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Sample records for poorly water-soluble drug

  1. Poorly water-soluble drug nanoparticles via solvent evaporation in water-soluble porous polymers.

    PubMed

    Roberts, Aled D; Zhang, Haifei

    2013-04-15

    A generic method is described to form poorly water-soluble drug nanoparticles within water-soluble porous polymer by solvent evaporation. The simple dissolution of porous polymer with drug nanoparticles results in stable aqueous drug nanoparticle suspension under the optimized conditions. The porous polymers were prepared by freeze-drying aqueous solutions of polyvinyl alcohol, polyethylene glycol, and a surfactant. They were then used as scaffolds for the formation of nanoparticles by initially soaking them in an organic drug solution, followed with removing the solvent via evaporation under ambient conditions. This process was optimized for an antifungal drug griseofulvin, before being translated to anticonvulsant carbamazepine and antineoplastic paclitaxel via a similar procedure, with an aim to improve the loading of drug nanoparticles. By varying certain process parameters a degree of control over the particle size and surface charge could be attained, as well as the drug to stabilizer ratio (drug payload). Noticeably, aqueous paclitaxel nanoparticles (500 nm) were prepared which used the equivalent of 46% less stabilizer than the formulation Taxol.

  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. Study on Mixed Solvency Concept in Formulation Development of Aqueous Injection of Poorly Water Soluble Drug

    PubMed Central

    Solanki, Shailendra Singh; Soni, Love Kumar; Maheshwari, Rajesh Kumar

    2013-01-01

    In the present investigation, mixed-solvency approach has been applied for the enhancement of aqueous solubility of a poorly water- soluble drug, zaltoprofen (selected as a model drug), by making blends (keeping total concentrations 40% w/v, constant) of selected water-soluble substances from among the hydrotropes (urea, sodium benzoate, sodium citrate, nicotinamide); water-soluble solids (PEG-4000, PEG-6000); and co-solvents (propylene glycol, glycerine, PEG-200, PEG-400, PEG-600). Aqueous solubility of drug in case of selected blends (12 blends) ranged from 9.091 ± 0.011 mg/ml–43.055 ± 0.14 mg/ml (as compared to the solubility in distilled water 0.072 ± 0.012 mg/ml). The enhancement in the solubility of drug in a mixed solvent containing 10% sodium citrate, 5% sodium benzoate and 25 % S cosolvent (25% S cosolvent contains PEG200, PEG 400, PEG600, Glycerine and Propylene glycol) was more than 600 fold. This proved a synergistic enhancement in solubility of a poorly water-soluble drug due to mixed cosolvent effect. Each solubilized product was characterized by ultraviolet and infrared techniques. Various properties of solution such as pH, viscosity, specific gravity and surface tension were studied. The developed formulation was studied for physical and chemical stability. This mixed solvency shall prove definitely a boon for pharmaceutical industries for the development of dosage form of poorly water soluble drugs. PMID:26555989

  4. Encapsulation of poorly water-soluble drugs into organic nanotubes for improving drug dissolution.

    PubMed

    Moribe, Kunikazu; Makishima, Takashi; Higashi, Kenjirou; Liu, Nan; Limwikrant, Waree; Ding, Wuxiao; Masuda, Mitsutoshi; Shimizu, Toshimi; Yamamoto, Keiji

    2014-07-20

    Hydrocortisone (HC), a poorly water-soluble drug, was encapsulated within organic nanotubes (ONTs), which were formed via the self-assembly of N-{12-[(2-α,β-d-glucopyranosyl) carbamoyl]dodecanyl}-glycylglycylglycine acid. The stability of the ONTs was evaluated in ten organic solvents, of differing polarities, by field emission transmission electron microscopy. The ONTs maintained their stable tubular structure in the highly polar solvents, such as ethanol and acetone. Furthermore, solution-state (1)H-NMR spectroscopy confirmed that they were practically insoluble in acetone at 25°C (0.015 mg/mL). HC-loaded ONTs were prepared by solvent evaporation using acetone. A sample with a 3/7 weight ratio of HC/ONT was analyzed by powder X-ray diffraction, which confirmed the presence of a halo pattern and the absence of any crystalline HC peak. HC peak broadening, observed by solid-state (13)C-NMR measurements of the evaporated sample, indicated the absence of HC crystals. These results indicated that HC was successfully encapsulated in ONT as an amorphous state. Improvements of the HC dissolution rate were clearly observed in aqueous media at both pH 1.2 and 6.8, probably due to HC amorphization in the ONTs. Phenytoin, another poorly water-soluble drug, also showed significant dissolution improvement upon ONT encapsulation. Therefore, ONTs can serve as an alternative pharmaceutical excipient to enhance the bioavailability of poorly water-soluble drugs.

  5. Pharmaceutical solid dispersion technology: a strategy to improve dissolution of poorly water-soluble drugs.

    PubMed

    Kumar, Shobhit; Gupta, Satish K

    2013-08-01

    Oral bioavailability is the major problem when a poorly water-soluble active agent is delivered via oral route. To overcome such problems, solid dispersion systems have been demonstrated in literature to enhance the dissolution property of poorly water-soluble drugs. In the present review, the important aspects to be considered during preparation of solid dispersion systems viz., properties of polymer and preparation techniques of solid dispersion which affect the dissolution rate are discussed. Formulation and evaluation techniques for solid dispersions have been described. The final section of article highlights the recent patents and studies related to solid dispersion systems.

  6. 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.

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

    PubMed

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

    2016-01-28

    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.

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

    PubMed

    Sun, Yongda

    2014-01-01

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

  9. 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

  10. 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

  11. Electrospun polycaprolactone nanofibers as a potential oromucosal delivery system for poorly water-soluble drugs.

    PubMed

    Potrč, Tanja; Baumgartner, Saša; Roškar, Robert; Planinšek, Odon; Lavrič, Zoran; Kristl, Julijana; Kocbek, Petra

    2015-07-30

    The number of poorly water-soluble drug candidates is rapidly increasing; this represents a major challenge for the pharmaceutical industry. As a consequence, novel formulation approaches are required. Furthermore, if such a drug candidate is intended for the therapy of a specific group of the population, such as geriatric or pediatric, the formulation challenge is even greater, with the need to produce a dosage form that is acceptable for specific patients. Therefore, the goal of our study was to explore electrospun polycaprolactone (PCL) nanofibers as a novel nanodelivery system adopted for the oromucosal administration of poorly water-soluble drugs. The nanofibers were evaluated in comparison with polymer films loaded with ibuprofen or carvedilol as the model drugs. Scanning electron microscopy revealed that the amount of incorporated drug affects the diameter and the morphology of the nanofibers. The average fiber diameter increased with a higher drug loading, whereas the morphology of the nanofibers was noticeably changed in the case of nanofibers with 50% and 60% ibuprofen. The incorporation of drugs into the electrospun PCL nanofibers was observed to reduce their crystallinity. Based on the morphology of the nanofibers and the films, and the differential scanning calorimetry results obtained in this study, it can be assumed that the drugs incorporated into the nanofibers were partially molecularly dispersed in the PCL matrix and partially in the form of dispersed nanocrystals. The incorporation of both model drugs into the PCL nanofibers significantly improved their dissolution rates. The PCL nanofibers released almost 100% of the incorporated ibuprofen in 4h, whereas only up to 77% of the incorporated carvedilol was released during the same time period, indicating the influence of the drug's properties, such as molecular weight and solubility, on its release from the PCL matrix. The obtained results clearly demonstrated the advantages of the new

  12. Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery.

    PubMed

    Brough, Chris; Williams, R O

    2013-08-30

    Poor water-solubility is a common characteristic of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate and bioavailability of these active ingredients belonging to BCS II and IV classifications. Over the last decade, nano-crystal delivery forms and amorphous solid dispersions have become well established in commercially available products and industry literature. This article is a comparative analysis of these two methodologies primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercial relevant scientific literature.

  13. 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.

  14. 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

  15. Improvement of dissolution property of poorly water-soluble drug by supercritical freeze granulation.

    PubMed

    Sonoda, Ryoichi; Hara, Yuko; Iwasaki, Tomohiro; Watano, Satoru

    2009-10-01

    The dissolution property of the poorly water-soluble drug, flurbiprofen (FP) was improved by a novel supercritical freeze granulation using supercritical carbon dioxide. Supercritical freeze granulation was defined as a production method of the granulated substances by using the dry ice to generate intentionally for the rapid atomization of the supercritical carbon dioxide to the atmospheric pressure. This process utilized a rapid expansion of supercritical solutions (RESS) process with the mixture of the drug and lactose. In the supercritical freeze granulation, needle-like FP fine particles were obtained which adhered to the surface of lactose particles, which did not dissolve in supercritical carbon dioxide. The number of FP particles that adhered to the surface of particles decreased with an increase in the ratio of lactose added, leading to markedly improve the dissolution rate. This improvement was caused not only by the increase in the specific surface area but also the improvement of the dispersibility of FP in water. It is thus concluded that the supercritical freeze granulation is a useful technique to improve the dissolution property of the poorly water-soluble flurbiprofen.

  16. Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica.

    PubMed

    Mellaerts, Randy; Mols, Raf; Jammaer, Jasper A G; Aerts, Caroline A; Annaert, Pieter; Van Humbeeck, Jan; Van den Mooter, Guy; Augustijns, Patrick; Martens, Johan A

    2008-05-01

    This study aims to evaluate the in vivo performance of ordered mesoporous silica (OMS) as a carrier for poorly water soluble drugs. Itraconazole was selected as model compound. Physicochemical characterization was carried out by SEM, TEM, nitrogen adsorption, DSC, TGA and in vitro dissolution. After loading itraconazole into OMS, its oral bioavailability was compared with the crystalline drug and the marketed product Sporanox in rabbits and dogs. Plasma concentrations of itraconazole and OH-itraconazole were determined by HPLC-UV. After administration of crystalline itraconazole in dogs (20mg), no systemic itraconazole could be detected. Using OMS as a carrier, the AUC0-8 was boosted to 681+/-566 nM h. In rabbits, the AUC0-24 increased significantly from 521+/-159 nM h after oral administration of crystalline itraconazole (8 mg) to 1069+/-278 nM h when this dose was loaded into OMS. Tmax decreased from 9.8+/-1.8 to 4.2+/-1.8h. No significant differences (AUC, Cmax, and Tmax) could be determined when comparing OMS with Sporanox in both species. The oral bioavailability of itraconazole formulated with OMS as a carrier compares well with the marketed product Sporanox, in rabbits as well as in dogs. OMS can therefore be considered as a promising carrier to achieve enhanced oral bioavailability for drugs with extremely low water solubility.

  17. 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.

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

    PubMed

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

    2016-11-20

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

  19. Nanosuspensions of poorly water soluble drugs prepared by top-down technologies.

    PubMed

    Zhang, Xin; Li, Luk Chiu; Mao, Shirui

    2014-01-01

    In recent years, nanosuspensions have been accepted as a valuable drug delivery system for poorly water-soluble drugs. Topdown and bottom-up technologies are the two main approaches for generating nanosuspensions. Several products manufactured by the top-down technologies have been successfully commercialized demonstrating that the processing features of the technologies are adaptable to industrial scale operation and meeting high pharmaceutical quality control standards. Nanosuspensions of poorly soluble drugs have shown to achieve dramatic improvements on the in vivo performance of the drugs including the enhancement of bioavailability and elimination of food effect when administered orally. This review will focus on the preparation of nanosuspensions by the top-down technologies. The influence of drug physicochemical properties on the nanosuspension forming process and the subsequent conversion into a dry powder form will be discussed with proposed mechanisms. In addition, the criteria for selection of stabilizers will be reviewed. The characteristics of drugs and stabilizers as well as their interaction effects on the redispersion properties of a dry powder prepared from a nanosuspension will be highlighted. The different administration routes of nanosuspensions are also presented with their potential therapeutic benefits.

  20. 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

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

    PubMed

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

    2014-11-04

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

  2. Swellable elementary osmotic pump (SEOP): an effective device for delivery of poorly water-soluble drugs.

    PubMed

    Shokri, Javad; Ahmadi, Parinaz; Rashidi, Parisa; Shahsavari, Mahbobeh; Rajabi-Siahboomi, Ali; Nokhodchi, Ali

    2008-02-01

    A new type of elementary osmotic pump (EOP) tablet for efficient delivery of poorly water-soluble/practically insoluble drugs has been designed. Drug release from the system, called swellable elementary osmotic pump (SEOP), is through a delivery orifice in the form of a very fine dispersion ready for dissolution and absorption. SEOP tablets were prepared by compressing the mixture of micronized drug and excipients into convex tablets. Factors affecting the release of drug from the SEOP tablets containing a poorly water-soluble drug, indomethacin, have been explored. The release behaviour of indomethacin from different formulations of this dosage form was studied at pH 6.8 for a period of 24h. The formulations were compared based on four comparative parameters, namely, D(24h) (total release after 24h), t(L) (lag time), RSQ(zero) (R square of zero order equation) and D%(zero) (percentage deviation from zero order kinetics). The drug release profile from osmotic devices showed that the type of polymer in the core formulation can markedly affect the drug release. The results showed that concentration of wetting agent in the core formulation was a very important parameter in D(24h) and release pattern of indomethacin from SEOP system. Increasing the amount of wetting agent to an optimum level (60mg) significantly increased D(24h) and improved zero order release pattern of indomethacin. Increasing concentration of caster oil (hydrophobic) in the semipermeable membrane of the device or hydrophilic plasticizer (glycerin) in coating formulation markedly increased t(L) and decreased D(24h). The results also demonstrated that aperture size is a critical parameter and should be optimized for each SEOP system. Optimum aperture diameter for the formulations studied here was determined to be 650microm for zero order release pattern. t(L) and D%(zero) were dramatically decreased whereas D(24h) and RSQ(zero) increased with increasing the aperture size to optimum level. This study

  3. 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...

  4. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2011-09-01

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

  6. Development of amorphous solid dispersion formulations of a poorly water-soluble drug, MK-0364.

    PubMed

    Sotthivirat, S; McKelvey, C; Moser, J; Rege, B; Xu, W; Zhang, D

    2013-08-16

    The goal of this study was to demonstrate that MK-0364 solid dispersions can be developed as a means to increase the solubility and bioavailability of a poorly water-soluble drug, MK-0364. The potential solid dispersions would enable an oral solid dosage form as a monotherapy or combination product of MK-0364. Preliminary screening included sample preparation via a solvent casting method, physical characterization, and in vitro dissolution testing. Lead formulations were subsequently manufactured using hot melt extrusion (HME) and spray-drying (SD). All HME (without polyvinyl pyrrolidone) and SD formulations exhibit characteristics of a single phase glass including an amorphous halo when analyzed with X-ray powder diffraction (XRPD), a single glass transition temperature (Tg) measured with differential scanning calorimetry (DSC), and supersaturation when dissolved in dissolution media. The oral absorption of MK-0364 from selected HME and SD formulations in monkeys results in marginally greater exposure with a consistently longer Tmax relative to a liquid filled capsule reference. Based on the processability, physical characterization, in vitro dissolution, and animal pharmacokinetic results, copovidone- and hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based solid dispersion formulations are viable product concepts. The physical stability of both the solid dispersion formulations was also evaluated for 54 weeks under different conditions. The copovidone-based solid dispersion requires protection from moisture.

  7. Wettability and surface chemistry of crystalline and amorphous forms of a poorly water soluble drug.

    PubMed

    Puri, Vibha; Dantuluri, Ajay K; Kumar, Mahesh; Karar, N; Bansal, Arvind K

    2010-05-12

    The present study compares energetics of wetting behavior of crystalline and amorphous forms of a poorly water soluble drug, celecoxib (CLB) and attempts to correlate it to their surface molecular environment. Wettability and surface free energy were determined using sessile drop contact angle technique and water vapor sorption energetics was measured by adsorption calorimetry. The surface chemistry was elucidated by X-ray photoelectron spectroscopy (XPS) and crystallographic evaluation. The two solid forms displayed distinctly different wetting with various probe liquids and in vitro dissolution media. The crystalline form surface primarily exhibited dispersive surface energy (47.3mJ/m(2)), while the amorphous form had a slightly reduced dispersive (45.2mJ/m(2)) and a small additional polar (4.8mJ/m(2)) surface energy. Calorimetric measurements, revealed the amorphous form to possess a noticeably high differential heat of absorption, suggesting hydrogen bond interactions between its polar energetic sites and water molecules. Conversely, the crystalline CLB form was found to be inert to water vapor sorption. The relatively higher surface polarity of the amorphous form could be linked to its greater oxygen-to-fluorine surface concentration ratio of 1.27 (cf. 0.62 for crystalline CLB), as determined by XPS. The crystallographic studies of the preferred cleavage plane (020) of crystalline CLB further supported its higher hydrophobicity. In conclusion, the crystalline and amorphous forms of CLB exhibited disparate surface milieu, which in turn can have implications on the surface mediated events.

  8. Continuous twin-screw granulation for enhancing the dissolution of poorly water soluble drug.

    PubMed

    Maniruzzaman, Mohammed; Nair, Arun; Renault, Maxcene; Nandi, Uttom; Scoutaris, Nicholaos; Farnish, Richard; Bradley, Michael S A; Snowden, Martin J; Douroumis, Dennis

    2015-12-30

    The article describes the application of a twin-screw granulation process to enhance the dissolution rate of the poorly water soluble drug, ibuprofen (IBU). A quality-by-design (QbD) approach was used to manufacture IBU loaded granules via hot-melt extrusion (HME) processing. For the purpose of the study, a design of experiment (DoE) was implemented to assess the effect of the formulation compositions and the processing parameters. This novel approach allowed the use of, polymer/inorganic excipients such as hydroxypropyl methylcellulose (HPMC) and magnesium aluminometasilicate (Neusilin(®)-MAS) with polyethylene glycol 2000 (PEG) as the binder without requiring a further drying step. IBU loaded batches were processed using a twin screw extruder to investigate the effect of MAS/polymer ratio, PEG amount (binder) and liquid to solid (L/S) ratios on the dissolution rates, mean particle size and the loss on drying (LoD) of the extruded granules. The DoE analysis showed that the defined independent variables of the twin screw granulation process have a complex effect on the measured outcomes. The solid state analysis showed the existence of partially amorphous IBU state which had a significant effect on the dissolution enhancement in acidic media. Furthermore, the analysis obtained from the surface mapping by Raman proved the homogenous distribution of the IBU in the extruded granulation formulations.

