency, and stability. They help in controlled release of drug at the site of action as well as in reduction in cost of therapy, drug leakage and toxicity, increased bioavailability of poorly soluble drugs, and restorative effects. There has been advancement in the scope of this delivery system for a number of drugs used for inflammation, heart diseases, cancer, and protein delivery along with a large number of herbal drugs. Hence, pharmacosomes open new challenges and opportunities for improved novel vesicular drug delivery system. PMID:24106615

  11. Immunomicelles: Targeted pharmaceutical carriers for poorly soluble drugs

    PubMed Central

    Torchilin, Vladimir P.; Lukyanov, Anatoly N.; Gao, Zhonggao; Papahadjopoulos-Sternberg, Brigitte

    2003-01-01

    To prepare immunomicelles, new targeted carriers for poorly soluble pharmaceuticals, a procedure has been developed to chemically attach mAbs to reactive groups incorporated into the corona of polymeric micelles made of polyethylene glycol–phosphatidylethanolamine conjugates. Micelle-attached antibodies retained their ability to specifically interact with their antigens. Immunomicelles with attached antitumor mAb 2C5 effectively recognized and bound various cancer cells in vitro and showed an increased accumulation in experimental tumors in mice when compared with nontargeted micelles. Intravenous administration of tumor-specific 2C5 immunomicelles loaded with a sparingly soluble anticancer agent, taxol, into experimental mice bearing Lewis lung carcinoma resulted in an increased accumulation of taxol in the tumor compared with free taxol or taxol in nontargeted micelles and in enhanced tumor growth inhibition. This family of pharmaceutical carriers can be used for the solubilization and enhanced delivery of poorly soluble drugs to various pathological sites in the body. PMID:12716967

  12. Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation

    PubMed Central

    Gaudana, Ripal; Parenky, Ashwin; Vaishya, Ravi; Samanta, Swapan K.; Mitra, Ashim K.

    2015-01-01

    The objective of this study was to develop and characterize a nanoparticulate-based sustained release formulation of a water soluble dipeptide prodrug of dexamethasone, valine–valine-dexamethasone (VVD). Being hydrophilic in nature, it readily leaches out in the external aqueous medium and hence partitions poorly into the polymeric matrix resulting in minimal entrapment in nanoparticles. Hence, hydrophobic ion pairing (HIP) complexation of the prodrug was employed with dextran sulphate as a complexing polymer. A novel, solid in oil in water emulsion method was employed to encapsulate the prodrug in HIP complex form in poly(lactic-co-glycolic acid) matrix. Nanoparticles were characterized with respect to size, zeta potential, crystallinity of entrapped drug and surface morphology. A significant enhancement in the entrapment of the prodrug in nanoparticles was achieved. Finally, a simple yet novel method was developed which can also be applicable to encapsulate other charged hydrophilic molecules, such as peptides and proteins. PMID:20939702

  13. Biochemical synthesis of water soluble conducting polymers

    NASA Astrophysics Data System (ADS)

    Bruno, Ferdinando F.; Bernabei, Manuele

    2016-05-01

    An efficient biomimetic route for the synthesis of conducting polymers/copolymers complexed with lignin sulfonate and sodium (polystyrenesulfonate) (SPS) will be presented. This polyelectrolyte assisted PEG-hematin or horseradish peroxidase catalyzed polymerization of pyrrole (PYR), 3,4 ethyldioxithiophene (EDOT) and aniline has provided a route to synthesize water-soluble conducting polymers/copolymers under acidic conditions. The UV-vis, FTIR, conductivity and cyclic voltammetry studies for the polymers/copolymer complex indicated the presence of a thermally stable and electroactive polymers. Moreover, the use of water-soluble templates, used as well as dopants, provided a unique combination of properties such as high electronic conductivity, and processability. These polymers/copolymers are nowadays tested/evaluated for antirust features on airplanes and helicopters. However, other electronic applications, such as photovoltaics, for transparent conductive polyaniline, actuators, for polypyrrole, and antistatic films, for polyEDOT, will be proposed.

  14. Understanding the impact of media viscosity on dissolution of a highly water soluble drug within a USP 2 mini vessel dissolution apparatus using an optical planar induced fluorescence (PLIF) method.

    PubMed

    Stamatopoulos, Konstantinos; Batchelor, Hannah K; Alberini, Federico; Ramsay, John; Simmons, Mark J H

    2015-11-10

    In this study, planar induced fluorescence (PLIF) was used for the first time to evaluate variability in drug dissolution data using Rhodamine-6G doped tablets within small volume USP 2 apparatus. The results were compared with tablets contained theophylline (THE) drug for conventional dissolution analysis. The impact of hydrodynamics, sampling point, dissolution media viscosity and pH were investigated to note effects on release of these two actives from the hydrophilic matrix tablets. As expected mixing performance was poor with complex and reduced velocities at the bottom of the vessel close to the tablet surface; this mixing became even worse as the viscosity of the fluid increased. The sampling point for dissolution can affect the results due to in-homogenous mixing within the vessel; this effect is exacerbated with higher viscosity dissolution fluids. The dissolution profiles of RH-6G measured via PLIF and THE measured using UV analysis were not statistically different demonstrating that RH-6G is an appropriate probe to mimic the release profile of a highly soluble drug. A linear correlation was accomplished between the release data of the drug and the dye (R(2)>0.9). The dissolution profile of the dye, obtained with the analysis of the PLIF images, can be used in order to evaluate how the viscosity and the mixing performance of USP 2 mini vessel affect the interpretation of the dissolution data of the targeted drug.

  15. Water-soluble titanium alkoxide material

    SciTech Connect

    Boyle, Timothy J.

    2010-06-22

    A water soluble, water stable, titanium alkoxide composition represented by the chemical formula (OC.sub.6H.sub.6N).sub.2Ti(OC.sub.6H.sub.2(CH.sub.2N(CH.sub.3).sub.2).sub- .3-2,4,6).sub.2 with a theoretical molecular weight of 792.8 and an elemental composition of 63.6% C, 8.1% H, 14.1% N, 8.1% O and 6.0% Ti.

  16. Anticoccidial efficacy of drinking water soluble diclazuril on experimental and field coccidiosis in broiler chickens.

    PubMed

    El-Banna, H A; El-Bahy, M M; El-Zorba, H Y; El-Hady, M

    2005-08-01

    Prophylactic and curative capacity of water soluble formulation of Diclazuril (Diclosol 1%) and feed additive form (Clinacox, 0.5%) were tested against Eimeria infection in broiler chickens. Such testing was performed both experimentally and in the field. Toltrazuril (Baycox, 2.5%) was used as reference control drug. Water soluble formulation of Diclazuril induced a marked inhibitory effect on the different stages of the parasite life cycle in experimentally infected treated birds especially when applied on the day when blood first appeared in the faeces [fifth day post-infection (d.p.i.)] as well as on the second day of blood dropping (6 d.p.i.). Both tested dosage levels of Diclazuril water soluble formulation in drinking water (5 and 10 ppm) showed the same effect in controlling coccidial infection and reducing the total oocyst numbers, lesion and faecal scores. Moreover, there was no significant difference in the efficacy of water soluble form of Diclazuril and the reference control drug (Toltrazuril, 25 ppm). In addition, testing the water soluble formulation (5 ppm) in naturally infected poultry farm (20,000 birds), showed the same anticoccidial effect observed when using Toltrazuril, as a treatment for coccidiosis. In conclusion, addition of Diclazuril at the dose of 5 ppm in the drinking water of naturally coccidia infected bird induced the same effect as 25 ppm of Toltrazuril as a treatment for coccidiosis in chickens.

  17. Water solubility in pyrope at high pressures

    NASA Astrophysics Data System (ADS)

    Mookherjee, M.; Karato, S.-

    2006-12-01

    To address how much water is stored within the Earth's mantle, we need to understand the water solubility in the nominally anhydrous minerals. Much is known about olivine and pyroxene. Garnet is another important component, approaching 40% by volume in the transition zone. Only two studies on water solubility in pyrope at high-pressures exist which contradict each other. Lu and Keppler (1997) observed increase in water solubility in a natural pyrope up to 200 ppm wt of water, till 10 GPa. They concluded that the proton is located in the interstitial site. Withers et al. (1998) on the contrary, observed increasing water content in Mg-rich pyrope till 6 GPa, then sudden decrease of water, beyond detection, at 7 GPa. Based on infrared spectra, Withers et al. (1998), concluded hydrogarnet (Si^{4+} replaced by 4H+ to form O4H4) substitution in synthetic magnesium rich pyrope. They argued that at high pressure owing to larger volume, hydrogarnet substitution is unstable and water is expelled out of garnet. In transition zone conditions, however, majorite garnet seems to contain around 600-700 ppm wt of water (Bolfan-Casanova et al. 2000; Katayama et al. 2003). The cause for such discrepancy is not clear and whether garnet could store a significant amount of water at mantle condition is unconstrained. In order to understand the solubility mechanism of water in pyrope at high-pressure, we have conducted high- pressure experiments on naturally occurring single crystals of pyrope garnet (from Arizona, Aines and Rossman, 1984). To ascertain water-saturated conditions, we use olivine single-crystal as an internal standard. Preliminary results indicate that natural pyrope is capable of dissolving water at high-pressures, however, water preferentially enters olivine than in pyrope. We are undertaking systematic study to estimate the solubility of water in pyrope as a function of pressure. This will enable us to develop solubility models to understand the defect mechanisms

  18. Novel nanogels as drug delivery systems for poorly soluble anticancer drugs.

    PubMed

    Li, Na; Wang, Jinli; Yang, Xingguo; Li, Lingbing

    2011-04-01

    Two types of novel nanogels were prepared using shell cross-linking of Pluronic F127 micelles with polyethylenimine (PEI) (F127/PEI nanogel), and penetrating network of poly(butylcyanoacrylate) (PBCA) in Pluronic F127 micelles (F127/PBCA nanogel). Poorly soluble anticancer drug, paclitaxel (PTX) and 10-hydroxycamptothecin (HCPT), were used as model drugs and incorporated into nanogels. The results obtained from FT-IR spectroscopy confirmed that the drugs were molecularly dispersed in the nanogels. DLS measurements demonstrated that the nanogel size distribution was narrow with average diameter less than 200 nm. TEM images indicated that the nanogels were spherical in shape and had smooth surfaces. The drug-loaded nanogels showed sustained release profiles compared with the free drugs as revealed by in vitro release experiments. Cytotoxicity tests showed that the cytotoxicity of drug-loaded nanogels against cancer cell in vitro was much higher than that of the free drug. The data demonstrate that these novel nanogels improved stability towards dilution, increased solubility and showed better cellular uptake by cells compared with free drug.

  19. Ice nucleation by water-soluble macromolecules

    NASA Astrophysics Data System (ADS)

    Pummer, B. G.; Budke, C.; Augustin-Bauditz, S.; Niedermeier, D.; Felgitsch, L.; Kampf, C. J.; Huber, R. G.; Liedl, K. R.; Loerting, T.; Moschen, T.; Schauperl, M.; Tollinger, M.; Morris, C. E.; Wex, H.; Grothe, H.; Pöschl, U.; Koop, T.; Fröhlich-Nowoisky, J.

    2015-04-01

    Cloud glaciation is critically important for the global radiation budget (albedo) and for initiation of precipitation. But the freezing of pure water droplets requires cooling to temperatures as low as 235 K. Freezing at higher temperatures requires the presence of an ice nucleator, which serves as a template for arranging water molecules in an ice-like manner. It is often assumed that these ice nucleators have to be insoluble particles. We point out that also free macromolecules which are dissolved in water can efficiently induce ice nucleation: the size of such ice nucleating macromolecules (INMs) is in the range of nanometers, corresponding to the size of the critical ice embryo. As the latter is temperature-dependent, we see a correlation between the size of INMs and the ice nucleation temperature as predicted by classical nucleation theory. Different types of INMs have been found in a wide range of biological species and comprise a variety of chemical structures including proteins, saccharides, and lipids. Our investigation of the fungal species Acremonium implicatum, Isaria farinosa, and Mortierella alpina shows that their ice nucleation activity is caused by proteinaceous water-soluble INMs. We combine these new results and literature data on INMs from fungi, bacteria, and pollen with theoretical calculations to develop a chemical interpretation of ice nucleation and water-soluble INMs. This has atmospheric implications since many of these INMs can be released by fragmentation of the carrier cell and subsequently may be distributed independently. Up to now, this process has not been accounted for in atmospheric models.

  20. Biological activities of water-soluble fullerene derivatives

    NASA Astrophysics Data System (ADS)

    Nakamura, S.; Mashino, T.

    2009-04-01

    Three types of water-soluble fullerene derivatives were synthesized and their biological activities were investigated. C60-dimalonic acid, an anionic fullerene derivative, showed antioxidant activity such as quenching of superoxide and relief from growth inhibition of E. coli by paraquat. C60-bis(7V,7V-dimethylpyrrolidinium iodide), a cationic fullerene derivative, has antibacterial activity and antiproliferative effect on cancer cell lines. The mechanism is suggested to be respiratory chain inhibition by reactive oxygen species produced by the cationic fullerene derivative. Proline-type fullerene derivatives showed strong inhibition activities on HIV-reverse transcriptase. The IC50 values were remarkably lower than nevirapine, a clinically used anti-HIV drug. Fullerene derivatives have a big potential for a new type of lead compound to be used as medicine.

  1. 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

  2. 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

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

    PubMed

    Kalepu, Sandeep; Nekkanti, Vijaykumar

    2015-09-01

    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.

  4. Risk assessment of premature drug release during wet granulation of ordered mesoporous silica loaded with poorly soluble compounds itraconazole, fenofibrate, naproxen, and ibuprofen.

    PubMed

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

    2012-05-01

    In this study, the potential of wet granulation of ordered mesoporous silica (OMS) material was evaluated to assess the risk of premature drug release during processing and to improve the bulk powder flow properties and compactibility for the development of an immediate release oral dosage form. The poorly water soluble model compounds, itraconazole, fenofibrate, naproxen, and ibuprofen were loaded into the model OMS, COK-12, and granulated using a polyvinylpyrrolidone (PVP) binder solution. Preliminary assessments were made with itraconazole loaded COK-12 to study the effects of the initial drug load, binder concentration, binder addition rate, and granulation temperature on premature drug release. Comparison to pure COK-12 revealed particle size enlargement and enhanced powder flow based on Carr Index and Hausner Ratio results. Following compression to 120 MPa, the compactibility of the granulated material also improved when compared to the untreated COK-12. In vitro release of itraconazole from the compressed granulated material was assessed with and without the disintegrant, croscarmellose sodium. Incorporation of 2.4 wt. croscarmellose sodium prior to compression successfully recovered the slight release loss following compression. To assess premature drug release, developments made with itraconazole loaded COK-12 were applied to loaded fenofibrate, naproxen, and ibuprofen. Results from modulated differential scanning calorimetry (MDSC) indicated that the risk of premature drug release during wet granulation was primarily compound dependent. These findings highlight challenges in preparation for a successful manufacturing process of OMS based formulations.

  5. Which Starch Fraction is Water-Soluble, Amylose or Amylopectin?

    ERIC Educational Resources Information Center

    Green, Mark M.; And Others

    1975-01-01

    A survey of 22 popular organic chemistry textbooks showed that only four correctly stated that of the two components of starch, amylopectin is the water-soluble, and amylose is the water-insoluble. (MLH)

  6. Solvent-free drug crystal engineering for drug nano- and micro suspensions.

    PubMed

    da Fonseca Antunes, André B; De Geest, Bruno G; Vervaet, Chris; Remon, Jean Paul

    2013-01-23

    Poor water-solubility is becoming the leading hurdle for novel drug molecules to reach the market. Enhancing the surface-to-volume ratio by reducing the drug particles size has emerged as a powerful method to enhance the drug dissolution rate of poorly water-soluble drugs. Here we present several approaches to produce micro- and nano-suspensions of febantel and itraconazole, as poorly water-soluble model drugs, in the presence of the self-emulsifying excipient Gelucire 44/14 as additional solubility enhancing agent. Two top-down approaches involving either ball milling or ultrasound treatment, to reduce the size of existing drug crystals, were used as reference processes. Both techniques allowed to significantly reduce the size of the drug crystals and enhance the dissolution of febantel with the ultrasound treated formulation performing the best. In case of itraconazole, no influence of both processing techniques was observed, which is likely to be attributed to it is extremely low water-solubility. To address this challenge, we developed a novel bottom up approach to produce nanosuspensions. This approach involved first dissolving the drug in molten Gelucire 44/14 followed by atomization into cold water. During the atomization, cavitation was induced by ultrasonication. This process yielded milky suspensions in the submicrometer range. Furthermore a fraction of the drug was found to be in amorphous state. Nanosuspensions produced by this technique showed improved dissolution behavior, both in case of febantel and itraconazole.

  7. Water-soluble fluorochemical surfactant well stimulation additives

    SciTech Connect

    Clark, H.B.; Pike, M.T.; Rengel, G.L.

    1982-07-01

    Water-soluble fluorochemical surfactants have been used in the oilfield since the early 1970's as surface tension depressants in a variety of aqueous stimulation fluids for low-permeability oil and gas wells. A discussion is presented of a laboratory study of the behavior of water-soluble fluorochemical surfactants relative to their oilfield use. Data are presented on surface tension depression, thermal stability, adsorption, fluid removal from sandpacks, flow rates, and emulsification tendencies. 7 refs.

  8. Water soluble folate-chitosan nanogels crosslinked by genipin.

    PubMed

    Pujana, Maite Arteche; Pérez-Álvarez, Leyre; Iturbe, L Carlos Cesteros; Katime, Issa

    2014-01-30

    Folate-chitosan conjugates were prepared by a concurrent functionalization and crosslinking reaction with the natural crosslinker genipin. Genipin molecule was employed simultaneously as crosslinker agent and spacer molecule in order to allow the functionalization with folic acid for active tumor targeting. The reaction was carried out in reverse microemulsion which provided colloidal size and monodisperse particle size distribution. The water solubility of the obtained folate-genipin-chitosan nanogels was studied as function of the pH of the medium and all nanoparticles were totally dispersible at physiological pH. The enzymatic degradability of the nanogels in a lysozyme solution was evaluated at acidic and physiological pH. QELS analyses of the swelling behavior of the nanogels with the pH did not show a clear pH-sensitivity. However, the study on the loading and release capacity of 5-fluorouracil revealed an interesting pH-responsive behavior of the nanogels that makes them promising as nanodevices for targeted anticancer drug delivery.

  9. Water-soluble ruthenium complexes bearing activity against protozoan parasites.

    PubMed

    Sarniguet, Cynthia; Toloza, Jeannette; Cipriani, Micaella; Lapier, Michel; Vieites, Marisol; Toledano-Magaña, Yanis; García-Ramos, Juan Carlos; Ruiz-Azuara, Lena; Moreno, Virtudes; Maya, Juan Diego; Azar, Claudio Olea; Gambino, Dinorah; Otero, Lucía

    2014-06-01

    Parasitic illnesses are major causes of human disease and misery worldwide. Among them, both amebiasis and Chagas disease, caused by the protozoan parasites, Entamoeba histolytica and Trypanosoma cruzi, are responsible for thousands of annual deaths. The lack of safe and effective chemotherapy and/or the appearance of current drug resistance make the development of novel pharmacological tools for their treatment relevant. In this sense, within the framework of the medicinal inorganic chemistry, metal-based drugs appear to be a good alternative to find a pharmacological answer to parasitic diseases. In this work, novel ruthenium complexes [RuCl2(HL)(HPTA)2]Cl2 with HL=bioactive 5-nitrofuryl containing thiosemicarbazones and PTA=1,3,5-triaza-7-phosphaadamantane have been synthesized and fully characterized. PTA was included as co-ligand in order to modulate complexes aqueous solubility. In fact, obtained complexes were water soluble. Their activity against T. cruzi and E. histolytica was evaluated in vitro. [RuCl2(HL4)(HPTA)2]Cl2 complex, with HL4=N-phenyl-5-nitrofuryl-thiosemicarbazone, was the most active compound against both parasites. In particular, it showed an excellent activity against E. histolytica (half maximal inhibitory concentration (IC50)=5.2 μM), even higher than that of the reference drug metronidazole. In addition, this complex turns out to be selective for E. histolytica (selectivity index (SI)>38). The potential mechanism of antiparasitic action of the obtained ruthenium complexes could involve oxidative stress for both parasites. Additionally, complexes could interact with DNA as second potential target by an intercalative-like mode. Obtained results could be considered a contribution in the search for metal compounds that could be active against multiple parasites. PMID:24740394

  10. Water-soluble ruthenium complexes bearing activity against protozoan parasites.

    PubMed

    Sarniguet, Cynthia; Toloza, Jeannette; Cipriani, Micaella; Lapier, Michel; Vieites, Marisol; Toledano-Magaña, Yanis; García-Ramos, Juan Carlos; Ruiz-Azuara, Lena; Moreno, Virtudes; Maya, Juan Diego; Azar, Claudio Olea; Gambino, Dinorah; Otero, Lucía

    2014-06-01

    Parasitic illnesses are major causes of human disease and misery worldwide. Among them, both amebiasis and Chagas disease, caused by the protozoan parasites, Entamoeba histolytica and Trypanosoma cruzi, are responsible for thousands of annual deaths. The lack of safe and effective chemotherapy and/or the appearance of current drug resistance make the development of novel pharmacological tools for their treatment relevant. In this sense, within the framework of the medicinal inorganic chemistry, metal-based drugs appear to be a good alternative to find a pharmacological answer to parasitic diseases. In this work, novel ruthenium complexes [RuCl2(HL)(HPTA)2]Cl2 with HL=bioactive 5-nitrofuryl containing thiosemicarbazones and PTA=1,3,5-triaza-7-phosphaadamantane have been synthesized and fully characterized. PTA was included as co-ligand in order to modulate complexes aqueous solubility. In fact, obtained complexes were water soluble. Their activity against T. cruzi and E. histolytica was evaluated in vitro. [RuCl2(HL4)(HPTA)2]Cl2 complex, with HL4=N-phenyl-5-nitrofuryl-thiosemicarbazone, was the most active compound against both parasites. In particular, it showed an excellent activity against E. histolytica (half maximal inhibitory concentration (IC50)=5.2 μM), even higher than that of the reference drug metronidazole. In addition, this complex turns out to be selective for E. histolytica (selectivity index (SI)>38). The potential mechanism of antiparasitic action of the obtained ruthenium complexes could involve oxidative stress for both parasites. Additionally, complexes could interact with DNA as second potential target by an intercalative-like mode. Obtained results could be considered a contribution in the search for metal compounds that could be active against multiple parasites.

  11. Supramolecular Complexation of Carbohydrates for the Bioavailability Enhancement of Poorly Soluble Drugs.

    PubMed

    Cho, Eunae; Jung, Seunho

    2015-10-27

    In this review, a comprehensive overview of advances in the supramolecular complexes of carbohydrates and poorly soluble drugs is presented. Through the complexation process, poorly soluble drugs could be efficiently delivered to their desired destinations. Carbohydrates, the most abundant biomolecules, have diverse physicochemical properties owing to their inherent three-dimensional structures, hydrogen bonding, and molecular recognition abilities. In this regard, oligosaccharides and their derivatives have been utilized for the bioavailability enhancement of hydrophobic drugs via increasing the solubility or stability. By extension, polysaccharides and their derivatives can form self-assembled architectures with poorly soluble drugs and have shown increased bioavailability in terms of the sustained or controlled drug release. These supramolecular systems using carbohydrate will be developed consistently in the field of pharmaceutical and medical application.

  12. Preparation of multiparticulate systems for oral delivery of a micronized or nanosized poorly soluble drug.

    PubMed

    Cerea, Matteo; Pattarino, Franco; Foglio Bonda, Andrea; Palugan, Luca; Segale, Lorena; Vecchio, Carlo

    2016-09-01

    The purpose of the present work was to prepare multiparticulate drug delivery systems for oral administration of a poorly soluble drug such as itraconazole. Multiparticulate systems were prepared by extrusion/spheronization technique using a mix of crospovidone, low viscosity hypromellose, microcrystalline cellulose, micronized drug and water. In order to improve the release performance of the multiparticulate systems, the micronized drug was suspended in water with polysorbate 20 and nanonized by a high-pressure homogenization. The suspension of drug nanoparticles was then spray-dried for enabling an easy handling of the drug and for preventing the over-wetting of the powders during extrusion/spheronization processing. Both multiparticulate units prepared with micronized or nanonized drug showed acceptable disintegrating properties. The nanosizing of micronized drug powder provided a significant improvement of drug dissolution rates of the multiparticulates.

  13. Preparation of multiparticulate systems for oral delivery of a micronized or nanosized poorly soluble drug.

    PubMed

    Cerea, Matteo; Pattarino, Franco; Foglio Bonda, Andrea; Palugan, Luca; Segale, Lorena; Vecchio, Carlo

    2016-09-01

    The purpose of the present work was to prepare multiparticulate drug delivery systems for oral administration of a poorly soluble drug such as itraconazole. Multiparticulate systems were prepared by extrusion/spheronization technique using a mix of crospovidone, low viscosity hypromellose, microcrystalline cellulose, micronized drug and water. In order to improve the release performance of the multiparticulate systems, the micronized drug was suspended in water with polysorbate 20 and nanonized by a high-pressure homogenization. The suspension of drug nanoparticles was then spray-dried for enabling an easy handling of the drug and for preventing the over-wetting of the powders during extrusion/spheronization processing. Both multiparticulate units prepared with micronized or nanonized drug showed acceptable disintegrating properties. The nanosizing of micronized drug powder provided a significant improvement of drug dissolution rates of the multiparticulates. PMID:26786555

  14. Self-assembly of amphiphilic anionic calix[4]arenes and encapsulation of poorly soluble naproxen and flurbiprofen.

    PubMed

    Barbera, Lucia; Gattuso, Giuseppe; Kohnke, Franz H; Notti, Anna; Pappalardo, Sebastiano; Parisi, Melchiorre F; Pisagatti, Ilenia; Patanè, Salvatore; Micali, Norberto; Villari, Valentina

    2015-06-21

    Supramolecular aggregates formed through the association of an amphiphilic tetra-O-butylsulfonate calix[4]arene 1 were investigated in aqueous solution by a combination of different techniques (NMR, DLS and AFM). The ability of the micellar aggregates of calixarene 1 to increase the solubility of poorly water-soluble drugs was studied.

  15. Water soluble cations and the fluvial history of Mars

    NASA Technical Reports Server (NTRS)

    Silverman, M. P.; Munoz, E. F.

    1975-01-01

    The electrical conductivity and water soluble Na, K, Ca, and Mg of aqueous solutions of terrestrial soils and finely divided igneous and metamorphic rocks were determined. Soils from dry terrestrial basins with a history of water accumulation as well as soils from the topographic lows of valleys accumulated water soluble cations, particularly Na and Ca. These soils as a group can be distinguished from the rocks or a second group of soils (leached upland soils and soils from sites other than the topographic lows of valleys) by significant differences in their mean electrical conductivity and water-soluble Na + Ca content. Similar measurements on multiple samples from the surface of Mars, collected by an automated long-range roving vehicle along a highlands-to-basin transect at sites with morphological features resembling dry riverlike channels, are suggested to determine the fluvial history of the planet.

  16. 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

  17. Selective Water-Soluble Gelatinase Inhibitor Prodrugs

    PubMed Central

    Gooyit, Major; Lee, Mijoon; Schroeder, Valerie A.; Ikejiri, Masahiro; Suckow, Mark A.; Mobashery, Shahriar; Chang, Mayland

    2011-01-01

    SB-3CT (1), a selective and potent thiirane-based gelatinase inhibitor, is effective in animal models of cancer metastasis and stroke; however, it is limited by poor aqueous solubility and extensive metabolism. We addressed these issues by blocking the primary site of metabolism and capitalizing on a prodrug strategy to achieve >5000-fold increased solubility. The amide prodrugs were quantitatively hydrolyzed in human blood to a potent gelatinase inhibitor, ND-322 (3). The arginyl amide prodrug (ND-478, 5d) was metabolically stable in mouse, rat, and human liver microsomes. Both 5d and 3 were non-mutagenic in the Ames II mutagenicity assay. The prodrug 5d showed moderate clearance of 0.0582 L/min/kg, remained mostly in the extracellular fluid compartment (Vd = 0.0978 L/kg), and had a terminal half-life of >4 h. The prodrug 5d had superior pharmacokinetic properties than 3, making the thiirane class of selective gelatinase inhibitors suitable for intravenous administration in treatment of acute gelatinase-dependent diseases. PMID:21866961

  18. Improved water solubility of neohesperidin dihydrochalcone in sweetener blends.

    PubMed

    Benavente-García, O; Castillo, J; Del Baño, M J; Lorente, J

    2001-01-01

    Significant technological advantages in terms of sweetness synergy and hence cost-saving can be obtained if neohesperidin dihydrochalcone (NHDC) is used in sweetener blends with other intense or bulk sweeteners. The combination of NHDC with sodium saccharin or sodium cyclamate is an excellent method to improve the water solubility at room temperature of NHDC. In the case of NHDC-sodium saccharin, two different methods for blend preparation, a simple mixture and a cosolubilized mixture, can be used, with similar results obtained for solubility and solution stability properties. To improve temporally the water solubility of NHDC in combination with sodium cyclamate, it is absolutely necessary to prepare cosolubilized blends.

  19. Mechanisms of membrane transport of poorly soluble drugs: role of micelles in oral absorption processes.

    PubMed

    Yano, Koji; Masaoka, Yoshie; Kataoka, Makoto; Sakuma, Shinji; Yamashita, Shinji

    2010-03-01

    Micelles formed in the GI tract by bile acid and lecithin play an important role in oral absorption of poorly soluble drugs. In this situation, the drug molecules are present in equilibrium between the free and micellar states. In this study, the relationship between the free drug concentration and the membrane permeability of poorly soluble drugs was examined. Permeability across a Caco-2 monolayer and a dialysis membrane were measured in a side-by-side chamber system. The concentrations of sodium taurocholate (NaTC) and lecithin were varied to allow measurement of membrane permeability at different concentrations of free drugs. For troglitazone, hexylparaben, and heptylparaben, an increase in the NaTC and lecithin concentrations caused the permeability across the Caco-2 monolayer to decrease slightly, whereas the permeability across the dialysis membrane decreased markedly. In contrast, the changes in permeability of griseofulvin with an increased micelle concentration were similar for the Caco-2 monolayer and the dialysis membrane. Assuming that the permeability for the dialysis membrane reflects the free drug concentration in the medium, these results suggest that troglitazone and alkylparabens, but not griseofulvin, can partition directly from micelles to Caco-2 monolayers. This mechanism may contribute to oral absorption of drugs that are poorly soluble in water. PMID:19743502

  20. Photochemistry within a water-soluble organic capsule.

    PubMed

    Ramamurthy, Vaidhyanathan

    2015-11-17

    in crystals and isotropic solution can be transformed into photoproducts selectivity. The results of our photochemical investigations elaborated in this Account demonstrate that OA with a medium sized cavity exerts better control on excited state processes than the more common and familiar organic hosts such as CD, CB, CA, and micelles. By examining the photochemistry of a number of molecules (olefins, carbonyls, aromatics and singlet oxygen) that undergo varied reactions (cleavage, cycloaddition, cis-trans isomerization, oxidation and cyclization) within OA capsule, we have demonstrated that the free space within the container, the capsule influenced conformation and preorientation of guest molecules, supramolecular steric control, and capsular dynamics contribute to the altered excited state behavior. In this Account, we have shown that photochemistry based on concepts of physical organic and supramolecular chemistry continues to be a discipline with unlimited potential. The future of supramolecular photochemistry lies in synthetic, materials, medicinal, and biological chemistries. Success in these areas depends on synthesizing well-designed water-soluble hosts that can emulate complex biological assemblies, organizing and examining the behavior of supramolecular assemblies on solid surfaces, rendering the photoreactions catalytic, and delivering encapsulated drugs in a targeted fashion. PMID:26488308

  1. Photochemistry within a water-soluble organic capsule.

    PubMed

    Ramamurthy, Vaidhyanathan

    2015-11-17

    in crystals and isotropic solution can be transformed into photoproducts selectivity. The results of our photochemical investigations elaborated in this Account demonstrate that OA with a medium sized cavity exerts better control on excited state processes than the more common and familiar organic hosts such as CD, CB, CA, and micelles. By examining the photochemistry of a number of molecules (olefins, carbonyls, aromatics and singlet oxygen) that undergo varied reactions (cleavage, cycloaddition, cis-trans isomerization, oxidation and cyclization) within OA capsule, we have demonstrated that the free space within the container, the capsule influenced conformation and preorientation of guest molecules, supramolecular steric control, and capsular dynamics contribute to the altered excited state behavior. In this Account, we have shown that photochemistry based on concepts of physical organic and supramolecular chemistry continues to be a discipline with unlimited potential. The future of supramolecular photochemistry lies in synthetic, materials, medicinal, and biological chemistries. Success in these areas depends on synthesizing well-designed water-soluble hosts that can emulate complex biological assemblies, organizing and examining the behavior of supramolecular assemblies on solid surfaces, rendering the photoreactions catalytic, and delivering encapsulated drugs in a targeted fashion.

  2. Responses to Medicare Drug Costs among Near-Poor versus Subsidized Beneficiaries

    PubMed Central

    Fung, Vicki; Reed, Mary; Price, Mary; Brand, Richard; Dow, William H; Newhouse, Joseph P; Hsu, John

    2013-01-01

    Objective There is limited information on the protective value of Medicare Part D low-income subsidies (LIS). We compared responses to drug costs for LIS recipients with near-poor (≤200 percent of the Federal Poverty Level) and higher income beneficiaries without the LIS. Data Sources/Study Setting Medicare Advantage beneficiaries in 2008. Study Design We examined three drug cost responses using multivariate logistic regression: cost-reducing behaviors (e.g., switching to generics), nonadherence (e.g., not refilling prescriptions), and financial stress (e.g., going without necessities). Data Collection Telephone interviews in a stratified random sample (N = 1,201, 70 percent response rate). Principal Findings After adjustment, a comparable percentage of unsubsidized near-poor (26 percent) and higher income beneficiaries reported cost-reducing behaviors (23 percent, p = .63); fewer LIS beneficiaries reported cost-reducing behaviors (15 percent, p = .019 vs near-poor). Unsubsidized near-poor beneficiaries were more likely to reduce adherence (8.2 percent) than higher income (3.5 percent, p = .049) and LIS beneficiaries (3.1 percent, p = .027). Near-poor beneficiaries also more frequently experienced financial stress due to drug costs (20 percent) than higher income beneficiaries (11 percent, p = .050) and LIS beneficiaries (11 percent, p = .015). Conclusions Low-income subsidies provide protection from drug cost-related nonadherence and financial stress. Beneficiaries just above the LIS income threshold are most at risk for these potentially adverse behaviors. PMID:23663197

  3. Polymersomes via Self-Assembly of Amphiphilic β-Cyclodextrin-Centered Triarm Star Polymers for Enhanced Oral Bioavailability of Water-Soluble Chemotherapeutics.

    PubMed

    Hu, Mengying; Shen, Yurun; Zhang, Lu; Qiu, Liyan

    2016-03-14

    To date, improving oral bioavailability of water-soluble drugs with poor membrane permeability is still challenging. An example of this includes doxorubicin hydrochloride (DOX·HCl), a widely used chemotherapeutic. We therefore developed a novel DOX·HCl-loaded polymersome (Ps-DOX·HCl) self-assembled by amphiphilic β-cyclodextrin-centered triarm star polymer (mPEG(2k)-PLA(3k))3-CD with the considerable drug loading capability. Using Madin-Darby canine kidney (MDCK) cells trans-well models, it was found that the cellular uptake and absorptive transport of DOX·HCl was significantly increased and the efflux was attenuated when delivered through polymersomes than free drugs. This phenomenon was further verified in mechanistic studies, which was attributed to the change in membrane transport pathway from paracellular route (free DOX·HCl) to active transcellular transport (drug-loaded polymersomes). Moreover, in vivo pharmacokinetic studies in mice demonstrated a significant increase in the oral bioavailability of Ps-DOX·HCl compared with free DOX·HCl (7.32-fold), as well as extended half-life (8.22-fold). This resulted in a substantial anticancer efficacy against mouse sarcoma 180 (S180) tumor in vivo. The cardiotoxicity, which is intrinsically induced by DOX·HCl, and toxicity toward gastrointestinal tissues were avoided according to histological studies. These findings indicate that (mPEG(2k)-PLA(3k))3-CD copolymer displays great potential as a vehicle for the effective oral delivery of water-soluble drugs with low permeability. PMID:26840277

  4. Polymersomes via Self-Assembly of Amphiphilic β-Cyclodextrin-Centered Triarm Star Polymers for Enhanced Oral Bioavailability of Water-Soluble Chemotherapeutics.

    PubMed

    Hu, Mengying; Shen, Yurun; Zhang, Lu; Qiu, Liyan

    2016-03-14

    To date, improving oral bioavailability of water-soluble drugs with poor membrane permeability is still challenging. An example of this includes doxorubicin hydrochloride (DOX·HCl), a widely used chemotherapeutic. We therefore developed a novel DOX·HCl-loaded polymersome (Ps-DOX·HCl) self-assembled by amphiphilic β-cyclodextrin-centered triarm star polymer (mPEG(2k)-PLA(3k))3-CD with the considerable drug loading capability. Using Madin-Darby canine kidney (MDCK) cells trans-well models, it was found that the cellular uptake and absorptive transport of DOX·HCl was significantly increased and the efflux was attenuated when delivered through polymersomes than free drugs. This phenomenon was further verified in mechanistic studies, which was attributed to the change in membrane transport pathway from paracellular route (free DOX·HCl) to active transcellular transport (drug-loaded polymersomes). Moreover, in vivo pharmacokinetic studies in mice demonstrated a significant increase in the oral bioavailability of Ps-DOX·HCl compared with free DOX·HCl (7.32-fold), as well as extended half-life (8.22-fold). This resulted in a substantial anticancer efficacy against mouse sarcoma 180 (S180) tumor in vivo. The cardiotoxicity, which is intrinsically induced by DOX·HCl, and toxicity toward gastrointestinal tissues were avoided according to histological studies. These findings indicate that (mPEG(2k)-PLA(3k))3-CD copolymer displays great potential as a vehicle for the effective oral delivery of water-soluble drugs with low permeability.

  5. Leaching behavior of water-soluble carbohydrates from almond hulls

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Over 58% of the dry matter content of the hulls from the commercial almond (Prunus dulcis (Miller) D.A. Webb) is soluble in warm water (50-70°C) extraction. The water-soluble extractables include useful amounts of fermentable sugars (glucose, fructose, sucrose), sugar alcohols (inositol and sorbito...

  6. Spectroscopic and Photochemical Properties of Water-Soluble Fullerenol

    EPA Science Inventory

    Fullerenol, a hydroxylated form of C60-fullerene, is of potential environmental and biological significance due to its buckyball structure, hydroxyl groups and high water solubility. Although fullerenol is known to be an efficient triplet photosensitizer, little is known about it...