  9. 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.

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

    PubMed Central

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

    2011-01-01

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

  11. 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

  12. Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs.

    PubMed

    Raina, Shweta A; Zhang, Geoff G Z; Alonzo, David E; Wu, Jianwei; Zhu, Donghua; Catron, Nathaniel D; Gao, Yi; Taylor, Lynne S

    2014-09-01

    Amorphous solid dispersions (ASDs) give rise to supersaturated solutions (solution concentration greater than equilibrium crystalline solubility). We have recently found that supersaturating dosage forms can exhibit the phenomenon of liquid-liquid phase separation (LLPS). Thus, the high supersaturation generated by dissolving ASDs can lead to a two-phase system wherein one phase is an initially nanodimensioned and drug-rich phase and the other is a drug-lean continuous aqueous phase. Herein, the membrane transport of supersaturated solutions, at concentrations above and below the LLPS concentration has been evaluated using a side-by-side diffusion cell. Measurements of solution concentration with time in the receiver cell yield the flux, which reflects the solute thermodynamic activity in the donor cell. As the nominal concentration of solute in the donor cell increases, a linear increase in flux was observed up to the concentration where LLPS occurred. Thereafter, the flux remained essentially constant. Both nifedipine and felodipine solutions exhibit such behavior as long as crystallization is absent. This suggests that there is an upper limit in passive membrane transport that is dictated by the LLPS concentration. These results have several important implications for drug delivery, especially for poorly soluble compounds requiring enabling formulation technologies.

  13. 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.

  14. Critical Material Attributes of Strip Films Loaded With Poorly Water-Soluble Drug Nanoparticles: II. Impact of Polymer Molecular Weight.

    PubMed

    Krull, Scott M; Ammirata, Jennifer; Bawa, Sonia; Li, Meng; Bilgili, Ecevit; Davé, Rajesh N

    2017-02-01

    Recent work established polymer strip films as a robust platform for delivery of poorly water-soluble drug particles. However, a simple means of manipulating rate of drug release from films with minimal impact on film mechanical properties has yet to be demonstrated. This study explores the impact of film-forming polymer molecular weight (MW) and concentration on properties of polymer films loaded with poorly water-soluble drug nanoparticles. Nanoparticles of griseofulvin, a model Biopharmaceutics Classification System class II drug, were prepared in aqueous suspension via wet stirred media milling. Aqueous solutions of 3 viscosity grades of hydroxypropyl methylcellulose (14, 21, and 88 kDa) at 3 viscosity levels (∼9500, ∼12,000, and ∼22,000 cP) were mixed with drug suspension, cast, and dried to produce films containing griseofulvin nanoparticles. Few differences in film tensile strength or elongation at break were observed between films within each viscosity level regardless of polymer MW despite requiring up to double the time to achieve 100% drug release. This suggests film-forming polymer MW can be used to manipulate drug release with little impact on film mechanical properties by matching polymer solution viscosity. In addition, changing polymer MW and concentration had no negative impact on drug content uniformity or nanoparticle redispersibility.

  15. Effects of nanosuspension formulations on transport, pharmacokinetics, in vivo targeting and efficacy for poorly water-soluble drugs.

    PubMed

    Wang, Yancai; Miao, Xiaoqing; Sun, Lin; Song, Ju; Bi, Chao; Yang, Xiao; Zheng, Ying

    2014-01-01

    A surprisingly large proportion of new chemical entities (NCE) is emerging from the drug discovery pipeline, and many active components extracted from herbal medicines are water insoluble, which represents a great challenge for their development. Nanosuspensions, which are submicron colloidal dispersions of pure drug particles that are stabilised by a small percentage of the excipients, could dramatically enhance the saturated solubility, dissolution rate and adhesion of drug particles to cell membranes. Nanosuspensions are the most suitable for drugs that require high dosing or have limited administrative volume. After 20 years of development, several oral products and one injectable product are commercially available. The aim of this review is to fill the gap between rational formulation designs and the in vivo performance of poorly water-soluble drug nanosuspensions. Specifically, this review will correlate characteristics of nanosuspension formulations, including drug property, particle size, crystallinity, stabiliser and surface property, with their transport, pharmacokinetics, bioactivity and toxicity after delivery by different administration routes. The elucidation of the mechanisms of targeted drug delivery, cellular transport and internalisation of nanosuspensions are also reviewed to interpret the in vivo performance of these nanosuspensions. Moreover, the recent application of nanosuspensions for poorly water-soluble herbal medicines is highlighted.

  16. 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.

  17. 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.

  18. 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

  19. Rational formulation development and in vitro assessment of SMEDDS for oral delivery of poorly water soluble drugs.

    PubMed

    Sprunk, Angela; Strachan, Clare J; Graf, Anja

    2012-08-15

    The aims of this study were to formulate a self-microemulsifying drug delivery system (SMEDDS) by a rational formulation approach using mixture experimental design and to derive general concepts that make the development of such systems more feasible. Various types of oils and surfactants were systematically combined and the phase behaviour upon dilution with simulated gastric fluid examined by construction of phase diagrams. The systems solubilising the highest amount of simulated gastric fluid in the continuous microemulsion area were selected for investigation and optimisation of drug solubility. Simvastatin was added as a poorly water-soluble, lipophilic model drug. Two different mixture experimental designs using D-optimal design were set up and used to investigate the solubility of simvastatin in the SMEDDS before and after dilution with simulated gastric fluid respectively. The solubility in each mixture region was analysed by fitting quadratic models using partial least squares analysis. The established models revealed the influence of mixture components on phase behaviour and drug solubility and gave the rationale for formulation optimisation. This study demonstrated that the development of complex self-emulsifying formulations with sufficient solubilisation capacity for poorly water-soluble drugs upon oral administration can be more feasible when using experimental design.

  20. 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.

  1. 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

  2. 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.

  3. A novel cubic phase of medium chain lipid origin for the delivery of poorly water soluble drugs.

    PubMed

    Kossena, Greg A; Charman, William N; Boyd, Ben J; Porter, Christopher J H

    2004-09-30

    The existence of a novel cubic liquid crystalline phase is described within the pseudo-ternary system comprising lauric acid, monolaurin, and simulated endogenous intestinal fluid (SEIF). This phase behaviour has been characterized using cross-polarizing light microscopy (CPLM), and the structure of the cubic phase identified by small angle X-ray scattering (SAXS). The presence of the cubic phase was found to be temperature sensitive within the 20-37 degrees C range making it putative material for in situ gelation purposes. The cubic phase was shown to have a high capacity to solubilise a model poorly water-soluble drug, cinnarizine, and initial in vitro release data highlight the potential of this phase to provide sustained release. Absorption of cinnarizine from the cubic phase was studied in an unconscious rat model via duodenal administration and blood sampling via the carotid artery. The rate of absorption was significantly reduced when compared to a simple suspension formulation, a likely combination of retarded erosion of the cubic phase together with hindered drug release from the cubic matrix. The results of this study suggest that this cubic phase may potentially be of benefit in the delivery of poorly water-soluble compounds due to its high loading capacity and potential for sustained release. The ability to manipulate this system using temperature may warrant further interest in delivery applications via other routes of administration.

  4. 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.

  5. 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.

  6. 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.

  7. The apparent solubilizing capacity of simulated intestinal fluids for poorly water-soluble drugs.

    PubMed

    Schwebel, Hervé J; van Hoogevest, Peter; Leigh, Mathew L S; Kuentz, Martin

    2011-06-01

    Drug solubility testing in biorelevant media has become an indispensable tool in pharmaceutical development. Despite this importance, there is still an incomplete understanding of how poorly soluble compounds interact with these media. The aim of this study was to apply the concept of the apparent solubilization capacity to fasted and fed state simulated intestinal fluid (FaSSIF and FeSSIF, respectively). A set of non-ionized poorly soluble compounds was studied in biorelevant media prepared from an instantly dissolving complex (SIF(™) Powder) at 37°C. The values of the solubilization capacity were different between FaSSIF and FeSSIF but correlated. Drug inclusion into the mixed micelles was highly specific for a given compound. The ratio of the FeSSIF to FaSSIF solubility was in particular considered and discussed in terms of the apparent solubilizing capacity. The apparent solubilization concept appears to be useful for the interpretation of biorelevant solubility tests. Further studies are needed to explore acidic and basic drugs.

  8. 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.

  9. Mucoadhesive amorphous solid dispersions for sustained release of poorly water soluble drugs.

    PubMed

    LaFountaine, Justin S; Prasad, Leena Kumari; Miller, Dave A; McGinity, James W; Williams, Robert O

    2017-04-01

    The oral delivery of mucoadhesive patches has been shown to enhance the absorption of large molecules such as peptides. We hypothesized that this mechanism could have utility for poorly soluble small molecules by utilizing a mucoadhesive polymer as the matrix for an amorphous solid dispersion. Binary dispersions of itraconazole and carbomer (Carbopol 71G) were prepared utilizing a thermokinetic mixing process (KinetiSol Dispersing) and the physicochemical properties were investigated by powder X-ray diffraction, calorimetry, and liquid chromatography. Adhesion of the dispersions to freshly excised porcine intestine was investigated with a texture analyzer. Minitablets were compressed from the optimal dispersion and further investigated in vitro and in vivo in rats. Thermokinetic mixing successfully processed amorphous dispersions up to 30% drug loading and each dispersion exhibited works of adhesion that were approximately an order of magnitude greater than a negative control in vitro. Ethylcellulose (EC) coated and uncoated minitablets prepared with the 30% drug load dispersion were delivered orally to rats and exhibited sustained release characteristics, with overall bioavailability greater for the uncoated minitablets compared to the EC-coated minitablets, similar to the rank order observed in our in vitro dissolution experiments. Necropsy studies showed that minitablets delivered with enteric-coated capsules targeted release to the distal small intestine and adhered to the intestinal mucosa, but the rat model presented limitations with respect to evaluating the overall performance. Based on the in vitro and in vivo results, further investigations in larger animals are a logical next step where fluid volumes, pH, and transit times are more favorable for the evaluated dosage forms.

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

    PubMed

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

    2009-05-01

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

  11. 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.

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

    PubMed

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

    2007-01-01

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

  13. 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

    2012-08-06

    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.

  14. Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis.

    PubMed

    Forster, A; Hempenstall, J; Tucker, I; Rades, T

    2001-09-11

    The aim of this study was to determine the miscibility of drug and excipient to predict if glass solutions are likely to form when drug and excipient are melt extruded. Two poorly water-soluble drugs, indomethacin and lacidipine, were selected along with 11 excipients (polymeric and non-polymeric). Estimation of drug/excipient miscibility was performed using a combination of the Hoy and Hoftzyer/Van Krevelen methods for Hansen solubility parameter calculation. Miscibility was experimentally investigated with differential scanning calorimetry (DSC) and hot stage microscopy (HSM). Studies were performed at drug/excipient ratios, 1:4, 1:1 and 4:1. Analysis of the glass transition temperature (T(g)) was performed by quench cooling drug/excipient melts in the DSC. Differences in the drug/excipient solubility parameters of <7.0 MPa(1/2) were predicted to indicate significant miscibility and, therefore, glass solution formation on melt extrusion. In comparison, differences of >10 MPa(1/2) were expected to indicate a lack of miscibility and not form glass solutions when melt extruded. Experimentally, miscibility was shown by changes in drug/excipient melting endotherms and confirmed by HSM investigations. Experimental results were in agreement with solubility parameter predictions. In addition, drug/excipient combinations predicted to be largely immiscible often exhibited more than one T(g) upon reheating in the DSC. Melt extrusion of miscible components resulted in amorphous solid solution formation, whereas extrusion of an "immiscible" component led to amorphous drug dispersed in crystalline excipient. In conclusion, combining calculation of Hansen solubility parameters with thermal analysis of drug/excipient miscibility can be successfully applied to predict formation of glass solutions with melt extrusion.

  15. 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.

  16. 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

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

    PubMed

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

    2016-02-01

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

  18. Effect of Cyclodextrin Types and Co-Solvent on Solubility of a Poorly Water Soluble Drug

    PubMed Central

    Charumanee, Suporn; Okonogi, Siriporn; Sirithunyalug, Jakkapan; Wolschann, Peter; Viernstein, Helmut

    2016-01-01

    The aim of the study was to investigate the solubility of piroxicam (Prx) depending on the inclusion complexation with various cyclodextrins (CDs) and on ethanol as a co-solvent. The phase-solubility method was applied to determine drug solubility in binary and ternary systems. The results showed that in systems consisting of the drug dissolved in ethanol–water mixtures, the drug solubility increased exponentially with a rising concentration of ethanol. The phase solubility measurements of the drug in aqueous solutions of CDs, β-CD and γ-CD exhibited diagrams of AL-type, whereas 2,6-dimethyl-β-CD revealed AP-type. The destabilizing effect of ethanol as a co-solvent was observed for all complexes regardless of the CD type, as a consequence of it the lowering of the complex formation constants. In systems with a higher concentration of ethanol, the drug solubility was increased in opposition to the decreasing complex formation constants. According to this study, the type of CDs played a more important role on the solubility of Prx, and the use of ethanol as a co-solvent exhibited no synergistic effect on the improvement of Prx solubility. The Prx solubility was increased again due to the better solubility in ethanol. PMID:27763573

  19. A comparative study of modified starches in direct compression of a poorly water soluble drug (hydrochlorothiazide).

    PubMed

    Okafor, I S; Ofoefule, S I; Udeala, O K

    2001-01-01

    The direct compression properties of four modified starches in hydrochlorothiazide (HCTZ) tablets were studied. The starches were obtained locally from common plant sources and were modified through physicochemical treatment. Each modified starch was used as the only filler-binder-disintegrant in the formulation of hydrochlorothiazide tablets containing 25 mg of the drug. The tablets were produced by the direct compression technology. Sta-Rx 1500, a directly compressible starch, was used as basis for comparison. Evaluated tablet properties included weight and drug content uniformity, hardness and friability as well as disintegration time and dissolution profile. The modified starches exhibited species specificity in terms of the tablet properties. The weight, drug content and disintegration time for all batches of tablets were within acceptable limits. Proper ranking of the starches on the basis of specific tablet properties was used to highlight their differences.

  20. A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs.

    PubMed

    Shin, Ho-Chul; Alani, Adam W G; Cho, Hyunah; Bae, Younsoo; Kolesar, Jill M; Kwon, Glen S

    2011-08-01

    Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles have a proven capacity for drug solubilization and have entered phase III clinical trials as a substitute for Cremophor EL in the delivery of paclitaxel in cancer therapy. PEG-b-PLA is less toxic than Cremophor EL, enabling a doubling of paclitaxel dose in clinical trials. We show that PEG-b-PLA micelles act as a 3-in-1 nanocontainer for paclitaxel, 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin for multiple drug solubilization. 3-in-1 PEG-b-PLA micelles were ca. 40 nm in diameter; dissolved paclitaxel, 17-AAG, and rapamycin in water at 9.0 mg/mL; and were stable for 24 h at 25 °C. The half-life for in vitro drug release (t(1/2)) for 3-in-1 PEG-b-PLA micelles was 1-15 h under sink conditions and increased in the order of 17-AAG, paclitaxel, and rapamycin. The t(1/2) values correlated with log P(o/w) values, implicating a diffusion-controlled mechanism for drug release. The IC(50) value of 3-in-1 PEG-b-PLA micelles for MCF-7 and 4T1 breast cancer cell lines was 114 ± 10 and 25 ± 1 nM, respectively; combination index (CI) analysis showed that 3-in-1 PEG-b-PLA micelles exert strong synergy in MCF-7 and 4T1 breast cancer cell lines. Notably, concurrent intravenous (iv) injection of paclitaxel, 17-AAG, and rapamycin using 3-in-1 PEG-b-PLA micelles was well-tolerated by FVB albino mice. Collectively, these results suggest that PEG-b-PLA micelles carrying paclitaxel, 17-AAG, and rapamycin will provide a simple yet safe and efficacious 3-in-1 nanomedicine for cancer therapy.

  1. 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.

  2. 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.

  3. 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.

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

    PubMed

    Wang, Xue-Qing; Zhang, Qiang

    2012-10-01

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

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

    PubMed

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

    2017-03-16

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

  6. 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

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

    PubMed

    Dahan, Arik; Hoffman, Amnon

    2008-07-02

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

  8. Nanocomposite formation between alpha-glucosyl stevia and surfactant improves the dissolution profile of poorly water-soluble drug.

    PubMed

    Uchiyama, Hiromasa; Tozuka, Yuichi; Nishikawa, Masahiro; Takeuchi, Hirofumi

    2012-05-30

    The formation of a hybrid-nanocomposite using α-glucosyl stevia (Stevia-G) and surfactant was explored to improve the dissolution of flurbiprofen (FP). As reported previously, the dissolution amount of FP was enhanced in the presence of Stevia-G, induced by the formation of an FP and Stevia-G-associated nanostructure. When a small amount of sodium dodecyl sulfate (SDS) was present with Stevia-G, the amount of dissolved FP was extremely enhanced. This dissolution-enhancement effect was also observed with the cationic surfactant of dodecyl trimethyl ammonium bromide, but not with the non-ionic surfactant of n-octyl-β-D-maltopyranoside. To investigate the dissolution-enhancement effect of Stevia-G/SDS mixture, the pyrene I(1)/I(3) ratio was plotted versus the Stevia-G concentration. The pyrene I(1)/I(3) ratio of Stevia-G/SDS mixture had a sigmoidal curve at lower Stevia-G concentrations compared to the Stevia-G solution alone. These results indicate that the Stevia-G/SDS mixture provides a hydrophobic core around pyrene molecules at lower Stevia-G concentrations, leading to nanocomposite formation between Stevia-G and SDS. The nanocomposite of Stevia-G/SDS showed no cytotoxicity to Caco-2 cells at a mixture of 0.1% SDS and 1% Stevia-G solution, whereas 0.1% SDS solution showed high toxicity. These results suggest that the nanocomposite formation of Stevia-G/SDS may be useful way to enhance the dissolution of poorly water-soluble drugs without special treatment.

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

    PubMed

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

    2011-04-01

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

  10. 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.

  11. 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.

  12. The use of polymer-based electrospun nanofibers containing amorphous drug dispersions for the delivery of poorly water-soluble pharmaceuticals.

    PubMed

    Brewster, M E; Verreck, G; Chun, I; Rosenblatt, J; Mensch, J; Van Dijck, A; Noppe, M; Ariën, A; Bruining, M; Peeters, J

    2004-05-01

    Electrostatic spinning was applied to the preparation of drug-laden nanofiber for potential use in oral and topical drug delivery. While this technique is in its infancy with regard to pharmaceutical applications, a number of recent publications suggest that it may be of high value in the formulation of poorly water-soluble drugs by combining nanotechnology and solid solution/dispersion methodologies. The purpose of this article is to describe some of these recently published applications. For immediate release oral application, a water-soluble cellulose polymer was selected (i.e., hydroxypropylmethylcellulose, HPMC) while for topical application, a nonbiodegradable, water-insoluble polymer was investigated (i.e., a segmented polyurethane, SPU). Solutions of the polymer and the drugs in appropriate solvents could be spun across various potentials (16-24 kV) generating nanofibers with diameters ranging from 300 to 2000 nm. Dissolution studies found that the non-woven fabrics derived from HPMC and containing itraconazole dissolved over a time course of minutes to hours depending on the formulation used as well as the drug/polymer ratios. Drug release from the SPU samples was dependent on the incorporated drug as well as nanostructure obtained.

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

    PubMed

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

    2011-05-30

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

  14. Improvement of dissolution behavior for poorly water-soluble drug by application of cyclodextrin in extrusion process: comparison between melt extrusion and wet extrusion.

    PubMed

    Yano, Hideki; Kleinebudde, Peter

    2010-06-01

    The purpose of this study was to improve dissolution behavior of poorly water-soluble drugs by application of cyclodextrin in extrusion processes, which were melt extrusion process and wet extrusion process. Indomethacin (IM) was employed as a model drug. Extrudates containing IM and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) in 1:1 w/w ratio were manufactured by both melt extrusion process and wet extrusion process. In vitro drug release properties of IM from extrudates and physiochemical properties of extrudates were investigated. The dissolution rates of IM from extrudates manufactured by melt extrusion and wet extrusion with HP-beta-CyD were significantly higher than that of the physical mixture of IM and HP-beta-CyD. In extrudate manufactured by melt extrusion, gamma-form of IM changed to amorphous completely during melt extrusion due to heating above melting point of IM. On the other hand, in extrudate manufactured by wet extrusion, gamma-form of IM changed to amorphous partially due to interaction between IM and HP-beta-CyD and mechanical agitating force during process. Application of HP-beta-CyD in extrusion process is useful for the enhancement of dissolution rate for poorly water-soluble drugs.

  15. 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.

  16. Novel spray freeze-drying technique using four-fluid nozzle-development of organic solvent system to expand its application to poorly water soluble drugs.

    PubMed

    Niwa, Toshiyuki; Shimabara, Hiroko; Danjo, Kazumi

    2010-02-01

    Spray freeze-drying (SFD) technique using four-fluid nozzle (4N), which is a novel particle design technique previously developed by authors, has been further developed to expand its application in pharmaceutical industry. The organic solvent was utilized as a spray solvent to dissolve the poorly soluble drug instead of conventional aqueous solution. Acetonitrile solution of the drug and aqueous solution of the polymeric carrier were separately and simultaneously atomized through 4N, and collided each other at the tip of nozzle edge. The spray mists were immediately frozen in the liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier according to our proprietary method developed before. The resultant composite particles with phenytoin prepared by using acetonitrile (4N-SFD-MeCN system) were deeply characterized compared to those using aqueous solution (4N-SFD-aqua system) from morphological and physicochemical perspectives. The characteristic porous structure was observed in 4N-SFD-MeCN particles as well as 4N-SFD-aqua particles. However, it was found that the size and quantity of pore in 4N-SFD-MeCN particles were smaller than those of 4N-SFD-aqua particles. As a result, the former particles had 2- to 3-times smaller specific surface area than the latter particles independent of the type of carrier loaded. The slight difference of release profiles from the particles prepared between both systems was discussed from the microscopically structural viewpoint. In addition, ciclosporin was applied to organic solvent SFD system because this drug was poorly water soluble and cannot be applied to conventional aqueous SFD system. The release profiles from SFD particles were dramatically improved compared to the bulk material, suggesting that the new SFD technique using organic solvent has potential to develop the novel solubilized formulation for poorly water-soluble active pharmaceutical

  17. Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet stirred media milling: a microhydrodynamic view.

    PubMed

    Afolabi, Afolawemi; Akinlabi, Olakemi; Bilgili, Ecevit

    2014-01-23

    Wet stirred media milling has proven to be a robust process for producing nanoparticle suspensions of poorly water-soluble drugs. As the process is expensive and energy-intensive, it is important to study the breakage kinetics, which determines the cycle time and production rate for a desired fineness. Although the impact of process parameters on the properties of final product suspensions has been investigated, scant information is available regarding their impact on the breakage kinetics. Here, we elucidate the impact of stirrer speed, bead concentration, and drug loading on the breakage kinetics via a microhydrodynamic model for the bead-bead collisions. Suspensions of griseofulvin, a model poorly water-soluble drug, were prepared in the presence of two stabilizers: hydroxypropyl cellulose and sodium dodecyl sulfate. Laser diffraction, scanning electron microscopy, and rheometry were used to characterize them. Various microhydrodynamic parameters including a newly defined milling intensity factor was calculated. An increase in either the stirrer speed or the bead concentration led to an increase in the specific energy and the milling intensity factor, consequently faster breakage. On the other hand, an increase in the drug loading led to a decrease in these parameters and consequently slower breakage. While all microhydrodynamic parameters provided significant physical insight, only the milling intensity factor was capable of explaining the influence of all parameters directly through its strong correlation with the process time constant. Besides guiding process optimization, the analysis rationalizes the preparation of a single high drug-loaded batch (20% or higher) instead of multiple dilute batches.

  18. 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.

  19. 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

  20. Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid.

    PubMed

    Miwa, Yasushi; Hamamoto, Hidetoshi; Ishida, Tatsuhiro

    2016-05-01

    Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption.

  1. Nanosizing: a formulation approach for poorly-water-soluble compounds.

    PubMed

    Merisko-Liversidge, Elaine; Liversidge, Gary G; Cooper, Eugene R

    2003-02-01

    Poorly-water-soluble compounds are difficult to develop as drug products using conventional formulation techniques and are frequently abandoned early in discovery. The use of media milling technology to formulate poorly-water-soluble drugs as nanocrystalline particles offers the opportunity to address many of the deficiencies associated with this class of molecules. NanoCrystal Technology is an attrition process wherein large micron size drug crystals are media milled in a water-based stabilizer solution. The process generates physically stable dispersions consisting of nanometer-sized drug crystals. Nanocrystalline particles are a suitable delivery system for all commonly used routes of administration, i.e. oral, injectable (IV, SC, and IM) and topical applications. In addition, aqueous dispersions of nanoparticles can be post-processed into tablets, capsules, fast-melts and lyophilized for sterile product applications. The technology has been successfully incorporated into all phases of the drug development cycle from identification of new chemical entities to refurbishing marketed products for improving their performance and value.

  2. 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.

  3. 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.

  4. Lipid-based liquid crystalline nanoparticles as oral drug delivery vehicles for poorly water-soluble drugs: cellular interaction and in vivo absorption

    PubMed Central

    Zeng, Ni; Gao, Xiaoling; Hu, Quanyin; Song, Qingxiang; Xia, Huimin; Liu, Zhongyang; Gu, Guangzhi; Jiang, Mengyin; Pang, Zhiqing; Chen, Hongzhuan; Chen, Jun; Fang, Liang

    2012-01-01

    Background Lipid-based liquid crystalline nanoparticles (LCNPs) have attracted growing interest as novel drug-delivery systems for improving the bioavailability of both hydrophilic and hydrophobic drugs. However, their cellular interaction and in vivo behavior have not been fully developed and characterized. Methods In this study, self-assembled LCNPs prepared from soy phosphatidylcholine and glycerol dioleate were developed as a platform for oral delivery of paclitaxel. The particle size of empty LCNPs and paclitaxel-loaded LCNPs was around 80 nm. The phase behavior of the liquid crystalline matrix was characterized using crossed polarized light microscopy and small-angle X-ray scattering, and showed both reversed cubic and hexagonal phase in the liquid crystalline matrix. Transmission electron microscopy and cryofield emission scanning electron microscopy analysis revealed an inner winding water channel in LCNPs and a “ ball-like”/“hexagonal” morphology. Results Cellular uptake of LCNPs in Caco-2 cells was found to be concentration-dependent and time-dependent, with involvement of both clathrin and caveolae/lipid raft-mediated endocytosis. Under confocal laser scanning microscopy, soy phosphatidylcholine was observed to segregate from the internalized LCNPs and to fuse with the cell membrane. An in vivo pharmacokinetic study showed that the oral bioavailability of paclitaxel-loaded LCNPs (13.16%) was 2.1 times that of Taxol® (the commercial formulation of paclitaxel, 6.39%). Conclusion The findings of this study suggest that this LCNP delivery system may be a promising candidate for improving the oral bioavailability of poorly water-soluble agents. PMID:22888230

  5. [Design push-pull osmotic pump tablets of famotidine based on an expert system for the formulation design of osmotic pump of poor water-soluble drug].

    PubMed

    Zhang, Zhi-Hong; Jin, Jie; Zhang, Hong-Wu; Xin, Wei; Jia, Guo-Bin; Wu, Wen-Fang; Pan, Wei-San

    2011-01-01

    The purpose of this study is to design push-pull osmotic pump (PPOP) tablets of famotidine using the expert system for the formulation design of osmotic pump of poor water-soluble drug which had been established by the authors. Firstly, the parameters which were requisite of the system input were obtained from literatures and experimental tests. Then the parameters were input into the system, and the program was run. The system displayed the designed formulations sequential. Finally, famotidine PPOP was prepared according to the designed formulations and the in vitro dissolution was carried out. It was found out that the target formulation of famotidine PPOP which could release for 24 hours was obtained in a very short period. Meanwhile, the practicability of the established expert system was proved.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Exploitation of 3D face-centered cubic mesoporous silica as a carrier for a poorly water soluble drug: influence of pore size on release rate.

    PubMed

    Zhu, Wenquan; Wan, Long; Zhang, Chen; Gao, Yikun; Zheng, Xin; Jiang, Tongying; Wang, Siling

    2014-01-01

    The purposes of the present work were to explore the potential application of 3D face-centered cubic mesoporous silica (FMS) with pore size of 16.0nm as a delivery system for poorly soluble drugs and investigate the effect of pore size on the dissolution rate. FMS with different pore sizes (16.0, 6.9 and 3.7nm) was successfully synthesized by using Pluronic block co-polymer F127 as a template and adjusting the reaction temperatures. Celecoxib (CEL), which is a BCS class II drug, was used as a model drug and loaded into FMS with different pore sizes by the solvent deposition method at a drug-silica ratio of 1:4. Characterization using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transformation infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), nitrogen adsorption, X-ray diffraction (XRD), and differential scanning calorimetry (DSC) was used to systematically investigate the drug loading process. The results obtained showed that CEL was in a non-crystalline state after incorporation of CEL into the pores of FMS-15 with pore size of 16.0nm. In vitro dissolution was carried out to demonstrate the effects of FMS with different pore sizes on the release of CEL. The results obtained indicated that the dissolution rate of CEL from FMS-15 was significantly enhanced compared with pure CEL. This could be explained by supposing that CEL encountered less diffusion resistance and its crystallinity decreased due to the large pore size of 16.0nm and the nanopore channels of FMS-15. Moreover, drug loading and pore size both play an important role in enhancing the dissolution properties for the poorly water-soluble drugs. As the pore size between 3.7 and 16.0nm increased, the dissolution rate of CEL from FMS gradually increased.

  12. 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

  13. Microfibrous Solid Dispersions of Poorly Water-Soluble Drugs Produced Via Centrifugal Spinning: Unexpected Dissolution Behaviour on Recrystallization.

    PubMed

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

    2017-03-15

    Temperature-controlled, solvent-free centrifugal spinning may be used as a means of rapid production of amorphous solid dispersions in the form of drug-loaded sucrose microfibers. However, due to the high content of amorphous sucrose in the formulations, such microfibers may be highly hygroscopic and unstable on storage. In this study, we explore both the effects of water uptake of the microfibers and the consequences of deliberate recrystallization for the associated dissolution profiles. The stability of sucrose microfibers loaded with three selected BCS class II model drugs (itraconazole (ITZ), olanzapine (OLZ) and piroxicam (PRX)) was investigated under four different relative humidity conditions (11, 33, 53 and 75% RH) at 25°C for 8 months, particularly focusing on the effect of the highest level of moisture (75% RH) on the morphology, size, drug distribution, physical state and dissolution performance of microfibers. While all samples were stable at 11% RH, at 33% RH the ITZ-sucrose system showed greater resistance against devitrification compared to the OLZ- and PRX-sucrose systems. For all three samples, the freshly prepared microfibers showed enhanced dissolution and supersaturation compared to the drug alone and physical mixes; surprisingly, the dissolution advantage was largely maintained or even enhanced (in the case of ITZ) following the moisture-induced recrystallization under 75% RH. Therefore, this study suggests that the moisture-induced recrystallization process may result in considerable dissolution enhancement compared to the drug alone, while overcoming the physical stability risks associated with the amorphous state.

  14. Eudragit-based nanosuspension of poorly water-soluble drug: formulation and in vitro-in vivo evaluation.

    PubMed

    Yadav, Sarita Kumari; Mishra, Shivani; Mishra, Brahmeshwar

    2012-12-01

    The present study was performed to investigate potential of Eudragit RLPO-based nanosuspension of glimepiride (Biopharmaceutical Classification System class II drug), for the improvement of its solubility and overall therapeutic efficacy, suitable for peroral administration. Nanoprecipitation method being simple and less sophisticated was optimized for the preparation of nanosuspension. Physicochemical characteristics of nanosuspension in terms of size, zeta potential, polydispersity index, entrapment efficiency (% EE) and in vitro drug release were found within their acceptable ranges. The size of the nanoparticles was most strongly affected by agitation time while % EE was more influenced by the drug/polymer ratio. Differential scanning calorimetry and X-ray diffraction studies provided evidence that enhancement in solubility of drug resulted due to change in crystallinity of drug within the formulation. Stability study revealed that nanosuspension was more stable at refrigerated condition with no significant changes in particle size distribution, % EE, and release characteristics for 3 months. In vivo studies were performed on nicotinamide-streptozotocin-induced diabetic rat models for pharmacokinetic and antihyperglycaemic activity. Nanosuspension increased maximum plasma concentration, area under the curve, and mean residence time values significantly as compared to aqueous suspension. Oral glucose tolerance test and antihyperglycaemic studies demonstrated plasma glucose levels were efficiently controlled in case of nanosuspension than glimepiride suspension. Briefly, sustained and prolonged activity of nanosuspensions could reduce dose frequency, decrease drug side effects, and improve patient compliance. Therefore, glimepiride nanosuspensions can be expected to gain considerable attention in the treatment of type 2 diabetes mellitus due to its improved therapeutic activity.

  15. Spray drying of a poorly water-soluble drug nanosuspension for tablet preparation: formulation and process optimization with bioavailability evaluation.

    PubMed

    Sun, Wei; Ni, Rui; Zhang, Xin; Li, Luk Chiu; Mao, Shirui

    2015-06-01

    Spray drying experiments of an itraconazole nanosuspension were conducted to generate a dry nanocrystal powder which was subsequently formulated into a tablet formulation for direct compression. The nanosuspension was prepared by high pressure homogenization and characterized for particle-size distribution and surface morphology. A central composite statistical design approach was applied to identify the optimal drug-to-excipient ratio and spray drying temperature. It was demonstrated that the spray drying of a nanosuspension with a mannitol-to-drug mass ratio of 4.5 and at an inlet temperature of 120 °C resulted in a dry powder with the smallest increase in particle size as compared with that of the nanosuspension. X-ray diffraction results indicated that the crystalline structure of the drug was not altered during the spray-drying process. The tablet formulation was identified by determining the micromeritic properties such as flowability and compressibility of the powder mixtures composed of the spray dried nanocrystal powder and other commonly used direct compression excipients. The dissolution rate of the nanocrystal tablets was significantly enhanced and was found to be comparable to that of the marketed Sporanox®. No statistically significant difference in oral absorption between the nanocrystal tablets and Sporanox® capsules was found. In conclusion, the nanosuspension approach is feasible to improve the oral absorption of a BCS Class II drug in a tablet formulation and capable of achieving oral bioavailability equivalent to other well established oral absorption enhancement method.