  7. Some physicochemical aspects of water-soluble mineral flotation.

    PubMed

    Wu, Zhijian; Wang, Xuming; Liu, Haining; Zhang, Huifang; Miller, Jan D

    2016-09-01

    Some physicochemical aspects of water-soluble mineral flotation including hydration phenomena, associations and interactions between collectors, air bubbles, and water-soluble mineral particles are presented. Flotation carried out in saturated salt solutions, and a wide range of collector concentrations for effective flotation of different salts are two basic aspects of water-soluble mineral flotation. Hydration of salt ions, mineral particle surfaces, collector molecules or ions, and collector aggregates play an important role in water-soluble mineral flotation. The adsorption of collectors onto bubble surfaces is suggested to be the precondition for the association of mineral particles with bubbles. The association of collectors with water-soluble minerals is a complicated process, which may include the adsorption of collector molecules or ions onto such surfaces, and/or the attachment of collector precipitates or crystals onto the mineral surfaces. The interactions between the collectors and the minerals include electrostatic and hydrophobic interactions, hydrogen bonding, and specific interactions, with electrostatic and hydrophobic interactions being the common mechanisms. For the association of ionic collectors with minerals with an opposite charge, electrostatic and hydrophobic interactions could have a synergistic effect, with the hydrophobic interactions between the hydrophobic groups of the previously associated collectors and the hydrophobic groups of oncoming collectors being an important attractive force. Association between solid particles and air bubbles is the key to froth flotation, which is affected by hydrophobicity of the mineral particle surfaces, surface charges of mineral particles and bubbles, mineral particle size and shape, temperature, bubble size, etc. The use of a collector together with a frother and the use of mixed surfactants as collectors are suggested to improve flotation. PMID:27346329

  8. Some physicochemical aspects of water-soluble mineral flotation.

    PubMed

    Wu, Zhijian; Wang, Xuming; Liu, Haining; Zhang, Huifang; Miller, Jan D

    2016-09-01

    Some physicochemical aspects of water-soluble mineral flotation including hydration phenomena, associations and interactions between collectors, air bubbles, and water-soluble mineral particles are presented. Flotation carried out in saturated salt solutions, and a wide range of collector concentrations for effective flotation of different salts are two basic aspects of water-soluble mineral flotation. Hydration of salt ions, mineral particle surfaces, collector molecules or ions, and collector aggregates play an important role in water-soluble mineral flotation. The adsorption of collectors onto bubble surfaces is suggested to be the precondition for the association of mineral particles with bubbles. The association of collectors with water-soluble minerals is a complicated process, which may include the adsorption of collector molecules or ions onto such surfaces, and/or the attachment of collector precipitates or crystals onto the mineral surfaces. The interactions between the collectors and the minerals include electrostatic and hydrophobic interactions, hydrogen bonding, and specific interactions, with electrostatic and hydrophobic interactions being the common mechanisms. For the association of ionic collectors with minerals with an opposite charge, electrostatic and hydrophobic interactions could have a synergistic effect, with the hydrophobic interactions between the hydrophobic groups of the previously associated collectors and the hydrophobic groups of oncoming collectors being an important attractive force. Association between solid particles and air bubbles is the key to froth flotation, which is affected by hydrophobicity of the mineral particle surfaces, surface charges of mineral particles and bubbles, mineral particle size and shape, temperature, bubble size, etc. The use of a collector together with a frother and the use of mixed surfactants as collectors are suggested to improve flotation.

  9. Novel third-generation water-soluble noscapine analogs as superior microtubule-interfering agents with enhanced antiproliferative activity

    PubMed Central

    Henary, Maged; Narayana, Lakshminarayana; Ahad, Shazia; Gundala, Sushma R.; Mukkavilli, Rao; Sharma, Vibhuti; Owens, Eric A.; Yadav, Yogesh; Nagaraju, Mulpuri; Hamelberg, Donald; Tandon, Vibha; Panda, Dulal; Aneja, Ritu

    2015-01-01

    Noscapine, an opium-derived ‘kinder-gentler’ microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a–c;8a–c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and 8c strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and 8c treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and 8c revealed at least 1–2 fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development. PMID:25124704

  10. Novel third-generation water-soluble noscapine analogs as superior microtubule-interfering agents with enhanced antiproliferative activity.

    PubMed

    Henary, Maged; Narayana, Lakshminarayana; Ahad, Shazia; Gundala, Sushma R; Mukkavilli, Rao; Sharma, Vibhuti; Owens, Eric A; Yadav, Yogesh; Nagaraju, Mulpuri; Hamelberg, Donald; Tandon, Vibha; Panda, Dulal; Aneja, Ritu

    2014-11-15

    Noscapine, an opium-derived 'kinder-gentler' microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a-c; 8a-c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and 8c strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, and 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and 8c treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and 8c revealed at least 1-2-fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development. PMID:25124704

  11. A step toward development of printable dosage forms for poorly soluble drugs.

    PubMed

    Raijada, Dhara; Genina, Natalja; Fors, Daniela; Wisaeus, Erik; Peltonen, Jouko; Rantanen, Jukka; Sandler, Niklas

    2013-10-01

    The purpose of this study was to formulate printable dosage forms for a poorly soluble drug (piroxicam; PRX) and to gain understanding of critical parameters to be considered during development of such dosage forms. Liquid formulations of PRX were printed on edible paper using piezoelectric inkjet printing (PIJ) and impression printing (flexography). The printed dosage forms were characterized using scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) and the amount of drug was determined using high-performance liquid chromatography. Solutions of PRX in polyethylene glycol 400 (PEG-400):ethanol (40:60) and in PEG-400 were found to be optimal formulations for PIJ and flexography, respectively. SEM-EDX analysis revealed no visible solid particles on the printed dosage forms indicating the drug most likely remained in solution after printing. More accurate drug deposition was obtained by PIJ as compared with flexography. More than 90% drug release was achieved within 5 min regardless of printing method used. The solubility of drug in solvents/cosolvents, rheological properties of formulations, properties of substrate, feasibility and accuracy of the printing methods, and detection limit of analytical techniques for characterization of printed dosage forms are some of the concerns that need to be addressed for development of printable dosage forms of poorly soluble drugs.

  12. [Improvement of intestinal absorption of poorly absorbable drugs by various sugar esters].

    PubMed

    Yamamoto, Akira; Katsumi, Hidemasa; Kusamori, Kosuke; Sakane, Toshiyasu

    2014-01-01

    Effects of sucrose fatty acid esters (sugar esters) on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF) and fluorescein isothiocyanate-dextrans (FDs) with various molecular weights were used as model drugs of poorly absorbable drugs. The absorption of CF from the rat small intestine was significantly enhanced in the presence of various sugar esters and a maximal absorption enhancing effect was observed in the presence of 0.5%(w/v) S-1670. The absorption enhancing effect of S-1670 in the small intestine decreased as the molecular weights of drugs increased. Moreover, we evaluated the intestinal membrane damage with or without various sugar esters. These sugar esters (0.5%(w/v)) did not increase the activities of lactate dehydrogenase (LDH), suggesting that these sugar esters did not cause serious membrane damage to the intestinal epithelium. Furthermore, these sugar esters increased membrane fluidity of lipid layers of the intestinal brush border membranes and decreased the transepithelial electrical resistance (TEER) of Caco-2 cells. Therefore, these findings suggested that these sugar esters might improve the intestinal absorption of poorly absorbable drugs via a transcellular and a paracellular pathways.

  13. Composition of the water-soluble fraction of different cheeses.

    PubMed

    Taborda, Gonzalo; Molina, Elena; Martínez-Castro, Isabel; Ramos, Mercedes; Amigo, Lourdes

    2003-01-01

    Volatile and nonvolatile compounds present in the water-soluble fraction (WSF) and water-soluble fraction with molecular weight lower than 1000 Da (WSF < 1000 Da) of six Spanish cheeses, Cabrales, Idiazábal, Mahón, Manchego, Roncal, and a goat's milk cheese, were analyzed. Different nitrogen fractions (determined by Kjeldahl method), caseins (by capillary electrophoresis), peptides and amino acids (by HPLC), and volatile components (by dynamic headspace coupled to GC-MS) as well as mineral content in the cheese fractions were analyzed and compared. The different nitrogen and volatile compounds identified in the WSF were characteristic of each cheese variety. Cabrales cheese displayed the highest content of free amino acids and the highest quantity and variety of volatile compounds. The WSF < 1000 Da fraction was less representative, especially for volatile compounds, as some of the components were lost in the ultrafiltration. Alcohols were better recovered than ketones and esters. PMID:12502420

  14. Poor quality drugs: grand challenges in high throughput detection, countrywide sampling, and forensics in developing countries†

    PubMed Central

    Fernandez, Facundo M.; Hostetler, Dana; Powell, Kristen; Kaur, Harparkash; Green, Michael D.; Mildenhall, Dallas C.; Newton, Paul N.

    2012-01-01

    Throughout history, poor quality medicines have been a persistent problem, with periodical crises in the supply of antimicrobials, such as fake cinchona bark in the 1600s and fake quinine in the 1800s. Regrettably, this problem seems to have grown in the last decade, especially afflicting unsuspecting patients and those seeking medicines via on-line pharmacies. Here we discuss some of the challenges related to the fight against poor quality drugs, and counterfeits in particular, with an emphasis on the analytical tools available, their relative performance, and the necessary workflows needed for distinguishing between genuine, substandard, degraded and counterfeit medicines. PMID:21107455

  15. Efficient synthesis of readily water-soluble sulfonic Acid carbamates.

    PubMed

    Idzik, Krzysztof R; Nödler, Karsten; Licha, Tobias

    2015-04-16

    A series of various readily water-soluble carbamates were synthesized with good yields. These compounds are useful chemical tracers for assessing the cooling progress in a georeservoir during geothermal power plant operation. Acylation of primary amines was carried out as well as using a solution of sodium bicarbonate and without the presence of salt. Products were characterized by 1H-NMR and 13C-NMR. Purity was confirmed through elemental analysis.

  16. Minimalist design of water-soluble cross-[beta] architecture

    SciTech Connect

    Biancalana, Matthew; Makabe, Koki; Koide, Shohei

    2010-08-13

    Demonstrated successes of protein design and engineering suggest significant potential to produce diverse protein architectures and assemblies beyond those found in nature. Here, we describe a new class of synthetic protein architecture through the successful design and atomic structures of water-soluble cross-{beta} proteins. The cross-{beta} motif is formed from the lamination of successive {beta}-sheet layers, and it is abundantly observed in the core of insoluble amyloid fibrils associated with protein-misfolding diseases. Despite its prominence, cross-{beta} has been designed only in the context of insoluble aggregates of peptides or proteins. Cross-{beta}'s recalcitrance to protein engineering and conspicuous absence among the known atomic structures of natural proteins thus makes it a challenging target for design in a water-soluble form. Through comparative analysis of the cross-{beta} structures of fibril-forming peptides, we identified rows of hydrophobic residues ('ladders') running across {beta}-strands of each {beta}-sheet layer as a minimal component of the cross-{beta} motif. Grafting a single ladder of hydrophobic residues designed from the Alzheimer's amyloid-{beta} peptide onto a large {beta}-sheet protein formed a dimeric protein with a cross-{beta} architecture that remained water-soluble, as revealed by solution analysis and x-ray crystal structures. These results demonstrate that the cross-{beta} motif is a stable architecture in water-soluble polypeptides and can be readily designed. Our results provide a new route for accessing the cross-{beta} structure and expanding the scope of protein design.

  17. Acquired Drug Resistance in Mycobacterium tuberculosis and Poor Outcomes among Patients with Multidrug-Resistant Tuberculosis

    PubMed Central

    Kipiani, Maia; Mirtskhulava, Veriko; Tukvadze, Nestani; Magee, Matthew J.; Blumberg, Henry M.

    2015-01-01

    Rates and risk factors for acquired drug resistance and association with outcomes among patients with multidrug-resistant tuberculosis (MDR TB) are not well defined. In an MDR TB cohort from the country of Georgia, drug susceptibility testing for second-line drugs (SLDs) was performed at baseline and every third month. Acquired resistance was defined as any SLD whose status changed from susceptible at baseline to resistant at follow-up. Among 141 patients, acquired resistance in Mycobacterium tuberculosis was observed in 19 (14%); prevalence was 9.1% for ofloxacin and 9.8% for capreomycin or kanamycin. Baseline cavitary disease and resistance to >6 drugs were associated with acquired resistance. Patients with M. tuberculosis that had acquired resistance were at significantly increased risk for poor treatment outcome compared with patients without these isolates (89% vs. 36%; p<0.01). Acquired resistance occurs commonly among patients with MDR TB and impedes successful treatment outcomes. PMID:25993036

  18. Compositional Analysis of Water-Soluble Materials in Corn Stover

    SciTech Connect

    Chen, S. F.; Mowery, R. A.; Scarlata, C. J.; Chambliss, C. K.

    2007-01-01

    Corn stover is one of the leading feedstock candidates for commodity-scale biomass-to-ethanol processing. The composition of water-soluble materials in corn stover has been determined with greater than 90% mass closure in four of five representative samples. The mass percentage of water-soluble materials in tested stover samples varied from 14 to 27% on a dry weight basis. Over 30 previously unknown constituents of aqueous extracts were identified and quantified using a variety of chromatographic techniques. Monomeric sugars (primarily glucose and fructose) were found to be the predominant water-soluble components of corn stover, accounting for 30-46% of the dry weight of extractives (4-12% of the dry weight of feedstocks). Additional constituents contributing to the mass balance for extractives included various alditols (3-7%), aliphatic acids (7-21%), inorganic ions (10-18%), oligomeric sugars (4-12%), and a distribution of oligomers tentatively identified as being derived from phenolic glycosides (10-18%).

  19. Quality medicines for the poor: experience of the Delhi programme on rational use of drugs.

    PubMed

    Chaudhury, R Roy; Parameswar, R; Gupta, U; Sharma, S; Tekur, U; Bapna, J S

    2005-03-01

    Prior to 1994, most Delhi hospitals and dispensaries experienced constant shortages of essential medicines. There was erratic prescribing of expensive branded products, frequent complaints about poor drug quality and low patient satisfaction. Delhi took the lead in developing a comprehensive Drug Policy in 1994 and was the only Indian state to have such a comprehensive policy. The policy's main objective is to improve the availability and accessibility of quality essential drugs for all those in need. The Delhi Society for the Promotion of Rational Use of Drugs (DSPRUD), a non-governmental organization, worked in close collaboration with the Delhi Government and with universities to implement various components of the policy. The first Essential Drugs List (EDL) was developed, a centralized pooled procurement system was set up and activities promoting rational use of drugs were initiated. In 1997, the Delhi Programme was designated the INDIA-WHO Essential Drugs Programme by the World Health Organization. The EDL was developed by a committee consisting of a multidisciplinary group of experts using balanced criteria of efficacy, safety, suitability and cost. The first list contained 250 drugs for hospitals and 100 drugs for dispensaries; the list is revised every 2 years. The pooled procurement system, including the rigorous selection of suppliers with a minimum annual threshold turnover and the introduction of Good Manufacturing Practice inspections, resulted in the supply of good quality drugs and in holding down the procurement costs of many drugs. Bulk purchasing of carefully selected essential drugs was estimated to save nearly 30% of the annual drugs bill for the Government of Delhi, savings which were mobilized for procuring more drugs, which in turn improved availability of drugs (more than 80%) at health facilities. Further, training programmes for prescribers led to a positive change in prescribing behaviour, with more than 80% of prescriptions being from

  20. 40 CFR 799.6786 - TSCA water solubility: Generator column method.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... relatively water soluble are more likely to be widely distributed by the hydrologic cycle than those which... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA water solubility: Generator column... TESTING REQUIREMENTS Product Properties Test Guidelines § 799.6786 TSCA water solubility: Generator...

  1. Planar Microdevices for Enhanced In Vivo Retention and Oral Bioavailability of Poorly Permeable Drugs

    PubMed Central

    Chirra, Hariharasudhan D.; Shao, Ling; Ciaccio, Natalie; Fox, Cade B.; Wade, Jennifer M.; Ma, Averil

    2014-01-01

    The development of novel oral drug delivery platforms for administering therapeutics in a safe and effective manner through the harsh gastrointestinal environment is of great importance. Here, the use of engineered thin planar poly(methyl methacrylate) (PMMA) microdevices is tested to enhance oral bioavailability of acyclovir, a poorly permeable drug. Acyclovir is loaded into the unidirectional drug releasing microdevice reservoirs using a drug entrapping photocross-linkable hydrogel matrix. An increase in acyclovir permeation across in vitro caco-2 monolayer is seen in the presence of microdevices as compared with acyclovir-entrapped hydrogels or free acyclovir solution. Cell proliferation studies show that microdevices are relatively nontoxic in nature for use in in vivo studies. Enhanced in vivo retention of microdevices is observed as their thin side walls experience minimal peristaltic shear stress as compared with spherical microparticles. Unidirectional acyclovir release and enhanced retention of microdevices achieve a 4.5-fold increase in bioavailability in vivo as compared with an oral gavage of acyclovir solution with the same drug mass. The enhanced oral bioavailability results suggest that thin, planar, bioadhesive, and unidirectional drug releasing microdevices will significantly improve the systemic and localized delivery of a broad range of oral therapeutics in the near future. PMID:24711341

  2. Dual strategies to improve oral bioavailability of oleanolic acid: Enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes.

    PubMed

    Jiang, Qikun; Yang, Xiaoxu; Du, Ping; Zhang, Huifen; Zhang, Tianhong

    2016-02-01

    Oleanolic acid (OA) is a typical BCS IV drug with low water-solubility and poor permeability, metabolized by cytochrome P450 (CYP) isozymes in the intestinal tract, such as CYP3A. These are the reasons for the low oral bioavailability of OA which have restricted its wide application. In this study, a solidified phospholipid complex (OPCH) composed of OA-phospholipid complex (OPC) and hydroxyapatite (HA) was prepared by simple solvent evaporation. OPC was used to improve the liposolubility of OA, and HA was used to improve the flowability of OPC. Ketoconazole (KCZ, inhibitor of CYP3A) was co-administrated with OPCH to inhibit the metabolism of OA by CYP3A in the intestine. DSC, PXRD, SEM and IR analysis confirmed the formation of OPC and OPCH. Compared with the water-solubility and n-octanol solubility of OA, that of OPCH was increased nearly 15.3-fold and 3.19-fold, respectively. An in vitro dissolution study showed that the cumulative dissolution rate of OPCH was nearly 2.23-fold and 4.57-fold higher than that of OA and OPC at 2h. Single-pass intestinal perfusion studies showed that the absorption of OA from OPCH was increased nearly 1.6-2.6-fold compared with that of pure OA and this was mainly due to the improved permeability and was further increased by OPCH with KCZ 1.2-2.4-fold compared with that of OPCH because KCZ inhibited metabolism of OA by CYP3A. A pharmacokinetic study of OPCH in rats following co-administration of KCZ was investigated. The Cmax was increased markedly from 59.5 to 78.7 and 131.3ng/mL in case of OA alone, OPCH alone and OPCH with KCZ. In parallel with the Cmax, the AUC0-24h was increased from 259.6 to 306.6 and 707.7ngh/mL, respectively. All the results obtained demonstrated that formulation of OPCH and co-administration of KCZ significantly improved the bioavailability of OA by increasing the solubility and permeability in combination with inhibiting the metabolism of OA.

  3. Self-assembled hydrophobin for producing water-soluble and membrane permeable fluorescent dye.

    PubMed

    Wang, Kunpeng; Xiao, Yunjie; Wang, Yanyan; Feng, Yaqing; Chen, Cheng; Zhang, Jie; Zhang, Qian; Meng, Shuxian; Wang, Zefang; Yang, Haitao

    2016-01-01

    Low water solubility and poor membrane permeability are major disadvantages that compromise applications of most fluorescent dyes. To resolve these problems, herein, using Boron-dipyrromethene (BODIPY) as a model fluorescent dye, for the first time, we provide a new strategy for the rapid and efficient production of a water-soluble and membrane-permeable dye by mixing with an amphiphilic protein named hydrophobin. Data shows BODIPY could be effectively solubilized and dispersed in 200 μg/mL hydrophobin by simple mixing and sonication. Subsequent experiments indicated that hydrophobin self-assembled into a protein film on the surface of BODIPY forming stable hydrophobin-BODIPY complexes with a size range of 10-30 nm. Furthermore, we demonstrated hydrophobin-functionalized BODIPY are toxicity free to cells. The hydrophobin-BODIPY complex could pass through both the cell plasma membrane and nuclear membrane efficiently. Our work opens a novel route to modify and functionalize fluorescent dyes and may be developed as a general strategy for broadening their applications. PMID:26976627

  4. Self-assembled hydrophobin for producing water-soluble and membrane permeable fluorescent dye

    PubMed Central

    Wang, Kunpeng; Xiao, Yunjie; Wang, Yanyan; Feng, Yaqing; Chen, Cheng; Zhang, Jie; Zhang, Qian; Meng, Shuxian; Wang, Zefang; Yang, Haitao

    2016-01-01

    Low water solubility and poor membrane permeability are major disadvantages that compromise applications of most fluorescent dyes. To resolve these problems, herein, using Boron-dipyrromethene (BODIPY) as a model fluorescent dye, for the first time, we provide a new strategy for the rapid and efficient production of a water-soluble and membrane-permeable dye by mixing with an amphiphilic protein named hydrophobin. Data shows BODIPY could be effectively solubilized and dispersed in 200 μg/mL hydrophobin by simple mixing and sonication. Subsequent experiments indicated that hydrophobin self-assembled into a protein film on the surface of BODIPY forming stable hydrophobin-BODIPY complexes with a size range of 10–30 nm. Furthermore, we demonstrated hydrophobin-functionalized BODIPY are toxicity free to cells. The hydrophobin-BODIPY complex could pass through both the cell plasma membrane and nuclear membrane efficiently. Our work opens a novel route to modify and functionalize fluorescent dyes and may be developed as a general strategy for broadening their applications. PMID:26976627

  5. Molecular connectivity. II: Relationship to water solubility and boiling point.

    PubMed

    Hall, L H; Kier, L B; Murray, W J

    1975-12-01

    The connectivity index, easily computed by arithmetic and based upon the degree of connectedness at each vertex in the molecular skeleton, is shown to give highly significant correlations with water solubility of branched, cyclic, and straight-chain alcohols and hydrocarbons as well as with boiling points of alcohols. These correlations are superior to those based on well-founded theory relating to solvent cavity surface area. An empirical modification to the connectivity index gave an improved correlation for both solubilities and boiling points.

  6. Generating Water-Soluble Noxious Gases: An Overhead Projector Demonstration

    NASA Astrophysics Data System (ADS)

    Solomon, Sally; Oliver-Hoyo, Maria; Hur, Chinhyu

    1998-12-01

    A simple, inexpensive apparatus to generate and collect water-soluble noxious gases as an overhead projector demonstration can be made from two small beakers and a Petri dish. The detection and generation of sulfur dioxide and nitrogen dioxide are described. Sulfur dioxide dissolved in water is detected using an acid-base indicator, decolorizing of anthocyanin, or reduction of permanganate. The SO2 is generated by addition of sulfite or bisulfite to a strong acid or by the addition of concentrated sulfuric acid to sugars. Nitrogen dioxide is generated by mixing copper and nitric acid and detected using an acid-base indicator.

  7. New water-soluble ruthenium(II) cytotoxic complex: biological activity and cellular distribution.

    PubMed

    Morais, Tânia S; Santos, Filipa C; Jorge, Tiago F; Côrte-Real, Leonor; Madeira, Paulo J Amorim; Marques, Fernanda; Robalo, M Paula; Matos, António; Santos, Isabel; Garcia, M Helena

    2014-01-01

    A novel water soluble organometallic compound, [RuCp(mTPPMSNa)(2,2'-bipy)][CF3SO3] (TM85, where Cp=η(5)-cyclopentadienyl, mTPPMS=diphenylphosphane-benzene-3-sulfonate and 2,2'-bipy=2,2'-bipyridine) is presented herein. Studies of interactions with relevant proteins were performed to understand the behavior and mode of action of this complex in the biological environment. Electrochemical and fluorescence studies showed that TM85 strongly binds to albumin. Studies carried out to study the formation of TM85 which adducts with ubiquitin and cytochrome c were performed by electrospray ionization mass spectrometry (ESI-MS). Antitumor activity was evaluated against a variety of human cancer cell lines, namely A2780, A2780cisR, MCF7, MDAMB231, HT29, PC3 and V79 non-tumorigenic cells and compared with the reference drug cisplatin. TM85 cytotoxic effect was reduced in the presence of endocytosis modulators at low temperatures, suggesting an energy-dependent mechanism consistent with endocytosis. Ultrastructural analysis by transmission electron microscopy (TEM) revealed that TM85 targets the endomembranar system disrupting the Golgi and also affects the mitochondria. Disruption of plasma membrane observed by flow cytometry could lead to cellular damage and cell death. On the whole, the biological activity evaluated herein combined with the water solubility property suggests that complex TM85 could be a promising anticancer agent. PMID:24145065

  8. Synthesis and anticancer properties of water-soluble zinc ionophores.

    PubMed

    Magda, Darren; Lecane, Philip; Wang, Zhong; Hu, Weilin; Thiemann, Patricia; Ma, Xuan; Dranchak, Patricia K; Wang, Xiaoming; Lynch, Vincent; Wei, Wenhao; Csokai, Viktor; Hacia, Joseph G; Sessler, Jonathan L

    2008-07-01

    Several water-solubilized versions of the zinc ionophore 1-hydroxypyridine-2-thione (ZnHPT), synthesized as part of the present study, have been found both to increase the intracellular concentrations of free zinc and to produce an antiproliferative activity in exponential phase A549 human lung cancer cultures. Gene expression profiles of A549 cultures treated with one of these water-soluble zinc ionophores, PCI-5002, reveal the activation of stress response pathways under the control of metal-responsive transcription factor 1 (MTF-1), hypoxia-inducible transcription factor 1 (HIF-1), and heat shock transcription factors. Additional oxidative stress response and apoptotic pathways were activated in cultures grown in zinc-supplemented media. We also show that these water-soluble zinc ionophores can be given to mice at 100 micromol/kg (300 micromol/m(2)) with no observable toxicity and inhibit the growth of A549 lung and PC3 prostate cancer cells grown in xenograft models. Gene expression profiles of tumor specimens harvested from mice 4 h after treatment confirmed the in vivo activation of MTF-1-responsive genes. Overall, we propose that water-solubilized zinc ionophores represent a potential new class of anticancer agents.

  9. Water soluble organic constituents in Arctic aerosols and snow pack

    SciTech Connect

    Li, Shaomeng ); Winchester, J.W. )

    1993-01-08

    Eight water-soluble organic anions were measured in 70 aerosol samples and 10 snow samples at Barrow, Alaska in March-April, 1989. The ranking of the ions in aerosols according to total (coarse + fine aerosol) median concentrations was acetate (44 ng m[sup [minus]3]), oxalate (27), benzoate (23), formate (22), propionate (6), methanesulfonate (5), lactate (4), and pyruvate (4). When added up, the median organic anion mass was 156 ng m[sup [minus]3]. The organic anions/nssSO[sub 4][sup =] mass ratio had a median of 0.18 and 0.07 in the coarse (>1 [mu]m) and fine (<1 [mu]m) size fractions, respectively, but can be very high on occasions. On average, the organic anions made up more than 10% of the water-soluble aerosol mass. A similar ranking in concentration was also found for the organic ions in the snow pack samples. The organic anion/nssSO[sub 4][sup =] mass ratio in these samples was >0.5, substantially higher than in aerosols. 18 refs., 2 tabs.

  10. Development and characterization of an orodispersible film containing drug nanoparticles.

    PubMed

    Shen, Bao-de; Shen, Cheng-ying; Yuan, Xu-dong; Bai, Jin-xia; Lv, Qing-yuan; Xu, He; Dai, Ling; Yu, Chao; Han, Jin; Yuan, Hai-long

    2013-11-01

    In this study, a novel orodispersible film (ODF) containing drug nanoparticles was developed with the goal of transforming drug nanosuspensions into a solid dosage form and enhancing oral bioavailability of drugs with poor water solubility. Nanosuspensions were prepared by high pressure homogenization and then transformed into ODF containing drug nanoparticles by mixing with hydroxypropyl methylcellulose solution containing microcrystalline cellulose, low substituted hydroxypropylcellulose and PEG-400 followed by film casting and drying. Herpetrione, a novel and potent antiviral agent with poor water solubility that extracted from Herpetospermum caudigerum, was chosen as a model drug and studied systematically. The uniformity of dosage units of the preparation was acceptable according to the criteria of Japanese Pharmacopoeia 15. The ODF was disintegrated in water within 30s with reconstituted nanosuspensions particle size of 280 ± 11 nm, which was similar to that of drug nanosuspensions, indicating a good redispersibility of the fast dissolving film. Result of X-ray diffraction showed that HPE in the ODF was in the amorphous state. In the in vitro dissolution test, the ODF containing HPE nanoparticles showed an increased dissolution velocity markedly. In the pharmacokinetics study in rats, compared to HPE coarse suspensions, the ODF containing HPE nanoparticles exhibited significant increase in AUC0-24h, Cmax and decrease in Tmax, MRT. The result revealed that the ODF containing drug nanoparticles may provide a potential opportunity in transforming drug nanosuspensions into a solid dosage form as well as enhancing the dissolution rate and oral bioavailability of poorly water-soluble drugs. PMID:24103635

  11. A macromolecular prodrug strategy for combinatorial drug delivery.

    PubMed

    Li, Nan-Nan; Lin, Jiantao; Gao, Di; Zhang, Li-Ming

    2014-03-01

    A novel macromolecular prodrug strategy was developed for the combinatorial delivery of two poorly water-soluble drugs, dexamethasone and doxorubicin. In this work, dexamethasone was firstly conjugated onto a water-soluble modified polysaccharide by an acid-labile hydrazone linkage. The resultant macromolecular prodrug had an amphiphilic character and could self-assemble into spherical polymeric micelles in aqueous system. With these micelles, doxorubicin was then encapsulated into their hydrophobic cores. For the conjugated dexamethasone and encapsulated doxorubicin, they could exhibit independent and acid-sensitive release characteristics. For the doxorubicin-loaded prodrug micelles, they were easily be internalized by living cells and showed obvious antitumor activity. PMID:24407691

  12. Prediction of mechanical properties of compacted binary mixtures containing high-dose poorly compressible drug.

    PubMed

    Patel, Sarsvatkumar; Bansal, Arvind Kumar

    2011-01-17

    The aim of the study was to develop, compare and validate predictive model for mechanical property of binary systems. The mechanical properties of binary mixtures of ibuprofen (IBN) a poorly compressible high dose drug, were studied in presence of different excipients. The tensile strength of tablets of individual components viz. IBN, microcrystalline cellulose (MCC), and dicalcium phosphate dihydrate (DCP) and binary mixtures of IBN with excipients was measured at various relative densities. Prediction of the mechanical property of binary mixtures, from that of single components, was attempted using Ryshkewitch-Duckworth (R-D) and Percolation theory, by assuming a linear mixing rule or a power law mixing rule. The models were compared, and the best model was proposed based on the distribution of residuals and the Akaike's information criterion. Good predictions were obtained with the power law combined with linear mixing rule, using R-D and Percolation models. The results indicated that the proposed model can well predict the mechanical properties of binary system containing predominantly poorly compressible drug candidate. The predictions of these models and conclusions can be systematically generalized to other pharmaceutical powders.

  13. Microemulsion formulation for enhanced absorption of poorly soluble drugs. II. In vivo study.

    PubMed

    Kawakami, Kohsaku; Yoshikawa, Takayoshi; Hayashi, Takashi; Nishihara, Yoshitaka; Masuda, Kazuyoshi

    2002-05-17

    Oral administration study of microemulsion formulations, which are known to improve the bioavailability of poorly soluble drugs, was performed using rats. Nitrendipine was used as a poorly soluble model drug, and its absorption was enhanced significantly by employing the microemulsion formulations compared to a suspension or an oil solution. The effect of the fed state on the oral absorption of nitrendipine became insignificant with the microemulsion formulations, although it affected the absorption from the suspension formulation significantly. The absorption behavior also varied with the type of surfactant. The absorption from Tween 80-based formulation was very rapid, while HCO-60-based formulation showed prolonged plasma concentration profile. However, the absorption from BL-9EX (polyoxyethylene alkyl ether)-based formulation was hardly observed. Damage to the gastrointestinal mucosa, which seems to be a serious problem of surfactant-based formulations, also differed with the type of surfactant employed. HCO-60 and Tween 80-based formulations were mild to the organs, while BL-9EX-based formulation caused serious damage. The behavior and absorption mechanism of the microemulsion formulations are discussed.

  14. Fabrication of water-soluble polymer-encapsulated As4S4 to increase oral bioavailability and chemotherapeutic efficacy in AML mice

    PubMed Central

    Ma, Qiang; Wang, Chuan; Li, Xiaojin; Guo, Hua; Meng, Jie; Liu, Jian; Xu, Haiyan

    2016-01-01

    Realgar (As4S4) has been demonstrated to be effective for the treatment of acute myeloid leukemia (AML); it has the advantages of no drug resistance and oral administration. Nevertheless, its poor solubility has been an obstacle to its bioavailability, requiring high-dose administration over a long period. We investigated whether crushing realgar crystals to the nanoscale and encapsulating the particles in a water-soluble polymer in one step using hot-melt extrusion would increase the bioavailability of As4S4. Raw As4S4 (r-As4S4) and water-soluble polymer were processed via co-rotating twin screw extrusion. The resulting product (e-As4S4) was characterized by SEM, XRD, and DLS. The cytotoxicity and therapeutic effects of e-As4S4 were evaluated in vivo and in vitro. The results show that e-As4S4 dissolved rapidly in water, forming a stable colloid solution. The average size of e-As4S4 particles was 680 nm, which was reduced by more than 40-fold compared with that of r-As4S4. The bioavailability of e-As4S4 was up to 12.6-fold higher than that of r-As4S4, and it inhibited the proliferation of HL-60 cells much more effectively than did r-As4S4, inducing apoptosis and significantly reducing the infiltration of HL-60 cells into the bone marrow, spleen, and liver. This in turn prolonged the survival of AML mice. PMID:27383126

  15. Release of a Poorly Soluble Drug from Hydrophobically Modified Poly (Acrylic Acid) in Simulated Intestinal Fluids

    PubMed Central

    Knöös, Patrik

    2015-01-01

    A large part of new pharmaceutical substances are characterized by a poor solubility and high hydrophobicity, which might lead to a difference in drug adsorption between fasted and fed patients. We have previously evaluated the release of hydrophobic drugs from tablets based on Pemulen TR2 and showed that the release can be manipulated by adding surfactants. Here we further evaluate the possibility to use Pemulen TR2 in controlled release tablet formulations containing a poorly soluble substance, griseofulvin. The release is evaluated in simulated intestinal media that model the fasted state (FaSSIF medium) or fed state (FeSSIF). The rheology of polymer gels is studied in separate experiments, in order to gain more information on possible interactions. The release of griseofulvin in tablets without surfactant varied greatly and the slowest release were observed in FeSSIF. Addition of SDS to the tablets eliminated the differences and all tablets showed a slow linear release, which is of obvious relevance for robust drug delivery. Comparing the data from the release studies and the rheology experiment showed that the effects on the release from the different media could to a large extent be rationalised as a consequence of the interactions between the polymer and the surfactants in the media. The study shows that Pemulen TR2 is a candidate for controlled release formulations in which addition of surfactant provides a way to eliminate food effects on the release profile. However, the formulation used needs to be designed to give a faster release rate than the tablets currently investigated. PMID:26473964

  16. Monolayer Silane-Coated, Water-Soluble Quantum Dots.

    PubMed

    Zhang, Xi; Shamirian, Armen; Jawaid, Ali M; Tyrakowski, Christina M; Page, Leah E; Das, Adita; Chen, Ou; Isovic, Adela; Hassan, Asra; Snee, Preston T

    2015-12-01

    A one-step method to produce ≈12 nm hydrodynamic diameter water-soluble CdSe/ZnS quantum dots (QDs), as well as CdS/ZnS, ZnSe/ZnMnS/ZnS, AgInS2 /ZnS, and CuInS2 /ZnS QDs, by ligand exchange with a near-monolayer of organosilane caps is reported. The method cross-links the surface-bound silane ligands such that the samples are stable on the order of months under ambient conditions. Furthermore, the samples may retain a high quantum yield (60%) over this time. Several methods to functionalize aqueous QD dispersions with proteins and fluorescent dyes have been developed with reaction yields as high as 97%. PMID:26476710

  17. Transfer molding of nanoscale oxides using water-soluble templates.

    PubMed

    Bass, John D; Schaper, Charles D; Rettner, Charles T; Arellano, Noel; Alharbi, Fahhad H; Miller, Robert D; Kim, Ho-Cheol

    2011-05-24

    We report a facile method for creating nanoscopic oxide structures over large areas that is capable of producing high aspect ratio nanoscale structures with feature sizes below 50 nm. A variety of nanostructured oxides including TiO(2), SnO(2) and organosilicates are formed using sol-gel and nanoparticle precursors by way of molding with water-soluble polymeric templates generated from silicon masters. Sequential stacking techniques are developed that generate unique 3-dimensional nanostructures with combinatorially mixed geometries, scales, and materials. Applicable to a variety of substrates, this scalable method allows access to a broad range of new thin film morphologies for applications in devices, catalysts, and functional surface coatings. PMID:21469708

  18. Self-assembly of water-soluble nanocrystals

    DOEpatents

    Fan, Hongyou; Brinker, C. Jeffrey; Lopez, Gabriel P.

    2012-01-10

    A method for forming an ordered array of nanocrystals where a hydrophobic precursor solution with a hydrophobic core material in an organic solvent is added to a solution of a surfactant in water, followed by removal of a least a portion of the organic solvent to form a micellar solution of nanocrystals. A precursor co-assembling material, generally water-soluble, that can co-assemble with individual micelles formed in the micellar solution of nanocrystals can be added to this micellar solution under specified reaction conditions (for example, pH conditions) to form an ordered-array mesophase material. For example, basic conditions are used to precipitate an ordered nanocrystal/silica array material in bulk form and acidic conditions are used to form an ordered nanocrystal/silica array material as a thin film.

  19. Reactivity of Metal Ions Bound to Water-Soluble Polymers

    SciTech Connect

    Sauer, N.N.; Watkins, J.G.; Lin, M.; Birnbaum, E.R.; Robison, T.W.; Smith, B.F.; Gohdes, J.W.; McDonald, J.G.

    1999-06-29

    The intent of this work is to determine the effectiveness of catalysts covalently bound to polymers and to understand the consequences of supporting the catalysts on catalyst efficiency and selectivity. Rhodium phosphine complexes with functional groups for coupling to polymers were prepared. These catalyst precursors were characterized using standard techniques including IR, NMR, and elemental analysis. Studies on the modified catalysts showed that they were still active hydrogenation catalysts. However, tethering of the catalysts to polyamines gave systems with low hydrogenation activity. Analogous biphasic systems were also explored. Phosphine ligands with a surfactant-like structure have been synthesized and used to prepare catalytically active complexes of palladium. The palladium complexes were utilized in Heck-type coupling reactions (e.g. coupling of iodobenzene and ethyl acrylate to produce ethyl cinnamate) under vigorously stirred biphasic reaction conditions, and were found to offer superior performance over a standard water-soluble palladium catalyst under analogous conditions.

  20. Monolayer Silane-Coated, Water-Soluble Quantum Dots.

    PubMed

    Zhang, Xi; Shamirian, Armen; Jawaid, Ali M; Tyrakowski, Christina M; Page, Leah E; Das, Adita; Chen, Ou; Isovic, Adela; Hassan, Asra; Snee, Preston T

    2015-12-01

    A one-step method to produce ≈12 nm hydrodynamic diameter water-soluble CdSe/ZnS quantum dots (QDs), as well as CdS/ZnS, ZnSe/ZnMnS/ZnS, AgInS2 /ZnS, and CuInS2 /ZnS QDs, by ligand exchange with a near-monolayer of organosilane caps is reported. The method cross-links the surface-bound silane ligands such that the samples are stable on the order of months under ambient conditions. Furthermore, the samples may retain a high quantum yield (60%) over this time. Several methods to functionalize aqueous QD dispersions with proteins and fluorescent dyes have been developed with reaction yields as high as 97%.