  16. 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.

  17. Influence of the intermediate digestion phases of common formulation lipids on the absorption of a poorly water-soluble drug.

    PubMed

    Kossena, Greg A; Charman, William N; Boyd, Ben J; Porter, Christopher J H

    2005-03-01

    The influence of different model intestinal phases (modelled on those likely to be produced in vivo after the digestion of commonly used formulation lipids) on the absorption profile of cinnarizine has been studied. Combinations of C8, C12, or C18:1 fatty acid and monoglyceride and simulated endogenous intestinal fluid were formulated to provide examples of liquid (L1), lamellar (L(alpha)), and cubic (C) liquid crystalline phases. Phases containing cinnarizine were dosed intraduodenally and absorption was assessed in an anesthetized rat model. Bile duct ligation was performed to inhibit the effects of digestion/dilution on the phase structure. Absorption from the L(alpha) phases (C8 and C12 lipids) was statistically higher (p < 0.05) than a cinnarizine suspension: however, a statistically significant difference was not observed from the L1 and C phases. The rigid C18:1 C phase showed evidence of providing for sustained drug absorption. Experiments in bile intact rats with the C8 L(alpha) and C18:1 C phase highlighted that the absorption-modifying properties of these phases were influenced by dilution in the endogenous bile milieu, with absorption from L(alpha) phase reducing (possibly through precipitation of solubilized drug) and increasing in the case of the C18:1 C phase, possibly through the coexistence of L1 and C upon dilution permitting more efficient transfer of solubilized drug.

  18. 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 Central

    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/cm2 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. PMID:24391965

  19. 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.

  20. Enhancement of the aqueous solubility and permeability of a poorly water soluble drug ritonavir via lyophilized milk-based solid dispersions.

    PubMed

    Dhore, Pradip W; Dave, Vivek S; Saoji, Suprit D; Bobde, Yamini S; Mack, Connor; Raut, Nishikant A

    2017-02-01

    In the present study, a lyophilized milk-based solid dispersion (SD) of ritonavir (RTV) was developed with the goal of improving its aqueous solubility. The SD was prepared by lyophilization, and characterized for its physicochemical and functional properties. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), photomicroscopy and powder X-ray diffraction (PXRD) were used to confirm the formation and robustness of the SD formulation. The prepared SD formulations were functionally evaluated by saturation solubility, in vitro drug release and ex vivo permeation studies. The optimized SD formulation exhibited a significantly higher (30-fold) aqueous solubility (11.36 ± 0.06 μg/mL), compared to the pure RTV (0.37 ± 0.03 μg/mL). The in vitro dissolution studies revealed a significantly higher (∼10-fold) efficiency of the optimized SD formulation in releasing the RTV, compared to the pure RTV. The ex vivo permeation studies with the everted intestine method showed that prepared SD formulation significantly improved the permeation of RTV (75.6 ± 3.09, % w/w), compared to pure RTV (20.45 ± 1.68, % w/w). Thus, SD formulation utilizing lyophilized milk as a carrier appears to be a promising alternative strategy to improve the aqueous solubility of poorly water soluble drugs.

  1. Lipid-Based Formulations Can Enable the Model Poorly Water-Soluble Weakly Basic Drug Cinnarizine To Precipitate in an Amorphous-Salt Form During In Vitro Digestion.

    PubMed

    Khan, Jamal; Rades, Thomas; Boyd, Ben J

    2016-11-07

    The tendency for poorly water-soluble weakly basic drugs to precipitate in a noncrystalline form during the in vitro digestion of lipid-based formulations (LBFs) was linked to an ionic interaction between drug and fatty acid molecules produced upon lipid digestion. Cinnarizine was chosen as a model weakly basic drug and was dissolved in a medium-chain (MC) LBF, which was subject to in vitro lipolysis experiments at various pH levels above and below the reported pKa value of cinnarizine (7.47). The solid-state form of the precipitated drug was analyzed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and crossed polarized light microscopy (CPLM). In addition, the phase distribution of cinnarizine upon lipolysis was analyzed using high-performance liquid chromatography (HPLC). Cinnarizine precipitated in a noncrystalline form during lipolysis experiments at pH 6.5, pH 5.5, and pH 4.0 but precipitated in a crystalline form at pH 8.0 according to XRD measurements on the pellets. Differences were also observed in the FTIR spectra of the pellet phases at pH 8.0 and pH 6.5, with the absorption bands in the C-N stretch region of the IR spectra supporting a shift from the starting free base crystalline material to the hydrochloride salt, thus supporting the case that ionic interactions between weak bases and fatty acid molecules during digestion are responsible for producing amorphous-salts upon precipitation. The conclusion has wide implications for understanding past in vitro and in vivo data for lipid-based formulations of basic drugs, as well as future formulation design and optimization.

  2. A novel particle engineering technology to enhance dissolution of poorly water soluble drugs: spray-freezing into liquid.

    PubMed

    Rogers, True L; Nelsen, Andrew C; Hu, Jiahui; Brown, Judith N; Sarkari, Marazban; Young, Timothy J; Johnston, Keith P; Williams, Robert O

    2002-11-01

    A novel cryogenic spray-freezing into liquid (SFL) process was developed to produce microparticulate powders consisting of an active pharmaceutical ingredient (API) molecularly embedded within a pharmaceutical excipient matrix. In the SFL process, a feed solution containing the API was atomized beneath the surface of a cryogenic liquid such that the liquid-liquid impingement between the feed and cryogenic liquids resulted in intense atomization into microdroplets, which were frozen instantaneously into microparticles. The SFL micronized powder was obtained following lyophilization of the frozen microparticles. The objective of this study was to develop a particle engineering technology to produce micronized powders of the hydrophobic drug, danazol, complexed with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and to compare these SFL micronized powders to inclusion complex powders produced from other techniques, such as co-grinding of dry powder mixtures and lyophilization of bulk solutions. Danazol and HPbetaCD were dissolved in a water/tetrahydrofuran cosolvent mixture prior to SFL processing or slow freezing. Identical quantities of the API and HPbetaCD used in the solutions were co-ground in a mortar and pestle and blended to produce a co-ground physical mixture for comparison. The powder samples were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR), scanning electron microscopy, surface area analysis, and dissolution testing. The results provided by DSC, XRD, and FTIR suggested the formation of inclusion complexes by both slow-freezing and SFL. However, the specific surface area was significantly higher for the latter. Dissolution results suggested that equilibration of the danazol/HPbetaCD solution prior to SFL processing was required to produce the most soluble conformation of the resulting inclusion complex following SFL. SFL micronized powders exhibited better dissolution

  3. Thermoresponsive ophthalmic poloxamer/tween/carbopol in situ gels of a poorly water-soluble drug fluconazole: preparation and in vitro-in vivo evaluation.

    PubMed

    Lihong, Wang; Xin, Che; Yongxue, Guo; Yiying, Bian; Gang, Cheng

    2014-10-01

    The purpose of the present study was to optimize the formulations of the thermoresponsive ophthalmic in situ gels of a poorly water-soluble drug fluconazole (FLU) and evaluate the in vitro and in vivo properties of the formulations. The thermoresponsive ophthalmic FLU in situ gels were prepared by mixing FLU, Poloxamer407, Tween80, benzalkonium chloride and carbopol934 in borate buffer solution. The in vivo eye irritation tests and ophthalmic absorption were carried out in rabbits. The formulation compositions influenced the physicochemical properties of FLU in situ gels. The amount of poloxamer407 in the formulation was the main factor that affected the sol-gel transition temperature of the products. Tween80 not only improved the solubility of the FLU but also affected the products' sol-gel transition temperature. In this study, sol-gel transition temperature was not affected by carbopol934. However, carbopol934 affected pH value, transparency and gelling capacity of the products. The product of the optimized formulation was a pseudoplastic fluid and its sol-gel transition temperature was 30.6 ± 1.2 °C. The autoclaving test showed that the sol-gel transition temperature, the flow ability and the flow behavior of the test samples did not change obviously after autoclaving sterilization at 121 °C and 15 psi for 20 min, thus the autoclaving was an acceptable sterilization method for this preparation. The thermoresponsive ophthalmic FLU in situ gels' in vivo ophthalmic absorption was superior to the conventional FLU eye drop. In conclusion, the thermoresponsive ophthalmic FLU in situ gel is a better alternative than the FLU eye drop.

  4. A solid phospholipid-bile salts-mixed micelles based on the fast dissolving oral films to improve the oral bioavailability of poorly water-soluble drugs

    NASA Astrophysics Data System (ADS)

    Lv, Qing-yuan; Li, Xian-yi; Shen, Bao-de; Dai, Ling; Xu, He; Shen, Cheng-ying; Yuan, Hai-long; Han, Jin

    2014-06-01

    The phospholipid-bile salts-mixed micelles (PL-BS-MMs) are potent carriers used for oral absorption of drugs that are poorly soluble in water; however, there are many limitations associated with liquid formulations. In the current study, the feasibility of preparing the fast dissolving oral films (FDOFs) containing PL-BS-MMs was examined. FDOFs incorporated with Cucurbitacin B (Cu B)-loaded PL-sodium deoxycholate (SDC)-MMs have been developed and characterized. To prepare the MMs and to serve as the micellar carrier, a weight ratio of 1:0.8 and total concentration of 54 mg/mL was selected for the PL/SDC based on the size, size distribution, zeta potential, encapsulation efficiency, and morphology. The concentration of Cu B was determined to be 5 mg/mL. Results showed that a narrow size distributed nanomicelles with a mean particle size of 86.21 ± 6.11 nm and a zeta potential of -31.21 ± 1.17 mV was obtained in our optimized Cu B-PL/SDC-MMs formulation. FDOFs were produced by solvent casting method and the formulation with 50 mg/mL of pullulan and 40 mg/mL of PEG 400 were deemed based on the physico-mechanical properties. The FDOFs containing Cu B-PL/SDC-MMs were easily reconstituted in a transparent and clear solution giving back a colloidal system with spherical micelles in the submicron range. In the in vitro dissolution test, the FDOFs containing Cu B-PL/SDC-MMs showed an increased dissolution velocity markedly. The pharmacokinetics study showed that the FDOFs containing PL-SDC-MMs not only kept the absorption properties as same as the PL-SDC-MMs, but also significantly increased the oral bioavailability of Cu B compared to the Cu B suspension ( p < 0.05). This study showed that the FDOFs containing Cu B-PL/SDC-MMs could represent a novel platform for the delivery of poorly water-soluble drugs via oral administration. Furthermore, the integration with the FDOFs could also provide a simple and cost-effective manner for the solidification of PL-SDC-MMs.

  5. Preliminary Studies on Two Vegetable Oil Based Self Emulsifying Drug Delivery System (SEDDS) for the Delivery of Metronidazole, A Poorly Water Soluble Drug

    NASA Astrophysics Data System (ADS)

    Obitte, N. C.; Ezeiruaku, H.; Onyishi, V. I.

    A preliminary evaluation was carried out on metronidazole-loaded Self Emulsifying Drug Delivery System (SEDDS) using two vegetable oils-Palm Kernel Oil (PKO) and Palm Oil (PO). Purification of oils, drug solubility in the oils, pre/post formulation isotropicity tests, emulsification times and release studies of metronidazole from the SEDDS were carried out. Results indicated solubility values of 4.441 and 4.654%w/w, respectively for metronidazole in PKO and PO. Preformulation isotropicity test revealed that out of the 24 batches evaluated 10 of the SEDDS formulations containing different oil: surfactant ratios and PKO:PO admixtures were found to be isotropic after 5 h. However when the SEDDS were loaded with metronidazole there was a reduction in the number (to 7) of formulations that maintained isotropicity and stability after 72 h. All the batches had emulsification times of less than two minutes except batch 4D with oil:surfactant concentration of 50:50. The release profile showed that most of the formulations released 50% of drug in less than 8 min and 85% of drug in less than 30 min. We therefore conclude that SEDDS containing the two vegetable oils are potential alternatives when immediate release and delivery of metronidazole is the primary motivation.

  6. The novel formulation design of self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion I: enhancing effects on oral bioavailability of poorly water soluble compounds in rats and beagle dogs.

    PubMed

    Araya, Hiroshi; Nagao, Shunsuke; Tomita, Mikio; Hayashi, Masahiro

    2005-08-01

    We examined the design of the versatile novel self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds. Namely, seven kinds of poorly water soluble compounds such as disopyramide, ibuprofen, ketoprofen, tolbutamide, and other new compounds, as the model compounds were used to compare the plasma concentration profile of the compound following single oral administration of each compound to rats and beagle dogs as a solution, an oily solution, a suspension (or a powder), an O/W microemulsion, and a SEDDS type O/W microemulsion. And the enhancing effect of the SEDDS type O/W microemulsion on the gastrointestinal absorption of these compounds was evaluated. In the components of the SEDDS type O/W microemulsion, medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40), and ethanol were used as an oil, a lipophilic surfactant, a hydrophilic surfactant, and a solubilizer, at the mixture ratio of 25/5/45/25 (w/w%), respectively. Thereby, to six kinds of the model compounds except disopyramide, the solubility was from 340 to 98,000 times that in water, and the AUCs in plasma concentration of the compound were equivalent to that of solution or O/W microemulsion administration, or was increased by 1.5 to 78 times that of suspension administration. Accordingly, this novel SEDDS type O/W microemulsion is the versatile, useful formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds.

  7. Microenvironmental pH-modified solid dispersions to enhance the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug: preparation, characterization and evaluation in vivo.

    PubMed

    Yang, Meiyan; He, Shaolong; Fan, Yunzhou; Wang, Yuli; Ge, Zhenzhong; Shan, Li; Gong, Wei; Huang, Xiaoli; Tong, Youzhi; Gao, Chunsheng

    2014-11-20

    The aim of the present work was to design a pH-modified solid dispersion (pH(M)-SD) that can improve the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug. To select the appropriate acidifiers, a solubility test was carried out first. Solid dispersions (SDs) containing GT0918 and polyvinylpyrrolidone (PVP) were prepared using a solvent evaporation method and were characterized using dissolution studies in different media. The solid states of the SDs were investigated using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transformed infrared spectroscopy (FTIR). The in vivo pharmacokinetics of the pH(M)-SDs tablets were also studied in beagle dogs compared to the conventional tablets. The optimized pH(M)-SD (GT0918/PVP/citric acid, 1:2:2 weight ratio) exhibited a significant improvement in the dissolution behavior compared to both the physical mixture and the binary SDs. Solid-state characterization revealed that the amorphous formation of GT0918 in the SDs and the strong H-bonding were only found in the pH(M)-SDs containing citric acid. Furthermore, the GT0918-loaded pH(M)-SD tablets showed a higher AUC and a lower tmax compared to the conventional tablets. Accordingly, the pH(M)-SD might be an efficient route for enhancing the dissolution and bioavailability of poorly water-soluble GT0918.

  8. Instant and supersaturated dissolution of naproxen and sesamin (poorly water-soluble drugs and supplements) nanoparticles prepared by continuous expansion of liquid carbon dioxide solution through long dielectric nozzle

    NASA Astrophysics Data System (ADS)

    Arita, Toshihiko; Manabe, Noriyoshi; Nakahara, Koichi

    2012-11-01

    Nanoparticles (NPs) of naproxen (a nonsteroidal anti-inflammatory drug, BCS Class 2) and sesamin (a poorly water-soluble lignan) were investigated. By applying a newly developed rapid expansion system of liquid carbon dioxide solutions equipped with a dielectric nozzle, well-separated and fine both naproxen NPs (averaged particle size (APS) = 46.9 nm) and sesamin NPs (APS = 60.2 nm) were obtained without heating, surfactants, and co-solvents. Obtained naproxen and sesamin NPs had large surface/weight ratio, therefore, they showed instant dissolution to water until about ten percent higher than the saturated concentrations. In addition, the technique developed in the study has big advantage on producing especially drug NPs because the NPs produced by the method never includes neither poisonous additives (especially co-solvents and detergents) nor thermally denatured compounds.

  9. Bile salts-containing vesicles: promising pharmaceutical carriers for oral delivery of poorly water-soluble drugs and peptide/protein-based therapeutics or vaccines.

    PubMed

    Aburahma, Mona Hassan

    2016-07-01

    Most of the new drugs, biological therapeutics (proteins/peptides) and vaccines have poor performance after oral administration due to poor solubility or degradation in the gastrointestinal tract (GIT). Though, vesicular carriers exemplified by liposomes or niosomes can protect the entrapped agent to a certain extent from degradation. Nevertheless, the harsh GIT environment exemplified by low pH, presence of bile salts and enzymes limits their capabilities by destabilizing them. In response to that, more resistant bile salts-containing vesicles (BS-vesicles) were developed by inclusion of bile salts into lipid bilayers constructs. The effectiveness of orally administrated BS-vesicles in improving the performance of vesicles has been demonstrated in researches. Yet, these attempts did not gain considerable attention. This is the first review that provides a comprehensive overview of utilizing BS-vesicles as a promising pharmaceutical carrier with a special focus on their successful applications in oral delivery of therapeutic macromolecules and vaccines. Insights on the possible mechanisms by which BS-vesicles improve the oral bioavailability of the encapsulated drug or immunological response of entrapped vaccine are explained. In addition, methods adopted to prepare and characterize BS-vesicles are described. Finally, the gap in the scientific researches tackling BS-vesicles that needs to be addressed is highlighted.

  10. 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.