  1. Water-soluble NHC-Cu catalysts: applications in click chemistry, bioconjugation and mechanistic analysis.

    PubMed

    Díaz Velázquez, Heriberto; Ruiz García, Yara; Vandichel, Matthias; Madder, Annemieke; Verpoort, Francis

    2014-12-14

    Copper(I)-catalyzed 1,3-dipolar cycloaddition of azides and terminal alkynes (CuAAC), better known as "click" reaction, has triggered the use of 1,2,3-triazoles in bioconjugation, drug discovery, materials science and combinatorial chemistry. Here we report a new series of water-soluble catalysts based on N-heterocyclic carbene (NHC)-Cu complexes which are additionally functionalized with a sulfonate group. The complexes show superior activity towards CuAAC reactions and display a high versatility, enabling the production of triazoles with different substitution patterns. Additionally, successful application of these complexes in bioconjugation using unprotected peptides acting as DNA binding domains was achieved for the first time. Mechanistic insight into the reaction mechanism is obtained by means of state-of-the-art first principles calculations.

  2. Lysosomal ATP imaging in living cells by a water-soluble cationic polythiophene derivative.

    PubMed

    Huang, Bing-Huan; Geng, Zhi-Rong; Ma, Xiao-Yan; Zhang, Cui; Zhang, Zhi-Yang; Wang, Zhi-Lin

    2016-09-15

    Lysosomes in astrocytes and microglia can release ATP as the signaling molecule for the cells through ca(2+)-dependent exocytosis in response to various stimuli. At present, fluorescent probes that can detect ATP in lysosomes have not been reported. In this work, we have developed a new water-soluble cationic polythiophene derivative that can be specifically localized in lysosomes and can be utilized as a fluorescent probe to sense ATP in cells. PEMTEI exhibits high selectivity and sensitivity to ATP at physiological pH values and the detection limit of ATP is as low as 10(-11)M. The probe has low cytotoxicity, good permeability and high photostability in living cells and has been applied successfully to real-time monitoring of the change in concentrations of ATP in lysosomes though fluorescence microscopy. We also demonstrated that lysosomes in Hela cells can release ATP through Ca(2+)-dependent exocytosis in response to drug stimuli.

  3. Stable nanocolloids of poorly soluble drugs with high drug content prepared using the combination of sonication and layer-by-layer technology.

    PubMed

    Agarwal, Anshul; Lvov, Yuri; Sawant, Rishikesh; Torchilin, Vladimir

    2008-06-24

    Stable nanocolloids of insoluble drugs with very high drug content (up to 90% wt) can be easily and reproducibly prepared through the application of the layer-by-layer (LbL) technology, alternate adsorption of oppositely charged polyelectrolytes on the surface of drug nanoparticles produced by ultrasonication of larger drug crystals. Such polymeric coating prevents drug nanoparticle aggregation and creates a firm polymeric shell on their surface. Drug release rate from such nanocolloidal particles can be easily controlled by assembling multilayer shells with variable shell density and thickness. Various additional functions, such as specific targeting ligands, can be easily attached to the surface on nanocolloidal particles of poorly soluble drugs by using a polymer with free reactive groups for the "outer" coating. This may represent a novel approach to preparing convenient dosage forms of poorly soluble drugs. PMID:18479772

  4. Stable nanocolloids of poorly soluble drugs with high drug content prepared using the combination of sonication and layer-by-layer technology.

    PubMed

    Agarwal, Anshul; Lvov, Yuri; Sawant, Rishikesh; Torchilin, Vladimir

    2008-06-24

    Stable nanocolloids of insoluble drugs with very high drug content (up to 90% wt) can be easily and reproducibly prepared through the application of the layer-by-layer (LbL) technology, alternate adsorption of oppositely charged polyelectrolytes on the surface of drug nanoparticles produced by ultrasonication of larger drug crystals. Such polymeric coating prevents drug nanoparticle aggregation and creates a firm polymeric shell on their surface. Drug release rate from such nanocolloidal particles can be easily controlled by assembling multilayer shells with variable shell density and thickness. Various additional functions, such as specific targeting ligands, can be easily attached to the surface on nanocolloidal particles of poorly soluble drugs by using a polymer with free reactive groups for the "outer" coating. This may represent a novel approach to preparing convenient dosage forms of poorly soluble drugs.

  5. Concomitant intake of alcohol may increase the absorption of poorly soluble drugs.

    PubMed

    Fagerberg, Jonas H; Sjögren, Erik; Bergström, Christel A S

    2015-01-25

    Ethanol can increase the solubility of poorly soluble and hence present a higher drug concentration in the gastrointestinal tract. This may produce a faster and more effective absorption resulting in variable and/or high drug plasma concentrations, both of which can lead to adverse drug reactions. In this work we therefore studied the solubility and absorption effects of nine diverse compounds when ethanol was present. The apparent solubility was measured using the μDiss Profiler Plus (pION, MA) in four media representing gastric conditions with and without ethanol. The solubility results were combined with in-house data on solubility in intestinal fluids (with and without ethanol) and pharmacokinetic parameters extracted from the literature and used as input in compartmental absorption simulations using the software GI-Sim. Apparent solubility increased more than 7-fold for non-ionized compounds in simulated gastric fluid containing 20% ethanol. Compounds with weak base functions (cinnarizine, dipyridamole and terfenadine) were completely ionized at the studied gastric pH and their solubility was therefore unaffected by ethanol. Compounds with low solubility in intestinal media and a pronounced solubility increase due to ethanol in the upper gastric compartments showed an increased absorption in the simulations. The rate of absorption of the acidic compounds indomethacin and indoprofen was slightly increased but the extent of absorption was unaffected as the complete doses were readily absorbed even without ethanol. This was likely due to a high apparent solubility in the intestinal compartment where the weak acids are ionized. The absorption of the studied non-ionizable compounds increased when ethanol was present in the gastric and intestinal media. These results indicate that concomitant intake of alcohol may significantly increase the solubility and hence, the plasma concentration for non-ionizable, lipophilic compounds with the potential of adverse drug

  6. Improved pH-dependent drug release and oral exposure of telmisartan, a poorly soluble drug through the formation of drug-aminoclay complex.

    PubMed

    Yang, Liang; Shao, Yating; Han, Hyo-Kyung

    2014-08-25

    Telmisartan (TEL) belongs to BCS class II (low solubility/high permeability) and exhibits the pH-dependent drug release. Since 3-aminopropyl functionalized magnesium phyllosilicate (aminoclay) can intercalate or adsorb the negatively charged molecules via the electrostatic interaction, TEL-aminoclay complex was synthesized to improve the pH dependent drug release and the oral exposure of TEL. Co-precipitation method was adopted to incorporate TEL into aminoclay with the variation of drug/aminoclay ratios, and then dissolution profiles of TEL from TEL-aminoclay complex were evaluated at different pHs. Structural characterization was performed by XRD, ATR-FTIR, and TEM, indicating the electrostatic interaction between TEL and the surface of the aminoclay lamellae. Furthermore, drug crystallinity was changed to an amorphous form via the molecular interactions between TEL and aminoclay. TEL exhibited rapid and complete dissolution at pH 1.2 within 15 min from all the tested formulations. However, while the untreated powder indicated negligible dissolution at pH 4 and pH 6.8, the formation of drug-clay complex significantly improved the dissolution rate as well as the extent of drug release at the higher pHs. In addition, following an oral administration of TEL-aminoclay, Cmax and AUC of TEL increased by about 8 and 5 fold respectively, while Tmax was shorten. The results suggest that formation of aminoclay complex should be promising to enhance the bioavailability of a poorly soluble drug, TEL.

  7. Water-soluble polymers for recovery of metal ions from aqueous streams

    DOEpatents

    Smith, Barbara F.; Robison, Thomas W.

    1998-01-01

    A process of selectively separating a target metal contained in an aqueous solution by contacting the aqueous solution containing a target metal with an aqueous solution including a water-soluble polymer capable of binding with the target metal for sufficient time whereby a water-soluble polymer-target metal complex is formed, and, separating the solution including the water-soluble polymer-target metal complex from the solution is disclosed.

  8. A novel solubilization technique for poorly soluble drugs through the integration of nanocrystal and cocrystal technologies.

    PubMed

    Karashima, Masatoshi; Kimoto, Kouya; Yamamoto, Katsuhiko; Kojima, Takashi; Ikeda, Yukihiro

    2016-10-01

    The aim of the present study was to develop a novel solubilization technique consisting of a nano-cocrystal suspension by integrating cocrystal and nanocrystal formulation technologies to maximize solubilization over current solubilizing technologies. Monodisperse carbamazepine-saccharin, indomethacin-saccharin, and furosemide-caffeine nano-cocrystal suspensions, as well as a furosemide-cytosine nano-salt suspension, were successfully prepared with particle sizes of less than 300nm by wet milling with the stabilizers hydroxypropyl methylcellulose and sodium dodecyl sulfate. Interestingly, the properties of resultant nano-cocrystal suspensions were dramatically changed depending on the physicochemical and structural properties of the cocrystals. In the formulation optimization, the concentration and ratio of the stabilizers also influenced the zeta potentials and particles sizes of the resultant nano-cocrystal suspensions. Raman spectroscopic analysis revealed that the crystalline structures of the cocrystals were maintained in the nanosuspensions, and were physically stable for at least one month. Furthermore, their dissolution profiles were significantly improved over current solubilization-enabling technologies, nanocrystals, and cocrystals. In the present study, we demonstrated that nano-cocrystal formulations can be a new promising option for solubilization techniques to improve the absorption of poorly soluble drugs, and can expand the development potential of poorly soluble candidates in the pharmaceutical industry. PMID:27393561

  9. Water-soluble characteristics of chlorine in char derived from municipal solid wastes.

    PubMed

    Hwang, I H; Matsuto, T; Tanaka, N

    2006-01-01

    Chlorine in char derived from municipal solid waste (MSW) was characterized and quantified based on its water solubility: easily water-soluble, hardly water-soluble, and non-water-soluble chlorine. For that, a four-cycle process of water-washing, heating or carbonation were carried out. In order to confirm the characteristics of non-water-soluble chlorine, additional thermal treatment and an alkali-acid washing process were applied to washed char. It was found that a large particle size of char (0.5-1.0 mm) significantly contributed to the amount of non-water-soluble chlorine. Pulverization and HNO3-HF digestion were performed to identify a factor to interfere chlorine release from char with a large particle size. Pulverization was proven ineffective for release of non-water-soluble chlorine, whereas approximately 32% of non-water-soluble chlorine was extracted by HNO3-HF digestion. Therefore, the presence of non-water-soluble chlorine is likely to originate from its chemical property rather than simply from its physical one.

  10. P16.31THERANOSTIC APPLICATION OF WATER-SOLUBLE GADOLINIUM FULLERENE (GD@FUL) IN EXPERIMENTAL GLIOMA MODEL

    PubMed Central

    Shevtsov, M.; Nikolaev, B.; Marchenko, Y.; Yakovleva, L.; Dobrodumov, A.; Török, G.; Pitkin, E.; Lebedev, V.

    2014-01-01

    Glioblastoma multiforme (GMB) is a highly invasive brain tumour with poor prognosis. Alternative treatments offering a better outcome are needed. Novel approach could be based on gadofullerenes that can be used as diagnostic MR imaging contrast agent and as a therapeutic drug. Water soluble gadofullerene Gd@Ful with composition Gd@C82(OH)x x ≥20 was synthesized for theranostic study. Nanosuspensions of Gd@Ful were used for magnetic relaxation measurements in vitro and for MR imaging of a rat with intracranially implanted C6 glioma. Gd@Ful was shown to reduce proton relaxation times in vitro, and provide dual contrast of T1- and T2-weighted images in a rat brain tumour model after paramagnetic intravenous delivery. Magnetic relaxation times and relaxivity of water protons under action of Gd@Ful were strongly shortened due to cluster formation and increase of motional correlation times of protons in the vicinity of the fulleren cage. The Gd@Ful administration promoted the improvement of glioma contrast enhancement at T2-weighted images due to accumulation of paramagnetic substance at the tumour site. The contrast efficiency of Gd@Ful corresponds to the characteristics of negative contrast agent. Retention of the Gd@Ful in the C6 glioma provides not only the tumor contrast enhancement but also has a high therapeutic relevance. We observed the increased survival rates in animals that were intravenously administered with Gd@Ful. Thus, in experimental group the survival was 75% higher then in the control group, constituting 34.2 ± 9.94 and 19.5 ± 3.02 days respectively (P < 0.001). The Gd@Ful solution is shown to be a contrast enhancer with high anti-tumour therapeutic potency.

  11. Vitamin B12 loaded polycaprolactone nanofibers: a novel transdermal route for the water soluble energy supplement delivery.

    PubMed

    Madhaiyan, Kalaipriya; Sridhar, Radhakrishnan; Sundarrajan, Subramanian; Venugopal, Jayarama Reddy; Ramakrishna, Seeram

    2013-02-28

    Biocompatible PCL polymer nanofiber mediated sustained release of hydrophilic drug and applicability as transdermal delivery system is attempted. This new attempt to investigate water soluble vitamin delivery with hydrophobic polymer nanofiber sustained the release of the vitamin and the method is suited for the transdermal patch applications. The drug loaded fibers were characterized with SEM for morphology, porometer for pore size measurements, mechanical strength calculation and FT-IR for drug load characterization. The contact angle measurement showed surface wettability and controlled release of drug was quantified with UV absorption measurements. To further enhance the release of vitamin, the polymer fiber was plasma treated at different time intervals and made hydrophilic gradually. Since the increased surface area and drug encapsulation in nano-reservoirs can able to release drug in small quantities and in a sustained manner we attempted the release of the energy supplement with nanofibrous delivery mode. PMID:23370432

  12. Vitamin B12 loaded polycaprolactone nanofibers: a novel transdermal route for the water soluble energy supplement delivery.

    PubMed

    Madhaiyan, Kalaipriya; Sridhar, Radhakrishnan; Sundarrajan, Subramanian; Venugopal, Jayarama Reddy; Ramakrishna, Seeram

    2013-02-28

    Biocompatible PCL polymer nanofiber mediated sustained release of hydrophilic drug and applicability as transdermal delivery system is attempted. This new attempt to investigate water soluble vitamin delivery with hydrophobic polymer nanofiber sustained the release of the vitamin and the method is suited for the transdermal patch applications. The drug loaded fibers were characterized with SEM for morphology, porometer for pore size measurements, mechanical strength calculation and FT-IR for drug load characterization. The contact angle measurement showed surface wettability and controlled release of drug was quantified with UV absorption measurements. To further enhance the release of vitamin, the polymer fiber was plasma treated at different time intervals and made hydrophilic gradually. Since the increased surface area and drug encapsulation in nano-reservoirs can able to release drug in small quantities and in a sustained manner we attempted the release of the energy supplement with nanofibrous delivery mode.

  13. Evaluation of spiking procedures for the introduction of poorly water soluble contaminants into soil

    SciTech Connect

    Reid, B.J.; Northcott, G.L.; Jones, K.C.; Semple, K.T.

    1998-10-15

    There is currently considerable interest in the fate and behavior of persistent organic pollutants (POPs) within the soil environment. Processes such as sorption, desorption, subsurface transport, and biodegradation have been the focus of much attention. The purpose of this study was to assess the suitability of various spiking procedures for the introduction of persistent organic pollutants (POPs) into soil environments. {sup 14}C-radiolabeled analogues of two representative polycyclic aromatic hydrocarbons (PAHs), phenanthrene (Phe), and benzo[a]pyrene (B[a]P), were introduced into soil using different spiking techniques, and the homogeneity of compound distribution in subsamples was assessed. It was established that under analogous spiking procedures dry soil could be spiked with greater homogeneity than wet soil. The procedure which gave the most homogeneous distribution of compound involved a single spiking/rehydration operation conducted on dry soil. Relative standard deviations of 2.40% for {sup 14}C-9-Phe and 3.65% for {sup 14}C-7-B[a]P were obtained for this procedure. An optimum procedure for the spiking of wet soil was established, giving relative standard deviations of 4.1% for {sup 14}C-9-Phe and 3.7% for {sup 14}C-7-B[a]P. This procedure employed a highly spiked wet soil inoculum to distribute the compound throughout the soil system. The influence of carrier solvent on microbial cell numbers determined as colony forming units was also evaluated and shown to have a dramatic negative impact at high volumes.

  14. [Emission Characteristics of Water-Soluble Ions in Fumes of Coal Fired Boilers in Beijing].

    PubMed

    Hu, Yue-qi; Ma, Zhao-hui; Feng, Ya-jun; Wang, Chen; Chen, Yuan-yuan; He, Ming

    2015-06-01

    Selecting coal fired boilers with typical flue gas desulfurization and dust extraction systems in Beijing as the study objects, the issues and characteristics of the water-soluble ions in fumes of coal fired boilers and theirs influence factors were analyzed and evaluated. The maximum mass concentration of total water-soluble ions in fumes of coal fired boilers in Beijing was 51.240 mg x m(-3) in the benchmark fume oxygen content, the minimum was 7.186 mg x m(-3), and the issues of the water-soluble ions were uncorrelated with the fume moisture content. SO4(2-) was the primary characteristic water-soluble ion for desulfurization reaction, and the rate of contribution of SO4(2-) in total water-soluble ions ranged from 63.8% to 81.0%. F- was another characteristic water-soluble ion in fumes of thermal power plant, and the rate of contribution of F- in total water-soluble ions ranged from 22.2% to 32.5%. The fume purification technologies significantly influenced the issues and the emission characteristics of water-soluble ions in fumes of coal fired boilers. Na+ was a characteristic water-soluble ion for the desulfurizer NaOH, NH4+ and NO3+ were characteristic for the desulfurizer NH4HCO3, and Mg2+ was characteristic for the desulfurizer MgO, but the Ca2+ emission was not increased by addition of the desulfurizer CaO or CaCO3 The concentrations of NH4+ and NO3- in fumes of thermal power plant were lower than those in fumes of industrial or heating coal fired boilers. The form of water-soluble ions was significantly correlated with fume temperature. The most water-soluble ions were in superfine state at higher fume temperature and were not easily captured by the filter membrane. PMID:26387296

  15. [Emission Characteristics of Water-Soluble Ions in Fumes of Coal Fired Boilers in Beijing].

    PubMed

    Hu, Yue-qi; Ma, Zhao-hui; Feng, Ya-jun; Wang, Chen; Chen, Yuan-yuan; He, Ming

    2015-06-01

    Selecting coal fired boilers with typical flue gas desulfurization and dust extraction systems in Beijing as the study objects, the issues and characteristics of the water-soluble ions in fumes of coal fired boilers and theirs influence factors were analyzed and evaluated. The maximum mass concentration of total water-soluble ions in fumes of coal fired boilers in Beijing was 51.240 mg x m(-3) in the benchmark fume oxygen content, the minimum was 7.186 mg x m(-3), and the issues of the water-soluble ions were uncorrelated with the fume moisture content. SO4(2-) was the primary characteristic water-soluble ion for desulfurization reaction, and the rate of contribution of SO4(2-) in total water-soluble ions ranged from 63.8% to 81.0%. F- was another characteristic water-soluble ion in fumes of thermal power plant, and the rate of contribution of F- in total water-soluble ions ranged from 22.2% to 32.5%. The fume purification technologies significantly influenced the issues and the emission characteristics of water-soluble ions in fumes of coal fired boilers. Na+ was a characteristic water-soluble ion for the desulfurizer NaOH, NH4+ and NO3+ were characteristic for the desulfurizer NH4HCO3, and Mg2+ was characteristic for the desulfurizer MgO, but the Ca2+ emission was not increased by addition of the desulfurizer CaO or CaCO3 The concentrations of NH4+ and NO3- in fumes of thermal power plant were lower than those in fumes of industrial or heating coal fired boilers. The form of water-soluble ions was significantly correlated with fume temperature. The most water-soluble ions were in superfine state at higher fume temperature and were not easily captured by the filter membrane.

  16. Water-soluble primary amine compounds in rural continental precipitation

    NASA Astrophysics Data System (ADS)

    Gorzelska, Krystyna; Galloway, James N.; Watterson, Karen; Keene, William C.

    Procedures for collecting, storing and analysing precipitation samples for organic nitrogen studies were developed. These procedures preserve chemical integrities of the species of interest, allow for up to 3 months storage and quantitative determination of water-soluble primary amine compounds, with the overall error at the 2 nM detection limit of less than 30%. This methodology was applied to study amino compounds in precipitation samples collected over a period of one year in central Virginia. Nitrogen concentrations of 13 amino acids and 3 aliphatic amines were summed to calculate the total amine nitrogen (TAN). The concentration of TAN ranged from below our detection level to 6658 nM, and possibly reflected a seasonal variation in the source strength of the atmospheric amines. Overall, the most commonly occurring amino compounds were methyl amine, ethyl amine, glutamic acid, glycine and serine. On average, the highest overall contribution to the TAN came from arginine, asparagine, glutamine, methyl amine, serine and alanine. However, large qualitative and quantitative variations observed among samples warrant caution in interpretation and application of the averaged values. TAN in Charlottesville precipitation contributed from less than 1 to ca 10% of the ammonium nitrogen level. However, our estimates show that amino compounds may contribute significantly to reduced nitrogen budget in precipitation in remote regions.

  17. Soft water-soluble microgel dispersions: structure and rheology.

    PubMed

    Omari, A; Tabary, R; Rousseau, D; Calderon, F Leal; Monteil, J; Chauveteau, G

    2006-10-15

    The size and structural characteristics of polyacrylamide-based water-soluble microgel dispersions were investigated by optical and rheological methods. Microgel hydrodynamic radii Rh were measured by light scattering and derived from intrinsic shear viscosity [eta]0. The variations of Rh3 and [eta]0 with the crosslink density Nx, follow the scaling law Rh3 congruent withNx(-alpha) with alpha close to 0.63, in good agreement with the simple structural model proposed in this paper showing how the exact value of alpha depends on inner structural details of the microgel. The plateau viscosity versus particle apparent volume fraction shows a monotonous change from hard sphere dispersions (high crosslink density of microgels) to flexible linear polymer solutions. Measurements of the first normal stress difference N1 show that increasing the microgel crosslink density affects the system viscosity more than its elasticity. Under oscillatory shear flow, loss and storage moduli undergo both qualitative and quantitative changes with crosslink density. At moderate concentrations, the elastic modulus is the most affected and its slope in low frequency regime decreases from two to less than one as Nx increases. We discuss the experimental results within the frame of knowledge on linear, branched polymer solutions and soft microgel suspensions.

  18. Water-soluble reaction products from ozonolysis of grasses

    SciTech Connect

    Morrison, W.H. III; Akin, D.E. )

    1990-03-01

    Ozone has been used to pretreat agricultural byproducts with the aim of increasing nutritive value for ruminants. However, not all treatments with ozone result in enhanced digestibility, suggesting reaction products from ozone treatment of plants might inhibit rumen microbial activity. Coastal Bermuda grass (Cynodon dactylon L. Pers.) (CBG) and Kentucky-31 tall fescue (Festuca arundinacea Schreb.) (K-31) were treated with ozone and the water-soluble products determined. The following acids were identified: caproic, levulinic, p-hydroxybenzoic, vinillic, azelaic, and malonic. In addition, vanillin and p-hydroxybenzaldehyde were also identified. Ozone treatment of the cell walls of CBG produced mainly p-hydroxybenzoic acid, vanillic acid, azelaic acid, p-hydroxybenzaldehyde, and vanillin. Ozone treatment of K-31 cell walls produced levulinic acid in addition to those products found from CBG cell walls. The production of vanillin and p-hydroxybenzaldehyde, which have been shown to be especially toxic to rumen microorganisms, offers an explanation for the negative affects of ozone treatment on forage.

  19. Monosaccharides as Versatile Units for Water-Soluble Supramolecular Polymers.

    PubMed

    Leenders, Christianus M A; Jansen, Gijs; Frissen, Martijn M M; Lafleur, René P M; Voets, Ilja K; Palmans, Anja R A; Meijer, E W

    2016-03-18

    We introduce monosaccharides as versatile water-soluble units to compatibilise supramolecular polymers based on the benzene-1,3,5-tricarboxamide (BTA) moiety with water. A library of monosaccharide-based BTAs is evaluated, varying the length of the alkyl chain (hexyl, octyl, decyl and dodecyl) separating the BTA and saccharide units, as well as the saccharide units (α-glucose, β-glucose, α-mannose and α-galactose). In all cases, the monosaccharides impart excellent water compatibility. The length of the alkyl chain is the determining factor to obtain either long, one-dimensional supramolecular polymers (dodecyl spacer), small aggregates (decyl spacer) or molecularly dissolved (octyl and hexyl) BTAs in water. For the BTAs comprising a dodecyl spacer, our results suggest that a cooperative self-assembly process is operative and that the introduction of different monosaccharides does not significantly change the self- assembly behaviour. Finally, we investigate the potential of post-assembly functionalisation of the formed supramolecular polymers by taking advantage of dynamic covalent bond formation between the monosaccharides and benzoxaboroles. We observe that the supramolecular polymers readily react with a fluorescent benzoxaborole derivative permitting imaging of these dynamic complexes by confocal fluorescence microscopy.

  20. Monosaccharides as Versatile Units for Water-Soluble Supramolecular Polymers.

    PubMed

    Leenders, Christianus M A; Jansen, Gijs; Frissen, Martijn M M; Lafleur, René P M; Voets, Ilja K; Palmans, Anja R A; Meijer, E W

    2016-03-18

    We introduce monosaccharides as versatile water-soluble units to compatibilise supramolecular polymers based on the benzene-1,3,5-tricarboxamide (BTA) moiety with water. A library of monosaccharide-based BTAs is evaluated, varying the length of the alkyl chain (hexyl, octyl, decyl and dodecyl) separating the BTA and saccharide units, as well as the saccharide units (α-glucose, β-glucose, α-mannose and α-galactose). In all cases, the monosaccharides impart excellent water compatibility. The length of the alkyl chain is the determining factor to obtain either long, one-dimensional supramolecular polymers (dodecyl spacer), small aggregates (decyl spacer) or molecularly dissolved (octyl and hexyl) BTAs in water. For the BTAs comprising a dodecyl spacer, our results suggest that a cooperative self-assembly process is operative and that the introduction of different monosaccharides does not significantly change the self- assembly behaviour. Finally, we investigate the potential of post-assembly functionalisation of the formed supramolecular polymers by taking advantage of dynamic covalent bond formation between the monosaccharides and benzoxaboroles. We observe that the supramolecular polymers readily react with a fluorescent benzoxaborole derivative permitting imaging of these dynamic complexes by confocal fluorescence microscopy. PMID:26890574

  1. [Functionally-relevant conformational dynamics of water-soluble proteins].

    PubMed

    Novikov, G V; Sivozhelezov, V S; Shaĭtan, K V

    2013-01-01

    A study is reported of the functional-relevant dynamics of three typical water-soluble proteins: Calmodulin, Src-tyrosine kinase as well as repressor of Trp operon. Application of the state-of-art methods of structural bioinformatics allowed to identify dynamics seen in the X-ray structures of the investigated proteins associated with their specific biological functions. In addition, Normal Mode analysis technique revealed the most probable directions of the functionally-relevant motions for all that proteins were also predicted. Importantly, overall type of the motions observed on the lowest-frequency modes was very similar to the motions seen from the analysis of the X-ray data of the examined macromolecules. Thereby it was shown that the large-scale as well as local conformational motions of the proteins might be predetermined already at the level of their tertiary structures. In particular, the determining factor might be the specific fold of the alpha-helixes. Thus functionally-relevant in vivo dynamics of the investigated proteins might be evolutionally formed by means of natural selection at the level of the spatial topology. PMID:23705506

  2. Soft water-soluble microgel dispersions: structure and rheology.

    PubMed

    Omari, A; Tabary, R; Rousseau, D; Calderon, F Leal; Monteil, J; Chauveteau, G

    2006-10-15

    The size and structural characteristics of polyacrylamide-based water-soluble microgel dispersions were investigated by optical and rheological methods. Microgel hydrodynamic radii Rh were measured by light scattering and derived from intrinsic shear viscosity [eta]0. The variations of Rh3 and [eta]0 with the crosslink density Nx, follow the scaling law Rh3 congruent withNx(-alpha) with alpha close to 0.63, in good agreement with the simple structural model proposed in this paper showing how the exact value of alpha depends on inner structural details of the microgel. The plateau viscosity versus particle apparent volume fraction shows a monotonous change from hard sphere dispersions (high crosslink density of microgels) to flexible linear polymer solutions. Measurements of the first normal stress difference N1 show that increasing the microgel crosslink density affects the system viscosity more than its elasticity. Under oscillatory shear flow, loss and storage moduli undergo both qualitative and quantitative changes with crosslink density. At moderate concentrations, the elastic modulus is the most affected and its slope in low frequency regime decreases from two to less than one as Nx increases. We discuss the experimental results within the frame of knowledge on linear, branched polymer solutions and soft microgel suspensions. PMID:16928380

  3. [An alarming threat to secondary prevention: low compliance (lifestyle) and poor adherence (drugs)].

    PubMed

    Fuster, Valentín

    2012-07-01

    The deteriorating health of the general population and the increasing prevalence of chronic disease combine to present a problem of global proportions whose causes are both multifactorial and complex. The consumer society we live in does not encourage healthy living, and the consequences are even most devastating when social inequalities, the economic situation and the population explosion in recent decades are taken into account. The growth of poor eating habits, obesity, and hypertension are relentlessly contributing to the development of an epidemic of cardiovascular disease. In this context, the ability of national and international bodies and regulatory agencies to have an effect on commercial interests is very limited and alternative ways of reducing the disease burden are needed. Recent studies on patient compliance with lifestyle changes and on adherence to prescribed medication have produced alarming findings. Over 50% of patients, on average, choose to abandon the treatment they have been prescribed, and the percentage that achieve the targets proposed for improving habitual behaviors (e.g. quitting smoking, losing weight or increasing physical activity) is similar or lower. It is essential that solutions to these problems are found because, in addition to their implications for the health of the individual, poor compliance and adherence threaten to undermine the relevance of clinical study findings and are associated with substantial economic costs, given that they result in the failure to achieve therapeutic goals and increase rates of hospitalization and death. Improved communication between doctors and patients, the active participation of other health professionals and the development of combination drug formulations (e.g. the polypill) appear to be the most promising strategies for improving patient adherence to treatment and reducing the economic burden.

  4. Preparation of biomaterials on the basis of a water-soluble cellulose acetate

    NASA Astrophysics Data System (ADS)

    Akmalova, G. Yu.; Gulyamova, N. S.; Zainutdinov, U. N.; Rakhmanberdiev, G. R.; Negmatova, K. S.; Negmatova, M. I.

    2012-07-01

    Biomaterials were obtained on the basis of water-soluble cellulose acetate and diterpenoids group of plants Lagohulusa intoxicating having hemostatic properties. It is established that these biomaterials on the basis of water-soluble cellulose acetate and lagohilina (or lagohirzina) had increased hemostatic activity and reduce parenchymal hemorrhage 5-6 times compared to control.

  5. Water-soluble fullerene materials for bioapplications: photoinduced reactive oxygen species generation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The photoinduced reactive oxygen species (ROS) generation from several water-soluble fullerenes was examined. Macromolecular or small molecular water-soluble fullerene complexes/derivatives were prepared and their 1O2 and O2•- generation abilities were evaluated by EPR spin-trapping methods. As a r...

  6. OCTANOL/WATER PARTITION COEFFICIENTS AND WATER SOLUBILITIES OF PHTHALATE ESTERS

    EPA Science Inventory

    Measurements of the octanol/water partition coefficients (K-ow) and water solubilities of di-n-octyl phthalate (DnOP) and di-n-decyl phthalate (DnDP) by the slow-stirring method are reported. The water solubility was also measured for di-n-hexyl phthalate (DnHP). The log K-ow val...

  7. The up-converted photoluminescence and cell imaging of water-soluble carbon dots

    NASA Astrophysics Data System (ADS)

    Sheng, Yingzhuo; Wei, Jumeng; Pan, Jiaqi; Huang, Peng; Guo, Shikuan; Zhang, Jingxiang; Zhang, Xin; Feng, Boxue

    2015-10-01

    Water-soluble carbon dots (CDs) have been successfully synthesized by green-one-pot hydrothermal method. The CDs with small particle size exhibit fairly good water solubility, tunable photoluminescence, up-converted photoluminescence, and low toxicity. What is more, the as-prepared CDs were successfully applied in the field of cell image.

  8. Formulation and comparative evaluation of HPMC and water soluble chitosan-based sparfloxacin nanosuspension for ophthalmic delivery.

    PubMed

    Ambhore, Nitin Prabhakar; Dandagi, Panchaxari Mallapa; Gadad, Anand Panchakshari

    2016-02-01

    Ophthalmic nanosuspensions (ONS) have shown a potential for ophthalmic delivery over the conventional ocular formulations. The objective of the study was to assess the effect of surfactants and polymers on particle size and drug release. Sparfloxacin ONS were prepared by optimizing the concentration of HPMC E5 and water soluble chitosan by using solvent diffusion method followed by probe sonication. The Poloxamer 407 and Kolliphor P188 were used as a surfactant. The produced nanosuspensions were characterized for particle size, shape, zeta potential and drug release. The average particle size of the nanosuspension was 300 to 500 nm. The in vitro drug release study showed that the optimized nanosuspension of water soluble chitosan sustained drug release up to 9 h compared to 6 h for the hydroxypropylmethylcellulose (HPMC) nanosuspension. Further, the sparfloxacin ONS formulation showed excellent ocular tolerance and biocompatibility as determined by hen's egg test chorioallantoic membrane (HET CAM) and resazurin assay on Vero cell lines. Moreover, optimized formulation was found to be stable, isotonic, non-toxic with higher in vitro and in vivo antimicrobial potential.

  9. Pharmacokinetics of a water-soluble fullerene in rats.

    PubMed

    Rajagopalan, P; Wudl, F; Schinazi, R F; Boudinot, F D

    1996-10-01

    Fullerenes are the recently discovered third allotropic form of carbon. The biological activities of these compounds are being studied for various purposes. The bis(monosuccinimide) derivative of p p'-bis(2-amino-ethyl)-diphenyl-C60 (MSAD-C60) is a water-soluble fullerene derivative. MSAD-C60 has been shown to have antiviral activity against human immunodeficiency virus types 1 and 2 in vitro and to have virucidal and anti-human immunodeficiency virus protease activities. Moreover, MSAD-C60 has been shown to be well tolerated in mice after intraperitoneal administration. The purpose of the present study was to develop a high-performance liquid chromatographic analytical methodology for MSAD-C60 and to characterize the preclinical pharmacokinetics of the compound in rats. Following intravenous administration of the fullerene derivative at a dose of 15 mg/kg of body weight, the concentrations of MSAD-C60 in plasma declined either bi- or triexponentially. The mean terminal-phase half-life of MSAD-C60 was 6.8 +/- 1.1 h (mean +/- standard deviation). Binding studies indicated that the compound is greater than 99% bound to plasma proteins. The average total clearance of the compound was 0.19 +/- 0.06 liter/h/kg. Urine samples obtained 24 h after intravenous administration did not contain detectable levels of the compound, indicating the absence of a significant renal clearance mechanism. The steady-state volume of distribution of MSAD-C60 averaged 2.1 +/- 0.8 liters/kg, indicating that the compound distributes into tissues. At a dose of 15 mg/kg, MSAD-C60 appeared to be well tolerated. However, a dose of 25 mg/kg resulted in shortness of breath and violent movement of the rats, followed by death within 5 min of dosing. Further controlled toxicity studies are needed to fully evaluate the toxicity of the compound.

  10. Linking Atomistic and Mesoscale Simulations of Water Soluble Polymers

    NASA Astrophysics Data System (ADS)

    Jones, J. L.

    2003-03-01

    There exist a range of techniques for studying surfactants and polymers in the mesoscale regime. One of the challenges is to link mesoscale theories and simulations to other calculation methods which address different length scales of the system. We introduce some mesoscale methods of calculation for polymers and surfactants and then present a case study of where mesoscale modelling is used for mechanistic understanding, by linking the method to high throughput in-silico screening methods. We look at the adsorption onto silica of ethylene oxide (EO)/ propylene oxide (PO) block copolymers (lutrols) which have been modified by end-grafting of short, cationic dimethylamino ethyl methacrylate (DMAEMA)chains. Given that the silica surface is negatively charged, it is remarkable that in some circumstances, polymers with longercationic chains have a lower adsorption. The effect is attributed to a competition between strong adsorption of the cationic DMAEMA groups driven by electrostatics, and weaker adsorption of the more numerous EO groups. This then raises the question of how we produce the values for the mesoscale parameters in these models and in the second part of the talk we describe a calculation method for doing this for water soluble polymers. The most promising route, but notoriously costly, is based on free energy calculations at the atomistic level. Free energy calculations are computationally intensive in general, but in an aqueous system one is also faced with the additional problem of using complex continuum models and/or accurate interaction potentials for water. Here we show how potential of mean force (PMF)calculations offer a practical alternative which avoids these drawbacks, though one is still faced with extremely long simulations.

  11. Investigating water soluble organic aerosols: Sources and evolution

    NASA Astrophysics Data System (ADS)

    Hecobian, Arsineh N.

    Many studies are being conducted on the different properties of organic aerosols (OA-s) as it is first emitted into the atmosphere and the consequent changes in these characteristics as OA-s age and secondary organic aerosol (SOA) is produced and in turn aged. This thesis attempts to address some of the significant and emerging issues that deal with the formation and transformation of water-soluble organic aerosols in the atmosphere. First, a proven method for the measurement of gaseous sulfuric acid, negative ion chemical ionization mass spectrometry (CIMS), has been modified for fast and sensitive measurements of particulate phase sulfuric acid (i.e. sulfate). The modifications implemented on this system have also been the subject of preliminary verifications for measurements of aerosol phase oxalic acid (an organic acid). Second, chemical and physical characteristics of a wide range of biomass-burning plumes intercepted by the NASA DC-8 research aircraft during the three phases of the ARCTAS experiment are presented here. A statistical summary of the emission (or enhancement) ratios relative to carbon monoxide is presented for various gaseous and aerosol species. Extensive investigations of fire plume evolutions were undertaken during the second part of this field campaign. For four distinct Boreal fires, where plumes were intercepted by the aircraft over a wide range of down-wind distances, emissions of various compounds and the effect of aging on them were investigated in detail. No clear evidence of production of secondary compounds (e.g., WSOC and OA) was observed. High variability in emissions between the different plumes may have obscured any clear evidence of changes in the mass of various species with increasing plume age. Also, the lack if tropospheric oxidizing species (e.g., O3 and OH) may have contributed to the lack of SOA formation. Individual intercepts of smoke plumes in this study were segregated by source regions. The normalized excess mixing

  12. Fabrication of distilled water-soluble chitosan/alginate functional multilayer composite microspheres.

    PubMed

    Xiao, Congming; Sun, Fei

    2013-11-01

    Polysaccharides-based functional microspheres were fabricated under mild conditions. Firstly, magnetic alginate microspheres were prepared by emulsification/internal gelation and acted as substrates. Then the multilayer composite microspheres (MCM) were obtained through the layer-by-layer assembly of the distilled water-soluble chitosan and alginate. The components, morphology, and size distribution of the microspheres were characterized by element analysis (EA), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM) and laser particle size analyzer (LPSA). Both EA and XPS analysis results indicated that alternate immersion was an effective method for preparing MCM. Vibrating sample magnetometer, SEM and LPSA results showed that the microspheres had good dispersion, uniform particle size and were superparamagnetic. In addition, in vitro drug release behaviors of the microspheres were investigated by using hemoglobin (HB) and Coomassie brilliant blue G250 (CBB) as model drugs. It was found that the release rates of both HB and CBB from the composite microspheres were slower than those from the substrates.

  13. Water-Soluble 2-Hydroxyisophthalamides for Sensitization of Lanthanide Luminescence

    SciTech Connect

    Samuel, Amanda P. S.; Moore, Evan G.; Melchior, Marco; Xu, Jide; Raymond, Kenneth N.