  11. Targeted delivery of a poorly water-soluble compound to hair follicles using polymeric nanoparticle suspensions.

    PubMed

    Morgen, Michael; Lu, Guang Wei; Du, Daniel; Stehle, Randall; Lembke, Franz; Cervantes, Jessica; Ciotti, Susan; Haskell, Roy; Smithey, Dan; Haley, Kevin; Fan, Conglin

    2011-09-15

    This study explored the utility of topically applied polymeric nanoparticle suspensions to target delivery of poorly water-soluble drugs to hair follicles. Several formulations of amorphous drug/polymer nanoparticles were prepared from ethyl cellulose and UK-157,147 (systematic name (3S,4R)-[6-(3-hydroxyphenyl)sulfonyl]-2,2,3-trimethyl-4-(2-methyl-3-oxo-2,3-dihydropyridazin-6-yloxy)-3-chromanol), a potassium channel opener, using sodium glycocholate (NaGC) as a surface stabilizer. Nanoparticle suspensions were evaluated to determine if targeted drug delivery to sebaceous glands and hair follicles could be achieved. In in vitro testing with rabbit ear tissue, delivery of UK-157,147 to the follicles was demonstrated with limited distribution to the surrounding dermis. Delivery to hair follicles was also demonstrated in vivo, based on stimulation of hair growth in tests of 100-nm nanoparticles with a C3H mouse model. The nanoparticles were well-tolerated, with no visible skin irritation. In vivo tests of smaller nanoparticles with a hamster ear model also indicated targeted delivery to sebaceous glands. The nanoparticles released drug rapidly in in vitro nonsink dissolution tests and were stable in suspension for 3 months. The present results show selective drug delivery to the follicle by follicular transport of nanoparticles and rapid release of a poorly water-soluble drug. Thus, nanoparticles represent a promising approach for targeted topical delivery of low-solubility compounds to hair follicles.

  12. The mechanism for increasing the oral bioavailability of poorly water-soluble drugs using uniform mesoporous carbon spheres as a carrier.

    PubMed

    Wang, Tianyi; Zhao, Peng; Zhao, Qinfu; Wang, Bing; Wang, Siling

    2016-01-01

    Uniform mesoporous carbon spheres (UMCS) were used as a carrier to improve the bioavailability of the model drug, celecoxib (CEL). Furthermore, we investigated the mechanism responsible for the improved bioavailability of CEL. The association, adhesion and uptake of UMCS by intestinal epithelial cells were studied by transmission electron microscopy (TEM), fluorescence-activated cell sorting (FACS) and laser confocal scanning microscopy (LCSM). UMCS was found to promote cellular uptake of CEL. Drug transport in Caco-2 cell monolayers proved that UMCS can significantly reduce the rate of drug efflux and improve CEL permeability. The dissolution rate of CEL from drug-loaded samples was markedly improved compared with pure crystalline CEL; moreover, oral bioavailability of CEL loaded into UMCS was also markedly improved compared with that of commercially available capsules. UMCS indicates the advantages and potential of this method to achieve improved oral absorption by increasing the dissolution rate, cellular uptake and permeability of the drug.

  13. Exploiting the Phenomenon of Liquid-Liquid Phase Separation for Enhanced and Sustained Membrane Transport of a Poorly Water-Soluble Drug.

    PubMed

    Indulkar, Anura S; Gao, Yi; Raina, Shweta A; Zhang, Geoff G Z; Taylor, Lynne S

    2016-06-06

    Recent studies on aqueous supersaturated lipophilic drug solutions prepared by methods including antisolvent addition, pH swing, or dissolution of amorphous solid dispersions (ASDs) have demonstrated that when crystallization is slow, these systems undergo liquid-liquid phase separation (LLPS) when the concentration of the drug in the medium exceeds its amorphous solubility. Following LLPS, a metastable equilibrium is formed where the concentration of drug in the continuous phase corresponds to the amorphous solubility while the dispersed phase is composed of a nanosized drug-rich phase. It has been reasoned that the drug-rich phase may act as a reservoir, enabling the rate of passive transport of the drug across a membrane to be maintained at the maximum value for an extended period of time. Herein, using clotrimazole as a model drug, and a flow-through diffusion cell, the reservoir effect is demonstrated. Supersaturated clotrimazole solutions at concentrations below the amorphous solubility show a linear relationship between the maximum flux and the initial concentration. Once the concentration exceeds the amorphous solubility, the maximum flux achieved reaches a plateau. However, the duration for which the high flux persists was found to be highly dependent on the number of drug-rich nanodroplets present in the donor compartment. Macroscopic amorphous particles of clotrimazole did not lead to the same reservoir effect observed with the nanodroplets formed through the process of LLPS. A first-principles mathematical model was developed which was able to fit the experimental receiver concentration-time profiles for concentration regimes both below and above amorphous solubility, providing support for the contention that the nanodroplet phase does not directly diffuse across the membrane but, instead, rapidly replenishes the drug in the aqueous phase that has been removed by transport across the membrane. This study provides important insight into the properties of

  14. 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

  15. Permeability assessment of poorly water-soluble compounds under solubilizing conditions: the reciprocal permeability approach.

    PubMed

    Katneni, Kasiram; Charman, Susan A; Porter, Christopher J H

    2006-10-01

    The objective of this study was to develop a general method to assess the intestinal permeability of poorly water-soluble drugs where low-aqueous drug solubility requires conduct of experiments under solubilizing experimental conditions. The permeability (Papp) of diazepam (DIA) was assessed across excised rat jejunum in the absence (Pappcontrol) and presence (Pappuncorr) of polysorbate-80 (PS-80). The micellar association constant (Ka) of DIA, estimated via equilibrium solubility studies, was used to correct Pappuncorr data and obtain an estimate of the true permeability coefficient (Pappcorr). An alternate approach was also developed (the reciprocal permeability approach) to allow direct estimation of Pappcorr without the need for independent estimation of Ka. The approach was further examined experimentally using a range of model drugs. DIA Pappcorr values obtained using the Ka from equilibrium solubility studies deviated from Papp(control) values, especially at PS-80 concentrations above 0.1% w/v. In contrast, data obtained using the reciprocal permeability method were consistent with Pappcontrol across the PS-80 concentration range. Similar trends were observed with propranolol (PRO), antipyrine (ANT), naproxen (NAP), and cinnarizine (CIN). The reciprocal permeability approach therefore provides a simple and accurate method by which the permeability of poorly water-soluble compounds may be estimated under solubilizing conditions.

  16. 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

  17. Polymer-surfactant nanoparticles for sustained release of water-soluble drugs.

    PubMed

    Chavanpatil, Mahesh D; Khdair, Ayman; Patil, Yogesh; Handa, Hitesh; Mao, Guangzhao; Panyam, Jayanth

    2007-12-01

    Poor drug encapsulation efficiency and rapid release of the encapsulated drug limit the use of nanoparticles in biomedical applications involving water-soluble drugs. We have developed a novel polymer-surfactant nanoparticle formulation, using the anionic surfactant Aerosol OT (AOT) and polysaccharide polymer alginate, for sustained release of water-soluble drugs. Particle size of nanoparticles, as determined by atomic force microscopy and transmission electron microscopy, was in the range of 40-70 nm. Weakly basic molecules like methylene blue, doxorubicin, rhodamine, verapamil, and clonidine could be encapsulated efficiently in AOT-alginate nanoparticles. In vitro release studies with basic drug molecules indicate that nanoparticles released 60-70% of the encapsulated drug over 4 weeks, with near zero-order release during the first 15 days. Studies with anionic drug molecules demonstrate poorer drug encapsulation efficiency and more rapid drug release than those observed with basic drugs. Further studies investigating the effect of sodium concentration in the release medium and the charge of the drug suggest that calcium-sodium exchange between nanoparticle matrix and release medium and electrostatic interaction between drug and nanoparticle matrix are important determinants of drug release. In conclusion, we have formulated a novel surfactant-polymer drug delivery carrier demonstrating sustained release of water-soluble drugs.

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

    PubMed

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

    2013-09-15

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

  19. 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

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

    NASA Astrophysics Data System (ADS)

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

    2012-03-01

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

  1. Inhibition of Ostwald ripening in model beverage emulsions by addition of poorly water soluble triglyceride oils.

    PubMed

    McClements, David Julian; Henson, Lulu; Popplewell, L Michael; Decker, Eric Andrew; Choi, Seung Jun

    2012-01-01

    Beverage emulsions containing flavor oils that have a relatively high water-solubility are unstable to droplet growth due to Ostwald ripening. The aim of this study was to improve the stability of model beverage emulsions to this kind of droplet growth by incorporating poorly water-soluble triglyceride oils. High pressure homogenization was used to prepare a series of 5 wt% oil-in-water emulsions stabilized by modified starch that had different lipid phase compositions (orange oil : corn oil). Emulsions prepared using only orange oil as the lipid phase were highly unstable to droplet growth during storage, which was attributed to Ostwald ripening resulting from the relatively high water-solubility of orange oil. Droplet growth could be effectively inhibited by incorporating ≥ 10% corn oil into the lipid phase prior to homogenization. In addition, creaming was also retarded because the lipid phase density was closer to that of the aqueous phase density. These results illustrate a simple method of improving the physical stability of orange oil emulsions for utilization in the food, beverage, and fragrance industries.

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

    PubMed

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

    2015-12-07

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

  3. 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.

  4. 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.

  5. Development of micellar reactive oxygen species assay for photosafety evaluation of poorly water-soluble chemicals.

    PubMed

    Seto, Yoshiki; Kato, Masashi; Yamada, Shizuo; Onoue, Satomi

    2013-09-01

    A reactive oxygen species (ROS) assay was previously developed for photosafety assessment; however, the phototoxic potential of some chemicals cannot be evaluated because of their limited aqueous solubility. The present study was undertaken to develop a new micellar ROS (mROS) assay system for poorly water-soluble chemicals using a micellar solution of 0.5% (v/v) Tween 20 for solubility enhancement. In repeated mROS assay, intra- and inter-day precisions (coefficient of variation) were found to be below 11%, and the Z'-factors for singlet oxygen and superoxide suggested a large separation band between positive and negative standards. The ROS and mROS assays were applied to 65 phototoxins and 18 non-phototoxic compounds for comparative purposes. Of all 83 chemicals, 25 were unevaluable in the ROS assay due to poor solubility, but only 2 were in the mROS assay. Upon mROS assay on these model chemicals, the individual specificity was 76.5%, and the positive and negative predictivities were found to be 93.9% and 86.7%, respectively. The mROS assay provided 2 false negative predictions, although negative predictivity for the ROS assay was found to be 100%. Considering the pros and cons of these assays, strategic combined use of the ROS and mROS assays might be efficacious for reliable photosafety assessment with high applicability and predictivity.

  6. 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.

  7. 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.

  8. Dissolution enhancement of poorly water-soluble APIs processed by hot-melt extrusion using hydrophilic polymers.

    PubMed

    Maniruzzaman, M; Rana, M M; Boateng, J S; Mitchell, J C; Douroumis, D

    2013-02-01

    The aim of this study was to investigate the efficiency of hydrophilic polymers to enhance the dissolution rate of poorly water-soluble active pharmaceutical ingredients (APIs) processed by hot-melt extrusion (HME). Indomethacin (INM) and famotidine (FMT) were selected as model active substances while polyvinyl caprolactam graft copolymer, soluplus (SOL) and vinylpyrrolidone-vinyl acetate copolymer grades, Kollidon VA64 (VA64) and Plasdone S630 (S630) were used as hydrophilic polymeric carriers. For the purpose of the study, drug-polymer binary blends at various ratios were processed by a Randcastle single screw extruder. The physicochemical properties and the morphology of the extrudates were evaluated through X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Increased drug loadings of up to 40% were achieved in the extruded formulations for both drugs. INM and FMT exhibited strong plasticization effects with increasing concentrations and were found to be molecularly dispersed within the polymer blends. The in vitro dissolution studies showed increased INM/FMT release rates for all formulations compared to that of pure APIs alone.

  9. Increasing the oral bioavailability of poorly water-soluble carbamazepine using immediate-release pellets supported on SBA-15 mesoporous silica

    PubMed Central

    Wang, Zhouhua; Chen, Bao; Quan, Guilan; Li, Feng; Wu, Qiaoli; Dian, Linghui; Dong, Yixuan; Li, Ge; Wu, Chuanbin

    2012-01-01

    Background and methods: The aim of this study was to develop an immediate-release pellet formulation with improved drug dissolution and adsorption. Carbamazepine, a poorly water-soluble drug, was adsorbed into mesoporous silica (SBA-15-CBZ) via a wetness impregnation method and then processed by extrusion/spheronization into pellets. Physicochemical characterization of the preparation was carried out by scanning electron microscopy, transmission electron microscopy, nitrogen adsorption, small-angle and wide-angle x-ray diffraction, and differential scanning calorimetry. Flowability and wettability of the drug-loaded silica powder were evaluated by bulk and tapped density and by the angle of repose and contact angle, respectively. The drug-loaded silica powder was formulated into pellets to improve flowability. Results: With maximum drug loading in SBA-15 matrices determined to be 20% wt, in vitro release studies demonstrated that the carbamazepine dissolution rate was notably improved from both the SBA-15 powder and the corresponding pellets as compared with the bulk drug. Correspondingly, the oral bioavailability of SBA-15-CBZ pellets was increased considerably by 1.57-fold in dogs (P < 0.05) compared with fast-release commercial carbamazepine tablets. Conclusion: Immediate-release carbamazepine pellets prepared from drug-loaded silica provide a feasible approach for development of a rapidly acting oral formulation for this poorly water-soluble drug and with better absorption. PMID:23209366

  10. The novel formulation design of O/W microemulsion for improving the gastrointestinal absorption of poorly water soluble compounds.

    PubMed

    Araya, Hiroshi; Tomita, Mikio; Hayashi, Masahiro

    2005-11-23

    The design of the novel O/W microemulsion formulation, which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds was examined. Using medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40), ethanol and PBS (pH 6.8) as an oil phase, a lipophilic surfactant, a hydrophilic surfactant, a solubilizer and an aqueous phase, at the mixture ratio of 5%/1%/9%/5%/80% (w/w), respectively, the O/W microemulsion with an average particle diameter of 20 nm or less was prepared. Moreover, for nine kinds of poorly water soluble compounds, such as Ibuprofen, Ketoprofen, Tamoxifen, Testosterone, Tolbutamide and other new compounds, the solubility to water was increased from 60 to 20,000 times by this O/W microemulsion formulation. The AUCs in plasma concentration of Ibuprofen and a new compound, ER-1039, following single oral administration of these compounds as the O/W microemulsion to fasted rats were equivalent to that of solution administration or increased by nine and two times that of suspension administration, respectively. Accordingly, this novel O/W microemulsion is a useful formulation, which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds.

  11. Drug incorporation and release of water soluble drugs from novel functionalized poly(glycerol adipate) nanoparticles.

    PubMed

    Puri, Sanyogita; Kallinteri, Paraskevi; Higgins, Sean; Hutcheon, Gillian A; Garnett, Martin C

    2008-01-04

    We have previously demonstrated the ability of poly(glycerol adipate) backbone (PGA) and PGA polymer backbone substituted with varying amounts of pendant C(18) chain length acyl groups to yield Dexamethasone phosphate DXMP loaded nanoparticles. The aim of this study was to obtain a deeper understanding of the underlying principles responsible for good drug incorporation and controlled release of drugs from poly (glycerol adipate) (PGA) nanoparticles. We compared the incorporation of the water soluble drugs DXMP and Cytosine arabinoside (CYT-ARA) in both unmodified and substituted PGA polymers. We investigated the effect of change in acyl group chain length and the degree of substitution on the physicochemical properties, drug loading and release of DXMP and CYT-ARA. Nanoparticles were prepared by the interfacial deposition technique and the simultaneous emulsification method. Amongst the nanoparticles prepared using acylated polymers with varying chain lengths (C(2) to C(10)) for DXMP incorporation, polymers with acyl group chain lengths containing 8 carbon atoms (C(8)) showed maximum drug incorporation. Amongst the C(8) series, polymers with 100% acylation provided both good drug incorporation and a controlled release for DXMP while for CYT-ARA it was the unsubstituted polymer backbone that had maximum drug loading and slower release. A number of inter-related factors are responsible for producing particles with particular size, zeta potential, drug loading and release characteristics. Drug loading and release from nanoparticles are primarily influenced by the nature of interactions between the drug and polymers which in turn depend upon the type of drug used and the physical chemistry of the polymer.

  12. Direct encapsulation of water-soluble drug into silica microcapsules for sustained release applications

    SciTech Connect

    Wang Jiexin; Wang Zhihui; Chen Jianfeng Yun, Jimmy

    2008-12-01

    Direct encapsulation of water-soluble drug into silica microcapsules was facilely achieved by a sol-gel process of tetraethoxysilane (TEOS) in W/O emulsion with hydrochloric acid (HCl) aqueous solution containing Tween 80 and drug as well as cyclohexane solution containing Span 80. Two water-soluble drugs of gentamicin sulphate (GS) and salbutamol sulphate (SS) were chosen as model drugs. The characterization of drug encapsulated silica microcapsules by scanning electronic microscopy (SEM), FTIR, thermogravimetry (TG) and N{sub 2} adsorption-desorption analyses indicated that drug was successfully entrapped into silica microcapsules. The as-prepared silica microcapsules were uniform spherical particles with hollow structure, good dispersion and a size of 5-10 {mu}m, and had a specific surface area of about 306 m{sup 2}/g. UV-vis and thermogravimetry (TG) analyses were performed to determine the amount of drug encapsulated in the microcapsules. The BJH pore size distribution (PSD) of silica microcapsules before and after removing drug was examined. In vitro release behavior of drug in simulated body fluid (SBF) revealed that such system exhibited excellent sustained release properties.

  13. A predictive model for the release of slightly water-soluble drugs from HPMC matrices.

    PubMed

    Fu, X C; Wang, G P; Wang, Y H; Liang, W Q

    2004-08-01

    A model to predict the fraction of slightly water-soluble drug released as a function of release time (t, h), HPMC concentration (C(H), w/w), drug solubility in distilled water at 37 degrees C (C(s), g/100 mL), and volume of drug molecule (V, nm3) was derived when theophyline, tinidazole, and propylthiouracil were selected as model drugs. The model is log (M(t)/M(infinity)) = 0.8683 logt-0.1930C(s) logt + 0.5406V logt-1.227C(H) + 0.1594C(s) + 0.4423C(H)C(s) - 0.8655 (n = 130, r = 0.9969), where Mt is the amount of drug released at time t, Minfinity is the amount of drug released over a very long time, which corresponds in principle to the initial loading, n is the number of samples, and r is the correlation coefficient. The model was validated using sulfamethoxazole and satisfactory results were obtained. The model can be used to predict the release fraction of variousslightly water-soluble drugs from HPMC matrices having different polymer levels.

  14. 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.

  15. A mathematical model to predict the release of water-soluble drugs from HPMC matrices.

    PubMed

    Fu, X C; Wang, G P; Fu, C Y; Liang, W Q

    2004-09-01

    A mathematical model to predict the fraction of water-soluble drug released as a function of release time (t, h), HPMC concentration (CH, w/w), and volume of drug molecule (V, nm3) was derived with ranitidine hydrochloride, diltiazem hydrochloride, and ribavirin as model drugs. The model is log (M(t)/M(infinity)) = 0.5 log t-0.3322CH-0.2222V-0.2988 (n = 140, r = 0.9848), where M(t) is the amount of drug released at time t, M(infinity) is the amount of drug released over a very long time, which corresponds in principle to the initial loading, n is the number of samples, and r is the correlation coefficient. The model was validated using isoniazid and satisfactory results were obtained. The model can be used to predict the release fraction of various soluble drugs from HPMC matrices having different polymer levels.

  16. Enhanced bioavailability of a poorly water-soluble weakly basic compound using a combination approach of solubilization agents and precipitation inhibitors: a case study.

    PubMed

    Li, Shu; Pollock-Dove, Crystal; Dong, Liang C; Chen, Jing; Creasey, Abla A; Dai, Wei-Guo

    2012-05-07

    Poorly water-soluble weakly basic compounds which are solubilized in gastric fluid are likely to precipitate after the solution empties from the stomach into the small intestine, leading to a low oral bioavailability. In this study, we reported an approach of combining solubilization agents and precipitation inhibitors to produce a supersaturated drug concentration and to prolong such a drug concentration for an extended period of time for an optimal absorption, thereby improving oral bioavailability of poorly water-soluble drugs. A weakly basic compound from Johnson and Johnson Pharmaceutical Research and Development was used as a model compound. A parallel microscreening precipitation method using 96-well plates and a TECAN robot was used to assess the precipitation of the tested compound in the simulated gastric fluid (SGF) and the simulated intestinal fluid (SIF), respectively, for lead solubilizing agents and precipitation inhibitors. The precipitation screening results showed vitamin E TPGS was an effective solubilizing agent and Pluronic F127 was a potent precipitation inhibitor for the tested compound. Interestingly, the combination of Pluronic F127 with vitamin E TPGS resulted in a synergistic effect in prolonging compound concentration upon dilution in SIF. In addition, HPMC E5 and Eudragit L100-55 were found to be effective precipitation inhibitors for the tested compounds in SGF. Furthermore, optimization DOE study results suggested a formulation sweet spot comprising HPMC, Eudragit L 100-55, vitamin E TPGS, and Pluronic F127. The lead formulation maintained the tested compound concentration at 300 μg/mL upon dilution in SIF, and more than 70% of the compound remained solubilized compared with the compound alone at <1 μg/mL of its concentration. Dosing of the solid dosage form predissolved in SGF in dogs resulted in 52% of oral bioavailability compared to 26% for the suspension control, a statistically significant increase (p = 0.002). The enhanced

  17. 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.

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

    PubMed

    Hayashi, Nobuyuki; Jin, Shigeki; Ujihara, Tomomi

    2012-11-02

    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.

  19. Investigation of preparation parameters of nanosuspension by top-down media milling to improve the dissolution of poorly water-soluble glyburide.

    PubMed

    Singh, Sachin Kumar; Srinivasan, K K; Gowthamarajan, K; Singare, Dhananjay S; Prakash, Dev; Gaikwad, Narayan Babulal

    2011-08-01

    The objective of this study was to identify and optimize formulation and process variables affecting characteristic and scale-up of nanosuspension manufacturing process on bead mill considering industrial perspective. Formulation factors evaluated were ratio of polymer to drug and ratio of surfactant to drug, whereas process parameters were milling time and milling speed. Responses measured in this study include zeta potential and mean particle size d(90). The test revealed that ratio of polymer to drug and milling speed have significant effect on zeta potential whereas milling time and milling speed have significant effect on the particle size distribution of nanosuspension. The X-ray powder diffraction pattern of drug milled at high and low speed reveals no form conversion when compared with unmilled drug. The formulated nanosuspension has shown a faster dissolution profile (98.97% in 10 min), relative to that of raw glyburide (18.17% in 10 min), mainly due to the formation of nanosized particles. The ANOVA test revealed that there was no significant difference in the dissolution profiles of fresh and aged nanosuspension. These results indicate the suitability of formulation procedure for preparation of nanosized poorly water-soluble drug with significantly improved in vitro dissolution rate and thus possibly enhance fast onset of therapeutic drug effect.

  20. Improved intestinal absorption of water-soluble drugs by acetylation of G2 PAMAM dendrimer nanocomplexes in rat.

    PubMed

    Yan, Chengyun; Gu, Jiwei; Lv, Yuguang; Shi, Weiguo; Jing, Hongying

    2017-03-16

    In search of an effective and less toxic absorption enhancer, we synthesized primary amine acetylation of generation 2 polyamidoamine (G2 PAMAM) dendrimer (Ac-G2) by the reaction of G2 PAMAM dendrimer with acetic anhydride, and evaluated the effects of Ac-G2 on the intestinal absorption of poorly absorbable water-soluble drugs using an in situ closed-loop method in rats. The results indicated that Ac50-G2 had a greatest absorption enhancing effect for 5(6)-carboxyfluorescein (CF) in various acetylation levels of G2 PAMAM dendrimers. Ac50-G2 with various concentrations (0.1-1.0%, w/v) could significantly improve the intestinal absorption of alendronate, CF, and fluorescein isothiocyanate-labeled dextrans (FD4), although they did not enhance the absorption of macromolecular drug of FD10, and the absorption enhancement effect of Ac50-G2 was concentration-dependent. Furthermore, we examined the intestinal membrane damage with or without Ac50-G2. The results displayed Ac50-G2 at lower concentrations (0.1-0.5%, w/v) did not cause any observed toxic effect to the intestinal membranes. These findings suggested Ac50-G2 at lower concentrations (below 0.5%, w/v) might be promising as an effective and safe absorption enhancers to promote the intestinal absorption of poorly absorbable drugs.

  1. 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

  2. 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

  3. Gold nanoparticles as scaffolds for poor water soluble and difficult to vehiculate antiparkinson codrugs

    NASA Astrophysics Data System (ADS)

    Di Crescenzo, A.; Cacciatore, I.; Petrini, M.; D'Alessandro, M.; Petragnani, N.; Del Boccio, P.; Di Profio, P.; Boncompagni, S.; Spoto, G.; Turkez, H.; Ballerini, P.; Di Stefano, A.; Fontana, A.

    2017-01-01

    We report the facile and non-covalent preparation of gold nanoparticles (AuNPs) stabilized by an antiparkinson codrug based on lipoic acid (LA). The obtained AuNPs appear stable in both dimethyl sulfoxide and fetal bovine serum and able to load an amount of codrug double the weight of gold. These NPs were demonstrated to be safe and biocompatible towards primary human blood cells and human neuroblastoma cells, one of the most widely used cellular models to study dopaminergic neural cells, therefore are ideal drug carriers for difficult to solubilize molecules. Very interestingly, the codrug-stabilized AuNPs were shown to reduce the accumulation of reactive oxygen species in SH-SY5Y cells treated with LD and did not change total oxidant status levels in cultured human blood cells, thus confirming the antioxidant role of LA although bound to AuNPs. The characterization of AuNPs in terms of loading and stability paves the way for their use in biomedical and pharmacological applications.

  4. Nanoemulsion-based delivery systems for poorly water-soluble bioactive compounds: Influence of formulation parameters on Polymethoxyflavone crystallization

    PubMed Central

    Li, Yan; Zheng, Jinkai; Xiao, Hang; McClements, David Julian

    2012-01-01

    Polymethoxyflavones (PMFs) extracted from citrus peel exhibit potent anti-cancer activity, but are highly hydrophobic molecules with poor solubility in both water and oil at ambient and body temperature, which limits their bioavailability. The possibility of encapsulating PMFs within nanoemulsion-based delivery systems to facilitate their application in nutraceutical and pharmaceutical products was investigated. The influence of oil type (corn oil, MCT, orange oil), emulsifier type (β-lactoglobulin, lyso-lecithin, Tween, and DTAB), and neutral cosolvents (glycerol and ethanol) on the formation and stability of PMF-loaded nanoemulsions was examined. Nanoemulsions (r < 100 nm) could be formed using high pressure homogenization for all emulsifier types, except DTAB. Lipid droplet charge could be altered from highly cationic (DTAB), to near neutral (Tween), to highly anionic (β-lactoglobulin, lyso-lecithin) by varying emulsifier type. PMF crystals formed in all nanoemulsions after preparation, which had a tendency to sediment during storage. The size, morphology, and aggregation of PMF crystals depended on preparation method, emulsifier type, oil type, and cosolvent addition. These results have important implications for the development of delivery systems for bioactive components that have poor oil and water solubility at application temperatures. PMID:22685367

  5. 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.

  6. A fibrin encapsulated liposomes-in-chitosan matrix (FLCM) for delivering water-soluble drugs. Influences of the surface properties of liposomes and the crosslinked fibrin network.

    PubMed

    Chung, Tze-Wen; Yang, Min-Chia; Tsai, Wei-Jean

    2006-03-27

    A depot drug delivery system, fibrin encapsulated liposome-in-chitosan matrix (FLCM), has been developed to deliver a water-soluble drug which is configured by a porous chitosan matrix containing a bovine fibrin network encapsulated different surface properties of liposomes. Quinacrine (QR), a water-soluble, low-molecular weight fluorescent marker, is used as a model drug to evaluate the delivery characteristics of the system. The SEM photographs show that the fibrin network adheres to the surfaces and pores of the chitosan matrix of a FLCM system. The QR release periods of the FLCM are sustained for about four times longer than those of QR encapsulated into the liposomes. However, the QR release periods and profiles of the FLCM are influenced by the surface properties of liposomes. The release of QR from FLCM is sustained for 9 days for neutral liposomes and only 5 days for PEG modified liposomes (PEG-liposome). After crosslinking the fibrin network of the FLCM with 0.5% of glutaldehyde, the release of QR is further sustained for 17 days with good linear profiles (e.g., 13 days) and with 50% of reduced burst release compared with those of without crosslinking, indicating that the stability of the fibrin network plays an important role on QR release of the system. More interestingly, the release periods and profiles of QR of the FLCM system are highly similar to those of Tirofiban, low-molecular weight of a water-soluble clinical cardiovascular drug, although the study has been done by human platelet poor plasma instead of bovine fibrinogen as a source of fibrin network. It suggests that the QR is a suitable model for investigating the drug delivery behaviors for water-soluble, low-molecular weight drugs of the FLCM. In conclusion, with QR as a model drug, FLCM with crosslinked fibrin network can effectively sustain the release of QR for 17 days but the release profiles are influenced by the surface properties of encapsulated liposomes. This study suggests that

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

    PubMed

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

    2014-06-01

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

  8. Drug carrier systems based on water-soluble cationic beta-cyclodextrin polymers.

    PubMed

    Li, Jianshu; Xiao, Huining; Li, Jiehua; Zhong, YinPing

    2004-07-08

    This study was designed to synthesize, characterize and investigate the drug inclusion property of a series of novel cationic beta-cyclodextrin polymers (CPbetaCDs). Proposed water-soluble polymers were synthesized from beta-cyclodextrin (beta-CD), epichlorohydrin (EP) and choline chloride (CC) through a one-step polymerization procedure by varying molar ratio of EP and CC to beta-CD. Physicochemical properties of the polymers were characterized with colloidal titration, nuclear magnetic resonance spectroscopy (NMR), gel permeation chromatography (GPC) and aqueous solubility determination. The formation of naproxen/CPbetaCDs inclusion complexes was confirmed by NMR and fourier transform infrared spectroscopy (FT-IR). Cationic beta-CD polymers showed better hemolytic activities than parent beta-CD and neutral beta-CD polymer in hemolysis test. The morphological study of erythrocytes revealed a cell membrane invagination induced by the cationic groups. The effects of molecular weight and charge density of the polymers on their inclusion and release performance of naproxen were also investigated through phase-solubility and dissolution studies. It was found that the cationic beta-CD polymers with high molecular weight or low charge density exhibited better drug inclusion and dissolution abilities.

  9. 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

  10. Reverse micelle-based water-soluble nanoparticles for simultaneous bioimaging and drug delivery.

    PubMed

    Chen, Ying; Liu, Yong; Yao, Yongchao; Zhang, Shiyong; Gu, Zhongwei

    2017-03-22

    With special confined water pools, reverse micelles (RMs) have shown potential for a wide range of applications. However, the inherent water-insolubility of RMs hinders their further application prospects, especially for applications related to biology. We recently reported the first successful transfer of RMs from organic media to an aqueous phase without changing the smart water pools by the hydrolysis of an arm-cleavable interfacial cross-linked reverse micelles. Herein, we employed another elaborate amphiphile 1 to construct new acrylamide-based cross-linked water-soluble nanoparticles (ACW-NPs) under much gentler conditions. The special property of the water pools of the ACW-NPs was confirmed by both the Förster resonance energy transfer (FRET) between 5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid (1,5-EDANS) and benzoic acid, 4-[2-[4-(dimethylamino)phenyl]diazenyl] (DABCYL) and satisfactory colloidal stability in 10% fetal bovine serum. Importantly, featured by the gentle synthetic strategy, confined water pool, and carboxylic acid-functionalized surface, the new ACW-NPs are well suitable for biological applications. As an example, the fluorescent reagent 8-hydroxy-1,3,6-pyrenetrisulfonic acid trisodium salt (HPTS) was encapsulated in the core and simultaneously, the anticancer drug gemcitabine (Gem) was covalently conjugated onto the surface exterior. As expected, the resulting multifunctional ACW-NPs@HPTS@Gem exhibits a high imaging effect and anticancer activity for non-small lung cancer cells.

  11. 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.

  12. Role of glucose transporters in the intestinal absorption of gastrodin, a highly water-soluble drug with good oral bioavailability.

    PubMed

    Cai, Zheng; Huang, Juan; Luo, Hui; Lei, Xiaolu; Yang, Zhaoxiang; Mai, Yang; Liu, Zhongqiu

    2013-07-01

    Gastrodin, a sedative drug, is a highly water-soluble phenolic glucoside with poor liposolubility but exhibits good oral bioavailability. The current study aims to investigate whether glucose transporters (GLTs) are involved in the intestinal absorption of gastrodin. The intestinal absorption kinetics of gastrodin was determined using the rat everted gut sac model, the Caco-2 cell culture model and the perfused rat intestinal model. In vivo pharmacokinetic studies using diabetic rats with high GLT expression were performed. Saturable intestinal absorption of gastrodin was observed in rat everted gut sacs. The apparent permeability (Papp) of gastrodin from the apical (A) to basolateral (B) side in Caco-2 cells was two-fold higher than that from B to A. Glucose or phlorizin, a sodium-dependent GLT (SGLT) inhibitor, reduced the absorption rates of gastrodin from perfused rat intestines. In vivo pharmacokinetic studies showed that the time of maximum plasma gastrodin concentration (Tmax) was prolonged from 28 to 72 min when orally co-administered with four times higher dose of glucose. However, the Tmax of gastrodin in diabetic rats was significantly lowered to 20 min because of the high intestinal SGLT1 level. In conclusion, our findings indicate that SGLT1 can facilitate the intestinal absorption of gastrodin.

  13. 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

  14. Film-coated matrix mini-tablets for the extended release of a water-soluble drug.

    PubMed

    Mohamed, Faiezah A A; Roberts, Matthew; Seton, Linda; Ford, James L; Levina, Marina; Rajabi-Siahboomi, Ali R

    2015-04-01

    Extended release (ER) of water-soluble drugs from hydroxypropylmethylcellulose (HPMC) matrix mini-tablets (mini-matrices) is difficult to achieve due to the large surface area to volume ratio of the mini matrices. Therefore, the aims of this study were to control the release of a water-soluble drug (theophylline) from mini-matrices by applying ER ethylcellulose film coating (Surelease®), and to assess the effects of Surelease®:pore former (Opadry®) ratio and coating load on release rates. Mini-matrices containing 40%w/w HPMC K100M CR were coated with 100:0, 85:15, 80:20, 75:25 or 70:30 Surelease®:Opadry® to different coating weight gains (6-20%). Non-matrix mini-tablets were also produced and coated with 80:20 Surelease®:Opadry® to different coating weight gains. At low coating weight gains, nonmatrix mini-tablets released the entire drug within 0.5 h, while at high coating weight gains only a very small amount (<5%) of drug was released after 12 h. The gel formation of HPMC prevented disintegration of mini-matrices at low coating weight gains but contributed to rupture of the film even at high coating weight gains. As a result, drug release from mini-matrices was slower than that from nonmatrix mini-tablets at low coating weight gains, yet faster at high coating weight gains. An increase in the lag time of drug release from mini-matrices was observed as the concentration of Opadry® reduced or the coating weight gain increased. This study has demonstrated the possibility of extending the release of a water-soluble drug from HPMC mini-matrices by applying ER film coating with appropriate levels of pore former and coating weight gains to tailor the release rate.