    2008-02-20

    A series of octadentate ligands featuring the 2-hydroxyisophthalamide (IAM) antenna chromophore (to sensitize Tb(III) and Eu(III) luminescence) has been prepared and characterized. The length of the alkyl amine scaffold that links the four IAM moieties has been varied in order to investigate the effect of the ligand backbone on the stability and photophysical properties of the Ln(III) complexes. The amine backbones utilized in this study are N,N,N{prime},N{prime}-tetrakis-(2-aminoethyl)-ethane-1,2-diamine [H(2,2)-], N,N,N{prime},N{prime}-tetrakis-(2-aminoethyl)-propane-1,3-diamine [H(3,2)-] and N,N,N{prime},N{prime}-tetrakis-(2-aminoethyl)-butane-1,4-diamine [H(4,2)-]. These ligands also incorporate methoxyethylene [MOE] groups on each of the IAM chromophores to increase their water solubility. The aqueous ligand protonation constants and Tb(III) and Eu(III) formation constants were determined from solution thermodynamic studies. The resulting values indicate that at physiological pH, the Eu(III) and Tb(III) complexes of H(2,2)-IAM-MOE and H(4,2)-IAM-MOE are sufficiently stable to prevent dissociation at nanomolar concentrations. The photophysical measurements for the Tb(III) complexes gave overall quantum yield values of 0.56, 0.39, and 0.52 respectively for the complexes with H(2,2)-IAM-MOE, H(3,2)-IAM-MOE and H(4,2)-IAM-MOE, while the corresponding Eu(III) complexes displayed significantly weaker luminescence, with quantum yield values of 0.0014, 0.0015, and 0.0058, respectively. Analysis of the steady state Eu(III) emission spectra provides insight into the solution symmetries of the complexes. The combined solubility, stability and photophysical performance of the Tb(III) complexes in particular make them well suited to serve as the luminescent reporter group in high sensitivity time-resolved fluoroimmunoassays.

  14. Antioxidant Activity of Water-soluble Polysaccharides from Brasenia schreberi

    PubMed Central

    Xiao, Huiwen; Cai, Xueru; Fan, Yijun; Luo, Aoxue

    2016-01-01

    Objective: In order to investigate the antioxidant activities of polysaccharides (BPL-1 and BPL-2), one of the most important functional constituents in Brasenia schreberi was isolated from the external mucilage of B. schreberi (BPL-1) and the plant in vivo (BPL-2). This paper examines the relationship between the content of sulfuric radicals and uronic acid in BPL and the antioxidant activity of BPL. Materials and Methods: The free radicals, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) and 1,1-diphnyl-2-picrylhydrazyl (DPPH-), were used to determine the antioxidant activity of BPL. The Fourier-transform infrared spectroscopy of BPL-1 and BPL-2 revealed typical characteristics of polysaccharides. Results: The two sample types had different contents. This was proved by their different adsorption peak intensities. The IC50 values of BPL-1 (31.189 mg/ml) and BPL-2 (1.863 mg/ml) showed significant DPPH radical scavenging activity. Based on the quantification of ABTS radical scavenging, the IC50 value of BPL-1 (5.460 mg/ml) was higher than that of BPL-2 (0.239 mg/ml). Therefore, in terms of the reducing power, the IC50 value of BPL-1 was too high to determine, and the IC50 value of BPL-2 was found to be 50.557 mg/ml. Hence, the antioxidant activity and total reducing power were high, and they were greater in BPL-2 than in BPL-1. In addition, BPL-2 was found to have more sulfuric radicals and uronic acid than BPL-1. Conclusion: The contents of sulfuric radicals and uronic acid are significantly correlated to the antioxidant activity and reducing power of BPL; the more sulfuric radicals and uronic acid, the more antioxidant activity and reducing power BPL has. SUMMARY The water-soluble crude polysaccharides obtained from the external mucilage and the Brasenia schreberi plant in vivo were confirmed to have high contents of sulfuric radicals and uronic acidBoth BPL-1 and BPL-2 exhibited antioxidative activity and reducing power, and their antioxidative

  15. Three bisphosphonate ligands improve the water solubility of quantum dots.

    PubMed

    Abdul Ghani, Siti Fatimah; Wright, Michael; Paramo, Juan Gallo; Bottrill, Melanie; Green, Mark; Long, Nicholas; Thanou, Maya

    2014-01-01

    Synthesised Quantum Dots (QDs) require surface modification in order to improve their aqueous dispersion and biocompatibility. Here, we suggest bisphosphonate molecules as agents to modify the surface of QDs for improved water solubility and biocompatibility. QDs_TOPO (CdSe/ZnS-trioctylphosphine oxide) were synthesised following modification of the method of Bawendi et al. (J. Phys. Chem. B, 1997, 101, 9463-9475). QDs surface modification is performed using a ligand exchange reaction with structurally different bisphosphonates (BIPs). The BIPs used were ethylene diphosphonate (EDP), methylenediphosphonate (MDP) and imidodiphosphonate (IDP). After ligand exchange, the QDs were extensively purified using centrifugation, PD-10 desalting columns and mini dialysis filters. Transmission electron microscopy (TEM) and fluorescent spectroscopy have been used to characterise the size and optical properties of the QDs. Cell toxicity was investigated using MTT (tetrazolium salt) and glutathione assays and intracellular uptake was imaged using confocal laser scanning microscopy and assessed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). QDs_TOPO and QDs-capped with BIPs (QDs_BIPs) were successfully synthesised. TEM showed the size and morphology of the QDs to be 5-7 nm with spherical shape. The stabilised QDs_BIPs showed significantly improved dispersion in aqueous solutions compared to QDs_TOPO. The cytotoxicity studies showed very rapid cell death for cells treated by QDs_TOPO and a minor effect on cell viability when QDs_BIPs were applied to the cells. Both EDP- and MDP-modified QDs did not significantly increase the intracellular levels of glutathione. In contrast, IDP-modified QDs substantially increased the intracellular glutathione levels, indicating potential cadmium leakage and inability of IDP to adequately cap and stabilise the QDs. EDP- and MDP-modified QDs were taken up by IGROV-1 (ovarian cancer) cells as shown by fluorescence microscopy, however, the

  16. Water-Soluble 2-Hydroxyisophthalamides for Sensitization of Lanthanide Luminescence

    PubMed Central

    Samuel, Amanda P. S.; Moore, Evan G.; Melchior, Marco; Xu, Jide; Raymond, Kenneth N.

    2011-01-01

    A series of octadentate ligands featuring the 2-hydroxyisophthalamide (IAM) antenna chromophore (to sensitize Tb(III) and Eu(III) luminescence) has been prepared and characterized. The length of the alkyl amine scaffold that links the four IAM moieties has been varied in order to investigate the effect of the ligand backbone on the stability and photophysical properties of the Ln(III) complexes. The amine backbones utilized in this study are N,N,N',N'-tetrakis-(2-aminoethyl)-ethane-1,2-diamine [H(2,2)-], N,N,N',N'-tetrakis-(2-aminoethyl)-propane-1,3-diamine [H(3,2)-] and N,N,N',N'-tetrakis-(2-aminoethyl)-butane-1,4-diamine [H(4,2)-]. These ligands also incorporate methoxyethylene [MOE] groups on each of the IAM chromophores to increase their water solubility. The aqueous ligand protonation constants and Tb(III) and Eu(III) formation constants were determined from solution thermodynamic studies. The resulting values indicate that at physiological pH, the Eu(III) and Tb(III) complexes of H(2,2)-IAM-MOE and H(4,2)-IAM-MOE are sufficiently stable to prevent dissociation at nanomolar concentrations. The photophysical measurements for the Tb(III) complexes gave overall quantum yield values of 0.56, 0.39, and 0.52 respectively for the complexes with H(2,2)-IAM-MOE, H(3,2)-IAM-MOE and H(4,2)-IAM-MOE, while the corresponding Eu(III) complexes displayed significantly weaker luminescence, with quantum yield values of 0.0014, 0.0015, and 0.0058, respectively. Analysis of the steady state Eu(III) emission spectra provides insight into the solution symmetries of the complexes. The combined solubility, stability and photophysical performance of the Tb(III) complexes in particular make them well suited to serve as the luminescent reporter group in high sensitivity time-resolved fluoroimmunoassays. PMID:18671388

  17. Antioxidant Activity of Water-soluble Polysaccharides from Brasenia schreberi

    PubMed Central

    Xiao, Huiwen; Cai, Xueru; Fan, Yijun; Luo, Aoxue

    2016-01-01

    Objective: In order to investigate the antioxidant activities of polysaccharides (BPL-1 and BPL-2), one of the most important functional constituents in Brasenia schreberi was isolated from the external mucilage of B. schreberi (BPL-1) and the plant in vivo (BPL-2). This paper examines the relationship between the content of sulfuric radicals and uronic acid in BPL and the antioxidant activity of BPL. Materials and Methods: The free radicals, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) and 1,1-diphnyl-2-picrylhydrazyl (DPPH-), were used to determine the antioxidant activity of BPL. The Fourier-transform infrared spectroscopy of BPL-1 and BPL-2 revealed typical characteristics of polysaccharides. Results: The two sample types had different contents. This was proved by their different adsorption peak intensities. The IC50 values of BPL-1 (31.189 mg/ml) and BPL-2 (1.863 mg/ml) showed significant DPPH radical scavenging activity. Based on the quantification of ABTS radical scavenging, the IC50 value of BPL-1 (5.460 mg/ml) was higher than that of BPL-2 (0.239 mg/ml). Therefore, in terms of the reducing power, the IC50 value of BPL-1 was too high to determine, and the IC50 value of BPL-2 was found to be 50.557 mg/ml. Hence, the antioxidant activity and total reducing power were high, and they were greater in BPL-2 than in BPL-1. In addition, BPL-2 was found to have more sulfuric radicals and uronic acid than BPL-1. Conclusion: The contents of sulfuric radicals and uronic acid are significantly correlated to the antioxidant activity and reducing power of BPL; the more sulfuric radicals and uronic acid, the more antioxidant activity and reducing power BPL has. SUMMARY The water-soluble crude polysaccharides obtained from the external mucilage and the Brasenia schreberi plant in vivo were confirmed to have high contents of sulfuric radicals and uronic acidBoth BPL-1 and BPL-2 exhibited antioxidative activity and reducing power, and their antioxidative

  18. Recreational drug use in type 1 diabetes: an invisible accomplice to poor glycaemic control?

    PubMed

    Lee, P; Greenfield, J R; Gilbert, K; Campbell, L V

    2012-02-01

    Recreational drug use during 'rave' parties is increasingly popular, but the impact of recreational drug use in type 1 diabetes (T1D) is not known. We determined the self-reported pattern and effects of recreational/illicit drug use in Australians with T1D people by inviting people with T1D to participate in an anonymous online/paper survey of drug use, through national radio broadcast and online/hospital advertising. Of the people with T1D who responded to our survey, more than three quarters reported having used recreational/illicit drug, but few people had informed health professionals about drug use. Drug use was associated with worse glycaemic control and higher risk of diabetic ketoacidosis. Medical awareness of common, currently underreported, drug use in young people with T1D is essential. It offers the possibility of helping such patients improve related suboptimal metabolic control. PMID:22356493

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

    PubMed

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

    2012-01-01

    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. PMID:22502598

  20. 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.

  1. Mixed PEG-PE/Vitamin E Tumor-Targeted Immunomicelles as Carriers for Poorly Soluble Anti-Cancer Drugs: Improved Drug Solubilization and Enhanced In Vitro Cytotoxicity

    PubMed Central

    Sawant, Rupa R.; Sawant, Rishikesh M.; Torchilin, Vladimir P.

    2008-01-01

    Two poorly soluble, potent anticancer drugs, paclitaxel and camptothecin, were successfully solubilized by mixed micelles of polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) and vitamin E. Drug containing micelles were additionally modified with anti-nucleosome monoclonal antibody 2C5 (mAb 2C5), which can specifically bring micelles to tumor cells in vitro. The optimized micelles had an average size of about 13-to-22 nm and the immuno-modification of micelles did not significantly change it. The solubilization of both drugs by the mixed micelles was more efficient than by micelles made of PEG-PE alone. Solubilization of camptothecin in micelles prevented also the hydrolysis of active lactone form of the drug to inactive carboxylate form. Drug loaded mixed micelles and mAb 2C5-immunomicelles demonstrated significantly higher in vitro cytotoxicity than free drug against various cancer cell lines. PMID:18583114

  2. [Study on Extraction Conditions of Water-Soluble Substances—Purity Test (4) for Polyvinylpolypyrrolidone Listed in Japan's Specifications and Standards for Food Additives].

    PubMed

    Yanagi, Tokue; Matsumoto, Makoto; Shimizu, Sachiko; Iwamura, Tetsuro; Ogaki, Mamiko

    2015-01-01

    The food additive polyvinylpolypyrrolidone is approved for use as a filter aid. The water-soluble substances test of polyvinylpolypyrrolidone often shows poor reproducibility. The instruction "boil gently while stirring using a stirrer" was considered critical, and so this issue was examined. The results showed that the use of a combination of both an oil bath and a stirrer provided good reproducibility without decomposition or other problems.

  3. 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.

  4. Melt dispersion granules: formulation and evaluation to improve oral delivery of poorly soluble drugs - a case study with valsartan.

    PubMed

    Chella, Naveen; Tadikonda, Ramarao

    2015-06-01

    Solid dispersion (SD) technique is a promising strategy to improve the solubility and dissolution of BCS class II drugs. However, only few products are marketed till today based on SD technology due to poor flow properties and stability. The present work was intended to solve these problems by using combination approach, melt dispersion and surface adsorption technologies. The main aim of the present work is to improve the absorption in the stomach (at lower pH) where the absorption window exists for the drug by improving the dissolution, resulting in the enhancement of oral bioavailability of poorly soluble, weakly acidic drug with pH dependant solubility, i.e. valsartan. Melt dispersion granules were prepared in different ratios using different carriers (Gelucire 50/13, PEG 8000 and Pluronic F-68) and lactose as an adsorbent. Similarly, physical mixtures were also prepared at corresponding ratios. The prepared dispersion granules and physical mixtures were characterized by FTIR, DSC and in vitro dissolution studies. DSC studies revealed reduction in the crystallinity with a possibility of presence of amorphous character of drug in the dispersion granules. From dissolution studies, valsartan Gelucire dispersion (GSD4; 1:4 ratio) showed complete drug release in 30 min against the plain drug which showed only 11.31% of drug release in 30 min. Pharmacokinetic studies of optimized formulation in male Wistar rats showed 2.65-fold higher bioavailability and 1.47-fold higher Cmax compared to pure drug. The melt dispersion technology has the potential to improve dissolution and the bioavailability of BCS class II drugs. PMID:24796274

  5. Water solubility in aluminous orthopyroxene and the origin of Earth's asthenosphere.

    PubMed

    Mierdel, Katrin; Keppler, Hans; Smyth, Joseph R; Langenhorst, Falko

    2007-01-19

    Plate tectonics is based on the concept of rigid lithosphere plates sliding on a mechanically weak asthenosphere. Many models assume that the weakness of the asthenosphere is related to the presence of small amounts of hydrous melts. However, the mechanism that may cause melting in the asthenosphere is not well understood. We show that the asthenosphere coincides with a zone where the water solubility in mantle minerals has a pronounced minimum. The minimum is due to a sharp decrease of water solubility in aluminous orthopyroxene with depth, whereas the water solubility in olivine continuously increases with pressure. Melting in the asthenosphere may therefore be related not to volatile enrichment but to a minimum in water solubility, which causes excess water to form a hydrous silicate melt. PMID:17234945

  6. Bidirectional Transformation of a Metamorphic Protein between the Water-Soluble and Transmembrane Native States.

    PubMed

    Tanaka, Koji; Caaveiro, Jose M M; Tsumoto, Kouhei

    2015-11-24

    The bidirectional transformation of a protein between its native water-soluble and integral transmembrane conformations is demonstrated for FraC, a hemolytic protein of the family of pore-forming toxins. In the presence of biological membranes, the water-soluble conformation of FraC undergoes a remarkable structural reorganization generating cytolytic transmembrane nanopores conducive to cell death. So far, the reverse transformation from the native transmembrane conformation to the native water-soluble conformation has not been reported. We describe the use of detergents with different physicochemical properties to achieve the spontaneous conversion of transmembrane pores of FraC back into the initial water-soluble state. Thermodynamic and kinetic stability data suggest that specific detergents cause an asymmetric change in the energy landscape of the protein, allowing the bidirectional transformation of a membrane protein.

  7. Explaining Ionic Liquid Water Solubility in Terms of Cation and Anion Hydrophobicity

    PubMed Central

    Ranke, Johannes; Othman, Alaa; Fan, Ping; Müller, Anja

    2009-01-01

    The water solubility of salts is ordinarily dictated by lattice energy and ion solvation. However, in the case of low melting salts also known as ionic liquids, lattice energy is immaterial and differences in hydrophobicity largely account for differences in their water solubility. In this contribution, the activity coefficients of ionic liquids in water are split into cation and anion contributions by regression against cation hydrophobicity parameters that are experimentally determined by reversed phase liquid chromatography. In this way, anion hydrophobicity parameters are derived, as well as an equation to estimate water solubilities for cation-anion combinations for which the water solubility has not been measured. Thus, a new pathway to the quantification of aqueous ion solvation is shown, making use of the relative weakness of interactions between ionic liquid ions as compared to their hydrophobicities. PMID:19399248

  8. Preparation, cytotoxicity and in vivo bioimaging of highly luminescent water-soluble silicon quantum dots

    NASA Astrophysics Data System (ADS)

    Fan, Jing-Wun; Vankayala, Raviraj; Chang, Chien-Liang; Chang, Chia-Hua; Chiang, Chi-Shiun; Hwang, Kuo Chu

    2015-05-01

    Designing various inorganic nanomaterials that are cost effective, water soluble, optically photostable, highly fluorescent and biocompatible for bioimaging applications is a challenging task. Similar to semiconducting quantum dots (QDs), silicon QDs are another alternative and are highly fluorescent, but non-water soluble. Several surface modification strategies were adopted to make them water soluble. However, the photoluminescence of Si QDs was seriously quenched in the aqueous environment. In this report, highly luminescent, water-dispersible, blue- and green-emitting Si QDs were prepared with good photostability. In vitro studies in monocytes reveal that Si QDs exhibit good biocompatibility and excellent distribution throughout the cytoplasm region, along with the significant fraction translocated into the nucleus. The in vivo zebrafish studies also reveal that Si QDs can be evenly distributed in the yolk-sac region. Overall, our results demonstrate the applicability of water-soluble and highly fluorescent Si QDs as excellent in vitro and in vivo bioimaging probes.

  9. Biological activity of water-soluble inclusion complexes of 1'-acetoxychavicol acetate with cyclodextrins.

    PubMed

    Azuma, Hideki; Aizawa, Yui; Higashitani, Nao; Tsumori, Takashi; Kojima-Yuasa, Akiko; Matsui-Yuasa, Isao; Nagasaki, Takeshi

    2011-06-15

    1'-Acetoxychavicol acetate (ACA), isolated from the rhizomes and the seeds of the Zingiberaceae plant, has a variety of biological activities such as antitumor, antiallergic and repellent effects. However, ACA seems to have some disadvantages which may limit for future possible clinical applications, for example, its poor water solubility. Furthermore, ACA is not stable in aqueous solutions and undergoes hydrolysis and/or isomerization. To improve the solubility and stability of ACA in water, we prepared the inclusion complexes with various β-cyclodextrins (β-CDs).In aqueous solution, the association constants of ACA with various CDs were estimated at 662±95 (β-CD), 336±70 (methyl-β-CD, Meβ-CD), and 322±44M(-1) (hydroxypropyl-β-CD, HPβ-CD), respectively, by a spectrofluorometric displacement method based on competition between a guest and a fluorescent probe for CDs. It was revealed that almost all ACAs existed as a free molecule in the CD-containing aqueous solution. However, in the case of preparing the inclusion complexes of CDs with ACA by a solid phase 'high-speed vibration milling' technique, the average inclusion rates of the obtained water-soluble complexes were calculated as 88±13% (β-CD), 70±1% (Meβ-CD), and 63±2% (HPβ-CD), respectively, by (1)H NMR analysis. To characterize the structures of the CD·ACA complexes, 2,3,6-trimethyl-β-CD (TMeβ-CD)·ACA complex was prepared as a model compound (inclusion rate: 40%). As a result of 2D ROESY experiments, it was considered that the aromatic ring of ACA is located in the narrow side of the hydrophobic cavity of the TMeβ-CD and both 1'- and 4-acetoxy groups of ACA positioned in the vicinity of the secondary and primary methoxy groups of TMeβ-CD, respectively. Furthermore, we examined the apoptogenic activity of CD·ACA complexes to evaluate whether or not the bioactivities of ACA were affected by their inclusion. Although the cytotoxicity of all CD·ACA complexes in human epithelial carcinoma

  10. Nanosuspension: An approach to enhance solubility of drugs

    PubMed Central

    Patel, Vishal R.; Agrawal, Y. K.

    2011-01-01

    One of the major problems associated with poorly soluble drugs is very low bioavailability. The problem is even more complex for drugs like itraconazole, simvastatin, and carbamazepine which are poorly soluble in both aqueous and nonaqueous media, belonging to BCS class II as classified by biopharmaceutical classification system. Formulation as nanosuspension is an attractive and promising alternative to solve these problems. Nanosuspension consists of the pure poorly water-soluble drug without any matrix material suspended in dispersion. Preparation of nanosuspension is simple and applicable to all drugs which are water insoluble. A nanosuspension not only solves the problems of poor solubility and bioavailability, but also alters the pharmacokinetics of drug and thus improves drug safety and efficacy. This review article describes the preparation methods, characterization, and applications of the nanosuspension. PMID:22171298

  11. Application of dry-polishing techniques to water-soluble glass ceramics

    SciTech Connect

    Healey, J.T.; McAllaster, M.E.

    1981-04-01

    A dry polishing technique is presented for the preparation of glass ceramics for microstructural characterization. The technique is shown to be applicable to water soluble phosphate based glass ceramics and also to a non-water soluble zinc silicate glass ceramic. Microstructural characterization is performed primarily with composition backscattered electron imaging in the scanning electron microscopy. Some relief is observed on the polished surface utilizing topographical backscattered electron imaging.

  12. Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs.

    PubMed

    Kleppe, Mary S; Forney-Stevens, Kelly M; Haskell, Roy J; Bogner, Robin H

    2015-07-01

    Poorly soluble drugs are increasingly formulated into supersaturating drug delivery systems which may precipitate during oral delivery. The link between in vitro drug concentration profiles and oral bioavailability is under intense investigation. The objective of the present work was to develop closed-form analytical solutions that relate in vitro concentration profiles to the amount of drug absorbed using several alternate assumptions and only six parameters. Three parameters define the key features of the in vitro drug concentration-time profile. An additional three parameters focus on physiological parameters. Absorption models were developed based on alternate assumptions; the drug concentration in the intestinal fluid: (1) peaks at the same time and concentration as in vitro, (2) peaks at the same time as in vitro, or (3) reaches the same peak concentration as in vitro. The three assumptions provide very different calculated values of bioavailability. Using Case 2 assumptions, bioavailability enhancement was found to be less than proportional to in silico examples of dissolution enhancement. Case 3 assumptions lead to bioavailability enhancements that are more than proportional to dissolution enhancements. Using Case 1 predicts drug absorption amounts that fall in between Case 2 and 3. The equations developed based on the alternate assumptions can be used to quickly evaluate the potential improvement in bioavailability due to intentional alteration of the in vitro drug concentration vs. time curve by reformulation. These equations may be useful in making decisions as to whether reformulation is expected to provide sufficient bioavailability enhancement to justify the effort.

  13. Tartrate/tripolyphosphate as co-crosslinker for water soluble chitosan used in protein antigens encapsulation.

    PubMed

    Srivastava, Gopal; Walke, Shilratna; Dhavale, Dilip; Gade, Wasudeo; Doshi, Jignesh; Kumar, Rakesh; Ravetkar, Satish; Doshi, Pooja

    2016-10-01

    In drug delivery research, several toxic chemical crosslinkers and non-toxic ionic crosslinkers have been exploited for the synthesis of microparticles from acetic acid soluble chitosan. This paper hypothesized the implementation of sodium potassium tartrate (SPT) as an alternative crosslinker for sodium tripolyphosphate (TPP) and SPT/TPP co-crosslinkers for synthesis of the microparticles using water soluble chitosan (WSC) for encapsulation of Bovine serum albumin (BSA) as a model protein, and Tetanus toxoid (TT) as a model vaccine. The crosslinking was confirmed by FT-IR, SEM with EDS. The XRD entailed molecular dispersion of proteins and thermal analysis confirmed the higher stability of STP/TPP co-crosslinked formulations. The resultant microparticles were exhibiting crosslinking degree (52-67%), entrapment efficiency (72-80%), particle size (0.3-1.7μm), zeta potential (+24 to 46mV) and mucoadhesion (41-68%). The superiority of SPT over TPP was confirmed by higher crosslinking degree and entrapment efficiency. However, co-crosslinking were advantageous in higher regression values for Langmuir adsorption isotherm, slower swelling tendency and extended 30days controlled in-vitro release study. TT release obeyed the Quasi-Fickian diffusion mechanism for single and cocrosslinked formulations. Overall, in crosslinking of chitosan as biological macromolecules, STP/TPP may be alternative for single ionic crosslinked formulations for protein antigen delivery. PMID:27246374

  14. Impact of biochar amendment on soil water soluble carbon in the context of extreme hydrological events.

    PubMed

    Wang, Daoyuan; Griffin, Deirdre E; Parikh, Sanjai J; Scow, Kate M

    2016-10-01

    Biochar amendments to soil have been promoted as a low cost carbon (C) sequestration strategy as well as a way to increase nutrient retention and remediate contaminants. If biochar is to become part of a long-term management strategy, it is important to consider its positive and negative impacts, and their trade-offs, on soil organic matter (SOM) and soluble C under different hydrological conditions such as prolonged drought or frequent wet-dry cycles. A 52-week incubation experiment measuring the influence of biochar on soil water soluble C under different soil moisture conditions (wet, dry, or wet-dry cycles) indicated that, in general, dry and wet-dry cycles increased water soluble C, and biochar addition further increased release of water soluble C from native SOM. Biochar amendment appeared to increase transformation of native SOM to water soluble C, based on specific ultraviolet absorption (SUVA) and C stable isotope composition; however, the increased amount of water soluble C from native SOM is less than 1% of total biochar C. The impacts of biochar on water soluble C need to be carefully considered when applying biochar to agricultural soil. PMID:27391051

  15. Does price reveal poor-quality drugs? Evidence from 17 countries.

    PubMed

    Bate, Roger; Jin, Ginger Zhe; Mathur, Aparna

    2011-12-01

    Focusing on 8 drug types on the WHO-approved medicine list, we constructed an original dataset of 899 drug samples from 17 low- and median-income countries and tested them for visual appearance, disintegration, and analyzed their ingredients by chromatography and spectrometry. Fifteen percent of the samples fail at least one test and can be considered substandard. After controlling for local factors, we find that failing drugs are priced 13.6-18.7% lower than non-failing drugs but the signaling effect of price is far from complete, especially for non-innovator brands. The look of the pharmacy, as assessed by our covert shoppers, is weakly correlated with the results of quality tests. These findings suggest that consumers are likely to suspect low quality from market price, non-innovator brand and the look of the pharmacy, but none of these signals can perfectly identify substandard and counterfeit drugs.

  16. Facile preparation of water soluble curcuminoids extracted from turmeric (Curcuma longa L.) powder by using steviol glucosides.

    PubMed

    Nguyen, Thi Thanh Hanh; Si, Jinbeom; Kang, Choongil; Chung, Byoungsang; Chung, Donghwa; Kim, Doman

    2017-01-01

    Curcuminoids from rhizomes of Curcuma longa possess various biological activities. However, low aqueous solubility and consequent poor bioavailability of curcuminoids are major limitations to their use. In this study, curcuminoids extracted from turmeric powder using stevioside (Ste), rebaudioside A (RebA), or steviol glucosides (SG) were solubilized in water. The optimum extraction condition by Ste, RebA, or SG resulted in 11.3, 9.7, or 6.7mg/ml water soluble curcuminoids. Curcuminoids solubilized in water showed 80% stability at pH from 6.0 to 10.0 after 1week of storage at 25°C. The particle sizes of curcuminoids prepared with Ste, RebA, and SG were 110.8, 95.7, and 32.7nm, respectively. The water soluble turmeric extracts prepared with Ste, RebA, and SG showed the 2,2-diphenyl-1-picrylhydrazyl radical scavenging (SC50) activities of 127.6, 105.4, and 109.8μg/ml, and the inhibition activities (IC50) against NS2B-NS3(pro) from dengue virus type IV of 14.1, 24.0 and 15.3μg/ml, respectively. PMID:27507487

  17. Facile preparation of water soluble curcuminoids extracted from turmeric (Curcuma longa L.) powder by using steviol glucosides.

    PubMed

    Nguyen, Thi Thanh Hanh; Si, Jinbeom; Kang, Choongil; Chung, Byoungsang; Chung, Donghwa; Kim, Doman

    2017-01-01

    Curcuminoids from rhizomes of Curcuma longa possess various biological activities. However, low aqueous solubility and consequent poor bioavailability of curcuminoids are major limitations to their use. In this study, curcuminoids extracted from turmeric powder using stevioside (Ste), rebaudioside A (RebA), or steviol glucosides (SG) were solubilized in water. The optimum extraction condition by Ste, RebA, or SG resulted in 11.3, 9.7, or 6.7mg/ml water soluble curcuminoids. Curcuminoids solubilized in water showed 80% stability at pH from 6.0 to 10.0 after 1week of storage at 25°C. The particle sizes of curcuminoids prepared with Ste, RebA, and SG were 110.8, 95.7, and 32.7nm, respectively. The water soluble turmeric extracts prepared with Ste, RebA, and SG showed the 2,2-diphenyl-1-picrylhydrazyl radical scavenging (SC50) activities of 127.6, 105.4, and 109.8μg/ml, and the inhibition activities (IC50) against NS2B-NS3(pro) from dengue virus type IV of 14.1, 24.0 and 15.3μg/ml, respectively.

  18. 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.

  19. Antibacterial effect of water-soluble chitosan on representative dental pathogens Streptococcus mutans and Lactobacilli brevis

    PubMed Central

    CHEN, Chih-YU; CHUNG, Ying-CHIEN

    2012-01-01

    Dental caries is still a major oral health problem in most industrialized countries. The development of dental caries primarily involves Lactobacilli spp. and Streptococcus mutans. Although antibacterial ingredients are used against oral bacteria to reduce dental caries, some reports that show partial antibacterial ingredients could result in side effects. Objectives The main objective is to test the antibacterial effect of water-soluble chitosan while the evaluation of the mouthwash appears as a secondary aim. Material and Methods The chitosan was obtained from the Application Chemistry Company (Taiwan). The authors investigated the antibacterial effects of water-soluble chitosan against oral bacteria at different temperatures (25-37ºC) and pH values (pH 5-8), and evaluated the antibacterial activities of a self-made water-soluble chitosan-containing mouthwash by in vitro and in vivo experiments, and analyzed the acute toxicity of the mouthwashes. The acute toxicity was analyzed with the pollen tube growth (PTG) test. The growth inhibition values against the logarithmic scale of the test concentrations produced a concentrationresponse curve. The IC50 value was calculated by interpolation from the data. Results The effect of the pH variation (5-8) on the antibacterial activity of water-soluble chitosan against tested oral bacteria was not significant. The maximal antibacterial activity of water-soluble chitosan occurred at 37ºC. The minimum bactericidal concentration (MBC) of water-soluble chitosan on Streptococcus mutans and Lactobacilli brevis were 400 µg/mL and 500 µg/mL, respectively. Only 5 s of contact between water-soluble chitosan and oral bacteria attained at least 99.60% antibacterial activity at a concentration of 500 µg/mL. The water-soluble chitosan-containin g mouthwash significantly demonstrated antibacterial activity that was similar to that of commercial mouthwashes (>99.91%) in both in vitro and in vivo experiments. In addition, the alcohol

  20. Anti-inflammatory effect of water-soluble complex of 1'-acetoxychavicol acetate with highly branched β-1,3-glucan on contact dermatitis.

    PubMed

    Li, Jiawei; Aizawa, Yui; Hiramoto, Keiichi; Kasahara, Emiko; Tsuruta, Daisuke; Suzuki, Toshio; Ikeda, Atsushi; Azuma, Hideki; Nagasaki, Takeshi

    2015-02-01

    The anti-inflammatory effect on contact dermatitis of the water solubilized 1'-Acetoxychavicol Acetate (ACA) by complexation with β-1,3-glucan isolated form Aureobasidium pullulans black yeast is reported. It is well-known that ACA possesses a function to inhibit the activation of NF-κB by which genes encoding proinflammatory cytokines, chemokines, and growth factors are regulated. However, because ACA is quite insoluble in water, its usefulness has been extremely limited. On the other hand, a triple-helical polysaccharide β-1,3-glucan can include hydrophobic compounds into intrastrand hydrophobic cavity and solubilize poorly water-soluble compounds. In this study, solubilization of ACA by complexation with highly branched β-1,3-glucan was achieved. The effect of anti-inflammatory response of water-soluble ACA complex with β-1,3-glucan was confirmed in vitro and in vivo.

  1. Strategies to address low drug solubility in discovery and development.

    PubMed

    Williams, Hywel D; Trevaskis, Natalie L; Charman, Susan A; Shanker, Ravi M; Charman, William N; Pouton, Colin W; Porter, Christopher J H

    2013-01-01

    Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

  2. Gonadal and Adrenal Abnormalities in Drug Users: Cause or Consequence of Drug Use Behavior and Poor Health Outcomes.

    PubMed

    Brown, Todd T; Wisniewski, Amy B; Dobs, Adrian S

    2006-01-01

    Opiates and cocaine both have effects on adrenal and gonadal function. Opiates suppress the hypothalamic-pituitary adrenal (HPA) axis, whereas cocaine leads to HPA activation. Opiates also cause gonadal dysfunction in both men and women. During withdrawal from opiates and cocaine, the HPA axis is activated which may reinforce relapse behavior. This review describes these hormonal effects and explores the potential consequences, including the effects on mood cognition and cardiovascular risk. Modification of the drug-induced hormonal dysfunction may represent a treatment strategy for drug rehabilitation.

  3. Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods.

    PubMed

    Sarnes, Annika; Østergaard, Jesper; Jensen, Sabrine Smedegaard; Aaltonen, Jaakko; Rantanen, Jukka; Hirvonen, Jouni; Peltonen, Leena

    2013-11-20

    Application of drug nanocrystals provides advantageous options for the pharmaceutical formulation development of poorly soluble drugs. The objective of this study was to investigate the dissolution behavior improving effects of differently sized nanocrystals of a poorly soluble model drug, indomethacin. Nanocrystal suspensions were prepared using a top-down wet milling technique with three stabilizers: poloxamer F68, poloxamer F127 and polysorbate 80. The dissolution of the differently sized indomethacin nanocrystals were investigated using a channel flow dissolution method and by UV imaging. Unmilled bulk indomethacin and physical mixtures were used as references. According to both the dissolution methods, the dissolution properties of indomethacin were improved by the particle size reduction. UV imaging was used for the first time as a dissolution testing method for fast dissolving nanoscale material. The technique provided new information about the concentration of the dissolved drug next to the sample surface; with the smallest nanocrystals (580 nm) the indomethacin concentration next to the particle surface exceeded five-fold the thermodynamic saturated indomethacin solution concentration. Thus the solubility improvement itself, not only the increased surface area for dissolution, may have an important role in the higher dissolution rates of nanocrystal formulations. Poloxamer F68 was the most optimal stabilizer in the preparation of the indomethacin nanocrystal suspensions and in the solubility and dissolution enhancement as well.

  4. 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. PMID:23614647

  5. U.S. blocks trade agreement on generic drug access in poor countries.

    PubMed

    James, John S

    2002-12-20

    Governments can override patents for legitimate purposes, including public health. But many small or poor countries hve no pharmaceutical industry to manufacture medicines themselves, and global trade rules being phased in will prevent others from exporting to them without the patent holder's permission. Negotiations to solve this problem broke down when the U.S. insisted that any agreement apply only to AIDS, tuberculosis, malaria, and similar major epidemics--excluding cancer, heart disease, and hundreds of other diseases. PMID:12569874

  6. Hepatitis C Is Poorly Associated With Drug Use in Cambodian Americans in Lowell, Massachusetts

    PubMed Central

    Yu, Catherine; Gifford, Allen L.; Christiansen, Cindy L.; Drainoni, Mari-Lynn

    2016-01-01

    Background. Hepatitis C (HCV) is the most common chronic blood-borne infection in the United States and affects Asian and non-Asian Americans comparably. Injection drug use, the most common national transmission risk, is not as prevalent in Asian-Americans, but prior studies do not include many Cambodian Americans. Lowell, Massachusetts has the second largest population of Cambodian Americans, allowing a direct comparison of HCV-infected Cambodian and non-Cambodian Americans not previously done. Improving our understanding of HCV risks in this unique community may improve their linkage to care. Methods. In this cross-sectional study, medical data were collected regarding HCV risk factors for HCV-infected Cambodian and non-Cambodian Americans seen at Lowell Community Health Center from 2009 to 2012. Results. Cambodian Americans (n = 128) were older (mean age 53 vs 43 years old) and less likely to be male (41% vs 67%, P < .001) compared with non-Cambodians (n = 541). Cambodians had lower rates of injection drug use (1.6% vs 33.6%, P < .001) and any drug use (2.3% vs 82.1%, P < .001). More Cambodians were born between 1945 and 1965 (66.4% vs 44.5%). Within this birth cohort, more Cambodians had no other risk factor (82% vs 69%, P = .02). Fewer Cambodians had chronic HCV (53% vs 74%, P < .001). Conclusions. Birth between 1945 and 1965 was the major HCV risk factor for Cambodian Americans. Cambodians had lower rates of injection drug use or any drug use history. Risk behavior screening fails to describe HCV transmission for Cambodian Americans and creates a barrier to their linkage to care. PMID:27419171

  7. Water-soluble aminocurdlan derivatives by chemoselective azide reduction using NaBH4.

    PubMed

    Zhang, Ruoran; Edgar, Kevin J

    2015-05-20

    Water-solubility can often enhance the utility of polysaccharide derivatives, for example in pharmaceutical and biomedical applications. Synthesis of water-soluble aminopolysaccharides, particularly those bearing other sensitive functional groups, can be a challenging endeavor. Curdlan is a bioactive β-1,3-glucan with considerable promise for biomedical applications. Aminocurdlans are intriguing target molecules for study of, for example, their interactions with the proteins that form tight junctions between enterocytes. Herein we report the preparation of two water-soluble 6-aminocurdlans starting from 6-bromo-6-deoxycurdlan. The 6-bromide was first displaced by nucleophilic substitution with sodium azide in dimethyl sulfoxide. The O-2 groups were acylated with hydrophilic oligo (ethylene oxide) esters, so as to enhance aqueous solubility. The resultant 6-azido-6-deoxy-2,4-di-O-trioxadecanoylcurdlan was then treated with excess sodium borohydride to reduce the azide; unexpectedly, the water-soluble product proved to be the amide, 6-trioxadecanamido-6-deoxycurdlan. Regioselectivity and degree of substitution (DS) of those derivatives were characterized by means of (1)H NMR, (13)C NMR and FTIR-spectroscopy, elemental analysis, and titration. Alternatively, direct borohydride reduction of the parent 6-azido-6-deoxycurdlan afforded 6-amino-6-deoxycurdlan that was also water-soluble. PMID:25817646

  8. Maximizing recovery of water-soluble proteins through acetone precipitation.

    PubMed

    Crowell, Andrew M J; Wall, Mark J; Doucette, Alan A

    2013-09-24

    Solvent precipitation is commonly used to purify protein samples, as seen with the removal of sodium dodecyl sulfate through acetone precipitation. However, in its current practice, protein loss is believed to be an inevitable consequence of acetone precipitation. We herein provide an in depth characterization of protein recovery through acetone precipitation. In 80% acetone, the precipitation efficiency for six of 10 protein standards was poor (ca. ≤15%). Poor recovery was also observed for proteome extracts, including bacterial and mammalian cells. As shown in this work, increasing the ionic strength of the solution dramatically improves the precipitation efficiency of individual proteins, and proteome mixtures (ca. 80-100% yield). This is obtained by including 1-30 mM NaCl, together with acetone (50-80%) which maximizes protein precipitation efficiency. The amount of salt required to restore the recovery correlates with the amount of protein in the sample, as well as the intrinsic protein charge, and the dielectric strength of the solution. This synergistic approach to protein precipitation in acetone with salt is consistent with a model of ion pairing in organic solvent, and establishes an improved method to recover proteins and proteome mixtures in high yield.

  9. An Extrusion Spheronization Approach to Enable a High Drug Load Formulation of a Poorly Soluble Drug with a Low Melting Surfactant.

    PubMed

    Tatavarti, Aditya; Kesisoglou, Filippos

    2015-11-01

    Vitamin E tocopherol polyethylene glycol succinate (TPGS) is a non-ionic surface active agent, known to enhance the bioavailability of lipophilic compounds via wettability, solubility, and in some cases permeability enhancement. MK-0536 is an anti-retroviral drug with poor wettability and solubility and a high dose. Based on pharmacokinetic studies in dogs and humans, use of vitamin E TPGS in oral solid formulations of MK-0536 provides desired PK characteristics. The use of vitamin E TPGS, however, in solid dosage forms is limited because of the processing challenges resulting from its waxy nature and low melting temperature (∼37°C). The current study, for the first time, demonstrates the use of an alternative low pressure extrusion and spheronization approach to enable high loadings of the poorly soluble, poorly compactable drug and relatively high levels of vitamin E TPGS. This approach not only aided in mitigating processing challenges arising from most high energy process steps such as milling, compression, and coating, but also enabled a higher drug load formulation that provided superior bioperformance relative to a conventional high shear wet granulated formulation. An encapsulated dosage form consisting of pellets prepared by extrusion spheronization with 75% (w/w) MK-0536 and 10% (w/w) vitamin E TPGS was developed.

  10. Novel dextran-spermine conjugates as transfecting agents: comparing water-soluble and micellar polymers.

    PubMed

    Eliyahu, H; Makovitzki, A; Azzam, T; Zlotkin, A; Joseph, A; Gazit, D; Barenholz, Y; Domb, A J

    2005-03-01

    Recently, a novel cationic polymer, dextran-spermine (D-SPM) was developed for gene delivery. An efficient transfection was obtained using this polycation for a variety of genes and cell lines in serum-free or serum-poor medium. However, transfection using the water-soluble D-SPM-based polyplexes decreased with increasing serum concentration in cell culture in a concentration-dependent manner, reaching 95% inhibition at 50% serum in the cell growth medium. In order to overcome this obstacle, oleyl derivatives of D-SPM (which form micelles in aqueous phase) were synthesized at 1, 10, and 20 mol% of oleyl moiety to polymer epsilon-NH2 to form N-oleyl-D-SPM (ODS). Polyplexes based on ODS transfected well in medium containing 50% serum. Comparison with polyplexes based on well-established polymers (branched and linear polyethyleneimine) and with DOTAP/Cholesterol lipoplexes showed that regarding beta-galactosidase transgene expression level and cytotoxicity in tissue culture, the D-SPM and ODS compare well with the above polyplexes and lipoplexes. Intracellular trafficking using FITC-labeled ODS and Rhodamine-labeled pGeneGrip plasmid cloned with hBMP2 monitored by confocal microscopy revealed that during the transfection process the fluorescent-labeled polymer concentrates in the Golgi apparatus and around the nucleus, while the cell cytoplasm was free of fluorescent particles, suggesting that the polyplexes move in the cell toward the nucleus by vesicular transport through the cytoplasm and not by a random diffusion. We found that the plasmids penetrate the cell nucleus without the polymer. Preliminary results in zebra fish and mice demonstrate the potential of ODS to serve as an efficient nonviral vector for in vivo transfection.

  11. Micellar systems: Novel family for drug carriers

    NASA Astrophysics Data System (ADS)

    Rana, Meenakshi; Chowdhury, Papia

    2016-05-01

    Micellar systems have attracted a great deal of interest, especially in the field of biomedical sciences. The paper deals with the encapsulation behavior of Pyrrole-2-carboxyldehyde (PCL) an anti-cancer drug in different micellar systems. The inculsion capability of PCL is verified experimentally (UV-Vis, Photoluminescence and Raman spectroscopy) in polymer matrix. Two-micellar systems sodium dodecyl sulfate (SDS) and Polysorbate 80 (TWEEN 80) have been studied with a poorly water soluble PCL. The present work provides the effects of biocompatible organic PCL molecule entrap in micellar system in polymer phase due to its vast applicability in drug industry.

  12. Nanosuspension Technology For Poorly Soluble Drugs: Recent Researches, Advances and Patents.

    PubMed

    Agarwal, Vijay; Bajpai, Meenakshi

    2015-01-01

    Nowadays, in pharmaceutical industries, the attention on nanosized materials is growing gradually due to their wide applications in drug delivery systems. Recently, out of different nanosize systems, nanosuspension system has undergone a lot of interest in such a way to rectify the solubility and bioavailability problem due to their technical simplicity and cost-effectiveness property compared to other colloidal systems. Nanosuspension technology has proven that it can be a superior substitute over alternative approaches, which are available for enhancing the bioavailability of different drugs having low solubility. Since today, nanosuspensions have been greatly evolved for a huge number of drugs and also investigated for their potential applications. The various unique features make the nanosuspension to enable their utilization in numerous dosage forms and given through different routes, including parenteral, oral, topical, peroral, ocular and pulmonary routes. A large number of products grounded in nanosuspension technology are present in the market, and some are on the way. In fact, the number of such types of products is much more in comparison of other nanotechnologies based products. Additionally, the different preparation methods used to prepare the nanosuspensions are also well- established and patented. This article reviews the recent research, advances in formulation and their approaches related to nanosuspensions with emphasis given on different patents related to nanosuspension methods.

  13. Liquid Salt as Green Solvent: A Novel Eco-Friendly Technique to Enhance Solubility and Stability of Poorly Soluble Drugs

    NASA Astrophysics Data System (ADS)

    Patel, Anant A.

    As a result of tremendous efforts in past few decades, various techniques have been developed in order to resolve solubility issues associated with class II and IV drugs, However, majority of these techniques offer benefits associated with certain drawbacks; majorly including low drug loading, physical instability on storage and excessive use of environmentally challenging organic solvents. Hence, current effort was to develop an eco-friendly technique using liquid salt as green solvent, which can offer improvement in dissolution while maintaining long term stability. The liquid salt formulations (LSF) of poorly soluble model drugs ibuprofen, gemfibrozil and indomethacin were developed using 1-Ethyl-3-methylimidazolium ethyl sulfate (EMIM ES) as a non-toxic and environmentally friendly alternate to organic solvents. Liquid medications containing clear solutions of drug, EMIM ES and polysorbate 20, were adsorbed onto porous carrier Neusilin US2 to form free flowing powder. The LSF demonstrated greater rate and extent of dissolution compared to crystalline drugs. The dissolution data revealed that more than 80% drug release from LSF within 20 mins compared to less than 18% release from pure drugs. As high as 70% w/w liquid loading was achieved while maintaining good flowability and compressibility. In addition, the LSF samples exposed to high temperature and high humidity i.e. 40°C/80% RH for 8 weeks, demonstrated excellent physical stability without any signs of precipitation or crystallization. As most desirable form of administration is tablet, the developed liquid salt formulations were transformed into tablets using design of experiment approach by Design Expert Software. The tablet formulation composition and critical parameter were optimized using Box-Behnken Design. This innovative liquid salt formulation technique offered improvement in dissolution rate and extent as well as contributed to excellent physical stability on storage. Moreover, this formulation

  14. Simultaneous extraction of oil- and water-soluble phase from sunflower seeds with subcritical water.

    PubMed

    Ravber, Matej; Knez, Željko; Škerget, Mojca

    2015-01-01

    In this study, the subcritical water extraction is proposed as an alternative and greener processing method for simultaneous removal of oil- and water-soluble phase from sunflower seeds. Extraction kinetics were studied at different temperatures and material/solvent ratios in a batch extractor. Degree of hydrothermal degradation of oils was observed by analysing amount of formed free fatty acids and their antioxidant capacities. Results were compared to oils obtained by conventional methods. Water soluble extracts were analysed for total proteins, carbohydrates and phenolics and some single products of hydrothermal degradation. Highest amount of oil was obtained at 130 °C at a material/solvent ratio of 1/20 g/mL after 30 min of extraction. For all obtained oils minimal degree of hydrothermal degradation could be identified. High antioxidant capacities of oil samples could be observed. Water soluble extracts were degraded at temperatures ≥100 °C, producing various products of hydrothermal degradation.

  15. Water-soluble prodrugs of paclitaxel containing self-immolative disulfide linkers.

    PubMed

    Gund, Machhindra; Khanna, Amit; Dubash, Nauzer; Damre, Anagha; Singh, Kishore S; Satyam, Apparao

    2015-01-01

    A new series of disulfide-containing prodrugs of paclitaxel were designed, synthesized and evaluated against 6 cancer cell lines. Some of these prodrugs exhibited nearly equal or slightly better anticancer activity when compared to that of paclitaxel. These prodrugs contain water-soluble groups such as amino, carboxyl, hydroxyl, amino acids, etc., and exhibited 6-140 fold increase in aqueous solubility when compared to paclitaxel. One of these prodrugs exhibited improved water solubility, better in vitro anticancer activity and significantly superior oral bioavailability in mice when compared to those of paclitaxel. Thus, we have identified a very promising lead compound for further optimization and evaluation as a potentially bioavailable water-soluble prodrug of paclitaxel.

  16. Effect of supplementation of water-soluble vitamins on oxidative stress and blood pressure in prehypertensives.

    PubMed

    Talikoti, Prashanth; Bobby, Zachariah; Hamide, Abdoul

    2015-01-01

    The objective of the study was to evaluate the effect of water-soluble vitamins on oxidative stress and blood pressure in prehypertensives. Sixty prehypertensives were recruited and randomized into 2 groups of 30 each. One group received water-soluble vitamins and the other placebo for 4 months. Further increase in blood pressure was not observed in the vitamin group which increased significantly in the placebo group at the end of 4 months. Malonedialdehyde and protein carbonylation were reduced during the course of treatment with vitamins whereas in the placebo group there was an increase in the level of malondialdehyde. In conclusion, supplementation of water-soluble vitamins in prehypertension reduces oxidative stress and its progression to hypertension.

  17. Coaxial electrospinning for encapsulation and controlled release of fragile water-soluble bioactive agents.

    PubMed

    Jiang, Hongliang; Wang, Liqun; Zhu, Kangjie

    2014-11-10

    Coaxial electrospinning is a robust technique for one-step encapsulation of fragile, water-soluble bioactive agents, including growth factors, DNA and even living organisms, into core-shell nanofibers. The coaxial electrospinning process eliminates the damaging effects due to direct contact of the agents with organic solvents or harsh conditions during emulsification. The shell layer serves as a barrier to prevent the premature release of the water-soluble core contents. By varying the structure and composition of the nanofibers, it is possible to precisely modulate the release of the encapsulated agents. Promising work has been done with coaxially electrospun non-woven mats integrated with bioactive agents for use in tissue engineering, in local delivery and in wound healing, etc. This paper reviews the origins of the coaxial electrospinning method, its updated status and potential future developments for controlled release of the class of fragile, water-soluble bioactive agents. PMID:24780265

  18. Cervical myelography of nerve root avulsion injuries using water-soluble contrast media.

    PubMed

    Cobby, M J; Leslie, I J; Watt, I

    1988-08-01

    Eight cases of cervical nerve root avulsion injury are presented which were investigated by cervical myelography using a water-soluble contrast medium. The previous literature describes the appearances of this lesion using an oil-based agent and has resulted in emphasis being placed on looking for a traumatic meningocele rather than an abnormality of the roots themselves. The excellent definition of the nerve rootlets and axillary pouch that are obtained with a water-soluble contrast medium resulted in more root lesions per patient being detected than with an oil-based medium. There was complete correlation with the surgical findings at all but one root level explored. The appearances of root avulsion injuries and the advantages of using a water-soluble contrast medium are discussed. PMID:3416107

  19. Effect of addition of water-soluble chitin on amylose film.

    PubMed

    Suzuki, Shiho; Shimahashi, Katsumasa; Takahara, Junichi; Sunako, Michihiro; Takaha, Takeshi; Ogawa, Kozo; Kitamura, Shinichi

    2005-01-01

    Amylose films blended with chitosan, which were free from additives such as acid, salt, and plasticizer, were prepared by casting mixtures of an aqueous solution of an enzymatically synthesized amylose and that of water-soluble chitin (44.1% deacetylated). The presence of a small amount of chitin (less than 10%) increased significantly the permeability of gases (N2, O2, CO2, C2H4) and improved the mechanical parameters of amylose film; particularly, the elastic modulus and elongation of the blend films were larger than those of amylose or chitin films. No antibacterial activity was observed with either amylose or water-soluble chitin films. But amylose films having a small amount of chitin showed strong antibacterial action, suggesting a morphological change in water-soluble chitin on the film surface by blending with amylose molecule. These facts suggested the presence of a molecular complex of amylose and chitosan. PMID:16283751

  20. Coaxial electrospinning for encapsulation and controlled release of fragile water-soluble bioactive agents.

    PubMed

    Jiang, Hongliang; Wang, Liqun; Zhu, Kangjie

    2014-11-10

    Coaxial electrospinning is a robust technique for one-step encapsulation of fragile, water-soluble bioactive agents, including growth factors, DNA and even living organisms, into core-shell nanofibers. The coaxial electrospinning process eliminates the damaging effects due to direct contact of the agents with organic solvents or harsh conditions during emulsification. The shell layer serves as a barrier to prevent the premature release of the water-soluble core contents. By varying the structure and composition of the nanofibers, it is possible to precisely modulate the release of the encapsulated agents. Promising work has been done with coaxially electrospun non-woven mats integrated with bioactive agents for use in tissue engineering, in local delivery and in wound healing, etc. This paper reviews the origins of the coaxial electrospinning method, its updated status and potential future developments for controlled release of the class of fragile, water-soluble bioactive agents.

  1. Characteristics of water-soluble ions before, during and after fog events

    NASA Astrophysics Data System (ADS)

    Li, P.; Du, H.; Yang, C.; Yao, J.; Du, J.; Chen, J.

    2010-07-01

    Two atmospheric processes of rain-fog-haze and haze-fog-rain were observed on Feb.8th and Mar. 14th, 2010 in urban Shanghai. On-line characterization of water-soluble ions of aerosol was performed before, during and after two fog episodes by an instrument of Monitoring AeRosoles and GAses (MARGA). Fog water samples were also collected to study the chemical ion characteristics for identifying the property of fogs. After rain, total water-soluble ion concentration in PM2.5 increased by 71.9%. Afterwards, a fog formation was observed as a frontal fog. Six fog water samples were collected to measure concentration of water-soluble ions, whose total concentrations decreased from beginning to end of fog. At the end of fog, the total water-soluble ion concentration of aerosol was continually increased. Meanwhile with a sharp decline of RH down to 70% in two hours, and a haze episode was observed. The reverse process, haze-fog-rain process, was also investigated. After the haze episode, total water-soluble ions concentration of aerosol rarely increased, but fog appeared with sharp increase of RH. Concentration of water-soluble ions in the fog water sample was higher than mean concentration of samples in 2009. When the fog started to disperse, the ion concentration hardly changed. As water vapor continued to increase, rain was observed. The inorganic compositions of aerosol in both fog events were dominated by sulfate and ammonium. The in situ investigation clearly illustrated that fog water mainly influenced by continental sources was dirtier and contained more sediment comparing with fog water influenced by marine sources.

  2. Surfactant-assisted synthesis of water-soluble and biocompatible semiconductor quantum dot-micelles.

    SciTech Connect

    Brinker, C. Jeffrey; Bunge, Scott D.; Gabaldon, John; Fan, Hongyou; Scullin, Chessa; Leve, Erik W.; Wilson, Michael C.; Tallant, David Robert; Boyle, Timothy J.

    2005-04-01

    We report a simple, rapid approach to synthesize water-soluble and biocompatible fluorescent quantum dot (QD) micelles by encapsulation of monodisperse, hydrophobic QDs within surfactant/lipid micelles. Analyses of UV-vis and photo luminescence spectra, along with transmission electron microscopy, indicate that the water-soluble semiconductor QD micelles are monodisperse and retain the optical properties of the original hydrophobic QDs. The QD micelles were shown to be biocompatible and exhibited little or no aggregation when taken up by cultured rat hippocampal neurons.

  3. Method of immobilizing water-soluble bioorganic compounds on a capillary-porous carrier

    DOEpatents

    Ershov, Gennady Moiseevich; Timofeev, Eduard Nikolaevich; Ivanov, Igor Borisovich; Florentiev, Vladimir Leonidovich; Mirzabekov, Andrei Darievich

    1998-01-01

    The method for immobilizing water-soluble bioorganic compounds to capillary-porous carrier comprises application of solutions of water-soluble bioorganic compounds onto a capillary-porous carrier, setting the carrier temperature equal to or below the dew point of the ambient air, keeping the carrier till appearance of water condensate and complete swelling of the carrier, whereupon the carrier surface is coated with a layer of water-immiscible nonluminescent inert oil and is allowed to stand till completion of the chemical reaction of bonding the bioorganic compounds with the carrier.

  4. Determination of water-soluble ions in soils from the dry valleys of Antarctica

    NASA Technical Reports Server (NTRS)

    Bustin, R.

    1981-01-01

    The soil chemistry of the dry valleys of Antarctica was studied. These valleys furnish a terrestrial analog for the surface of Mars. The abundance of the water-soluble ions magnesium, calcium, potassium, sodium chloride, and nitrate in soil samples was determined. All samples examined contained water-soluble salts reflecting the aridity of the area. Movement of salts to low-lying areas was verified. Upward ionic migration was evident in all core samples. Of all cations observed, sodium showed the greatest degree of migration.

  5. A green route to water soluble carbon nanotubes and in situ loading of silver nanoparticles

    NASA Astrophysics Data System (ADS)

    Xue, Chao-Hua; Zhou, Ren-Jia; Shi, Min-Min; Gao, Yan; Wu, Gang; Zhang, Xiao-Bin; Chen, Hong-Zheng; Wang, Mang

    2008-08-01

    A green approach has been developed to synthesize water soluble multi-walled carbon nanotubes (MWNTs). Ag nanoparticles have been loaded on the as-synthesized MWNTs via the in situ solution method. The strategy is based on the introduction of hydroxyl and carboxyl groups through a mild modification of MWNTs via polycondensation of citric acid and D-sorbitol, improving the water solubility of MWNTs, giving rise to preferred sites of Ag nucleation, and providing mild in situ reducing agents. The modification of MWNTs and loading of Ag nanoparticles on MWNTs were demonstrated by Fourier transform infrared spectroscopy, thermogravimetric analysis, transmission electron microscopy, and scanning electron microscopy.

  6. Surfactant-assisted synthesis of water-soluble and biocompatible semiconductor quantum dot-micelles

    NASA Astrophysics Data System (ADS)

    Fan, Hongyou; Leve, Erik W.; Scullin, Chessa; Tallant, David; Wilson, Michael C.; Brinker, C. J.

    2005-04-01

    We report a simple and rapid method to synthesize water-soluble and biocompatible fluorescent quantum dot (QD)-micelles by encapsulation of monodisperse, hydrophobic QDs inside surfactant/lipid micelles. Analysis of UV-vis spectra, transmission electron microscopy, and photo luminescence spectra indicate that the water-soluble semiconductor QD-micelles are monodisperse and retain the optical properties of the original hydrophobic QDs. The QD-micelles were shown to be biocompatible and exhibited little or no aggregation when taken up by cultured rat hippocampal neurons.

  7. Novel Water-Soluble Amphotericin B-PEG Conjugates with Low Toxicity and Potent in Vivo Efficacy.

    PubMed

    Halperin, Assaf; Shadkchan, Yana; Pisarevsky, Evgeni; Szpilman, Alex M; Sandovsky, Hani; Osherov, Nir; Benhar, Itai

    2016-02-11

    Systemic fungal infections are an increasingly prevalent health problem, especially among immunocompromised patients. Antifungal drug development lags far behind in comparison to other types of antimicrobial drugs. Current commercially available antifungals are limited by their insufficient potency, side effects, drug-drug interactions, developing drug-resistance, and narrow formulation options. Here, we report the preparation and evaluation of two novel PEG amide conjugates of amphotericin B (AMB (1)): AB1 (4) and AM2 (5). These compounds are nonlabile, they are prepared in only two and three synthetic steps, respectively, and they show antifungal activity against a wide range of clinical fungal isolates. Their toxicity is significantly lower, and their water solubility is up to 5000-fold higher than that of AMB (1). In vivo efficacy studies in a mouse model of systemic candidiasis showed that AM2 (5) successfully cured all the mice at concentrations above 3.5 mg/kg body weight. In conclusion, these properties make AB1 (4) and AM2 (5) promising candidates for clinical use. PMID:26816333

  8. Panax Notoginseng Saponins as a Novel Nature Stabilizer for Poorly Soluble Drug Nanocrystals: A Case Study with Baicalein.

    PubMed

    Xie, Yuanbiao; Ma, Yueqin; Xu, Junnan; Liu, Yang; Yue, Pengfei; Zheng, Qin; Hu, Pengyi; Yang, Ming

    2016-01-01

    This study is aimed at seeking a nature saponin-based stabilizer for drug nanosuspensions. A poorly soluble drug (baicalein, BCL) was used as a model drug. BCL nanosuspensions with particle size of 156 nm were prepared by means of homogenization and converted into BCL nanocrystals (BCL-NC) stabilized with panax notoginseng saponins (PNS). It was found that PNS was able to prevent the aggregation of BCL-NS during storage and improve the redispersibility of BCL-NC after freeze-drying and spray-drying, compared with polymer stabilizer PVPK30. The freeze-dried and spray-dried BCL-NC with PNS exhibited excellent performance as evidenced by scanning_electron_microscope (SEM) analysis. It was the reason that PNS possessed the interfacial property (41.69 ± 0.32 mN/m) and electrostatic effect (-40.1 ± 1.6 mV), which could easily adsorb onto the surface of hydrophobic BCL nanocrystals and prevent from its aggregation. It is concluded that PNS can be used as an effective nature stabilizer for production of drug nanocrystals. PMID:27589712

  9. Characteristics of size-fractionated atmospheric metals and water-soluble metals in two typical episodes in Beijing

    NASA Astrophysics Data System (ADS)

    Wang, Qingqing; Ma, Yongliang; Tan, Jihua; Zheng, Naijia; Duan, Jingchun; Sun, Yele; He, Kebin; Zhang, Yuanxun

    2015-10-01

    The abundance and behaviour of metals and water-soluble metals (V, Cr, Mn, Fe, Cu, Zn, As, Sr, Ag, Cd, Sn, Sb, Ba and Pb) in size-fractionated aerosols were investigated during two typical episodes in Beijing. Water-soluble inorganic ions (Na+, K+, Mg2+, Ca2+, NH4+ , F-, Cl-, SO42- and NO3-) were also measured. Atmospheric metals and water-soluble metals were both found at high levels; for PM2.5, average As, Cr, Cd, Cu, Mn and Pb concentrations were 14.8, 203.3, 2.5, 18.5, 42.6 and 135.3 ng/m3, respectively, and their water-soluble components were 11.1, 1.7, 2.4, 14.5, 19.8 and 97.8 ng/m3, respectively. Daily concentrations of atmospheric metals and water-soluble metals were generally in accordance with particle mass. The highest concentrations of metals and water-soluble metals were generally located in coarse mode and droplet mode, respectively. The lowest mass of metals and water-soluble metals was mostly in Aitken mode. The water solubility of all metals was low in Aitken and coarse modes, indicating that freshly emitted metals have low solubility. Metal water solubility generally increased with the decrease in particle size in the range of 0.26-10 μm. The water solubility of metals for PM10 was: 50% ≤ Cd, As, Sb, Pb; 26% < V, Mn, Cu, Zn and Sr ≤ 50%; others ≤20%. Most metals, water-soluble metals and their water solubility increased when polluted air mass came from the near west, near north-west, south-west and south-east of the mainland, and decreased when clean air mass came from the far north-west and far due south. The influence of dust-storms and clean days on water-soluble metals and size distribution was significant; however, the influence of rainfall was negligible. Aerosols with high concentrations of SO42- , K+ and NH4+ might indicate increased potential for human health effects because of their high correlation with water-soluble metals. Industrial emissions contribute substantially to water-soluble metal pollution as water-soluble metals

  10. Pharmaceutical properties of freeze-dried formulations of egg albumin, several drugs and olive oil.

    PubMed

    Tsuji, Y; Kakegawa, H; Miyataka, H; Nishiki, M; Matsumoto, H; Satoh, T

    1996-04-01

    The freeze-dried ternary formulations of meclizine (MZ, an anti-motion sickness drug), prednisolone (PRED, an anti-inflammatory drug) and norfloxacin (NFLX, an anti-microbial drug) which are poorly water-soluble and are low bioavailability drugs, were prepared using egg albumin and olive oil. The powder X-ray diffractions, the dissolution rate and the bioavailabilities in vivo of these formulations were studied in comparison with each drug alone. By forming ternary formulations of these drugs, the dissolution rates of the drugs from the formulations were significantly improved compared with each drug alone. The results of their powder X-ray diffraction measurements showed that these drugs in the ternary formulations presented in an amorphous form, indicating increased dissolution rates. On the other hand, the plasma concentrations of these drugs increased significantly after oral administration in formulations to rats, except for the NFLX formulation, and the areas under the concentration-time curves (AUC) of the ternary formulations of MZ, PRED and NFLX were 2.1, 1.6 and 1.3 times those of the drugs alone, respectively. From these results, it was proven that formulations consisting of egg albumin, olive oil and poorly water-soluble drugs were useful preparations for improving the drug's disadvantageous pharmaceutical properties. PMID:9132174

  11. Antiretroviral Drug Diversion Links Social Vulnerability to Poor Medication Adherence in Substance Abusing Populations

    PubMed Central

    Tsuyuki, Kiyomi; Surratt, Hilary L.

    2015-01-01

    Antiretroviral (ARV) medication diversion to the illicit market has been documented in South Florida, and linked to sub-optimal adherence in people living with HIV. ARV diversion reflects an unmet need for care in vulnerable populations that have difficulty engaging in consistent HIV care due to competing needs and co-morbidities. This study applies the Gelberg-Andersen Behavioral Model of Health Care Utilization for Vulnerable Populations to understand how social vulnerability is linked to ARV diversion and adherence. Cross-sectional data were collected from a targeted sample of vulnerable people living with HIV in South Florida between 2010 and 2012 (n=503). Structured interviews collected quantitative data on ARV diversion, access and utilization of care, and ARV adherence. Logistic regression was used to estimate the goodness-of-fit of additive models that test domain fit. Linear regression was used to estimate the effects of social vulnerability and ARV diversion on ARV adherence. The best fitting model to predict ARV diversion identifies having a low monthly income and unstable HIV care as salient enabling factors that promote ARV diversion. Importantly, health care need factors did not protect against ARV diversion, evidence that immediate competing needs are prioritized even in the face of poor health for this sample. We also find that ARV diversion provides a link between social vulnerability and sub-optimal ARV adherence, with ARV diversion and domains from the Behavioral Model explaining 25% of the variation in ARV adherence. Our analyses reveal great need to improve engagement in HIV care for vulnerable populations by strengthening enabling factors (e.g. patient-provider relationship) to improve retention in HIV care and ARV adherence for vulnerable populations. PMID:25893656

  12. Antiretroviral drug diversion links social vulnerability to poor medication adherence in substance abusing populations.

    PubMed

    Tsuyuki, Kiyomi; Surratt, Hilary L

    2015-05-01

    Antiretroviral (ARV) medication diversion to the illicit market has been documented in South Florida, and linked to sub-optimal adherence in people living with HIV. ARV diversion reflects an unmet need for care in vulnerable populations that have difficulty engaging in consistent HIV care due to competing needs and co-morbidities. This study applies the Gelberg-Andersen behavioral model of health care utilization for vulnerable populations to understand how social vulnerability is linked to ARV diversion and adherence. Cross-sectional data were collected from a targeted sample of vulnerable people living with HIV in South Florida between 2010 and 2012 (n = 503). Structured interviews collected quantitative data on ARV diversion, access and utilization of care, and ARV adherence. Logistic regression was used to estimate the goodness-of-fit of additive models that test domain fit. Linear regression was used to estimate the effects of social vulnerability and ARV diversion on ARV adherence. The best fitting model to predict ARV diversion identifies having a low monthly income and unstable HIV care as salient enabling factors that promote ARV diversion. Importantly, health care need factors did not protect against ARV diversion, evidence that immediate competing needs are prioritized even in the face of poor health for this sample. We also find that ARV diversion provides a link between social vulnerability and sub-optimal ARV adherence, with ARV diversion and domains from the Behavioral Model explaining 25 % of the variation in ARV adherence. Our analyses reveal great need to improve engagement in HIV care for vulnerable populations by strengthening enabling factors (e.g. patient-provider relationship) to improve retention in HIV care and ARV adherence for vulnerable populations.

  13. Profiling and relationship of water-soluble sugar and protein compositions in soybean seeds.

    PubMed

    Yu, Xiaomin; Yuan, Fengjie; Fu, Xujun; Zhu, Danhua

    2016-04-01

    Sugar and protein are important quality traits in soybean seeds for making soy-based food products. However, the investigations on both compositions and their relationship have rarely been reported. In this study, a total of 35 soybean germplasms collected from Zhejiang province of China, were evaluated for both water-soluble sugar and protein. The total water-soluble sugar (TWSS) content of the germplasms studied ranged from 84.70 to 140.91 mg/g and the water-soluble protein (WSP) content varied from 26.5% to 36.0%. The WSP content showed positive correlations with the TWSS and sucrose contents but negative correlations with the fructose and glucose contents. The clustering showed the 35 germplasms could be divided into four groups with specific contents of sugar and protein. The combination of water-soluble sugar and protein profiles provides useful information for future breeding and genetic research. This investigation will facilitate future work for seed quality improvement.

  14. Simultaneous Determination of Water Soluble Vitamins in Dietary Supplements and Fortified Foods by LC-MS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent work in our laboratory has focused on development of LC methods with diode array and/or mass spectrometry (ms) detection for the simultaneous determination in supplement tablets and fortified foods of several water-soluble vitamins (WSV) including: thiamin, niacin, pyridoxine, pantothenic ac...

  15. Isolation, purification and physicochemical characterization of water-soluble Bacillus thuringiensis melanin.

    PubMed

    Aghajanyan, Armen E; Hambardzumyan, Artur A; Hovsepyan, Anichka S; Asaturian, Rafael A; Vardanyan, Andranik A; Saghiyan, Ashot A

    2005-04-01

    Melanins are widely used in medicine, pharmacology, cosmetics and other fields. Although several technologies for the purification of water-insoluble dioxyphenylalanine (DOPA) melanins have been described, a source of water-soluble melanin is highly desirable. Here we describe an effective procedure for the isolation and purification of water-soluble melanin using the culture medium of Bacillus thuringiensis subsp. galleriae strain K1. Water-soluble melanin from this organism has an isoelectric point (pI=3.0-3.2) and was purified optimally by adsorbtion using the IA-1r resin and elution as a concentrated solution. The purified melanin obtained exhibited a similar infra-red absorbtion spectrum to synthetic melanin and contained quinolic and phenolic structures and an amino acid content of around 20% after acid hydrolysis. The molecular weight of the purified melanin determined by SDS-PAGE was 4 kDa and the electromagnetic spin resonance spectrum of the purified microbial melanin was a slightly asymmetric singlet without hyperfine structure with about 7 Gauss width of the line between points of the maximum incline and g=2.006. The concentration of paramagnetic centers in melanin is 0.21x10(18) spin/g. The results obtained provide a rapid, simple and inexpensive method for the large scale purification of water soluble melanin that may have widespread applications.

  16. Water-soluble lead in cathode ray tube funnel glass melted in a reductive atmosphere.

    PubMed

    Okada, Takashi

    2016-10-01

    In the reduction-melting process, lead can be recovered from cathode ray tube funnel glass (PbO=25wt%); however, resulting glass residues still contain approximately 1-2wt% of unrecovered lead. For environmental protection in the residue disposal or recycling, it is important to evaluate the quantities of water-soluble species among the unrecovered lead. This study examined water-soluble lead species generated in the reduction-melting process of the funnel glass and factors determining their generation. In the reduction-melting, metallic lead was generated by reducing lead oxides in the glass, and a part of the metallic lead remained in the glass residue. Such unrecovered metallic lead can dissolve in water depending on its pH level and was regarded as water-soluble lead. When 10g Na2CO3 was added to 20g funnel glass during reduction-melting, the resulting glass contained high concentrations of sodium. In a water leaching of the glass, the obtained leachate was alkalized by the sodium-rich glass (pH=12.7-13.0). The unrecovered metallic lead in the glass was extracted in the alkalized leachate. The quantity of the unrecovered metallic lead (water-soluble lead) in the glass decreased when the melting time, melting temperature, and carbon dosage were controlled during reduction-melting. PMID:27209518

  17. Fabrication and multifunctional properties of ultrasmall water-soluble tungsten oxide quantum dots.

    PubMed

    Peng, Huaping; Liu, Pan; Lin, Danwei; Deng, Yani; Lei, Yun; Chen, Wei; Chen, Yuanzhong; Lin, Xinhua; Xia, Xinghua; Liu, Ailin

    2016-07-21

    A facile and green method has been demonstrated to synthesize ultrasmall tungsten oxide quantum dots (WOx QDs). The water-soluble WOx QDs present high luminescence stability, strong peroxidase-like activity, and excellent electrochemiluminescence properties. This work provides an eco-friendly strategy to prepare multifunctional WOx QDs, and opens the door for bioapplications of the WOx QDs. PMID:27381501

  18. Antioxidative activity of water soluble polysaccharide in pumpkin fruits (Cucurbita maxima Duchesne).

    PubMed

    Nara, Kazuhiro; Yamaguchi, Akira; Maeda, Naomi; Koga, Hidenori

    2009-06-01

    We evaluated the antioxidative activity of a water soluble polysaccharide fraction (WSP) from pumpkin fruits (Cucurbita maxima Duchesne). In the WSP, DPPH radical scavenging and superoxide dismutase-like activity increased depending on the total sugar content. Furthermore, the WSP can serve as an inhibitor of ascorbic acid oxidation. The efficacy was also affected by the total sugar content.

  19. Water-soluble constituents of caraway: carvone derivatives and their glucosides.

    PubMed

    Matsumura, Tetsuko; Ishikawa, Toru; Kitajima, Junichi

    2002-01-01

    Nine monoterpenoids related to carvone and seven glucosides were isolated from the water-soluble portion of the methanolic extract of the caraway (fruit of Carum carvi L.), and their structures were clarified by spectral investigation. Among them, eight monoterpenoids and six glucosides were new.

  20. Water-soluble constituents of caraway: aromatic compound, aromatic compound glucoside and glucides.

    PubMed

    Matsumura, Tetsuko; Ishikawa, Toru; Kitajima, Junichi

    2002-10-01

    From the water-soluble portion of the methanolic extract of caraway (fruit of Carum carvi L.), an aromatic compound, an aromatic compound glucoside and a glucide were isolated together with 16 known compounds. Their structures were clarified as 2-methoxy-2-(4'-hydroxyphenyl)ethanol, junipediol A 2-O-beta-D-glucopyranoside and L-fucitol, respectively.

  1. Profiling and relationship of water-soluble sugar and protein compositions in soybean seeds.

    PubMed

    Yu, Xiaomin; Yuan, Fengjie; Fu, Xujun; Zhu, Danhua

    2016-04-01

    Sugar and protein are important quality traits in soybean seeds for making soy-based food products. However, the investigations on both compositions and their relationship have rarely been reported. In this study, a total of 35 soybean germplasms collected from Zhejiang province of China, were evaluated for both water-soluble sugar and protein. The total water-soluble sugar (TWSS) content of the germplasms studied ranged from 84.70 to 140.91 mg/g and the water-soluble protein (WSP) content varied from 26.5% to 36.0%. The WSP content showed positive correlations with the TWSS and sucrose contents but negative correlations with the fructose and glucose contents. The clustering showed the 35 germplasms could be divided into four groups with specific contents of sugar and protein. The combination of water-soluble sugar and protein profiles provides useful information for future breeding and genetic research. This investigation will facilitate future work for seed quality improvement. PMID:26593554

  2. Water-soluble lead in cathode ray tube funnel glass melted in a reductive atmosphere.

    PubMed

    Okada, Takashi

    2016-10-01

    In the reduction-melting process, lead can be recovered from cathode ray tube funnel glass (PbO=25wt%); however, resulting glass residues still contain approximately 1-2wt% of unrecovered lead. For environmental protection in the residue disposal or recycling, it is important to evaluate the quantities of water-soluble species among the unrecovered lead. This study examined water-soluble lead species generated in the reduction-melting process of the funnel glass and factors determining their generation. In the reduction-melting, metallic lead was generated by reducing lead oxides in the glass, and a part of the metallic lead remained in the glass residue. Such unrecovered metallic lead can dissolve in water depending on its pH level and was regarded as water-soluble lead. When 10g Na2CO3 was added to 20g funnel glass during reduction-melting, the resulting glass contained high concentrations of sodium. In a water leaching of the glass, the obtained leachate was alkalized by the sodium-rich glass (pH=12.7-13.0). The unrecovered metallic lead in the glass was extracted in the alkalized leachate. The quantity of the unrecovered metallic lead (water-soluble lead) in the glass decreased when the melting time, melting temperature, and carbon dosage were controlled during reduction-melting.

  3. FATE OF WATER SOLUBLE AZO DYES IN THE ACTIVATED SLUDGE PROCESS

    EPA Science Inventory

    The objective of this study was to determine the partitioning of water soluble azo dyes in the activated sludge process (ASP). Azo dyes are of concern because some of the dyes, dye precursors , and/or their degradation products such as aromatic amines (which are also dye precurso...

  4. Young Age Predicts Poor Antiretroviral Adherence and Viral Load Suppression Among Injection Drug Users

    PubMed Central

    Hadland, Scott E.; Milloy, M.-J.; Kerr, Thomas; Zhang, Ruth; Guillemi, Silvia; Hogg, Robert S.; Montaner, Julio S.

    2012-01-01

    Abstract Previous studies of adherence to antiretroviral therapy (ART) for HIV among young injection drug users (IDU) have been limited because financial barriers to care disproportionately affect youth, thus confounding results. This study examines adherence among IDU in a unique setting where all medical care is provided free-of-charge. From May 1996 to April 2008, we followed a prospective cohort of 545 HIV-positive IDU of 18 years of age or older in Vancouver, Canada. Using generalized estimating equations (GEE), we studied the association between age and adherence (obtaining ART≥95% of the prescribed time), controlling for potential confounders. Using Cox proportional hazards regression, we also studied the effect of age on time to viral load suppression (<500 copies per milliliter), and examined adherence as a mediating variable. Five hundred forty-five participants were followed for a median of 23.8 months (interquartile range [IQR]=8.5–91.6 months). Odds of adherence were significantly lower among younger IDU (adjusted odds ratio [AOR]=0.76 per 10 years younger; 95% confidence interval [CI], 0.65–0.89). Younger IDU were also less likely to achieve viral load suppression (adjusted hazard ratio [AHR]=0.75 per 10 years younger; 95% CI, 0.64–0.88). Adding adherence to the model eliminated this association with age, supporting the role of adherence as a mediating variable. Despite absence of financial barriers, younger IDU remain less likely to adhere to ART, resulting in inferior viral load suppression. Interventions should carefully address the unique needs of young HIV-positive IDU. PMID:22429003

  5. Wetting Kinetics: an Alternative Approach Towards Understanding the Enhanced Dissolution Rate for Amorphous Solid Dispersion of a Poorly Soluble Drug.