  15. 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.

  16. Chitosan citrate as film former: compatibility with water-soluble anionic dyes and drug dissolution from coated tablet.

    PubMed

    Phaechamud, T; Koizumi, T; Ritthidej, G C

    2000-03-30

    Chitosan citrate solution containing 25% w/w propylene glycol was prepared and tested for its compatibility with some water soluble anionic dyes. The immiscibility between erythrosine, ponceau 4R, sunset yellow or tartrazine solutions and chitosan citrate solution was evident. The Fourier transform-infrared spectra revealed charged interaction between anionic dye and chitosan. Brilliant blue and green FS at concentration of 0.02-1.00% w/w polymer could be miscible with chitosan citrate solution due to the decrease in charge interaction by the positive charge on molecule of brilliant blue, which was also the composition in green FS. Propranolol HCl tablets coated with these colored film-coating solutions exhibited good appearance and no color migration. Drug dissolution from coated tablets was pH dependent, corresponding to the ability of chitosan to protonate in the medium. Color incorporation slightly retarded drug dissolution in acidic medium. Drug dissolved from coated tablet colored with brilliant blue was faster than from that colored with green FS. This was because brilliant blue had positive charge and more SO(3)H groups on its molecular structure, and exhibited higher water solubility. Accelerated condition could alter dissolution characteristics, and the Td+t(0) value from curve fitting between the dissolution profiles and Weibull equation was increased. However, drug dissolution from freshly prepared coated tablets, coated tablets after exposure to accelerated condition and after storage at room temperature for 12 months conformed to the monograph in USP XXIII.

  17. Pectin/anhydrous dibasic calcium phosphate matrix tablets for in vitro controlled release of water-soluble drug.

    PubMed

    Mamani, Pseidy Luz; Ruiz-Caro, Roberto; Veiga, María Dolores

    2015-10-15

    Different pectin/anhydrous dibasic calcium phosphate (ADCP) matrix tablets have been developed in order to obtain controlled release of a water-soluble drug (theophylline). Swelling, buoyancy and dissolution studies have been carried out in different aqueous media (demineralized water, progressive pH medium, simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid), to characterize the matrix tablets. When the pectin/ADCP ratio was ≥0.26 (P1, P2, P3 and P4 tablets) a continuous swelling and low theophylline dissolution rate from the matrices were observed. So, pectin gel forming feature predominated over the ADCP properties, yielding pH-independent drug release behavior from these matrices. On the contrary, pectin/ADCP ratios ≤0.11 (P5 and P6 tablets) allowed to achieve drug dissolution pH dependent. Consequently, the suitable selection of the pectin/ADCP ratio will allow to tailor matrix tablets for controlled release of water-soluble drugs in a specific manner in the gastrointestinal tract.

  18. 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.

  19. 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.

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

    PubMed

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

    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.

  1. 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

  2. Sustained release of a water-soluble drug from alginate matrix tablets prepared by wet granulation method.

    PubMed

    Mandal, Sanchita; Basu, Sanat Kumar; Sa, Biswanath

    2009-01-01

    Alginate matrix tablet of diltiazem hydrochloride (DTZ), a water-soluble drug, was prepared using sodium alginate (SAL) and calcium gluconate (CG) by the conventional wet granulation method for sustained release of the drug. The effect of formulation variables like SAL/CG ratio, drug load, microenvironmental pH modulator, and processing variable like compression force on the extent of drug release was examined. The tablets prepared with 1:2 w/w ratio of SAL/CG produced the most sustained release of the drug extending up to 13.5 h. Above and below this ratio, the drug release was faster. The drug load and the hardness of the tablets produced minimal variation in drug release. The addition of alkaline or acidic microenvironmental modulators did not extend the release; instead, these excipients produced somewhat faster release of diltiazem. This study revealed that proper selection of SAL/CG ratio is important to produce alginate matrix tablet by wet granulation method for sustained release of DTZ.

  3. Synthesis and Anchoring of Antineoplastic Ferrocene and Phthalocyanine Derivatives on Water-Soluble Polymeric Drug Carriers Derived from Lysine and Aspartic Acid

    PubMed Central

    Maree, M. David; Neuse, Eberhard W.; Erasmus, Elizabeth; Swarts, Jannie C.

    2008-01-01

    The general synthetic strategy towards water-soluble biodegradable drug carriers and the properties that they must have are discussed. The syntheses of water-soluble biodegradable copolymers of lysine and aspartic acid as potential drug-delivering devices, having amine-functionalised side chains are then described. Covalent anchoring of carboxylic acid derivatives of the antineoplastic ferrocene and photodynamically active phthalocyanine moieties to the amine-containing drug carrier copolymers under mild coupling conditions has been achieved utilising the coupling reagent O-benzotriazolyl-N,N,N′,N′-tetramethyluronium hexafluorophosphate to promote formation of the biodegradable amide bond. Even though the parent antineoplastic ferrocene and phthalocyanine derivatives are themselves insoluble in water at pH < 7, the new carrier-drug conjugates that were obtained are well water-soluble. PMID:18288243

  4. Floating elementary osmotic pump tablet (FEOPT) for controlled delivery of diethylcarbamazine citrate: a water-soluble drug.

    PubMed

    Khan, Zulfequar Ahamad; Tripathi, Rahul; Mishra, Brahmeshwar

    2011-12-01

    The present work investigates the feasibility of the design of a novel floating elementary osmotic pump tablet (FEOPT) to prolong the gastric residence of a highly water-soluble drug. Diethylcarbamazine citrate (DEC) was chosen as a model drug. The FEOPT consisted of an osmotic core (DEC, mannitol, and hydrophilic polymers) coated with a semipermeable layer (cellulose acetate) and a gas-generating gelling layer (sodium bicarbonate, hydrophilic polymers) followed by a polymeric film (Eudragit RL 30D). The effect of formulation variables such as concentration of polymers, types of diluent, and coat thickness of semipermeable membrane was evaluated in terms of physical parameters, floating lag time, duration of floatation, and in vitro drug release. The Fourier transform infrared and X-ray diffraction analysis were carried out to study the physicochemical changes in the drug excipients powder blend. The integrity of the orifice and polymeric film layer was confirmed from scanning electron microscopy image. All the developed FEOPT showed floating lag time of less than 8 min and floating duration of 24 h. A zero-order drug release could be attained for DEC. The formulations were found to be stable up to 3 months of stability testing at 40°C/75% relative humidity.

  5. Tunable release of multiclass anti-HIV drugs that are water-soluble and loaded at high drug content in polyester blended electrospun fibers

    PubMed Central

    Carson, Daniel; Jiang, Yonghou; Woodrow, Kim

    2015-01-01

    Objectives Sustained release of small molecule hydrophilic drugs at high doses remains difficult to achieve from electrospun fibers and limits their use in clinical applications. Here we investigate tunable release of several water-soluble anti-HIV drugs from electrospun fibers fabricated with blends of two biodegradable polyesters. Methods Drug-loaded fibers were fabricated by electrospinning using ratios of PCL and PLGA. Fiber morphology was imaged using SEM, and DSC was used to measure thermal properties. HPLC was used to measure drug loading and release from fibers. Cytotoxicity and antiviral activity of drug-loaded fibers were measured in an in vitro cell culture assay. Results We show programmable release of hydrophilic antiretroviral drugs loaded up to 40 wt%. Incremental tuning of highly-loaded drug fibers within 24 hours or >30 days was achieved by controlling the ratio of PCL and PLGA. Fiber compositions containing higher PCL content yielded greater burst release whereas fibers with higher PLGA content resulted in greater sustained release kinetics. We also demonstrated that our drug-loaded fibers are safe and can sustain inhibition of HIV in vitro. Conclusions These data suggest that we were able to overcome current limitations associated with sustained release of small hydrophilic drugs at clinically relevant doses. We expect that our system represents an effective strategy to sustain delivery of water-soluble molecules that will benefit a variety of biomedical applications. PMID:26286184

  6. Water-soluble polymer–drug conjugates for combination chemotherapy against visceral leishmaniasis

    PubMed Central

    Nicoletti, Salvatore; Seifert, Karin; Gilbert, Ian H.

    2010-01-01

    There is a need for new safe, effective and short-course treatments for leishmaniasis; one strategy is to use combination chemotherapy. Polymer–drug conjugates have shown promise for the delivery of anti-leishmanial agents such as amphotericin B. In this paper, we report on the preparation and biological evaluation of polymer–drug conjugates of N-(2-hydroxypropyl)methacrylamide (HPMA), amphotericin B and alendronic acid. The combinatorial polymer–drug conjugates were effective anti-leishmanial agents in vitro and in vivo, but offered no advantage over the single poly(HPMA)–amphotericin B conjugates. PMID:20338769

  7. Multistimuli-responsive supramolecular vesicles based on water-soluble pillar[6]arene and SAINT complexation for controllable drug release.

    PubMed

    Cao, Yu; Hu, Xiao-Yu; Li, Yan; Zou, Xiaochun; Xiong, Shuhan; Lin, Chen; Shen, Ying-Zhong; Wang, Leyong

    2014-07-30

    Supramolecular binary vesicles based on the host-guest complexation of water-soluble pillar[6]arene (WP6) and SAINT molecule have been successfully constructed, which showed pH-, Ca(2+)-, and thermal-responsiveness. These supramolecular vesicles can efficiently encapsulate model substrate calcein, which then can be efficiently released either by adjusting the solution pH to acidic condition due to the complete disruption of vesicular structure, or particularly, by adding a certain amount of Ca(2+) due to the Ca(2+)-induced vesicle fusion and accompanied by the structure disruption. More importantly, drug loading and releasing experiments demonstrate that an anticancer drug, DOX, can be successfully encapsulated by the supramolecular vesicles, and the resulting DOX-loaded vesicles exhibit efficient release of the encapsulated DOX with the pH adjustment or the introduction of Ca(2+). Cytotoxicity experiments suggest that the resulting DOX-loaded supramolecular vesicles exhibit comparable therapeutic effect for cancer cells as free DOX and the remarkably reduced damage for normal cells as well. The present multistimuli-responsive supramolecular vesicles have great potential applications in the field of controlled drug delivery. In addition, giant supramolecular vesicles (~3 μm) with large internal volume and good stability can be achieved by increasing the temperature of WP6 ⊃ SAINT vesicular solution, and they might have potential applications for bioimaging.

  8. 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

  9. Solubilization and preformulation of poorly water soluble and hydrolysis susceptible N-epoxymethyl-1,8-naphthalimide (ENA) compound.

    PubMed

    Dong, Yuancai; Ng, Wai Kiong; Surana, Uttam; Tan, Reginald B H

    2008-05-22

    N-Epoxymethyl-1,8-naphthalimide (ENA) is a novel antiproliferative drug candidate with potent anticancer and antifungal activity. It has an aqueous solubility of 0.0116mg/mL and also exhibits hydrolytic instability with a first-order hydrolysis rate of 0.051 h(-1). The present preformulation study aimed to characterize the physicochemical properties of ENA and develop an early injectable solution formulation for preclinical studies. To minimize hydrolysis, ENA is proposed to be formulated as either lyophilized powders or nonaqueous solutions followed by solubilization/reconstitution prior to administration. ENA solubilization was investigated in both aqueous media (by cosolvency, micellization and complexation) and nonaqueous solutions (mixture of Cremophor EL and ethanol). It is found that none of the solubilization techniques in aqueous media could increase ENA solubility to a desired level of several hundreds microg/mL at pharmaceutically acceptable excipient concentrations (< or =10%). In contrast, a combination of 70% Cremophor EL and 30% ethanol (v/v) proved effective in solubilizing ENA at 4 mg/mL, which exhibited good physical and chemical stability on storage at both 4 degrees C and room temperature over 4 months. No precipitation was observed upon 5-20 times dilution by the saline; in addition, less than 5% of ENA was hydrolyzed in 4h for the saline-diluted aqueous solutions. This nonaqueous ENA formulation is thus proposed for further preclinical studies, which can be reconstituted, prior to administration, by the 5-20 times infusion fluids (saline, 5% dextrose, etc.) to the desired drug dosing concentration at the acceptable excipient level. The approach used in this work could serve as a useful reference in formulating nonpolar drugs with hydrolytic instability.

  10. 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

  11. Water-soluble drug partitioning and adsorption in HEMA/MAA hydrogels.

    PubMed

    Dursch, Thomas J; Taylor, Nicole O; Liu, David E; Wu, Rong Y; Prausnitz, John M; Radke, Clayton J

    2014-01-01

    Two-photon confocal microscopy and back extraction with UV/Vis-absorption spectrophotometry quantify equilibrium partition coefficients, k, for six prototypical drugs in five soft-contact-lens-material hydrogels over a range of water contents from 40 to 92%. Partition coefficients were obtained for acetazolamide, caffeine, hydrocortisone, Oregon Green 488, sodium fluorescein, and theophylline in 2-hydroxyethyl methacrylate/methacrylic acid (HEMA/MAA, pKa≈5.2) copolymer hydrogels as functions of composition, aqueous pH (2 and 7.4), and salinity. At pH 2, the hydrogels are nonionic, whereas at pH 7.4, hydrogels are anionic due to MAA ionization. Solute adsorption on and nonspecific electrostatic interaction with the polymer matrix are pronounced. To express deviation from ideal partitioning, we define an enhancement or exclusion factor, E ≡ k/φ1, where φ1 is hydrogel water volume fraction. All solutes exhibit E > 1 in 100 wt % HEMA hydrogels owing to strong specific adsorption to HEMA strands. For all solutes, E significantly decreases upon incorporation of anionic MAA into the hydrogel due to lack of adsorption onto charged MAA moieties. For dianionic sodium fluorescein and Oregon Green 488, and partially ionized monoanionic acetazolamide at pH 7.4, however, the decrease in E is more severe than that for similar-sized nonionic solutes. Conversely, at pH 2, E generally increases with addition of the nonionic MAA copolymer due to strong preferential adsorption to the uncharged carboxylic-acid group of MAA. For all cases, we quantitatively predict enhancement factors for the six drugs using only independently obtained parameters. In dilute solution for solute i, Ei is conveniently expressed as a product of individual enhancement factors for size exclusion (Ei(ex)), electrostatic interaction (Ei(el)), and specific adsorption (Ei(ad)):Ei≡Ei(ex)Ei(el)Ei(ad). To obtain the individual enhancement factors, we employ an extended Ogston mesh-size distribution for Ei

  12. 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.

  13. 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

  14. Water Soluble Polymer Films for Intravascular Drug Delivery of Antithrombotic Biomolecules

    PubMed Central

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

    2012-01-01

    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 two minutes. DS-SILY, up to 6.26 μg/cm2, 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

  15. 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.

  16. Synthesis of silica nanoparticles for encapsulation of oncology drugs with low water solubility: effect of processing parameters on structural evolution

    NASA Astrophysics Data System (ADS)

    Bürglová, Kristýna; Hlaváč, Jan; Bartlett, John R.

    2015-12-01

    Silica nanoparticles with tailored properties have been developed for a variety of biomedical applications, with particular emphasis on their use as carriers for the encapsulation and controlled release of bioactive species. Among the various strategies described, silica nanoparticles with uniform mesoporosity (MSN) prepared in aqueous solution at elevated temperatures using cetyltrimethylammonium bromide as a template have a range of desirable properties. However, the processing windows available to control the dimensions and other key properties of such nanoparticles prepared using fluoride salts as catalysts have not been elucidated, with mixed products containing gel fragments and non-uniform products obtained under many conditions. Here, we present a parametric study of the synthesis of MSN under fluoride-catalysed conditions using tetraethylorthosilicate as silica precursor. The processing conditions required to produce uniform nanoparticles with controlled dimensions are elucidated, together with the conditions under which dried powders can be re-dispersed in aqueous solution after long-term storage to regenerate unaggregated nanospheres with dimensions (as measured by dynamic light scattering) comparable to those measured via scanning electron microscopy analysis of the dried material. The ability to dry and store such powders for extended periods of time is an important requirement for the use of such materials in drug delivery applications. Preliminary results demonstrating the use of such MSNs as hosts for oncology drugs [substituted 3-hydroxyquinolinones ( 3-HQ)] with low water solubility (≪1 µg/g H2O) are presented, with loadings of several wt% demonstrated. The ability of the silica host to protect the 3-HQ from oxidative degradation during impregnation and release is discussed.

  17. Double-walled microspheres for the sustained release of a highly water soluble drug: characterization and irradiation studies.