    PubMed

    Verma, Sanjay; Rudraraju, Varma S

    2015-10-01

    Developing amorphous solid dispersions of water-insoluble molecules using polymeric materials is a well-defined approach to improve the dissolution rate and bioavailability. While the selected polymer plays a vital role in stabilizing the amorphous solid dispersion physically, it is equally important to improve the dissolution profile by inhibiting crystallization from the supersaturated solution generated by dissolution of the amorphous material. Furthermore, understanding the mechanism of dissolution rate enhancement is of vital importance. In this work, wetting kinetics was taken up as an alternative approach for understanding the enhanced dissolution rate for amorphous solid dispersion of a poorly soluble drug. While cilostazol (CIL) was selected as the model drug, povidone (PVP), copovidone, and hypromellose (HPMC) were the polymers of choice. The concentrations against time profiles were evaluated for the supersaturated solutions of CIL in the presence and absence of the selected polymers. The degree of supersaturation increased significantly with increase in polymer content within the solid dispersion. While povidone was found to maintain the highest level of supersaturation for the greatest length of time both in dissolution and solution crystallization experiments, copovidone and hypromellose were found to be the less effective as crystallization inhibitor. The ability of polymers to generate and maintain supersaturated drug solutions was assessed by dissolution studies. The wetting kinetics was compared against the solid dispersion composition to establish a correlation with enhanced dissolution rate.

  6. Water solubility of synthetic pyrope at high temperature and pressure up to 12GPa

    NASA Astrophysics Data System (ADS)

    Huang, S.; Chen, J.

    2012-12-01

    Water can be incorporated into normally anhydrous minerals as OH- defects and transported into the mantle. Its existence in the mantle may affect property of minerals, such as elasticity, electrical conductivity and rheological properties. As the secondary mineral in the mantle, garnet has not been extensively studied for its water solubility and there is discrepancies among the existing experiments on the water solubility in the garnet change at pressures and temperatures. Geiger et al., 1991 investigated water content in synthetic pyrope and concluded 0.02wt% to 0.07wt% OH- substitution. Lu et al., 1997 found 198ppm water in the Dora Miara pyrope at 100Kbar and 1000°C. Withers et al., 1998 claimed that water solubility in pyrope reached 1000ppm at 5GPa and then decreased as pressure increasing; above 7GPa, no water was detected. Mookherjee et al., 2009 also explored pyrope-rich garnet, which contains water up to 0.1%wt at 5-9GPa and temperatures 1373K-1473K. Here we report a study of water solubility of synthetic single crystal pyrope at pressures 4-12GPa and temperature 1000°C. Single crystals of pyrope were synthesized using multi-anvil press and water contents in these samples were measured using FTIR. We have observed OH- peak at 3650 cm-1 along this pressure range, although Withers, 1998 reported water contents decrease to undetectable level above 7GPa. Water solubility in pyrope will be reported as a function of pressure up to 12 GPa at 1000°C.

  7. [Water-soluble eumelanin as a PCR-inhibitor and a simple method for its removal].

    PubMed

    Yoshii, T; Tamura, K; Taniguchi, T; Akiyama, K; Ishiyama, I

    1993-08-01

    It has been confirmed that water-soluble eumelanins often extracted together with DNAs from natural black hairs act as an inhibitor of Taq DNA polymerase in the polymerase chain reaction (PCR). In the present investigation, an attempt to amplify the non-coding 333-bp region of mitochondrial DNA (mt333DNA) produced the following results: 1) Water-soluble preparations made from chemically synthesized melanin (Sigma products), as well as natural black eumelanins, inhibited the PCR amplification of mt333DNA at concentrations of more than 2 micrograms/ml. 2) Quantitative measurement of Taq DNA polymerase-catalyzed DNA synthesis in terms of the amount of [alpha-32P] dCMP incorporated into activated calf thymus DNA showed that both of the water-soluble melanins had the same inhibition activity as represented by the sigmoidal curve derived from a quadratic equation of melanin concentration. This observation suggested that Taq DNA polymerase combined with two molecules of melanin to form an inactivated complex. 3) Melanins did not appear to affect either the thermostability of Taq DNA polymerase at 94 degrees C, or the step of primer-annealing to template DNAs. On the other hand, we established a simple and useful method for removal of water-soluble eumelanins contaminating DNA preparations from hairs. The method was based on the adsorption of melanins to Bio-Gel. When a Bio-Gel P-60 minicolumn was equilibrated with 10 mM sodium acetate buffer, pH 4.2, water-soluble melanins were completely adsorpted to it whereas DNAs passed through, although the melanins showed incomplete adsorption to the gel when it was equilibrated with TE (10 mM Tris-HCl, pH 7.5, 0.1 mM EDTA).(ABSTRACT TRUNCATED AT 250 WORDS)

  8. A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin

    PubMed Central

    Schoemaker, N E; van Kesteren, C; Rosing, H; Jansen, S; Swart, M; Lieverst, J; Fraier, D; Breda, M; Pellizzoni, C; Spinelli, R; Porro, M Grazia; Beijnen, J H; Schellens, J H M; ten Bokkel Huinink, WW

    2002-01-01

    Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m−2 day−1. Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m−2 day−1 and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1–3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4–5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting. British Journal of Cancer (2002) 21, 608–614. doi:10.1038/sj.bjc.6600516 www.bjcancer.com © 2002 Cancer Research UK PMID:12237769

  9. Novel Dosing Strategies Increase Exposures of the Potent Antituberculosis Drug Rifapentine but Are Poorly Tolerated in Healthy Volunteers

    PubMed Central

    Savic, Radojka M.; Park, Jeong-Gun; Cramer, Yoninah; Hafner, Richard; Hogg, Evelyn; Janik, Jennifer; Marzinke, Mark A.; Patterson, Kristine; Benson, Constance A.; Hovind, Laura; Dorman, Susan E.; Haas, David W.

    2015-01-01

    Rifapentine is a potent antituberculosis drug currently in phase III trials. Bioavailability decreases with increasing dose, yet high daily exposures are likely needed to improve efficacy and shorten the tuberculosis treatment duration. Further, the limits of tolerability are poorly defined. The phase I multicenter trial in healthy adults described here investigated two strategies to increase rifapentine exposures: dividing the dose or giving the drug with a high-fat meal. In arm 1, rifapentine was administered at 10 mg/kg of body weight twice daily and 20 mg/kg once daily, each for 14 days, separated by a 28-day washout; the dosing sequence was randomized. In arm 2, 15 mg/kg rifapentine once daily was given with a high-fat versus a low-fat breakfast. Sampling for pharmacokinetic analysis was performed on days 1 and 14. Population pharmacokinetic analyses were performed. This trial was stopped early for poor tolerability and because of safety concerns. Of 44 subjects, 20 discontinued prematurely; 11 of these discontinued for protocol-defined toxicity (a grade 3 or higher adverse event or grade 2 or higher rifamycin hypersensitivity). Taking rifapentine with a high-fat meal increased the median steady-state area under the concentration-time curve from time zero to 24 h (AUC0–24ss) by 31% (relative standard error, 6%) compared to that obtained when the drug was taken with a low-fat breakfast. Dividing the dose increased exposures substantially (e.g., 38% with 1,500 mg/day). AUC0–24ss was uniformly higher in our study than in recent tuberculosis treatment trials, in which toxicity was rare. In conclusion, two strategies to increase rifapentine exposures, dividing the dose or giving it with a high-fat breakfast, successfully increased exposures, but toxicity was common in healthy adults. The limits of tolerability in patients with tuberculosis remain to be defined. (AIDS Clinical Trials Group study A5311 has been registered at ClinicalTrials.gov under registration

  10. Formation of water-soluble soybean polysaccharides from spent flakes by hydrogen peroxide treatment.

    PubMed

    Pierce, Brian C; Wichmann, Jesper; Tran, Tam H; Cheetamun, Roshan; Bacic, Antony; Meyer, Anne S

    2016-06-25

    In this paper we propose a novel chemical process for the generation of water-soluble polysaccharides from soy spent flake, a by-product of the soy food industry. This process entails treatment of spent flake with hydrogen peroxide at an elevated temperature, resulting in the release of more than 70% of the original insoluble material as high molar mass soluble polysaccharides. A design of experiment was used to quantify the effects of pH, reaction time, and hydrogen peroxide concentration on the reaction yield, average molar mass, and free monosaccharides generated. The resulting product is low in protein, fat, and minerals and contains predominantly water-soluble polysaccharides of high molar mass, including arabinan, type I arabinogalactan, homogalacturonan, xyloglucan, rhamnogalacturonan, and (glucurono)arabinoxylan. This treatment provides a straightforward approach for generation of soluble soy polysaccharides and opens a new range of opportunities for this abundant and underutilized material in future research and industrial applications. PMID:27083842

  11. Comparison of water solubilities by the flask and micro-column methods

    SciTech Connect

    Hashimoto, Y.; Tokura, K.; Ozaki, K.; Strachan, W.M.J.

    1982-01-01

    A comparative examination of the two procedures of the ''OECD Test Guildeline: Water Solubility'' was undertaken using carbazole, fluoranthene, anthracene, hexachlorobenzene, p-nitroaniline and diphenylamine. The flask method was modified to provide for dissolution of the solute from the surface of glass beads. By the proposed flask method, one can accurately measure the water solubility down to the order of 10 ..mu..g/L as well as those of the order of %. The micro-column method, which requires a number of concentration determinations to ensure that a saturated solution has been obtained, is recommended for the solubility range of 10 mg/L through 10 ..mu..g/L. The flask method using the procedures described in this study, covers the range of solubility above 10 ..mu..g/L with only two determinations one being a simple preliminary test and the other a precise measurement.

  12. [Analysis and identification of water soluble components of water buffalo horn].

    PubMed

    Liu, Rui; Duan, Jin-ao; Wu, Hao; Liu, Pei; Shang, Er-xin; Qian, Da-wei

    2015-05-01

    This study is to analyze and identify the water soluble components of water buffalo horn (Bubali Cornu, WBH), and also establish a method for investigating these components. Shotgun proteomic analysis identified proteins in WBH aqueous extraction: keratin, collagen, desmoglein, etc. Ultrafiltration and LC-MS/MS were used to separate and identify the peptides in WBH aqueous extract, as a result, identified peptides were mainly derived from nonspecific degradation products of keratin and collagen, which including C-terminal peptides and non C-terminal peptides. Hypoxanthine, uridine, guanosine, and adenosine were identified by comparing with the standards. The strategy in present study could be used in analyzing water soluble components of animal horn derived TCM. It provides a reference for investigation of the material basis of animal horn derived TCM. PMID:26234143

  13. Physico-chemical qualification of a universal portable sampler for aerosols and water-soluble gases

    NASA Astrophysics Data System (ADS)

    Roux, Jean-Maxime; Sarda-Estève, Roland

    2015-10-01

    Developing a universal portable air sampler based on electrostatic precipitation. The challenge is to collect micro and nanoparticles, microorganisms as well as toxic molecules with a portable device. Electrostatic precipitation is an efficient and gentle method to collect airborne microorganisms and preserve their cultivability. But the collection of toxic gases required is not possible in such a device. The collection of such gases requires a liquid into which they have to be solubilized. Two concepts are being evaluated. The first one is based on electrospray. The goal is to investigate the collection efficiency of water-soluble gases. The second concept is based on the semi-humid electrostatic precipitator. Their high collection efficiencies for particles were already demonstrated. In the present study they are both tested with water-soluble gases. Concentrations are measured in the liquid solution by Ion Chromatography and in the gas phase by Proton Transfer Reaction Mass Spectrometry.

  14. Water soluble nanocurcumin extracted from turmeric challenging the microflora from human oral cavity.

    PubMed

    Gopal, Judy; Muthu, Manikandan; Chun, Se-Chul

    2016-11-15

    Water soluble nanocurcumin prepared from commercial turmeric powders was compared against ethanol extracted curcumin particles. The oral microflora from five different human volunteers was collected and the efficacy of solvent extracted curcumin versus water extracted nanocurcumin was demonstrated. Nanocurcumin activity against oral microflora confirms its antimicrobial potency. Confocal laser scanning microscopic results revealed the enhanced entry of nanocurcumin particles into microbial cells. The nanosized nature of nanocurcumin appears to have led to increased cellular interaction and thereby efficient destruction of microbial cells in the mouth. In addition, solubility of nanocurcumin is also believed to be a crucial factor behind its successful antimicrobial activity. This study proves that the bioactivity of a compound is greatly influenced by its solubility in water. This work recommends the use of water soluble nanocurcumin (extracted from turmeric) as potent substitute for curcumin in dental formulations. PMID:27283711

  15. Synthesis, Characterization and Application of Water-soluble Gold and Silver Nanoclusters

    NASA Astrophysics Data System (ADS)

    Kumar, Santosh

    The term `nanotechnology' has emerged as a buzzword since the last few decades. It has found widespread applications across disciplines, from medicine to energy. The synthesis of gold and silver nanoclusters has found much excitement, due to their novel material properties. Seminal work by various groups, including ours, has shown that the size of these clusters can be controlled with atomic precision. This control gives access to tuning the optical and electronic properties. The majority of nanoclusters reported thus far are not water soluble, which limit their applications in biology that requires water-solubility. Going from organic to aqueous phase is by no means a simple task, as it is associated with many challenges. Their stability in the presence of oxygen, difficulty in characterization, and separation of pure nanoclusters are some of the major bottlenecks associated with the synthesis of water-soluble gold nanoclusters. Water-soluble gold nanoclusters hold great potential in biological labeling, bio-catalysis and nano-bioconjugates. To overcome this problem, a new ligand with structural rigidity is needed. After considering various possibilities, we chose Captopril as a candidate ligand. In my thesis research, the synthesis of Au25 nanocluster capped with captopril has been reported. Captopril-protected Au25 nanocluster showed significantly higher thermal stability and enhanced chiroptical properties than the Glutathione-capped cluster, which confirms our initial rationale, that the ligand is critical in protecting the nanocluster. The optical absorption properties of these Au25 nanoclusters are studied and compared to the plasmonic nanoparticles. The high thermal stability and solubility of Au25 cluster capped with Captopril motivated us to explore this ligand for the synthesis of other gold clusters. Captopril is a chiral molecule with two chiral centers. The chiral ligand can induce chirality to the overall cluster, even if the core is achiral

  16. Synthesis and characterization of a hyper-branched water-soluble β-cyclodextrin polymer.

    PubMed

    Trotta, Francesco; Caldera, Fabrizio; Cavalli, Roberta; Mele, Andrea; Punta, Carlo; Melone, Lucio; Castiglione, Franca; Rossi, Barbara; Ferro, Monica; Crupi, Vincenza; Majolino, Domenico; Venuti, Valentina; Scalarone, Dominique

    2014-01-01

    A new hyper-branched water-soluble polymer was synthesized by reacting β-cyclodextrin with pyromellitic dianhydride beyond the critical conditions that allow the phenomenon of gelation to occur. The molar ratio between the monomers is a crucial parameter that rules the gelation process. Nevertheless, the concentration of monomers in the solvent phase plays a key role as well. Hyper-branched β-cyclodextrin-based polymers were obtained performing the syntheses with excess of solvent and cross-linking agent, and the conditions for critical dilution were determined experimentally. A hyper-branched polymer with very high water solubility was obtained and fully characterized both as for its chemical structure and for its capability to encapsulate substances. Fluorescein was used as probe molecule to test the complexation properties of the new material. PMID:25550720

  17. [Analysis and identification of water soluble components of water buffalo horn].

    PubMed

    Liu, Rui; Duan, Jin-ao; Wu, Hao; Liu, Pei; Shang, Er-xin; Qian, Da-wei

    2015-05-01

    This study is to analyze and identify the water soluble components of water buffalo horn (Bubali Cornu, WBH), and also establish a method for investigating these components. Shotgun proteomic analysis identified proteins in WBH aqueous extraction: keratin, collagen, desmoglein, etc. Ultrafiltration and LC-MS/MS were used to separate and identify the peptides in WBH aqueous extract, as a result, identified peptides were mainly derived from nonspecific degradation products of keratin and collagen, which including C-terminal peptides and non C-terminal peptides. Hypoxanthine, uridine, guanosine, and adenosine were identified by comparing with the standards. The strategy in present study could be used in analyzing water soluble components of animal horn derived TCM. It provides a reference for investigation of the material basis of animal horn derived TCM.

  18. Method of cross-linking polyvinyl alcohol and other water soluble resins

    NASA Technical Reports Server (NTRS)

    Phillipp, W. H.; May, C. E.; Hsu, L. C.; Sheibley, D. W. (Inventor)

    1980-01-01

    A self supporting sheet structure comprising a water soluble, noncrosslinked polymer such as polyvinyl alcohol which is capable of being crosslinked by reaction with hydrogen atom radicals and hydroxyl molecule radicals is contacted with an aqueous solution having a pH of less than 8 and containing a dissolved salt in an amount sufficient to prevent substantial dissolution of the noncrosslinked polymer in the aqueous solution. The aqueous solution is then irradiated with ionizing radiation to form hydrogen atom radicals and hydroxyl molecule radicals and the irradiation is continued for a time sufficient to effect crosslinking of the water soluble polymer to produce a water insoluble polymer sheet structure. The method has particular application in the production of battery separators and electrode envelopes for alkaline batteries.

  19. Consequences of chirality on the dynamics of a water-soluble supramolecular polymer.

    PubMed

    Baker, Matthew B; Albertazzi, Lorenzo; Voets, Ilja K; Leenders, Christianus M A; Palmans, Anja R A; Pavan, Giovanni M; Meijer, E W

    2015-01-01

    The rational design of supramolecular polymers in water is imperative for their widespread use, but the design principles for these systems are not well understood. Herein, we employ a multi-scale (spatial and temporal) approach to differentiate two analogous water-soluble supramolecular polymers: one with and one without a stereogenic methyl. Initially aiming simply to understand the molecular behaviour of these systems in water, we find that while the fibres may look identical, the introduction of homochirality imparts a higher level of internal order to the supramolecular polymer. Although this increased order does not seem to affect the basic dimensions of the supramolecular fibres, the equilibrium dynamics of the polymers differ by almost an order of magnitude. This report represents the first observation of a structure/property relationship with regard to equilibrium dynamics in water-soluble supramolecular polymers. PMID:25698667

  20. Consequences of chirality on the dynamics of a water-soluble supramolecular polymer

    PubMed Central

    Baker, Matthew B.; Albertazzi, Lorenzo; Voets, Ilja K.; Leenders, Christianus M.A.; Palmans, Anja R.A.; Pavan, Giovanni M.; Meijer, E.W.

    2015-01-01

    The rational design of supramolecular polymers in water is imperative for their widespread use, but the design principles for these systems are not well understood. Herein, we employ a multi-scale (spatial and temporal) approach to differentiate two analogous water-soluble supramolecular polymers: one with and one without a stereogenic methyl. Initially aiming simply to understand the molecular behaviour of these systems in water, we find that while the fibres may look identical, the introduction of homochirality imparts a higher level of internal order to the supramolecular polymer. Although this increased order does not seem to affect the basic dimensions of the supramolecular fibres, the equilibrium dynamics of the polymers differ by almost an order of magnitude. This report represents the first observation of a structure/property relationship with regard to equilibrium dynamics in water-soluble supramolecular polymers. PMID:25698667

  1. Consequences of chirality on the dynamics of a water-soluble supramolecular polymer

    NASA Astrophysics Data System (ADS)

    Baker, Matthew B.; Albertazzi, Lorenzo; Voets, Ilja K.; Leenders, Christianus M. A.; Palmans, Anja R. A.; Pavan, Giovanni M.; Meijer, E. W.

    2015-02-01

    The rational design of supramolecular polymers in water is imperative for their widespread use, but the design principles for these systems are not well understood. Herein, we employ a multi-scale (spatial and temporal) approach to differentiate two analogous water-soluble supramolecular polymers: one with and one without a stereogenic methyl. Initially aiming simply to understand the molecular behaviour of these systems in water, we find that while the fibres may look identical, the introduction of homochirality imparts a higher level of internal order to the supramolecular polymer. Although this increased order does not seem to affect the basic dimensions of the supramolecular fibres, the equilibrium dynamics of the polymers differ by almost an order of magnitude. This report represents the first observation of a structure/property relationship with regard to equilibrium dynamics in water-soluble supramolecular polymers.

  2. Synthesis and characterization of a hyper-branched water-soluble β-cyclodextrin polymer.

    PubMed

    Trotta, Francesco; Caldera, Fabrizio; Cavalli, Roberta; Mele, Andrea; Punta, Carlo; Melone, Lucio; Castiglione, Franca; Rossi, Barbara; Ferro, Monica; Crupi, Vincenza; Majolino, Domenico; Venuti, Valentina; Scalarone, Dominique

    2014-01-01

    A new hyper-branched water-soluble polymer was synthesized by reacting β-cyclodextrin with pyromellitic dianhydride beyond the critical conditions that allow the phenomenon of gelation to occur. The molar ratio between the monomers is a crucial parameter that rules the gelation process. Nevertheless, the concentration of monomers in the solvent phase plays a key role as well. Hyper-branched β-cyclodextrin-based polymers were obtained performing the syntheses with excess of solvent and cross-linking agent, and the conditions for critical dilution were determined experimentally. A hyper-branched polymer with very high water solubility was obtained and fully characterized both as for its chemical structure and for its capability to encapsulate substances. Fluorescein was used as probe molecule to test the complexation properties of the new material.

  3. Bioavailability of water-soluble CoQ10 in beagle dogs.

    PubMed

    Prosek, Mirko; Butinar, Janos; Lukanc, Barbara; Fir, Maja Milivojevic; Milivojevic, Luka; Krizman, Mitja; Smidovnik, Andrej

    2008-08-01

    The bioavailability of a novel water-soluble inclusion complex of CoQ10, prepared in our laboratory was determined and compared with the bioavailability of commercially available oil-based form of CoQ10. Experimental work consisted of single dose comparative bioavailability study on seven beagle dogs, with a 14-day washout period between treatments. Identification and quantification of CoQ10 was done with HPLC-MS method using positive APCI ionization and SIM mode, M+ m/z 863.4. The bioavailability results confirm that the water-soluble formulation has nearly three times higher AUC(0-48 h), two times higher Cmax, and Tmax is shortened from 6 to 4 h. PMID:18495407

  4. Water-soluble polymer exfoliated graphene: as catalyst support and sensor.

    PubMed

    Wang, Haibo; Xia, Baoyu; Yan, Ya; Li, Nan; Wang, Jing-Yuan; Wang, Xin

    2013-05-01

    In this paper, we obtained various water-soluble polymer functionalized graphene in dimethyl sulfoxide under ultrasonication. The atomic force microscope analysis and control experiment shows the water-soluble polymer is the crucial part to help solvent molecules separate interlayer. Such polymer/graphene exhibits high conductivity and tunable surface property, as confirmed by the selected area electron diffraction and Raman and electrochemical impedance spectroscopy. As a result, a catalyst based on polyvinyl pyrrolidone (PVP)/graphene shows better methanol oxidation performance than that based on PVP/reduced graphene oxide. By changing to another polymer, poly(4-vinylpyridine)/graphene shows a stable and reversible response to pH, and demonstrates its potential for sensor application. PMID:23574310

  5. Chemical synthesis of water-soluble, chiral conducting-polymer complexes

    DOEpatents

    Wang, Hsing-Lin; McCarthy, Patrick A.; Yang, Sze Cheng

    2003-01-01

    The template-guided synthesis of water-soluble, chiral conducting polymer complexes is described. Synthesis of water-soluble polyaniline complexes is achieved by carefully controlling the experimental parameters such as; acid concentration, ionic strength, monomer/template ratio, total reagent concentration, and order of reagent addition. Chiral (helical) polyaniline complexes can be synthesized by addition of a chiral inducing agent (chiral acid) prior to polymerization, and the polyaniline helix can be controlled by the addition of the (+) or (-) form of the chiral acid. Moreover the quantity of chiral acid and the salt content has a significant impact on the degree of chirality in the final polymer complexes. The polyaniline and the template have been found to be mixed at the molecular level which results in chiral complexes that are robust through repeated doping and dedoping cycles.

  6. Invisible Security Ink Based on Water-Soluble Graphitic Carbon Nitride Quantum Dots.

    PubMed

    Song, Zhiping; Lin, Tianran; Lin, Lihua; Lin, Sen; Fu, Fengfu; Wang, Xinchen; Guo, Liangqia

    2016-02-18

    Stimuli-responsive photoluminescent (PL) materials have been widely used as fluorescent ink for data security applications. However, traditional fluorescent inks are limited in maintaining the secrecy of information because the inks are usually visible by naked eyes either under ambient light or UV-light illumination. Here, we introduced metal-free water-soluble graphitic carbon nitride quantum dots (g-CNQDs) as invisible security ink for information coding, encryption, and decryption. The information written by the g-CNQDs is invisible in ambient light and UV light, but it can be readable by a fluorescence microplate reader. Moreover, the information can be encrypted and decrypted by using oxalic acid and sodium bicarbonate as encryption reagent and decryption reagent, respectively. Our findings provide new opportunities for high-level information coding and protection by using water-soluble g-CNQDs as invisible security ink.

  7. Stearic acid and high molecular weight PEO as matrix for the highly water soluble metoprolol tartrate in continuous twin-screw melt granulation.

    PubMed

    Monteyne, Tinne; Adriaensens, Peter; Brouckaert, Davinia; Remon, Jean-Paul; Vervaet, Chris; De Beer, Thomas

    2016-10-15

    Granules with release-sustaining properties were developed by twin screw hot melt granulation (HMG) using a combination of stearic acid (SA) and high molecular weight polyethylene oxide (PEO) as matrix for a highly water soluble model drug, metoprolol tartrate (MPT). Earlier studies demonstrated that mixing molten SA and PEO resulted in hydrogen bond formation between hydroxyl groups of fatty acid molecules and ether groups in PEO chains. These molecular interactions might be beneficial in order to elevate the sustained release effect of drugs from a SA/PEO matrix. This study aims to investigate the continuous twin screw melt granulation technique to study the impact of a SA/PEO matrix on the dissolution rate of a highly water soluble drug (MPT). Decreasing the SA/PEO ratio improved the release-sustaining properties of the matrix. The solid state of the granules was characterized using differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared (FTIR) and near infrared chemical imaging (NIR-CI) in order to understand the dissolution behavior. The results revealed a preferential interaction of the MPT molecules with stearic acid impeding the PEO to form hydrogen bonds with the stearic acid chains. However, this allowed the PEO chains to recrystallize inside the stearic acid matrix after granulation, hence, elevating the release-sustaining characteristics of the formulation.

  8. Stearic acid and high molecular weight PEO as matrix for the highly water soluble metoprolol tartrate in continuous twin-screw melt granulation.

    PubMed

    Monteyne, Tinne; Adriaensens, Peter; Brouckaert, Davinia; Remon, Jean-Paul; Vervaet, Chris; De Beer, Thomas

    2016-10-15

    Granules with release-sustaining properties were developed by twin screw hot melt granulation (HMG) using a combination of stearic acid (SA) and high molecular weight polyethylene oxide (PEO) as matrix for a highly water soluble model drug, metoprolol tartrate (MPT). Earlier studies demonstrated that mixing molten SA and PEO resulted in hydrogen bond formation between hydroxyl groups of fatty acid molecules and ether groups in PEO chains. These molecular interactions might be beneficial in order to elevate the sustained release effect of drugs from a SA/PEO matrix. This study aims to investigate the continuous twin screw melt granulation technique to study the impact of a SA/PEO matrix on the dissolution rate of a highly water soluble drug (MPT). Decreasing the SA/PEO ratio improved the release-sustaining properties of the matrix. The solid state of the granules was characterized using differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared (FTIR) and near infrared chemical imaging (NIR-CI) in order to understand the dissolution behavior. The results revealed a preferential interaction of the MPT molecules with stearic acid impeding the PEO to form hydrogen bonds with the stearic acid chains. However, this allowed the PEO chains to recrystallize inside the stearic acid matrix after granulation, hence, elevating the release-sustaining characteristics of the formulation. PMID:27452420

  9. The removal of kaolinite suspensions by acid-soluble and water-soluble chitosans.

    PubMed

    Chung, Ying-Chien; Wu, Li-Chun; Chen, Chih-Yu

    2013-01-01

    Chitosan is a potential substitute for traditional aluminium salts in water treatment systems. This research compared the coagulant performance of acid-soluble chitosan with water-soluble chitosan and with coagulant mixtures of chitosan and aluminium sulfate (alum). We also assessed the coagulant performance of chitosan and poly-aluminium chloride (PAC) to remove kaolinite from turbid water. In addition, we evaluated their respective coagulation efficiencies under different coagulant concentrations, degrees of turbidity (NTU) and pH levels. Furthermore, we determined the size and settling velocity of flocs formed by these coagulants in order to illustrate major factors affecting kaolinite coagulation. The optimal concentrations of acid- versus water- soluble chitosan required to remove kaolinite from a 300 NTU suspension were 4.0 and 10.0 mg/l, respectively-with individual efficiencies of 79.3 and 92.4%, in that order. Optimum concentrations ofwater-soluble chitosan demonstrated a broader range than that of acid-soluble chitosan. In addition, it is of note that chitosan/alum and chitosan/PAC water-soluble coagulant mixtures demonstrated much wider ranges of optimal concentrations for turbidity reduction than either alum or PAC alone. Moreover, our water-soluble chitosan coagulant mixtures produced denser floc with elevated settling velocities that favour cost savings relevant to both installation and operational expenses. Based on our observations of these noteworthy performances, we confidently propose that a coagulant mixture with a 1:1 mass ratio of chitosan and alum presents a remarkably more cost-effective alternative to the use of chitosan alone in water treatment systems. PMID:23530342

  10. Formamide: an efficient solvent to synthesize water-soluble and sub-ten-nanometer nanocrystals

    NASA Astrophysics Data System (ADS)

    Xu, Biao; Zhang, Zhicheng; Wang, Xun

    2013-05-01

    Nanocrystals have drawn lots of attention in many fields. The main-stream synthetic routes usually produced hydrophobic nanocrystals (NCs). Organometallic precursors and long-alkyl-chain ligands are adopted and for further use surface modification to render them water-soluble is needed. A direct protocol to synthesize water-soluble NCs in an environmental-friendly and convenient way is still quite deficient, especially for sub-10 nm NCs. We report here a formamide solvent-system to prepare high-quality metal, metal alloy, metal sulfide, metal selenide and ternary sulfide NCs in the sub-10 nm region, with simple inorganic metal salts as precursors. The as-obtained NCs exhibit monodisperse size and can be dispersed in aqueous solution for further applications.Nanocrystals have drawn lots of attention in many fields. The main-stream synthetic routes usually produced hydrophobic nanocrystals (NCs). Organometallic precursors and long-alkyl-chain ligands are adopted and for further use surface modification to render them water-soluble is needed. A direct protocol to synthesize water-soluble NCs in an environmental-friendly and convenient way is still quite deficient, especially for sub-10 nm NCs. We report here a formamide solvent-system to prepare high-quality metal, metal alloy, metal sulfide, metal selenide and ternary sulfide NCs in the sub-10 nm region, with simple inorganic metal salts as precursors. The as-obtained NCs exhibit monodisperse size and can be dispersed in aqueous solution for further applications. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr00643c

  11. High Throughput Identification, Purification and Structural Characterization of Water Soluble Protein Complexes in Desulfovibrio vulgaris

    SciTech Connect

    Dong,, Ming; Han, Bong-Gyoon; Liu, Hui-Hai; Malik, J.; Geller, Jil; Yang, Li; Choi, M.; Chandonia, John-Marc; Arbelaez, Pablo; Sterling, H. J.; Typke, Dieter; Shatsky, Max; Brenner, Steve; Fisher, Susan; Williams, Evan; Szakal, Evelin; Allen, S.; Hall, S. C.; Hazen, Terry; Witkowska, H. E.; Jin, Jiming; Glaeser, Robert; Biggin, Mark

    2010-05-17

    Our scheme for the tagless purification of water soluble complexes. 10 g of protein from a crude bacterial extract is first fractionated by ammonium sulfate precipitation and then by a series of chromatographic steps: anion exchange (IEX), hydrophobic interaction (HIC), and finally size exclusion (Gel Filtration). Fractions from the last chromatography step are trypsin digested and peptides labeled with iTRAQ reagents to allow multiplexing and quantitation during mass spectrometric analysis. Elution profiles of identified proteins are then subjected to clustering analysis.

  12. Effect of water-soluble reduced chitosan on Streptococcus mutans, plaque regrowth and biofilm vitality.

    PubMed

    Bae, K; Jun, E J; Lee, S M; Paik, D I; Kim, J B

    2006-06-01

    The purpose of the present study was to examine the effects of a newly developed water-soluble reduced chitosan on Streptococcus mutans, plaque regrowth, and biofilm vitality. A 1.0%, water-soluble reduced chitosan, with pH ranging from 6.0 to 6.5, molecular weights between 3,000 and 5,000 Da, and 70% degree of deacetylation, was used. To determine antibacterial and antiplaque potency of chitosan, minimal inhibitory concentrations (MICs) for S. mutans and S. sanguinis (formerly S. sanguis), short-term exposure to S. mutans, and clinical trial of plaque regrowth and biofilm vitality were conducted. Twelve dental students volunteered to participate in the 6-week, double blind, randomized clinical trial using the classical 4-day plaque regrowth design. The MIC of water-soluble reduced chitosan for S. mutans was 1.25 g/l. While the cells exposed to distilled water (DW) grew rapidly, with a maximum turbidity reached by 16 h postinoculation, S. mutans exposed to chitosan (5.0 g/l) exhibited a substantial delay in growth and reached a maximum turbidity by 32 h postinoculation. The chitosan solution reduced the plaque index and the vitality of the plaque flora significantly when compared to DW, but this was less than the reductions found with the positive control of 0.1% chlorhexidine solution. The water-soluble reduced chitosan exhibited potent antibacterial effect on S. mutans, and displayed a significant antibacterial and plaque-reducing action during the 4-day plaque regrowth.

  13. Biosorption of water-soluble dyes on magnetically modified Saccharomyces cerevisiae subsp. uvarum cells.

    PubMed

    Safaríková, M; Ptácková, L; Kibriková, I; Safarík, I

    2005-05-01

    Brewer's yeast (bottom yeast, Saccharomyces cerevisiae subsp. uvarum) cells were magnetically modified using water based magnetic fluid stabilized with perchloric acid. Magnetically modified yeast cells efficiently adsorbed various water soluble dyes. The dyes adsorption can be described by the Langmuir adsorption model. The maximum adsorption capacity of the magnetic cells differed substantially for individual dyes; the highest value was found for aniline blue (approx. 220 mg per g of dried magnetic adsorbent). PMID:15811411

  14. NASA Workmanship Hot Topics: Water Soluble Flux and ESD Charge Device Model

    NASA Technical Reports Server (NTRS)

    Plante, Jeannette F.

    2009-01-01

    This slide presentation reviews two topics of interest to NASA Workmanship: (1) Water Soluble Flux (WSF) and Electrostatic Discharge (ESD) safety. In the first topic, WSF, the presentation reviews voiding and the importance of cleanliness in using WSF for welding and soldering operations. The second topic reviews the NASA-HDBK-8739.21 for Human Body Model, and Machine Model safety methods, and challenges associated with the Charged Device Model (CDM)

  15. Water solubility measurements in supercritical fluids and high-pressure liquids using near-infrared spectroscopy

    SciTech Connect

    Jackson, K.; Bowman, L.E.; Fulton, J.L.

    1995-07-15

    A small amount of water added to a supercritical fluid can greatly increase the solubility of polar species in nonpolar fluids. These modified supercritical solutions significantly expand the use of the fluids in separations and reactions. In order to successfully utilize these systems, information on the miscibility or solubility of water in the fluid is required. Often solubility data are not available for water in a supercritical fluid under a given set of temperature and pressure conditions, and a costly set of equipment must be assembled in order to make these measurements. A relatively fast and inexpensive technique to measure water solubilities using a simple long path length optical cell in an FT-IR spectrometer is described. This technique is also applicable to common and newly developed refrigerants where water solubilities are often unknown at temperatures much above ambient. In this paper, water solubility data in carbon dioxide and two types of refrigerants (chlorodifluoromethane, R22; 1,1,1,2-tetrafluoroethane, R134a) are presented for temperatures from approximately 40 to 110{degree}C and pressures from approximately 10 to 344.8 bar. 26 refs., 6 figs., 4 tabs.

  16. Determination of water-soluble forms of oxalic and formic acids in soils by ion chromatography

    NASA Astrophysics Data System (ADS)

    Karicheva, E.; Guseva, N.; Kambalina, M.

    2016-03-01

    Carboxylic acids (CA) play an important role in the chemical composition origin of soils and migration of elements. The content of these acids and their salts is one of the important characteristics for agrochemical, ecological, ameliorative and hygienic assessment of soils. The aim of the article is to determine water-soluble forms of same carboxylic acids — (oxalic and formic acids) in soils by ion chromatography with gradient elution. For the separation and determination of water-soluble carboxylic acids we used reagent-free gradient elution ion-exchange chromatography ICS-2000 (Dionex, USA), the model solutions of oxalate and formate ions, and leachates from soils of the Kola Peninsula. The optimal gradient program was established for separation and detection of oxalate and formate ions in water solutions by ion chromatography. A stability indicating method was developed for the simultaneous determination of water-soluble organic acids in soils. The method has shown high detection limits such as 0.03 mg/L for oxalate ion and 0.02 mg/L for formate ion. High signal reproducibility was achieved in wide range of intensities which correspond to the following ion concentrations: from 0.04 mg/g to 10 mg/L (formate), from 0.1 mg/g to 25 mg/L (oxalate). The concentration of formate and oxalate ions in soil samples is from 0.04 to 0.9 mg/L and 0.45 to 17 mg/L respectively.

  17. Synthesis and characterization of water-soluble chitosan grafted with hydrophilic aliphatic polyester.

    PubMed

    Chen, Jiajia; Zheng, Liuchun; Chen, Xiaonong; Wang, Zhaodong; Li, Chuncheng; Xiao, Yaonan; Guan, Guohu; Zhu, Wenxiang

    2015-03-01

    Traditionally, hydrophobic aliphatic polyester has been employed to modify chitosan and organic soluble or swellable graft copolymers have been obtained. In this work, linear poly(butylene tartrate) (PBT) with hydrophilic pendant hydroxyl groups, which was synthesized by direct polycondensation of tartaric acid and butanediol under mild condition, was chosen to modify chitosan and synthesize PBT grafted chitosan (CS-g-PBT) with the mediation of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide in aqueous solution of an ionic liquid. The chain length of the grafted PBT could be facilely controlled by varying the molecular weight of PBT. The chemical structures of CS-g-PBT were systematically characterized by 1H NMR, attenuated total reflectance Fourier transform infrared and wide-angle X-ray diffraction. The thermal properties were investigated by thermogravimetric analysis and differential scanning calorimetry. The water solubility of chitosan has been effectively improved after grafting with PBT and a water-soluble chitosan derivative has been synthesized. Meanwhile, the water solubility of grafts varies regularly with chain length of grafted PBT. PMID:25576746

  18. Synthesis of water soluble glycine capped silver nanoparticles and their surface selective interaction

    SciTech Connect

    Agasti, Nityananda; Singh, Vinay K.; Kaushik, N.K.

    2015-04-15

    Highlights: • Synthesis of water soluble silver nanoparticles at ambient reaction conditions. • Glycine as stabilizing agent for silver nanoparticles. • Surface selective interaction of glycine with silver nanoparticles. • Glycine concentration influences crystalinity and optical property of silver nanoparticles. - Abstract: Synthesis of biocompatible metal nanoparticles has been an area of significant interest because of their wide range of applications. In the present study, we have successfully synthesized water soluble silver nanoparticles assisted by small amino acid glycine. The method is primarily based on reduction of AgNO{sub 3} with NaBH{sub 4} in aqueous solution under atmospheric air in the presence of glycine. UV–vis spectroscopy, transmission electron microscopy (TEM), X–ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, thermogravimetry (TG) and differential thermal analysis (DTA) techniques used for characterization of resulting silver nanoparticles demonstrated that, glycine is an effective capping agent to stabilize silver nanoparticles. Surface selective interaction of glycine on (1 1 1) face of silver nanoparticles has been investigated. The optical property and crystalline behavior of silver nanoparticles were found to be sensitive to concentration of glycine. X–ray diffraction studies ascertained the phase specific interaction of glycine on silver nanoparticles. Silver nanoparticles synthesized were of diameter 60 nm. We thus demonstrated an efficient synthetic method for synthesis of water soluble silver nanoparticles capped by amino acid under mild reaction conditions with excellent reproducibility.

  19. Abalone water-soluble matrix for self-healing biomineralization of tooth defects.

    PubMed

    Wen, Zhenliang; Chen, Jingdi; Wang, Hailiang; Zhong, Shengnan; Hu, Yimin; Wang, Zhili; Zhang, Qiqing

    2016-10-01

    Enamel cannot heal by itself if damaged. Hydroxyapatite (HAP) is main component of human enamel. Formation of enamel-like materials for healing enamel defects remains a challenge. In this paper, we successfully isolated the abalone water-soluble matrix (AWSM) with 1.53wt% the abalone water-soluble protein (AWSPro) and 2.04wt% the abalone water-soluble polysaccharide (AWSPs) from abandoned abalone shell, and self-healing biomineralization of tooth defects was successfully achieved in vitro. Based on X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), hot field emission scanning electron microscopy (HFESEM) and energy dispersive spectrometer (EDS) analysis, the results showed that the AWSM can efficiently induce remineralization of HAP. The enamel-like HAP was successfully achieved onto etched enamel's surface due to the presence of the AWSM. Moreover, the remineralized effect of eroded enamel was growing with the increase of the AWSM. This study provides a solution to the resource waste and environmental pollution caused by abandoned abalone shell, and we provides a new method for self-healing remineralization of enamel defects by AWSM and develops a novel dental material for potential clinical dentistry application.

  20. Abalone water-soluble matrix for self-healing biomineralization of tooth defects.

    PubMed

    Wen, Zhenliang; Chen, Jingdi; Wang, Hailiang; Zhong, Shengnan; Hu, Yimin; Wang, Zhili; Zhang, Qiqing

    2016-10-01

    Enamel cannot heal by itself if damaged. Hydroxyapatite (HAP) is main component of human enamel. Formation of enamel-like materials for healing enamel defects remains a challenge. In this paper, we successfully isolated the abalone water-soluble matrix (AWSM) with 1.53wt% the abalone water-soluble protein (AWSPro) and 2.04wt% the abalone water-soluble polysaccharide (AWSPs) from abandoned abalone shell, and self-healing biomineralization of tooth defects was successfully achieved in vitro. Based on X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), hot field emission scanning electron microscopy (HFESEM) and energy dispersive spectrometer (EDS) analysis, the results showed that the AWSM can efficiently induce remineralization of HAP. The enamel-like HAP was successfully achieved onto etched enamel's surface due to the presence of the AWSM. Moreover, the remineralized effect of eroded enamel was growing with the increase of the AWSM. This study provides a solution to the resource waste and environmental pollution caused by abandoned abalone shell, and we provides a new method for self-healing remineralization of enamel defects by AWSM and develops a novel dental material for potential clinical dentistry application. PMID:27287112

  1. Cationic sulfonium functionalization renders Znsalens with high fluorescence, good water solubility and tunable cell-permeability.

    PubMed

    Tang, Juan; Xie, Da; Yin, Hao-Yan; Jing, Jing; Zhang, Jun-Long

    2016-04-01

    In this study, we report for the first time that incorporation of cationic sulfonium to the Znsalens skeleton achieves water soluble fluorescent metal complex probes for living cell imaging. To circumvent Znsalen aggregation arising from intermolecular ZnO interactions (found between Zn and the phenoxyl group of another Znsalen molecule), we synthesized a series of sulfonium Znsalens based on alkylation of the 3-thioether or 3,5-dithioether moieties of salicylaldehydes. Such functionalization not only provides positive charge(s) to enhance electrostatic repulsion, but also increases steric hindrance, which renders the Znsalen complex water soluble as a monomeric species in aqueous media as revealed by diffusion ordered NMR spectroscopy (DOSY). More interestingly, these sulfonium Znsalens display "switched on" fluorescence when compared to thioether analogues, which was attributed to the electron-withdrawing sulfonium moiety that perturbs the photoinduced electron transfer (PET) process as suggested by computational calculations based on time-dependent density functional theory (TD-DFT). Most interestingly, live cell imaging experiments showed that modulation of the sulfonium moieties, such as the number or alkyl substituents, significantly tunes the cell-permeability of the fluorescent Znsalens. Thus, this study has demonstrated the importance of sulfonium functionalization on dissociating the intermolecular metal-ligand interactions and thus, modulating water solubility, photophysical properties and even cell-permeability of the fluorophores, which provides a new approach to the design of functional metal complexes for biological studies. PMID:26883310

  2. A New Porphyrin for the Preparation of Functionalized Water-Soluble Gold Nanoparticles with Low Intrinsic Toxicity

    PubMed Central

    Penon, Oriol; Patiño, Tania; Barrios, Lleonard; Nogués, Carme; Amabilino , David B; Wurst, Klaus; Pérez-García, Lluïsa

    2015-01-01

    A potential new photosensitizer based on a dissymmetric porphyrin derivative bearing a thiol group was synthesized. 5-[4-(11-Mercaptoundecyloxy)-phenyl-10,15,20-triphenylporphyrin (PR-SH) was used to functionalize gold nanoparticles in order to obtain a potential drug delivery system. Water-soluble multifunctional gold nanoparticles GNP-PR/PEG were prepared using the Brust–Schiffrin methodology, by immobilization of both a thiolated polyethylene glycol (PEG) and the porphyrin thiol compound (PR-SH). The nanoparticles were fully characterized by transmission electron microscopy and 1H nuclear magnetic resonance spectroscopy, UV/Vis absorption spectroscopy, and X-ray photoelectron spectroscopy. Furthermore, the ability of GNP-PR/PEGs to induce singlet oxygen production was analyzed to demonstrate the activity of the photosensitizer. Cytotoxicity experiments showed the nanoparticles are nontoxic. Finally, cellular uptake experiments demonstrated that the functionalized gold nanoparticles are internalized. Therefore, this colloid can be considered to be a novel nanosystem that could potentially be suitable as an intracellular drug delivery system of photosensitizers for photodynamic therapy. PMID:25969810

  3. 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

  4. Design and development of a self-nanoemulsifying drug delivery system for telmisartan for oral drug delivery

    PubMed Central

    Patel, Jaydeep; Kevin, Garala; Patel, Anjali; Raval, Mihir; Sheth, Navin

    2011-01-01

    Background and Aim: Telmisartan (TEL) is an angiotensin II receptor blocker (ARB) antihypertensive agent. The aim of the present investigation was to develop a self-nanoemulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of poorly water soluble TEL. Materials and Methods: The solubility of TEL in various oils was determined to identify the oil phase of a SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify the selected oil. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region. A SNEDDS was further evaluated for its percentage transmittance, emulsification time, drug content, phase separation, dilution, droplet size, zeta potential, pH, refractive index, and viscosity. Results: The developed SNEDDS formulation contained TEL (20 mg), Tween® 20 (43.33%w/w), Carbitol® (21.67%w/w), and Acrysol® EL 135 (32%w/w). The optimized formulation of the TEL-loaded SNEDDS exhibited a complete in vitro drug release in 15 min as compared with the plain drug, which had a limited dissolution rate. It was also compared with the pure drug suspension by oral administration in male Wister rats. The in vivo study exhibited a 7.5-fold increase in the oral bioavailability of TEL from the SNEDDS compared with the pure drug suspension. Conclusions: These results suggest the potential use of the SNEDDS to improve the dissolution and oral bioavailability of poorly water soluble TEL. PMID:23071930

  5. Electrospun fibers as potential carrier systems for enhanced drug release of perphenazine.

    PubMed

    Bruni, Giovanna; Maggi, Lauretta; Tammaro, Loredana; Lorenzo, Rosadele Di; Friuli, Valeria; D'Aniello, Sharon; Maietta, Mariarosa; Berbenni, Vittorio; Milanese, Chiara; Girella, Alessandro; Marini, Amedeo

    2016-09-10

    Solubility represents an important challenge for formulation of drugs, because the therapeutic efficacy of a drug depends on the bioavailability and ultimately on its solubility. Low aqueous solubility is one of the main issues related with formulation design and development of new molecules. Many drug molecules present bioavailability problems due to their poor solubility. For this reason there is a great interest in the development of new carrier systems able to enhance the dissolution of poorly water-soluble drugs. In this work, fibers containing an insoluble model drug and prepared by an electrospinning method, are proposed and evaluated to solve this problem. Two hydrophilic polymers, polyvinylpyrrolidone (Plasdone® K29/32) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) were used to increase the water solubility of perphenazine. The physico-chemical characterization suggests that the drug loaded in the fibers is in the amorphous state. Both polymeric carriers are effective to promote the drug dissolution rate in water, where this active pharmaceutical ingredient is insoluble, due to the fine dispersion of the drug into the polymeric matrices, obtained with this production technique. In fact, the dissolution profiles of the fibers, compared to the simple physical mixture of the two components, and to the reference commercial product Trilafon® 8mg tablets, show that a strong enhancement of the drug dissolution rate can be achieved with the electrospinning technique. PMID:27418562

  6. Electrospun fibers as potential carrier systems for enhanced drug release of perphenazine.

    PubMed

    Bruni, Giovanna; Maggi, Lauretta; Tammaro, Loredana; Lorenzo, Rosadele Di; Friuli, Valeria; D'Aniello, Sharon; Maietta, Mariarosa; Berbenni, Vittorio; Milanese, Chiara; Girella, Alessandro; Marini, Amedeo

    2016-09-10

    Solubility represents an important challenge for formulation of drugs, because the therapeutic efficacy of a drug depends on the bioavailability and ultimately on its solubility. Low aqueous solubility is one of the main issues related with formulation design and development of new molecules. Many drug molecules present bioavailability problems due to their poor solubility. For this reason there is a great interest in the development of new carrier systems able to enhance the dissolution of poorly water-soluble drugs. In this work, fibers containing an insoluble model drug and prepared by an electrospinning method, are proposed and evaluated to solve this problem. Two hydrophilic polymers, polyvinylpyrrolidone (Plasdone® K29/32) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) were used to increase the water solubility of perphenazine. The physico-chemical characterization suggests that the drug loaded in the fibers is in the amorphous state. Both polymeric carriers are effective to promote the drug dissolution rate in water, where this active pharmaceutical ingredient is insoluble, due to the fine dispersion of the drug into the polymeric matrices, obtained with this production technique. In fact, the dissolution profiles of the fibers, compared to the simple physical mixture of the two components, and to the reference commercial product Trilafon® 8mg tablets, show that a strong enhancement of the drug dissolution rate can be achieved with the electrospinning technique.

  7. 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.

  8. Dipeptidyl-peptidase IV (DPP IV/CD26)-activated prodrugs: a successful strategy for improving water solubility and oral bioavailability.

    PubMed

    Velázquez, Sonsoles; de Castro, Sonia; Diez-Torrubia, Alberto; Balzarini, Jan; Camarasa, María-José

    2015-01-01

    In the search of novel enzyme-based prodrug approaches to improve pharmacological properties of therapeutic drugs such as solubility and bioavailability, dipeptidyl-peptidase IV (DPP IV, also termed as CD26) enzyme activity provides a previously unexplored successful prodrug strategy. This review covers key aspects of the enzyme useful for the design of CD26-directed prodrugs. The proof-of-concept of this prodrug technology is provided for amine-containing agents by directly linking appropriate di- (or oligo)peptide moieties to a free amino group of a non-peptidic drug through an amide bond which is specifically hydrolized by DPP IV/CD26. Special emphasis is also made in discussing the design and synthesis of more elaborated tripartite prodrug systems, for further extension of the strategy to hydroxy-containing drugs. The application of this technology to improve water solubility and oral bioavailability of prominent examples of antiviral nucleosides is highlighted.

  9. The utility of self-emulsifying oil formulation to improve the poor solubility of the anti HIV drug CSIC

    PubMed Central

    2013-01-01

    Background CSIC (5-chloro-3-phenylsulfonylindole-2-carboxamide), a non-nucleoside reverse transcriptase inhibitor (NNRTI) has not been advanced as a therapeutic anti-HIV candidate drug due to its low aqueous solubility and poor bioavailability. Objective The objective of this work was to formulate CSIC into self-emulsifying oil formulations for the purpose of improving its aqueous solubility and evaluating in vitro antiretroviral activity. Methods CSIC self-emulsifying oil formulations (SEFs) were formulated and evaluated for droplet size, zeta potential, polydispersity index (PDI), viscosity, emulsification time, stability and bioactivity. Results Results showed significantly improved solubility of CSIC in the SEFs.The concentration of co-surfactant affected the droplet size, zeta potential and polydispersity index. In vitro bioactivity studies showed that the CSIC SEFs retained full anti-HIV activity. Conclusion The in vitro data from this first attempt to formulate CSIC SEFs suggest that improvement on the aqueous solubility of CSIC through this delivery system may accentuate its antiretroviral effectiveness in vivo via bioavailability enhancement. The formulation is therefore intended as an oral anti-HIV agent for prophylactic and therapeutic uses. PMID:23721408

  10. Hygroscopic properties of internally mixed particles composed of NaCl and water-soluble organic acids.

    PubMed

    Ghorai, Suman; Wang, Bingbing; Tivanski, Alexei; Laskin, Alexander

    2014-02-18

    Atmospheric aging of naturally emitted marine aerosol often leads to formation of internally mixed particles composed of sea salts and water-soluble organic compounds of anthropogenic origin. Mixing of sea salt and organic components has profound effects on the evolving chemical composition and hygroscopic properties of the resulted particles, which are poorly understood. Here, we have studied chemical composition and hygroscopic properties of laboratory generated NaCl particles mixed with malonic acid (MA) and glutaric acid (GA) at different molar ratios using micro-FTIR spectroscopy, atomic force microscopy, and X-ray elemental microanalysis. Hygroscopic properties of internally mixed NaCl and organic acid particles were distinctly different from pure components and varied significantly with the type and amount of organic compound present. Experimental results were in a good agreement with the AIM modeling calculations of gas/liquid/solid partitioning in studied systems. X-ray elemental microanalysis of particles showed that Cl/Na ratio decreased with increasing organic acid component in the particles with MA yielding lower ratios relative to GA. We attribute the depletion of chloride to the formation of sodium malonate and sodium glutarate salts resulted by HCl evaporation from dehydrating particles. PMID:24437520

  11. Hygroscopic Properties of Internally Mixed Particles Composed of NaCl and Water-Soluble Organic Acids

    SciTech Connect

    Ghorai, Suman; Wang, Bingbing; Tivanski, Alexei V.; Laskin, Alexander

    2014-02-18

    Atmospheric aging of naturally emitted marine aerosol often leads to formation of internally mixed particles composed of sea salts and water soluble organic compounds of anthropogenic origin. Mixing of sea salt and organic components has profound effects on the evolving chemical composition and hygroscopic properties of the resulted particles, which are poorly understood. Here, we have studied chemical composition and hygroscopic properties of laboratory generated NaCl particles mixed with malonic acid (MA) and glutaric acid (GA) at different molar ratios using micro-FTIR spectroscopy and X-ray elemental microanalysis.Hygroscopic properties of inte rnally mixed NaCl and organic acid particles were distinctly different from pure components and varied significantly with the type and amount of organic compound present. Experimental results were in a good agreement with the AIM modeling calculations of gas/liquid/solid partitioning in studied systems. X-ray elemental microanalysis of particles showed that Cl/Na ratio decreased with increasing organic acid component in the particles with MA yielding lower ratios relative to GA. We attribute the depletion of chloride to the formation of Na-malonate and Na-glutarate salts resulted by HCl evaporation from dehydrating particles.

  12. Floating lipid beads for the improvement of bioavailability of poorly soluble basic drugs: in-vitro optimization and in-vivo performance in humans.

    PubMed

    Abouelatta, Samar M; Aboelwafa, Ahmed A; Khalil, Rawia M; ElGazayerly, Omaima N

    2015-01-01

    The challenge in developing oral drug delivery systems of poorly soluble basic drugs is primarily due to their pH dependent solubility. Cinnarizine (CNZ), a model for a poorly soluble basic drug, has pH dependent solubility; where it dissolves readily at low pH in the stomach and exhibits a very low solubility at pH values greater than 4. It is also characterized by a short half life of 3-6h, which requires frequent daily administration resulting in poor patient compliance. In an attempt to solve these problems, extended release floating lipid beads were formulated. A 2(4) full factorial design was utilized for optimization of the effects of various independent variables; lipid:drug ratio, % Pluronic F-127, % Sterotex, and Gelucire 43/01:Gelucire 50/13 ratio, on the loading efficiency and release of CNZ from the lipid beads. In-vivo pharmacokinetic study of the optimized CNZ-lipid beads compared to Stugeron® (reference standard) was performed in healthy human volunteers. A promising approach for enhancing the bioavailability of the poorly soluble basic drug, CNZ, utilizing novel and simple floating lipid beads was successfully developed. Zero order release profile of CNZ was achieved for 12h. Mean AUC0-24 and AUC0-∞ of the optimized CNZ-loaded lipid beads were 4.23 and 6.04 times that of Stugeron® tablets respectively.

  13. Water Soluble Usnic Acid-Polyacrylamide Complexes with Enhanced Antimicrobial Activity against Staphylococcus epidermidis

    PubMed Central

    Francolini, Iolanda; Taresco, Vincenzo; Crisante, Fernanda; Martinelli, Andrea; D’Ilario, Lucio; Piozzi, Antonella

    2013-01-01

    Usnic acid, a potent antimicrobial and anticancer agent, poorly soluble in water, was complexed to novel antimicrobial polyacrylamides by establishment of strong acidic-base interactions. Thermal and spectroscopic analysis evidenced a molecular dispersion of the drug in the polymers and a complete drug/polymer miscibility for all the tested compositions. The polymer/drug complexes promptly dissolved in water and possessed a greater antimicrobial activity against Staphylococcus epidermidis than both the free drug and the polymer alone. The best results were obtained with the complex based on the lowest molecular weight polymer and containing a low drug content. Such a complex showed a larger inhibition zone of bacterial growth and a lower minimum inhibitory concentration (MIC) with respect to usnic acid alone. This improved killing effect is presumably due to the reduced size of the complexes that allows an efficient cellular uptake of the antimicrobial complexes. The killing effect extent seems to be not significantly dependent on usnic acid content in the samples. PMID:23549269

  14. A Water-Soluble Polysaccharide from the Fruit Bodies of Bulgaria inquinans (Fries) and Its Anti-Malarial Activity

    PubMed Central

    Bi, Hongtao; Han, Han; Li, Zonghong; Ni, Weihua; Chen, Yan; Zhu, Jingjing; Gao, Tingting; Hao, Miao; Zhou, Yifa

    2011-01-01

    A water-soluble polysaccharide (BIWS-4b) was purified from the fruit bodies of Bulgaria inquinans (Fries). It is composed of mannose (27.2%), glucose (15.5%) and galactose (57.3%). Its molecular weight was estimated to be 7.4 kDa (polydispersity index, Mw/Mn: 1.35). Structural analyses indicated that BIWS-4b mainly contains (1 → 6)-linked, (1 → 5)-linked and (1 → 5,6)-linked β-Galf units; (1 → 4)-linked and non-reducing terminal β-Glcp units; and (1 → 2)-linked, (1 → 6)-linked, (1 → 2,6)-linked and non-reducing terminal α-Manp units. When examined by the 4-day method and in a prophylactic assay in mice, BIWS-4b exhibited markedly suppressive activity against malaria while enhancing the activity of artesunate. Immunological tests indicated that BIWS-4b significantly enhanced macrophage phagocytosis and splenic lymphocyte proliferation in malaria-bearing mice and normal mice. The anti-malarial activity of BIWS-4b might be intermediated by enhancing immune competence and restoring artesunate-suppressed immune function. Thus, BIWS-4b is a potential adjuvant of anti-malaria drugs. PMID:21785644

  15. Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme.

    PubMed

    Diez-Torrubia, Alberto; Cabrera, Silvia; de Castro, Sonia; García-Aparicio, Carlos; Mulder, Gwenn; De Meester, Ingrid; Camarasa, María-José; Balzarini, Jan; Velázquez, Sonsoles

    2013-01-01

    We herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solid-phase synthesis of the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding tetrapeptide amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug.

  16. Follow-up barium study after a negative water-soluble contrast examination for suspected esophageal leak: is it necessary?

    PubMed

    Sanchez, Thomas R; Holz, Grant S; Corwin, Michael T; Wood, Robert J; Wootton-Gorges, Sandra L

    2015-10-01

    The purpose of this study was to determine the value of follow-up barium esophogram in diagnosing esophageal injury or leak if the initial water-soluble contrast examination of the esophagus is normal. An institutional review board (IRB)-approved retrospective review of all pediatric patients less than 18 years old referred to the radiology department for evaluation of esophageal injury or leak was performed for a 9-year period from 2005 to 2014. The majority of patients had unexplained pneumomediastinum, chest trauma (gunshot or puncture wound), or foreign body ingestion as the reason for the referral. Forty-nine patients (age range 10 days to 17 years) underwent an initial water-soluble esophogram immediately followed by a barium esophogram. Forty-six studies were negative on both water-soluble contrast and barium studies. Two studies were both positive on the initial water-soluble contrast and subsequent barium studies. A single study showed the esophageal leak only in the water-soluble study, with the follow-up barium exam being normal. The result of this study indicates that a single-contrast water-soluble esophogram alone is sensitive in the diagnosis of esophageal injury or leak. It has a 100 % sensitivity and negative predictive value. A follow-up barium esophogram only increases the study time and radiation dose to the patient.

  17. Water solubility of selected C9-C18 alkanes using a slow-stir technique: Comparison to structure - property models.

    PubMed

    Letinski, Daniel J; Parkerton, Thomas F; Redman, Aaron D; Connelly, Martin J; Peterson, Brian

    2016-05-01

    Aqueous solubility is a fundamental physical-chemical substance property that strongly influences the distribution, fate and effects of chemicals upon release into the environment. Experimental water solubility was determined for 18 selected C9-C18 normal, branched and cyclic alkanes. A slow-stir technique was applied to obviate emulsion formation, which historically has resulted in significant overestimation of the aqueous solubility of such hydrophobic liquid compounds. Sensitive GC-MS based methods coupled with contemporary sample extraction techniques were employed to enable reproducible analysis of low parts-per billion aqueous concentrations. Water solubility measurements for most of the compounds investigated, are reported for the first time expanding available data for branched and cyclic alkanes. Measured water solubilities spanned four orders of magnitude ranging from 0.3 μg/L to 250 μg/L. Good agreement was observed for selected alkanes tested in this work and reported in earlier literature demonstrating the robustness of the slow-stir water solubility technique. Comparisons of measured alkane water solubilities were also made with those predicted by commonly used quantitative structure-property relationship models (e.g. SPARC, EPIWIN, ACD/Labs). Correlations are also presented between alkane measured water solubilities and molecular size parameters (e.g. molar volume, solvent accessible molar volume) affirming a mechanistic description of empirical aqueous solubility results and prediction previously reported for a more limited set of alkanes. PMID:26924078

  18. The levels of water-soluble and triton-soluble Aβ are increased in Alzheimer's disease brain

    PubMed Central

    Mc Donald, Jessica M.; Cairns, Nigel J.; Taylor-Reinwald, Lisa; Holtzman, David; Walsh, Dominic M.

    2012-01-01

    Although plaques composed of the amyloid β-protein (Aβ) are considered a defining feature of Alzheimer's disease (AD), they are also found in cognitively normal individuals and extensive evidence suggests that non-plaque, water-soluble forms of Aβ may play a role in AD pathogenesis. However, the relationship between the levels of water-soluble Aβ and the clinical severity of disease has never been investigated. Here, we present results of a pilot study designed to examine the levels of water-soluble forms of Aβ in brains of individuals who died at clinically distinct stages of AD. Using a serial extraction method, we also investigated the levels of triton-soluble and formic acid-soluble Aβ. We found that water-soluble and detergent-soluble Aβ monomer and SDS-stable dimer were elevated in AD and that the levels of water soluble Aβ did not increase with plaque pathology. These results support the notion that both water- and detergent-soluble Aβ are important in AD and are not simply released from plaques by mechanical disruption. Moreover, the fact that the levels of water- and triton-soluble Aβ were similar in very mild/mild AD and moderate/severe AD suggests that once a certain level of these species is attained, further accumulation is not necessary for the disease to progress. Consequently, therapeutic targeting of water-soluble Aβ should best benefit individuals in earliest phases of the disease process. PMID:22440675

  19. Urinary water-soluble vitamins and their metabolite contents as nutritional markers for evaluating vitamin intakes in young Japanese women.

    PubMed

    Fukuwatari, Tsutomu; Shibata, Katsumi

    2008-06-01

    Little information is available to estimate water-soluble vitamin intakes from urinary vitamins and their metabolite contents as possible nutritional markers. Determination of the relationships between the oral dose and urinary excretion of water-soluble vitamins in human subjects contributes to finding valid nutrition markers of water-soluble vitamin intakes. Six female Japanese college students were given a standard Japanese diet in the first week, the same diet with a synthesized water-soluble vitamin mixture as a diet with approximately onefold vitamin mixture based on Dietary Reference Intakes (DRIs) for Japanese in the second week, with a threefold vitamin mixture in the third week, and a sixfold mixture in the fourth week. Water-soluble vitamins and their metabolites were measured in the 24-h urine collected each week. All urinary vitamins and their metabolite levels except vitamin B(12) increased linearly in a dose-dependent manner, and highly correlated with vitamin intake (r=0.959 for vitamin B(1), r=0.927 for vitamin B(2), r=0.965 for vitamin B(6), r=0.957 for niacin, r=0.934 for pantothenic acid, r=0.907 for folic acid, r=0.962 for biotin, and r=0.952 for vitamin C). These results suggest that measuring urinary water-soluble vitamins and their metabolite levels can be used as good nutritional markers for assessing vitamin intakes.

  20. Antibacterial activities of peptides from the water-soluble extracts of Italian cheese varieties.

    PubMed

    Rizzello, C G; Losito, I; Gobbetti, M; Carbonara, T; De Bari, M D; Zambonin, P G

    2005-07-01

    Water-soluble extracts of 9 Italian cheese varieties that differed mainly for type of cheese milk, starter, technology, and time of ripening were fractionated by reversed-phase fast protein liquid chromatography, and the antimicrobial activity of each fraction was first assayed toward Lactobacillus sakei A15 by well-diffusion assay. Active fractions were further analyzed by HPLC coupled to electrospray ionization-ion trap mass spectrometry, and peptide sequences were identified by comparison with a proteomic database. Parmigiano Reggiano, Fossa, and Gorgonzola water-soluble extracts did not show antibacterial peptides. Fractions of Pecorino Romano, Canestrato Pugliese, Crescenza, and Caprino del Piemonte contained a mixture of peptides with a high degree of homology. Pasta filata cheeses (Caciocavallo and Mozzarella) also had antibacterial peptides. Peptides showed high levels of homology with N-terminal, C-terminal, or whole fragments of well known antimicrobial or multifunctional peptides reported in the literature: alphaS1-casokinin (e.g., sheep alphaS1-casein (CN) f22-30 of Pecorino Romano and cow alphaS1-CN f24-33 of Canestrato Pugliese); isracidin (e.g., sheep alphaS1-CN f10-21 of Pecorino Romano); kappacin and casoplatelin (e.g., cow kappa-CN f106-115 of Canestrato Pugliese and Crescenza); and beta-casomorphin-11 (e.g., goat beta-CN f60-68 of Caprino del Piemonte). As shown by the broth microdilution technique, most of the water-soluble fractions had a large spectrum of inhibition (minimal inhibitory concentration of 20 to 200 microg/mL) toward gram-positive and gram-negative bacterial species, including potentially pathogenic bacteria of clinical interest. Cheeses manufactured from different types of cheese milk (cow, sheep, and goat) have the potential to generate similar peptides with antimicrobial activity.

  1. Styrene-maleic acid copolymer-encapsulated CORM2, a water-soluble carbon monoxide (CO) donor with a constant CO-releasing property, exhibits therapeutic potential for inflammatory bowel disease.

    PubMed

    Yin, Hongzhuan; Fang, Jun; Liao, Long; Nakamura, Hideaki; Maeda, Hiroshi

    2014-08-10

    Carbon monoxide (CO), the physiological product of heme oxygenase during catabolic breakdown of heme, has versatile functions and fulfills major anti-oxidative and anti-apoptotic roles in cell systems. Administration of CO is thus thought to be a reasonable therapeutic approach in diseases-such as inflammatory bowel disease-that are induced by reactive oxygen species (ROS). Tricarbonyldichlororuthenium(II) dimer (CORM2) is a commonly used CO donor, but it has poor aqueous solubility and a very short CO-releasing half-life (t1/2). In the present study, we prepared micelles consisting of water-soluble styrene-maleic acid copolymer (SMA) encapsulating CORM2 (SMA/CORM2) that had a hydrodynamic size of 165.3nm. Compared with free CORM2, SMA/CORM2 demonstrated better water solubility (>50mg/ml in a physiological water solution). Moreover, because of micelle formation in an aqueous environment, the CO release rate was slow and sustained. These properties resulted in much longer in vivo bioactivity of SMA/CORM2 compared with that of free CORM2, i.e. the t1/2 in blood of SMA/CORM2 in mice after intravenous (i.v.) injection was about 35 times longer than that of free CORM2. We then evaluated the therapeutic potential of SMA/CORM2 in a murine model of inflammatory colitis induced by dextran sulfate sodium (DSS). Administration (either i.v. or oral) of SMA/CORM2 once at the beginning of colitis, 3days after DSS treatment, significantly improved colitis symptoms-loss of body weight, diarrhea, and hematochezia-as well as histopathological colonic changes-shortening of the colon and necrosis or ulcers in the colonic mucosa. Up-regulation of inflammatory cytokines including monocyte chemotactic protein-1, tumor necrosis factor-α, and interleukin-6 in this DSS-induced colitis was significantly suppressed in SMA/CORM2-treated mice. SMA/CORM2 may thus be a superior CO donor and may be a candidate drug, which involves cytokine suppression, for ROS-related diseases including

  2. Styrene-maleic acid copolymer-encapsulated CORM2, a water-soluble carbon monoxide (CO) donor with a constant CO-releasing property, exhibits therapeutic potential for inflammatory bowel disease.

    PubMed

    Yin, Hongzhuan; Fang, Jun; Liao, Long; Nakamura, Hideaki; Maeda, Hiroshi

    2014-08-10

    Carbon monoxide (CO), the physiological product of heme oxygenase during catabolic breakdown of heme, has versatile functions and fulfills major anti-oxidative and anti-apoptotic roles in cell systems. Administration of CO is thus thought to be a reasonable therapeutic approach in diseases-such as inflammatory bowel disease-that are induced by reactive oxygen species (ROS). Tricarbonyldichlororuthenium(II) dimer (CORM2) is a commonly used CO donor, but it has poor aqueous solubility and a very short CO-releasing half-life (t1/2). In the present study, we prepared micelles consisting of water-soluble styrene-maleic acid copolymer (SMA) encapsulating CORM2 (SMA/CORM2) that had a hydrodynamic size of 165.3nm. Compared with free CORM2, SMA/CORM2 demonstrated better water solubility (>50mg/ml in a physiological water solution). Moreover, because of micelle formation in an aqueous environment, the CO release rate was slow and sustained. These properties resulted in much longer in vivo bioactivity of SMA/CORM2 compared with that of free CORM2, i.e. the t1/2 in blood of SMA/CORM2 in mice after intravenous (i.v.) injection was about 35 times longer than that of free CORM2. We then evaluated the therapeutic potential of SMA/CORM2 in a murine model of inflammatory colitis induced by dextran sulfate sodium (DSS). Administration (either i.v. or oral) of SMA/CORM2 once at the beginning of colitis, 3days after DSS treatment, significantly improved colitis symptoms-loss of body weight, diarrhea, and hematochezia-as well as histopathological colonic changes-shortening of the colon and necrosis or ulcers in the colonic mucosa. Up-regulation of inflammatory cytokines including monocyte chemotactic protein-1, tumor necrosis factor-α, and interleukin-6 in this DSS-induced colitis was significantly suppressed in SMA/CORM2-treated mice. SMA/CORM2 may thus be a superior CO donor and may be a candidate drug, which involves cytokine suppression, for ROS-related diseases including

  3. In silico prediction of the solubility advantage for amorphous drugs - Are there property-based rules for drug discovery and early pharmaceutical development?

    PubMed

    Kuentz, Martin; Imanidis, Georgios

    2013-02-14

    Oral delivery of poorly water-soluble compounds is often a substantial challenge. Once a drug candidate is selected, it is desirable to predict, based on chemical structure, which formulation technology has the highest potential to enhance drug solubility and absorption. Due to the importance of amorphous drug formulations, this work aimed at calculating the solubility ratio of amorphous and crystalline drug using in silico methods only. Molecular modeling together with multivariate methods was employed and a particular aim was to find simple structure-based rules for the technology selection of amorphous drug formulations. As a result, calculated estimates for reference compounds were generally higher than experimentally obtained amorphous solubility ratios; however, the rank order of the values revealed a significant correlation (p=0.036). Subsequently, a set of 56 neutral poorly water-soluble compounds resulted in a good partial least square model with R² of 0.803. Most important for the amorphous solubility ratio was molecular weight, number of hydrogen bond acceptors, melting point, number of torsional bonds and polar surface area. By considering the Lipinsky rules, we proposed suitable ranges of these molecular predictors with respect to selecting promising amorphous drug formulations. Such structure-based guidance can help in early formulation development of challenging drug candidates, thereby leading to substantial cost savings. However, there is certainly more experimental research needed to finally assess how broadly the presented concepts can be applied. PMID:23262058

  4. In silico prediction of the solubility advantage for amorphous drugs - Are there property-based rules for drug discovery and early pharmaceutical development?

    PubMed

    Kuentz, Martin; Imanidis, Georgios

    2013-02-14

    Oral delivery of poorly water-soluble compounds is often a substantial challenge. Once a drug candidate is selected, it is desirable to predict, based on chemical structure, which formulation technology has the highest potential to enhance drug solubility and absorption. Due to the importance of amorphous drug formulations, this work aimed at calculating the solubility ratio of amorphous and crystalline drug using in silico methods only. Molecular modeling together with multivariate methods was employed and a particular aim was to find simple structure-based rules for the technology selection of amorphous drug formulations. As a result, calculated estimates for reference compounds were generally higher than experimentally obtained amorphous solubility ratios; however, the rank order of the values revealed a significant correlation (p=0.036). Subsequently, a set of 56 neutral poorly water-soluble compounds resulted in a good partial least square model with R² of 0.803. Most important for the amorphous solubility ratio was molecular weight, number of hydrogen bond acceptors, melting point, number of torsional bonds and polar surface area. By considering the Lipinsky rules, we proposed suitable ranges of these molecular predictors with respect to selecting promising amorphous drug formulations. Such structure-based guidance can help in early formulation development of challenging drug candidates, thereby leading to substantial cost savings. However, there is certainly more experimental research needed to finally assess how broadly the presented concepts can be applied.

  5. The effect of dual ligand-targeted micelles on the delivery and efficacy of poorly soluble drug for cancer therapy.

    PubMed

    Sawant, Rupa R; Jhaveri, Aditi M; Koshkaryev, Alexander; Qureshi, Farooq; Torchilin, Vladimir P

    2013-08-01

    We prepared and evaluated transferrin (Tf) and monoclonal antibody (mAb) 2C5-modified dual ligand-targeted poly(ethylene glycol)-phosphatidylethanolamine micelles loaded with a poorly soluble drug, R547 (a selective adenosine triphosphate-competitive cyclin-dependent kinase inhibitor) for enhancement of targeting efficiency and cytotoxicity in vitro and in vivo to A2780 ovarian carcinoma compared to single ligand-targeted micelles. Micellar solubilization significantly improved the solubility of R547 from 1 to 800 μg/mL. The size of modified and non-modified micelles was 13-16 nm. Flow cytometry indicated significantly enhanced cellular association of dual ligand-targeted micelles compared to single ligand-targeted micelles. Confocal microscopy confirmed the Tf receptor-mediated endocytosis of rhodamine-labeled Tf-modified micelles after staining the micelle-treated cells with the endosomal marker Tf-Alexa488. The optimized dual-targeted micelles enhanced cytotoxicity in vitro against A2780 ovarian cancer cells compared to plain and single ligand-targeted micelles. Interestingly, in vivo anti-tumor efficacy was more pronounced for the preparation with a single-targeting ligand (Tf). The specific combination Tf and mAb 2C5 did not yield the expected increase in efficacy as was observed in vitro. This observation suggests that the relationships between targeting ligands in vivo could be more complex than in simplified in vitro systems, and the results of the optimization process should always be verified in vivo. PMID:23594094

  6. Injected nanocrystals for targeted drug delivery

    PubMed Central

    Lu, Yi; Li, Ye; Wu, Wei

    2016-01-01

    Nanocrystals are pure drug crystals with sizes in the nanometer range. Due to the advantages of high drug loading, platform stability, and ease of scaling-up, nanocrystals have been widely used to deliver poorly water-soluble drugs. Nanocrystals in the blood stream can be recognized and sequestered as exogenous materials by mononuclear phagocytic system (MPS) cells, leading to passive accumulation in MPS-rich organs, such as liver, spleen and lung. Particle size, morphology and surface modification affect the biodistribution of nanocrystals. Ligand conjugation and stimuli-responsive polymers can also be used to target nanocrystals to specific pathogenic sites. In this review, the progress on injected nanocrystals for targeted drug delivery is discussed following a brief introduction to nanocrystal preparation methods, i.e., top-down and bottom-up technologies. PMID:27006893

  7. Bottom-up approach to eumelanin photoprotection: emission dynamics in parallel sets of water-soluble 5,6-dihydroxyindole-based model systems.

    PubMed

    Corani, Alice; Huijser, Annemarie; Iadonisi, Alfonso; Pezzella, Alessandro; Sundström, Villy; d'Ischia, Marco

    2012-11-01

    The molecular mechanisms by which the black eumelanin biopolymers exert their photoprotective action on human skin and eyes are still poorly understood, owing to critical insolubility and structural heterogeneity issues hindering direct investigation of excitation and emission behavior. Recently, we set up strategies to obtain water-soluble 5,6-dihydroxyindole (DHI)-based polymers as useful models for disentangling intrinsic photophysical properties of eumelanin components from aggregation and scattering effects. Herein, we report the absorption properties and ultrafast emission dynamics of two separate sets of DHI-based monomer-dimer-polymer systems which were made water-soluble by means of poly(vinyl alcohol) or by galactosyl-thio substitution. Data showed that dimerization and polymerization of DHI result in long-lived excited states with profoundly altered properties relative to the monomer and that glycosylation of DHI imparts monomer-like behavior to oligomers and polymers, due to steric effects hindering planar conformations and efficient interunit electron communication. The potential of S-glycation as an effective tool to probe and control emission characteristics of eumelanin-like polymers is disclosed.

  8. Solid inclusion complexes of oleanolic acid with amino-appended β-cyclodextrins (ACDs): Preparation, characterization, water solubility and anticancer activity.

    PubMed

    Ren, Yufeng; Liu, Ying; Yang, Zhikuan; Niu, Raomei; Gao, Kai; Yang, Bo; Liao, Xiali; Zhang, Jihong

    2016-12-01

    Oleanolic acid (OA) is a pentacyclic triterpenoid acid of natural abundance in plants which possesses important biological activities. However, its medicinal applications were severely impeded by the poor water solubility and resultant low bioavailability and potency. In this work, studies on solid inclusion complexes of OA with a series of amino-appended β-cyclodextrins (ACDs) were conducted in order to address this issue. These complexes were prepared by suspension method and were well characterized by NMR, SEM, XRD, TG, DSC and Zeta potential measurement. The 2:1 inclusion mode of ACDs/OA complexes was elucidated by elaborate 2D NMR (ROESY). Besides, water solubility of OA was dramatically promoted by inclusion complexation with ACDs. Moreover, in vitro anticancer activities of OA against human cancer cell lines HepG2, HT29 and HCT116 were significantly enhanced after formation of inclusion complexes, while the apoptotic response results indicated their induction of apoptosis of cancer cells. This could provide a novel approach to development of novel pharmaceutical formulations of OA. PMID:27612690

  9. In vitro and in vivo antioxidant activity of a water-soluble polysaccharide from dendrobium denneanum

    USGS Publications Warehouse

    Luo, A.; Ge, Z.; Fan, Y.; Chun, Z.; Jin, He X.

    2011-01-01

    The water-soluble crude polysaccharide (DDP) obtained from the aqueous extracts of the stem of Dendrobium denneanum through hot water extraction followed by ethanol precipitation, was found to have an average molecular weight (Mw) of about 484.7 kDa. Monosaccharide analysis revealed that DDP was composed of arabinose, xylose, mannose, glucose and galactose in a molar ratio of 1.00:2.66:8.92:34.20:10.16. The investigation of antioxidant activity both in vitro and in vivo showed that DDP is a potential antioxidant. ?? 2011.

  10. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo.

    PubMed

    Larson, Daniel R; Zipfel, Warren R; Williams, Rebecca M; Clark, Stephen W; Bruchez, Marcel P; Wise, Frank W; Webb, Watt W

    2003-05-30

    The use of semiconductor nanocrystals (quantum dots) as fluorescent labels for multiphoton microscopy enables multicolor imaging in demanding biological environments such as living tissue. We characterized water-soluble cadmium selenide-zinc sulfide quantum dots for multiphoton imaging in live animals. These fluorescent probes have two-photon action cross sections as high as 47,000 Goeppert-Mayer units, by far the largest of any label used in multiphoton microscopy. We visualized quantum dots dynamically through the skin of living mice, in capillaries hundreds of micrometers deep. We found no evidence of blinking (fluorescence intermittency) in solution on nanosecond to millisecond time scales.

  11. Water-Soluble Quantum Dots for Multiphoton Fluorescence Imaging in Vivo

    NASA Astrophysics Data System (ADS)

    Larson, Daniel R.; Zipfel, Warren R.; Williams, Rebecca M.; Clark, Stephen W.; Bruchez, Marcel P.; Wise, Frank W.; Webb, Watt W.

    2003-05-01

    The use of semiconductor nanocrystals (quantum dots) as fluorescent labels for multiphoton microscopy enables multicolor imaging in demanding biological environments such as living tissue. We characterized water-soluble cadmium selenide-zinc sulfide quantum dots for multiphoton imaging in live animals. These fluorescent probes have two-photon action cross sections as high as 47,000 Goeppert-Mayer units, by far the largest of any label used in multiphoton microscopy. We visualized quantum dots dynamically through the skin of living mice, in capillaries hundreds of micrometers deep. We found no evidence of blinking (fluorescence intermittency) in solution on nanosecond to millisecond time scales.

  12. Relationship between water solubility of chlorobenzenes and their effects on a freshwater green alga

    SciTech Connect

    Wong, P.T.S.; Chau, Y.K.; Rhamey, J.S.; Docker, M.

    1984-01-01

    The effective concentrations of benzene and 12 chlorobenzenes that reduced 50% of the primary productivity (EC/sub 50/) of a freshwater green alga, Ankistrodesmus falcatus, were determined. Benzene was the least toxic chemical and the toxicity increased as the degree of chlorine substitution in the aromatic ring increased. No EC/sub 50/ value could be obtained for HCB. A quantitative relationship was found to exist between water solubility, lipophilicity and the EC/sub 50/. A good correlation was also observed between the EC/sub 50/ for this alga and other toxicity data for various aquatic biota.

  13. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo.

    PubMed

    Larson, Daniel R; Zipfel, Warren R; Williams, Rebecca M; Clark, Stephen W; Bruchez, Marcel P; Wise, Frank W; Webb, Watt W

    2003-05-30

    The use of semiconductor nanocrystals (quantum dots) as fluorescent labels for multiphoton microscopy enables multicolor imaging in demanding biological environments such as living tissue. We characterized water-soluble cadmium selenide-zinc sulfide quantum dots for multiphoton imaging in live animals. These fluorescent probes have two-photon action cross sections as high as 47,000 Goeppert-Mayer units, by far the largest of any label used in multiphoton microscopy. We visualized quantum dots dynamically through the skin of living mice, in capillaries hundreds of micrometers deep. We found no evidence of blinking (fluorescence intermittency) in solution on nanosecond to millisecond time scales. PMID:12775841

  14. Evaluation of hydration in a water-soluble polymer by terahertz spectroscopy

    NASA Astrophysics Data System (ADS)

    Kawabe, Shunsuke; Seki, Munetoshi; Tabata, Hitoshi

    2016-02-01

    In this study, we have evaluated the hydration properties of water-soluble polymers by terahertz spectroscopy. In particular, we focused on polyvinylpyrrolidone which has potential use for a wide range of applications as a biomaterial. The dielectric loss of samples obtained by the terahertz spectroscopy was found to strongly depend on the molecular weight of the polymers and the density of the solution. We revealed that the hydration number per monomer depends on the molecular weight of the polymer. It is also deduced that the hydration number is affected by the conformation of the polymer in the solution.

  15. Characteristics of new particle formation events in Nanjing, China: Effect of water-soluble ions

    NASA Astrophysics Data System (ADS)

    An, Junlin; Wang, Honglei; Shen, Lijuan; Zhu, Bin; Zou, Jianan; Gao, Jinhui; Kang, Hanqing

    2015-05-01

    New particle formation (NPF) events and water-soluble ions were studied at the meteorological building on the campus of the Nanjing University of Information Science and Technology (NUIST), which is located in the western part of the Yangtze River Delta (YRD). A wide-range particle spectrometer (WPS) provided particle number size distributions between 10 nm and 10 μm, whereas water-soluble ions for particles with diameters between 10 nm and 18 μm were measured using a 13-stage Nano-MOUDI aerosol sampler and 850 professional Ion Chromatography (IC). Additionally, meteorological data, trace gas concentrations and mass concentration were recorded. Ten NPF days were captured during the measurement period from 08 July to 02 August 2012. The mean aerosol number concentration, which was primarily composed of Aitken-mode particles, i.e., with diameters of 20-100 nm, was 13,664 cm-3, which was 1.9 times larger than that on non-NPF days. The results suggest that the NPF events were only slightly affected by O3, SO2, and NO2; the primary factors affecting NPF events were meteorological factors and air mass directions. NPF events were found to be favorable during the summer in the presence of high temperatures, strong radiation, low humidity, strong winds and clean air masses originating from the southeastern coast. The mean growth rate (GR), formation rate (J10), condensational sink (CS), condensing vapor rate (Q), and condensation vapor (C) were determined to be 7.6 nm h-1, 3.7 cm-3 s-1, 2.8 × 10-2 s-1, 2.9 × 106 cm-3 s-1, and 10.5 × 107 cm-3, respectively, on NPF days. The largest effects of the studied NPF events were on the mass and water-soluble ion concentrations of Aitken-mode particles, followed by nuclei-mode particles; few contributions to accumulation- and coarse-mode particles were observed. Different water-soluble ions were observed to have distinct interactions with the NPF events. The proportions of NH4+, SO42-, NO3-, K+ and Mg2+ in nuclei- and Aitken

  16. Harnessing medically relevant metals onto water-soluble subphthalocyanines: towards bimodal imaging and theranostics.

    PubMed

    Bernhard, Yann; Winckler, Pascale; Perrier-Cornet, Jean-Marie; Decréau, Richard A

    2015-02-21

    Subphthalocyanine (SubPc), a putative fluorophore for optical imaging (OI), was conjugated to chelating ligands (DOTA, DTPA) affording water-soluble conjugates complexed with (non-radioactive) metals relevant to the following medical imaging techniques/therapies: MRI (Gd), PET (Cu, Ga), SPECT (In, Ga, Lu), RIT (Cu, Lu, Y), and NCT (Gd). Magneto-optical properties of ditopic gadolinium species (and optical properties of other metal containing species) were examined (brightness (ε × ΦF) and relaxivity R1) and fluorescence confocal/biphoton microscopy studies were conducted.

  17. Efficient Route to Highly Water-Soluble Aromatic Cyclic Hydroxamic Acid Ligands

    SciTech Connect

    Seitz, Michael; Raymond, Kenneth N.

    2008-02-06

    2-Hydroxyisoquinolin-1-one (1,2-HOIQO) is a new member of the important class of aromatic cyclic hydroxamic acid ligands which are widely used in metal sequestering applications and metal chelating therapy. The first general approach for the introduction of substituents at the aromatic ring of the chelating moiety is presented. As a useful derivative, the highly water-soluble sulfonic acid has been synthesized by an efficient route that allows general access to 1,2-HOQIO 3-carboxlic acid amides, which are the most relevant for applications.

  18. Water-soluble chelating polymers for removal of actinides from watewater

    SciTech Connect

    Jarvinen, G.

    1996-10-01

    Polymer filtration is a technology being developed to recover valuable or regulated metal ions selectively from process or wastewaters. Water-soluble chelating polymers are specially designed to bind selectively with metal ions in aqueous solutions. The polymers molecular weight is large enough so they can be separated and concentrated using available ultrafiltration technology. Water and smaller unbound components of the solution pass freely through the ultrafiltration membrane. The polymers can then be reused by changing the solution conditions to release the metal ions, which are recovered in concentrated form, for recycle or disposal.

  19. Imidazolium-based warheads strongly influence activity of water-soluble peptidic transglutaminase inhibitors.

    PubMed

    Badarau, Eduard; Mongeot, Alexandre; Collighan, Russell; Rathbone, Dan; Griffin, Martin

    2013-08-01

    New peptidic water-soluble inhibitors are reported. In addition to the carboxylate moiety, a new polar warhead was explored. Depending on the size of its substituents, the newly appended imidazolium scaffold designed to enhance the hydrophilic character of the inhibitors could induce a good inhibition for tissue transglutaminase (TG2) and blood coagulation factor XIIIa (FXIIIa). Correlated with the narrow tunnel that hosts the target catalytic cysteine residue, the various modulations suggest a bent conformation of the ligands as the binding pattern mode. Analogues in the dialkylsulfonium series were also tested and showed specificity for TG2 over FXIIIa.

  20. Fluorescence quenching of water-soluble conjugated polymer by metal cations and its application in sensor.

    PubMed

    Chen, Yan-Guo; Zhao, Dan; He, Zhi-Ke; Ai, Xin-Ping

    2007-02-01

    The effects of different metal cations on the fluorescence of water-soluble conjugated polymer (CP) and their quenching mechanism have been explored. Most transition metal cations, especially noble metal cations, such as Pd2+, Ru3+, and Pt2+ possessed higher quenching efficiency to CP fluorescence than that of the main group metal cations and other transition metal cations, which have filled or half-full outmost electron layer configurations. Base on this, rapid, sensitive detection of noble metal cations can be realized and a novel quencher-tether-ligand (QTL) probe was developed to detect avidin and streptavidin.

  1. Encapsulation of Polythiophene by Glycopolymer for Water Soluble Nano-wire

    SciTech Connect

    T Fukuda; Y Inoue; T Koga; M Matsuoka; Y Miura

    2011-12-31

    A water-soluble polythiophene (PT) was prepared by the self-assembling complex with a glycopolymer. The glycopolymer of poly(N-p-vinylbenzyl-D-lactonamide) (PVLA) formed self-assembling cylindrical structure based on the amphiphilicity even after the complexation with PT. We confirmed the improved optical functionality of PT due to the longer conjugated {pi}-orbital. It suggested that PT behaved like molecular nanowire with the self-assembled structure in the hydrophobic core of PVLA. PVLA-PT also showed specific biorecognition against corresponding lectin. These results suggested that the bioactive nanowire formation of PT with the glycopolymer was developed.

  2. Water-soluble mitochondria-specific ytterbium complex with impressive NIR emission.

    PubMed

    Zhang, Tao; Zhu, Xunjin; Cheng, Chopen C W; Kwok, Wai-Ming; Tam, Hoi-Lam; Hao, Jianhua; Kwong, Daniel W J; Wong, Wai-Kwok; Wong, Ka-Leung

    2011-12-21

    A water-soluble porphyrinato ytterbium complex linked with rhodamine B (Yb-2) showed mitochondria-specific subcellular localization and strong two-photon-induced NIR emissions (λ(em) = 650 nm, porphyrinate ligand π → π* transition; λ(em) = 1060 nm, Yb(III) (5)F(5/2) → (5)F(7/2) transitions; σ(2) = 375 GM in DMSO) with an impressive Yb(III) NIR emission quantum yield (1% at λ(ex) = 340 nm; 2.5% at λ(ex) = 430 nm) in aqueous solution.

  3. Droplet-based microreactor for synthesis of water-soluble Ag₂S quantum dots.

    PubMed

    Shu, Yun; Jiang, Peng; Pang, Dai-Wen; Zhang, Zhi-Ling

    2015-07-10

    A droplet-based microreactor was used for synthesis of water-soluble Ag2S quantum dots (QDs). Monodispersed Ag2S nanoparticles with a surface of carboxylic acid-terminated were synthesized in the droplet microreactor. The x-ray powder diffraction results indicated products were monoclinic Ag2S nanocrystals. Furthermore, different-sized Ag2S QDs that were near-infrared-emitting or visible-emitting were continuously stably synthesized in droplet microreactors at different temperatures. We believe we offer a new method for obtaining different-sized Ag2S nanoparticles. PMID:26067160

  4. Water-soluble material on aerosols collected within volcanic eruption clouds ( Fuego, Pacaya, Santiaguito, Guatamala).

    USGS Publications Warehouse

    Smith, D.B.; Zielinski, R.A.; Rose, W.I.; Huebert, B.J.

    1982-01-01

    In Feb. and March of 1978, filter samplers mounted on an aircraft were used to collect the aerosol fraction of the eruption clouds from three active Guatemalan volcanoes (Fuego, Pacaya, and Santiaguito). The elements dissolved in the aqueous extracts represent components of water-soluble material either formed directly in the eruption cloud or derived from interaction of ash particles and aerosol components of the plume. Calculations of enrichment factors, based upon concentration ratios, showed the elements most enriched in the extracts relative to bulk ash composition were Cd, Cu, V, F, Cl, Zn, and Pb.-from Authors

  5. A Water-Soluble Polythiophene for Organic Field-Effect Transistors

    SciTech Connect

    Shao, Ming; He, Youjun; Hong, Kunlun; Rouleau, Christopher M; Geohegan, David B; Xiao, Kai

    2013-01-01

    Synthesis of a non-ionic, water-soluble poly(thiophene) (PT) derivative, poly(3-(2-(2-methoxyethoxy) ethoxy)ethoxy) methylthiophene) (P3TEGT) with a hydrophilic tri-ethylene glycol side group, is reported and thin films of the polymer suitable for organic field-effect transistors (OFETs) are characterized by combining analysis techniques that include UV-Vis absorption and fluorescence spectroscopy, x-ray diffraction, and atomic force microscopy. After thermal annealing, P3TEGT films exhibit a well-organized nanofibrillar lamellar nanostructure that originates from the strong - stacking of the thiophene backbones. P-type organic field-effect transistors (OFETs) with hole mobilities of 10-5 cm2V-1s-1 were fabricated from this water-soluble poly(thiophene) derivative, demonstrating the possibility that environmentally-friendly solvents may be promising alternatives for the low-cost, green solution-based organic electronic device manufacturing of OFETs, organic photovoltaics (OPVs), and biosensors.

  6. Lightsticks content toxicity: effects of the water soluble fraction on the oyster embryonic development.

    PubMed

    de Araujo, Milena Maria Sampaio; Menezes Filho, Adalberto; Nascimento, Iracema Andrade; Pereira, Pedro Afonso P

    2015-11-01

    Lightsticks are artifacts used as attractors in a type of commercial fishery, known as surface longline gear. Despite the excessive use, the contamination risks of these devices have not yet been properly investigated. This research aimed to fill up this gap by determining the chemical composition and the toxicity of lightsticks recently activated, compared to those one year after activation and to the ones collected on the beaches. The analyzes were carried out by Gas Chromatography coupled with Mass Spectrometry (GC-MS). Additionally, the variations in composition and the toxicity of their sea Water Soluble Fractions (WSF) were evaluated based on the WSF-effects of Crassostrea rhizophorae embryonic development. The GC-MS analysis made possible the identification of nineteen substances in the water soluble fraction of the lightsticks, such as dibutyl phthalate (DBP) and dimethyl phthalate (DMP). The value of the WSF-effective concentration (EC50) was in an average of 0.35%. After one year of the lightsticks activation, the toxicity was even higher (0.65%). Furthermore, other substances, also present in the lightsticks-WSF caused persistent toxicity even more dangerous to the environment than DBP and DMP. This essay discusses their toxicity effects and possible environment damages.

  7. Aerosol water soluble organic nitrogen and carbon over the remote Atlantic Ocean

    NASA Astrophysics Data System (ADS)

    Pollard, Liam; Baker, Alex; Jickels, Tim

    2014-05-01

    Nitrogen is a limiting or co-limiting nutrient in large parts of the world's oceans particularly in oligotrophic regions such as gyres. In the open ocean there are two pathways by which new nutrient nitrogen can enter the oligotrophic system: biological nitrogen fixation and atmospheric deposition. Aerosol matter contributes to the latter route via dry and wet deposition, therefore it is important to understand and quantify the nitrogen containing material in aerosols and establish its major sources. Until recently, the organic nitrogen component of aerosol nitrogen was largely ignored, however, it is now known to contribute between 25-30 % of total water soluble nitrogen in aerosols, globally. This organic nitrogen is known to be chemically complex, shows high spatial and temporal variability and a large proportion of it has been shown to be bioavailable. It is important that this material is further quantified and characterised (including its carbon component) to determine its biogeochemical impact. Data gathered from fine and coarse mode aerosol samples collected on three Atlantic cruises (AMT21, AMT22 and ANT26-4) will be presented. Bulk and water soluble organic carbon and nitrogen data will be shown alongside major ion and inorganic nitrogen data. Potential sources of organic nitrogen and carbon material will be evaluated using a combination of inter-component correlations with known tracers and air-parcel back trajectories, allowing estimates of the anthropogenic impact on nutrient deposition to the remote Atlantic Ocean to be made.

  8. Size-controlled synthesis of highly water-soluble silver nanocrystals

    SciTech Connect

    Hu Yongxing; Ge Jianping; Lim, Donna; Zhang Tierui; Yin Yadong

    2008-07-15

    We describe a modified polyol process for the synthesis of silver nanocrystals with uniform sizes ranging from several nanometers to {approx}20 nm. The use of polyacrylic acid, in place of polyvinylpyrrolidone in the conventional polyol process, significantly limits the growth of silver nanocrystals, prevents the interparticle aggregation and fusion, and leads to a uniform population of samples with high water solubility. The size of nanocrystals can be conveniently tuned by controlling the reaction time, the concentration and chain length of the polymeric surfactants, and the reaction temperature. Uniform silver nanocrystals within sizes below 20 nm are preferred candidates over larger particles for applications where high density of optical absorption is required, for example, for photothermal conversion in cancer therapy. - Graphical abstract: Silver nanocrystals with uniform and controllable sizes (<20 nm) have been synthesized using a modified polyol process. The use of polyacrylic acid as the surfactant significantly limits the nanocrystal growth, prevents the interparticle aggregation and fusion, and leads to a uniform population of samples with high water solubility.

  9. Novel water-soluble fisetin/cyclodextrins inclusion complexes: Preparation, characterization, molecular docking and bioavailability.

    PubMed

    Zhang, Jian-qiang; Jiang, Kun-ming; An, Kun; Ren, Si-hao; Xie, Xiao-guang; Jin, Yi; Lin, Jun

    2015-12-11

    Novel water-soluble inclusion complexes for fisetin (FIT) were developed by introducing β-cyclodextrin (β-CD) and γ-CD. Properties of the obtained complexes, as well as the interactions between each component, were systematically investigated in both solution and solid states by means of ESI-MS, NMR, FT-IR, XRD, DSC, SEM etc. All characterization information demonstrated that FIT/CDs inclusion complexes were formed, and exhibited different spectroscopic features and properties from FIT. A complex with 1:1 stoichiometry of FIT and CDs was confirmed with Job's method. Meanwhile, as supported by molecular modeling calculations, we suggested that phenyl group (C ring) of FIT molecule was included in the CDs cavity from the wide side. Moreover, the water solubility of FIT/CDs was successfully improved from 2.8 mg/mL (in ethanol aqueous solution) to 4.5 mg/mL (FIT/β-CD complex) and 7.8 mg/mL (FIT/γ-CD complex), and higher thermal stability results were shown by thermal analysis for those complexes. Notably, the inclusion complexes displayed almost two times higher cytotoxicity compared to free FIT against Hela and MCF-7 cells. These results suggested that FIT/CDs complexes could be potentially useful in food industry and healthcare area.

  10. Uncertainties in the measurements of water-soluble organic nitrogen in the aerosol

    NASA Astrophysics Data System (ADS)

    Matsumoto, Kiyoshi; Yamato, Koki

    2016-11-01

    In order to evaluate the positive and negative artifacts in the measurements of the water-soluble organic nitrogen (WSON) in the aerosols by filter sampling, comparative experiments between the filter sampling and denuder-filter sampling were conducted during both the warm and cold seasons. The results suggest that the traditional filter sampling underestimates the concentrations of the particulate WSON due to its volatilization loss, but this effect on the ratio of the WSON to the water-soluble total nitrogen (WSTN) was small probably because inorganic nitrogen species were also lost during the filter sampling. Approximately 32.5% of the WSON in the PM2.5 was estimated to be lost during the filter sampling. The denuder-filter sampling also demonstrated the existence of the WSON in the gas phase with approximately quarter concentrations of the WSON in the PM2.5. On the other hand, the filter sampling would overestimate the gaseous WSON concentration due to the loss of the WSON from the aerosol collection filter.

  11. Chemical composition of water-soluble fraction in soils on glaciolacustrine deposits of the Russian Plain

    NASA Astrophysics Data System (ADS)

    Panova, E. G.; Oleinikova, G. A.; Matinyan, N. N.; Bakhmatova, K. A.

    2016-06-01

    The behavior of some chemical elements was studied in soils and their liquid phase. Two reference soil profiles on glaciolacustrine clays (soddy-eluvial-metamorphic soil) and sands (soddy podzol) were investigated on the Russian Plain. A colloidal fraction (particles <1 μm) was isolated with deionized hot water from a soil sample of 30 g at the soil: water ratio of 1: 10. The suspension was mixed for 6 h, settled for 24 h, and filtrated using a membrane filter (<1 μm). The soil sample and its water-soluble fraction (WSF) were analyzed by mass spectrometry with inductively coupled plasma. The chemical characteristics of the extracted liquid phase of the soil reflect its water-soluble component properties. The comparison of the data obtained with the results of the analysis for the whole soil allows assessment of a share of easily mobile and difficultly mobile forms of chemical compounds. This is the necessary basis for the development of a model describing the transport of metals in soil.

  12. Formation of water-soluble metal cyanide complexes from solid minerals by Pseudomonas plecoglossicida.

    PubMed

    Faramarzi, Mohammad A; Brandl, Helmut

    2006-06-01

    A few Pseudomonas species are able to form hydrocyanic acid (HCN), particularly when grown under glycine-rich conditions. In the presence of metals, cyanide can form water-soluble metal complexes of high chemical stability. We studied the possibility to mobilize metals as cyanide complexes from solid minerals using HCN-forming microorganisms. Pseudomonas plecoglossicida was cultivated in the presence of copper- and nickel-containing solid minerals. On powdered elemental nickel, fast HCN generation within the first 12 h of incubation was observed and water-soluble tetracyanaonickelate was formed. Cuprite, tenorite, chrysocolla, malachite, bornite, turquoise, millerite, pentlandite as well as shredded electronic scrap was also subjected to a biological treatment. Maximum concentrations of cyanide-complexed copper corresponded to a solubilization of 42% and 27% when P. plecoglossicida was grown in the presence of cuprite or tenorite, respectively. Crystal system, metal oxidation state and mineral hydrophobicity might have a significant influence on metal mobilization. However, it was not possible to allocate metal mobilization to a single mineral property. Cyanide-complexed gold was detected during growth on manually cut circuit boards. Maximum dicyanoaurate concentration corresponded to a 68.5% dissolution of the total gold added. These findings represent a novel type of microbial mobilization of nickel and copper from solid minerals based on the ability of certain microbes to form HCN.

  13. Formation of water-soluble metal cyanide complexes from solid minerals by Pseudomonas plecoglossicida.

    PubMed

    Faramarzi, Mohammad A; Brandl, Helmut

    2006-06-01

    A few Pseudomonas species are able to form hydrocyanic acid (HCN), particularly when grown under glycine-rich conditions. In the presence of metals, cyanide can form water-soluble metal complexes of high chemical stability. We studied the possibility to mobilize metals as cyanide complexes from solid minerals using HCN-forming microorganisms. Pseudomonas plecoglossicida was cultivated in the presence of copper- and nickel-containing solid minerals. On powdered elemental nickel, fast HCN generation within the first 12 h of incubation was observed and water-soluble tetracyanaonickelate was formed. Cuprite, tenorite, chrysocolla, malachite, bornite, turquoise, millerite, pentlandite as well as shredded electronic scrap was also subjected to a biological treatment. Maximum concentrations of cyanide-complexed copper corresponded to a solubilization of 42% and 27% when P. plecoglossicida was grown in the presence of cuprite or tenorite, respectively. Crystal system, metal oxidation state and mineral hydrophobicity might have a significant influence on metal mobilization. However, it was not possible to allocate metal mobilization to a single mineral property. Cyanide-complexed gold was detected during growth on manually cut circuit boards. Maximum dicyanoaurate concentration corresponded to a 68.5% dissolution of the total gold added. These findings represent a novel type of microbial mobilization of nickel and copper from solid minerals based on the ability of certain microbes to form HCN. PMID:16684101

  14. Structural, functional, and ACE inhibitory properties of water-soluble polysaccharides from chickpea flours.

    PubMed

    Mokni Ghribi, Abir; Sila, Assaâd; Maklouf Gafsi, Ines; Blecker, Christophe; Danthine, Sabine; Attia, Hamadi; Bougatef, Ali; Besbes, Souhail

    2015-04-01

    The present study aimed to characterize and investigate the functional and angiotensin-I converting enzyme (ACE) inhibition activities of chickpea water-soluble polysaccharides (CPWSP). Physico-chemical characteristics were determined by nuclear magnetic resonance spectroscopy (NMR), Fourier transform-infrared spectroscopy (FT-IR) analysis, and X-ray diffractometry (XRD). Functional properties (water holding capacity: WHC, water solubility index: WSI, swelling capacity: SC, oil holding capacity: OHC, foaming, and emulsion properties) and ACE activities were also investigated using well-established procedures. The FT-IR spectra obtained for the CPWSP revealed two significant peaks, at about 3500 and 500 cm(-1), which corresponded to the carbohydrate region and were characteristic of polysaccharides. All spectra showed the presence of a broad absorption between 1500 and 670 cm(-1), which could be attributed to CH, CO, and OH bands in the polysaccharides. CPWSP had an XRD pattern that was typical for a semi-crystalline polymer with a major crystalline reflection at 19.6 °C. They also displayed important techno-functional properties (SWC, WSI, WHC, and OHC) that can be modulated according to temperature. The CPWSP were also noted to display good anti-hypertensive activities. Overall, the results indicate that CPWSP have attractive chemical, biological, and functional properties that make them potential promising candidates for application as alternative additives in various food, cosmetic, and pharmaceutical preparations.

  15. [Characteristics of water soluble inorganic ions in fine particles emitted from coal-fired power plants].

    PubMed

    Duan, Lei; Ma, Zi-Zhen; Li, Zhen; Jiang, Jing-Kun; Ye, Zhi-Xiang

    2015-03-01

    Currently, China suffers from serious pollution of fine particulate matter (PM2.5). Coal-fired power plant is one of the most important sources of PM2.5 in the atmosphere. To achieve the national goals of total emission reductions of sulfur dioxide (SO2) and nitrogen oxides (NO(x)) during the 11th and 12th Five-Year Plan, most of coal-fired power plants in China have installed or will install flue gas desulfurization (FGD) and flue gas denitrification (DNO(x)) systems. As a result, the secondary PM2.5, generated from gaseous pollutants in the atmosphere, would be decreased. However, the physical and chemical characteristics of PM2.5 in flue gas would be affected, and the emission of primary PM2.5 might be increased. This paper summarized the size distributions of PM2.5 and its water soluble ions emitted from coal-fired power plants, and highlighted the effects of FGD and DNO(x) on PM2.5 emission, especially on water soluble ions (such as SO4(2-), Ca2+ and NH4+) in PM2.5. Under the current condition of serious PM2.5 pollution and wide application of FGD and DNO(x), quantitative study on the effects of FGD and DNO(x) installation on emission characteristics of PM2.5 from coal-fired power plants is of great necessity.

  16. Preparation of water-soluble nanographite and its application in water-based cutting fluid

    NASA Astrophysics Data System (ADS)

    Chen, Qiang; Wang, Xue; Wang, Zongting; Liu, Yu; You, Tingzheng

    2013-01-01

    Water-soluble nanographite was prepared by in situ emulsion polymerization using methacrylate as polymeric monomer. The dispersion stability and dispersion state of graphite particles were evaluated by UV-visible spectrophotometry and scanning electron microscopy, respectively. The water-soluble nanographite was then added into the water-based cutting fluid as lubricant additive. The lubrication performance of water-based cutting fluid with the nanographite additive was studied on four-ball friction tester and surface tensiometer. Results indicate that the modification method of in situ emulsion polymerization realizes the uniform and stabilized dispersion of nanographite in aqueous environment. The optimal polymerization condition is 70°C (polymerization temperature) and 5 h (polymerization time). The addition of nanographite decreases the friction coefficient and wear scar diameter by 44% and 49%. Meanwhile, the maximum non-seizure load ( P B ) increases from 784 to 883 N, and the value of surface tension (32.76 × 10-3 N/m) is at low level. Nanographite additive improves apparently the lubrication performance of water-based cutting fluid.

  17. [Immunoproteomics of non water-soluble allergens from 4 legumes flours: peanut, soybean, sesame and lentil].

    PubMed

    Bouakkadia, Hayette; Boutebba, Aissa; Haddad, Iman; Vinh, Joëlle; Guilloux, Laurence; Sutra, Jean-Pierre; Sénéchal, Hélène; Poncet, Pascal

    2015-01-01

    Peanut, soybean, sesame and lentil are members of legumes worldwide consumed by human that can induce food allergy in genetically predisposed individuals. Several protein allergens, mainly water-soluble, have been described. We studied the non water-soluble fraction from these 4 food sources using immunoproteomics tools and techniques. Flour extracts were solubilized in detergent and chaotropes and analysed in 1 and 2 dimensional gel electrophoresis (2D). Results showed numerous proteins exhibiting wide ranges of isoelectric points and relative molecular masses. When IgE immunoreactivities of 18 food allergy patients were individually tested in 1 and 2D western-blots, a very diversified IgE repertoire was observed, reflecting extensive cross-reactivities but also co-sensitizations. Besides already well known and characterized allergens, mass spectrometry analysis allowed the identification of 22 allergens undescribed until now: 10 in peanut, 2 in soybean, 3 in sesame and 7 in lentil. Three allergens are legume storage proteins and the others belong to transport proteins, nucleotide binding proteins and proteins involved in the regulation of metabolism. Seven proteins are potentially similar to allergens described in plants and fungi and 11 are not related to any known allergen. Our results contribute to increase the repertoire of legume allergens that may improve the diagnosis, categorize patients and thus provide a better treatment of patients.

  18. Liposomal buccal mucoadhesive film for improved delivery and permeation of water-soluble vitamins.

    PubMed

    Abd El Azim, Heba; Nafee, Noha; Ramadan, Alyaa; Khalafallah, Nawal

    2015-07-01

    This study aims at improving the buccal delivery of vitamin B6 (VB6) as a model highly water-soluble, low permeable vitamin. Two main strategies were combined; first VB6 was entrapped in liposomes, which were then formulated as mucoadhesive film. Both plain and VB6-loaded liposomes (LPs) containing Lipoid S100 and propylene glycol (∼ 200 nm) were then incorporated into mucoadhesive film composed of SCMC and HPMC. Results showed prolonged release of VB6 (72.65%, T50% diss 105 min) after 6h from LP-film compared to control film containing free VB6 (96.37%, T50% diss 30 min). Mucoadhesion was assessed both ex vivo on chicken pouch and in vivo in human. Mucoadhesive force of 0.2N and residence time of 4.4h were recorded. Ex vivo permeation of VB6, across chicken pouch mucosa indicated increased permeation from LP-systems compared to corresponding controls. Interestingly, incorporation of the vesicles in mucoadhesive film reduced the flux by 36.89% relative to LP-dispersion. Meanwhile, both films provided faster initial permeation than the liquid forms. Correlating the cumulative percent permeated ex vivo with the cumulative percent released in vitro indicated that LPs retarded VB6 release but improved permeation. These promising results represent a step forward in the field of buccal delivery of water-soluble vitamins.

  19. [Immunoproteomics of non water-soluble allergens from 4 legumes flours: peanut, soybean, sesame and lentil].

    PubMed

    Bouakkadia, Hayette; Boutebba, Aissa; Haddad, Iman; Vinh, Joëlle; Guilloux, Laurence; Sutra, Jean-Pierre; Sénéchal, Hélène; Poncet, Pascal

    2015-01-01

    Peanut, soybean, sesame and lentil are members of legumes worldwide consumed by human that can induce food allergy in genetically predisposed individuals. Several protein allergens, mainly water-soluble, have been described. We studied the non water-soluble fraction from these 4 food sources using immunoproteomics tools and techniques. Flour extracts were solubilized in detergent and chaotropes and analysed in 1 and 2 dimensional gel electrophoresis (2D). Results showed numerous proteins exhibiting wide ranges of isoelectric points and relative molecular masses. When IgE immunoreactivities of 18 food allergy patients were individually tested in 1 and 2D western-blots, a very diversified IgE repertoire was observed, reflecting extensive cross-reactivities but also co-sensitizations. Besides already well known and characterized allergens, mass spectrometry analysis allowed the identification of 22 allergens undescribed until now: 10 in peanut, 2 in soybean, 3 in sesame and 7 in lentil. Three allergens are legume storage proteins and the others belong to transport proteins, nucleotide binding proteins and proteins involved in the regulation of metabolism. Seven proteins are potentially similar to allergens described in plants and fungi and 11 are not related to any known allergen. Our results contribute to increase the repertoire of legume allergens that may improve the diagnosis, categorize patients and thus provide a better treatment of patients. PMID:26635049

  20. Chemical constituents: water-soluble vitamins, free amino acids and sugar profile from Ganoderma adspersum.

    PubMed

    Kıvrak, İbrahim

    2015-01-01

    Ganoderma adspersum presents a rigid fruiting body owing to chitin content and having a small quantity of water or moisture. The utility of bioactive constituent of the mushroom can only be available by extraction for human usage. In this study, carbohydrate, water-soluble vitamin compositions and amino acid contents were determined in G. adspersum mushroom. The composition in individual sugars was determined by HPLC-RID, mannitol (13.04 g/100 g) and trehalose (10.27 g/100 g) being the most abundant sugars. The examination of water-soluble vitamins and free amino acid composition was determined by UPLC-ESI-MS/MS. Essential amino acid constituted 67.79% of total amino acid, which is well worth the attention with regard to researchers and consumers. In addition, G. adspersum, which is also significantly rich in B group vitamins and vitamin C, can provide a wide range of notable applications in the pharmaceutics, cosmetics, food and dietary supplement industries. G. adspersum revealed its value for pharmacy and nutrition fields.

  1. Synthesis and Molecular Recognition of Water-Soluble S6-Corona[3]arene[3]pyridazines.

    PubMed

    Guo, Qing-Hui; Zhao, Liang; Wang, Mei-Xiang

    2015-07-13

    We report the efficient and scalable synthesis and molecular-recognition properties of novel and water-soluble S6-corona[3]arene[3]pyridazines. The synthesis comprises a one-pot nucleophilic aromatic substitution reaction between diesters of 2,5-dimercaptoterephthalate and 3,6-dichlorotetrazine followed by the inverse electron-demand Diels-Alder reaction of the tetrazine moieties with an enamine and exhaustive saponification of esters. The resulting S6-corona[3]arene[3]pyridazines, which adopt a 1,3,5-alternate conformation in the crystalline state, are able to selectively form stable 1:1 complexes with dicationic guest species in water with association constants ranging from (1.10±0.06)×10(3)  M(-1) to (1.18±0.06)×10(5)  M(-1). The easy availability, large cavity size, strong and selective binding power render the water-soluble S6-corona[3]arene[3]pyridazines useful macrocyclic hosts in various disciplines of supramolecular chemistry.

  2. Role of water-soluble enema before takedown of diverting ileostomy for low pelvic anastomosis.

    PubMed

    Karsten, Benjamin J; King, Justin B; Kumar, Ravin R

    2009-10-01

    The integrity of a low pelvic anastomosis is often studied radiographically before takedown of a diverting ileostomy. The aim of this study is to determine the impact of routine water-soluble enema studies (WSE) in our patient population with low pelvic anastomosis. We retrospectively reviewed the operative database for a county teaching hospital from 1998 to 2008. All patients with low pelvic anastomosis (ultralow colorectal, coloanal, and ileoanal pouch anastomosis) with diverting ileostomy who underwent subsequent takedown were identified. Fifty patients met inclusion criteria. Thirty-eight patients were evaluated by WSE and 12 were not. Twenty-five patients (66%) were noted to have normal WSE studies before ostomy takedown. Thirteen patients (26%) were noted to have abnormalities on WSE. Two stenoses were clinically significant. Water-soluble enema study was 100 per cent sensitive and 69 per cent specific for detecting significant pathology. Digital rectal examination (DRE), colonoscopy, and flexible sigmoidoscopy were also 100 per cent sensitive in detecting substantial pathology. Routine use of WSE failed to demonstrate a significant impact on patients with low pelvic anastomosis undergoing ileostomy takedown. Routine DRE and rigid proctoscopy can be used to evaluate low pelvic anastomosis. WSE can be used selectively on patients with abnormal findings. PMID:19886140