    PubMed

    Lee, Teng Huar; Wang, Jianjun; Wang, Chi-Hwa

    2002-10-30

    Composite double-walled microspheres with biodegradable poly(L-lactic acid) (PLLA) shells and poly(D,L-lactic-co-glycolic acid) (PLGA) cores were fabricated with highly water-soluble etanidazole entrapped within the core as solid crystals. This paper discusses the characterization, in vitro release and the effects of irradiation on this class of microsphere. Through the variation of polymer mass ratios, predictable shell and core dimensions could be fabricated and used to regulate the release rates. A direct and simple method was devised to determine the composition of the shell and core polymer based on the different solubilities of the polymer pair in ethyl acetate. A distribution theory based on solubility parameter explains why highly hydrophilic etanidazole has the tendency to be distributed consistently to the more hydrophilic polymer. Release profiles for normal double-walled samples have about 80% of drug released over 10 days after the initial time lag, while for irradiated double-walled samples, the sustained release lasted for more than 3 weeks. Although sustained release was short of the desired 6-8 weeks required for therapy, a low initial burst of less than 5% and time lags that can be manipulated, allows for administration of these microspheres together with traditional ones to generate pulsatile or new type of releases. The effects of irradiation were also investigated to determine the suitability of these double-walled microspheres as delivery devices to be used in conjunction with radiotherapy. Typical therapeutic dosage of 50 Gy was found to be too mild to have noticeable effects on the polymer and its release profiles, while, sterilization dosages of 25 kGy, lowered the glass transition temperatures and crystalline melting point, indirectly indicating a decrease in molecular weight. This accelerated degradation of the polymer, hence releasing the drug.

  18. Preparation of amorphous solid dispersions by rotary evaporation and KinetiSol Dispersing: approaches to enhance solubility of a poorly water-soluble gum extract.

    PubMed

    Bennett, Ryan C; Brough, Chris; Miller, Dave A; O'Donnell, Kevin P; Keen, Justin M; Hughey, Justin R; Williams, Robert O; McGinity, James W

    2015-03-01

    Acetyl-11-keto-β-boswellic acid (AKBA), a gum resin extract, possesses poor water-solubility that limits bioavailability and a high melting point making it difficult to successfully process into solid dispersions by fusion methods. The purpose of this study was to investigate solvent and thermal processing techniques for the preparation of amorphous solid dispersions (ASDs) exhibiting enhanced solubility, dissolution rates and bioavailability. Solid dispersions were successfully produced by rotary evaporation (RE) and KinetiSol® Dispersing (KSD). Solid state and chemical characterization revealed that ASD with good potency and purity were produced by both RE and KSD. Results of the RE studies demonstrated that AQOAT®-LF, AQOAT®-MF, Eudragit® L100-55 and Soluplus with the incorporation of dioctyl sulfosuccinate sodium provided substantial solubility enhancement. Non-sink dissolution analysis showed enhanced dissolution properties for KSD-processed solid dispersions in comparison to RE-processed solid dispersions. Variances in release performance were identified when different particle size fractions of KSD samples were analyzed. Selected RE samples varying in particle surface morphologies were placed under storage and exhibited crystalline growth following solid-state stability analysis at 12 months in comparison to stored KSD samples confirming amorphous instability for RE products. In vivo analysis of KSD-processed solid dispersions revealed significantly enhanced AKBA absorption in comparison to the neat, active substance.

  19. 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.

  20. Transporting and shielding photosensitisers by using water-soluble organometallic cages: a new strategy in drug delivery and photodynamic therapy.

    PubMed

    Therrien, Bruno

    2013-06-24

    Skin photosensitivity remains one of the main limitations in photodynamic therapy. In this Concept article a strategy to overcome this limitation is described, in which the photosensitizer is hidden inside the hydrophobic cavity of a water-soluble organometallic cage. The metallacage not only protects the photosensitizer from light, it also facilitates its delivery to cancer cells.

  1. Assessment of Labrasol/Labrafil/Transcutol (4/4/2, v/v/v) as a non-clinical vehicle for poorly water-soluble compounds after 4-week oral toxicity study in Wistar rats.

    PubMed

    Delongeas, J-L; de Conchard, G Vermeil; Beamonte, A; Bertheux, H; Spire, C; Maisonneuve, C; Becourt-Lhote, N; Goldfain-Blanc, F; Claude, N

    2010-01-01

    Drug safety research is frequently faced with the challenge of the selection of appropriate vehicles for use in in vivo non-clinical safety assessment studies. Reported here are the results of blend Labrasol, Labrafil and Transcutol, [L/L/T, (4/4/2, v/v/v)], excipients used as bioavailability enhancer and solubilizer for poorly water-soluble compounds and tested daily for 4 weeks by oral route in Wistar rats (10/sex/group) at dose volumes of 5, 10 or 20 mL/kg/day and compared to controls given 20 mL/kg/day of 1% (w/v) hydroxyethylcellulose in purified water. L/L/T was broadly well tolerated at 5 mL/kg/day and lethal at 20 mL/kg/day in 1 of 20 rats treated at this level. Changes in appearance and behaviour were observed from 10 mL/kg/day with volume-related incidence, severity and duration. Reduced feed intake observed from 5 (females) or 10 mL/kg/day (males) resulted in low bodyweights for high volume males only (-11% of controls). There was a volume-related induction of hepatic CYP 1A1/2, 2B1/2 and/or 2E1 subfamilies from 5 mL/kg/day, with high liver weight, centrilobular hepatocellular hypertrophy and high ALT, triglyceride and cholesterol serum values at 20 mL/kg/day. Renal tubular dilation in medulla, cortical cell degeneration/necrosis with granular material in adjacent glomerular spaces, crystal deposits in the inner medulla, papilla and/or renal pelvis, and tubular mineralization, associated with proteinuria and calcium oxalate crystalluria, were observed at 20 mL/kg/day as well as vacuolation in the adrenal cortex, with a sex-dependant localization. According to these results, 5 mL/kg/day was considered as an acceptable volume for further use of L/L/T (4/4/2, v/v/v) blend as a vehicle for poorly water soluble drugs in Wistar rat toxicity studies.

  2. 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.

  3. [Drug access in poor countries].

    PubMed

    Sebbag, Robert

    2007-11-01

    As a responsible player in the global pharmaceutical industry, Sanofi-Aventis recognizes its special responsibility to provide poor countries with access to drugs and vaccines. This is a key component of the Group's approach to sustainable development. As such, the Access to Medicines department draws on Sanofi-Aventis' expertise in order to address major public health issues, starting with the treatment of malaria, tuberculosis, sleeping sickness, leishmaniasis and epilepsy, as well as access to vaccines. The department has four main activities: research and development of new drugs; improvement of existing treatments; information, communication and education of patients and healthcare professionals; and development of a differential pricing and distribution policy adapted to patients' income, with a "no profit-no loss" equilibrium.

  4. 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

  5. [Lead compound optimization strategy (3)--Structure modification strategies for improving water solubility].

    PubMed

    Li, Zeng; Wang, Jiang; Zhou, Yu; Liu, Hong

    2014-09-01

    Water solubility is an essential physical chemistry property of organic small molecule drug and is also a very important issue in drug discovery. Good water solubility often leads to a good drug potency and pleasant pharmacokinetic profiles. To improve water solubility, structure modification is a straight and effective way based on the theory of water solubility. This review summarized valid structure modification strategies for improving water solubility including salt formation, polar group introduction, liposolubility reduction, conformation optimization and prodrug.

  6. Experiments and synthesis of bone-targeting epirubicin with the water-soluble macromolecular drug delivery systems of oxidized-dextran.

    PubMed

    Yu, Li; Cai, Lin; Hu, Hao; Zhang, Yi

    2014-05-01

    Epirubicin (EPI) is a broad spectrum antineoplastic drug, commonly used as a chemotherapy method to treat osteosarcoma. However, its application has been limited by many side-effects. Therefore, targeted drug delivery to bone has been the aim of current anti-bone-tumor drug studies. Due to the exceptional affinity of Bisphosphonates (BP) to bone, 1-amino-ethylene-1, 1-dephosphate acid (AEDP) was chosen as the bone targeting moiety for water-soluble macromolecular drug delivery systems of oxidized-dextran (OXD) to transport EPI to bone in this article. The bone targeting drug of AEDP-OXD-EPI was designed for the treatment of malignant bone tumors. The successful conjugation of AEDP-OXD-EPI was confirmed by analysis of FTIR and (1)H-NMR spectra. To study the bone-seeking potential of AEDP-OXD-EPI, an in vitro hydroxyapatite (HAp) binding assay and an in vivo experiment of bone-targeting capacity were established. The effectiveness of AEDP-OXD-EPI was demonstrated by inducing apoptosis and necrosis of MG-63 tumor cell line. The obtained experimental data indicated that AEDP-OXD-EPI is an ideal bone-targeting anti-tumor drug.

  7. 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.

  8. Application of hot-melt extrusion technology for designing an elementary osmotic pump system combined with solid dispersion for a novel poorly water-soluble antidepressant.

    PubMed

    Zhang, Xuemei; Wang, Meng; Li, Pei; Wang, Aiping; Liang, Rongcai; Gai, Yunyun; Liu, Wanhui; Li, Youxin; Sun, Kaoxiang

    2016-12-01

    TP1 is a novel antidepressant with poor solubility. To reduce fluctuations in blood concentration and increase oral bioavailability, a controlled-release system was developed by combining a solid dispersion (SD) and an elementary osmotic pump (EOP). The study compared different methods of preparing SDs. Hot-melt extrusion (HME) exhibited clear advantages over the traditional melting technique. An in vitro release study demonstrated that HME-EOP tablets released TP1 in a zero-order manner over 12 h and the drug release was in dependent of the release medium and agitation speed, whereas release from molten-EOP tablets lasted only 8 h. In contrast to immediate-release tablets, the HME-EOP tablets exhibited less fluctuation in blood concentration and higher bioavailability in vivo. In summary, the osmotic pump system combined with an HME-based SD of TP1 presented controlled release in vitro, high bioavailability in vivo and a good in vivo-in vitro correlation.

  9. Synthesis and application of the reduction-sensitive drug delivery system based on water-soluble ZnInAgS quantum dots

    NASA Astrophysics Data System (ADS)

    Deng, Dawei; Zhang, Rong; Qu, Lingzhi; Bao, Fangjian; Wang, Jie; Deng, Tao

    2016-10-01

    High-quality water-soluble quantum dots had been synthesized following the one-step method. Furtherly, the impact factors on the optical properties of quantum dots, which were the feed ratio of S/In and the reflux time, had been concerned emphatically. By changing the reaction parameters, we made the fluorescence emission of ZnInAgS quantum dot tunable from green to orange, and the maximum fluorescence quantum efficiency was up to 30%. Then we modified bovine serum albumin (BSA) on the surface of ZnInAgS quantum dot, which was conjugated with BSA-QDs through the linker of 3'3-dimercapto-diacetate DOX. Finally, the reduction-sensitive drug delivery system based on ZnInAgS quantum dots (QBSSD) was successfully constructed. The resultant QBSSD complex were observed to be significantly stable in aqueous solution. In addition, owing to their cellular reduction responsiveness at the cleavable disulfide linker, the QBSSD complex were able to release DOX rapidly. In vitro drug release and cell level release experiments proved that our QBSSD complexes could make a quick drug release in the environment with GSH. The efficacy experiments showed that our QBSSD complexes exhibited a strong killing effect to cancer cells, and low toxic to normal cells. All the results indicated that the reduction-sensitive drug delivery system was a promising model of administration.

  10. Development of a nanoprecipitation method for the entrapment of a very water soluble drug into Eudragit RL nanoparticles

    PubMed Central

    Salatin, Sara; Barar, Jaleh; Barzegar-Jalali, Mohammad; Adibkia, Khosro; Kiafar, Farhad; Jelvehgari, Mitra

    2017-01-01

    Rivastigmine hydrogen tartrate (RHT), one of the potential cholinesterase inhibitors, has received great attention as a new drug candidate for the treatment of Alzheimer's disease. However, the bioavailability of RHT from the conventional pharmaceutical forms is low because of the presence of the blood brain barrier. The main aim of the present study was to prepare positively charged Eudragit RL 100 nanoparticles as a model scaffold for providing a sustained release profile for RHT. The formulations were evaluated in terms of particle size, zeta potential, surface morphology, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). Drug entrapment efficiency and in vitro release properties of lyophilized nanoparticles were also examined. The resulting formulations were found to be in the size range of 118 nm to 154 nm and zeta potential was positive (+22.5 to 30 mV). Nanoparticles showed the entrapment efficiency from 38.40 ± 8.94 to 62.00 ± 2.78%. An increase in the mean particle size and the entrapment efficiency was observed with an increase in the amount of polymer. The FTIR, XRD, and DSC results ruled out any chemical interaction between the drug and Eudragit RL100 polymer. RHT nanoparticles containing low ratio of polymer to drug (4:1) presented a faster drug release and on the contrary, nanoparticles containing high ratio of polymer to drug (10:1) were able to give a more sustained release of the drug. The study revealed that RHT nanoparticles were capable of releasing the drug in a prolonged period of time and increasing the drug bioavailability. PMID:28255308

  11. 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

  12. Release mechanisms of a sparingly water-soluble drug from controlled porosity-osmotic pump pellets using sulfobutylether-beta-cyclodextrin as both a solubilizing and osmotic agent.

    PubMed

    Sotthivirat, Sutthilug; Haslam, John L; Lee, Ping I; Rao, Venkatramana M; Stella, Valentino J

    2009-06-01

    The purpose of this work is to delineate the release mechanisms of a sparingly water-soluble drug, prednisolone (PDL), from a microporous or controlled porosity-osmotic pump pellet (CP-OPP) using sulfobutylether-beta-cyclodextrin (CD) as both a solubilizing and osmotic agent. All factors, osmotic and diffusional, influencing drug release as described by the Theeuwes and Zentner equation were partially demonstrated in an earlier paper1 and are further quantitatively evaluated here to determine whether the equation may be applied to CP-OPPs. The PDL release rate from the CP-OPPs containing precomplexed PDL follows the zero-order kinetics for up to 30-40% of drug release during the first 1-2 h and subsequently nonzero order kinetics. The zero-order drug release phase reveals the main contribution is from osmotic pumping with a negligible diffusion component, resulting from the nearly constant driving forces in the system. The nonzero order drug release phase is associated with the dynamic changes in the system (e.g., declining osmotic driving force and greater diffusion component with time). In addition, the parameters related to membrane characteristics were determined, and the effect of viscosity was evaluated for the pellet system. The membranes coated on the CP-OPPs are less permeable to water or solutes than the membranes coated on the previously reported tablets. The viscosity due to the CD decreases as a function of CD concentration, which partly affects the observed drug release profiles. The viscosity effect of CD is significant and captured in a hydraulic permeability term.

  13. Nanoencapsulation of water-soluble drug, lamivudine, using a double emulsion spray-drying technique for improving HIV treatment

    NASA Astrophysics Data System (ADS)

    Tshweu, Lesego; Katata, Lebogang; Kalombo, Lonji; Swai, Hulda

    2013-11-01

    Current treatments available for human immunodeficiency virus, namely antiretrovirals, do not completely eradicate the virus from the body, leading to life-time commitment. Many antiretrovirals suffer drawbacks from toxicity and unpleasant side effects, causing patience non-compliance. To minimize challenges associated with the antiretrovirals, biodegradable nanoparticles used as drug delivery systems hold tremendous potential to enhance patience compliance. The main objective of this work was to load lamivudine (LAM) into poly(epsilon-caprolactone) (PCL) nanoparticles. LAM is a hydrophilic drug with low plasma half-life of 5-7 h and several unpleasant side effects. LAM was nanoencapsulated into PCL polymer via the double emulsion spray-drying method. Formulation parameters such as the effect of solvent, excipient and drug concentration were optimized for the synthesis of the nanoparticles. Spherical nanoparticles with an average size of 215 ± 3 nm and polydispersity index (PDI) of 0.227 ± 0.01 were obtained, when ethyl acetate and lactose were used in the preparation. However, dichloromethane presented sizes larger than 454 ± 11 nm with PDI of more than 0.4 ± 0.05, irrespective of whether lactose or trehalose was used in the preparation. Some of the nanoparticles prepared with trehalose resulted in crystal formation. UV spectroscopy showed encapsulation efficiency ranging from 68 ± 4 to 78 ± 4 % for LAM depending on the starting drug concentration. Fourier transform infrared spectroscopy and X-ray diffraction confirmed the possibility of preparing amorphous PCL nanoparticles containing LAM. Drug release extended for 4 days in pH 1.3, pH 4.5 and pH 6.8. These results indicated that LAM-loaded PCL nanoparticles show promise for controlled delivery.

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

    PubMed

    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.

  15. A water-soluble extract from cultured medium of Ganoderma lucidum (Reishi) mycelia attenuates the small intestinal injury induced by anti-cancer drugs.

    PubMed

    Kashimoto, Naoki; Ishii, Satomi; Myojin, Yuki; Ushijima, Mitsuyasu; Hayama, Minoru; Watanabe, Hiromitsu

    2010-01-01

    The present study investigated whether a water-soluble extract from the culture medium of Ganoderma lucidum (Reishi) mycelia (MAK) is able to protect the small intestine against damage induced by anti-cancer drugs. Six-week-old male B6C3F1/Crlj mice were fed a basal diet (MF) alone or with various doses of MAK or Agarics blazei Murrill (AGA) beginning one week before treatment with the anti-cancer drugs. Mice were sacrificed 3.5 days after injection of the anti-cancer drug, the small intestine was removed and tissue specimens were examined for the regeneration of small intestinal crypts. In experiment 1, the number of regenerative crypts after the administration of 5-fluorouracil (5FU) intravenously (250 mg/kg) or intraperitoneally (250 or 500 mg/kg) was compared after treatment with MAK or AGA. MAK protected against 5FU-induced small intestinal injury whereas AGA did not. In experiment 2, we investigated the protective effect of MAK against small intestinal injury induced by the anti-cancer drugs: UFT (tegafur with uracil; 1,000 mg/kg, orally), cisplatin (CDDP; 12.5 and 25 mg/kg, intraperitoneally), cyclophosphamide (CPA; 250 mg/kg, orally) and gefitinib (Iressa; 2,000 and 4,000 mg/kg, orally). UFT and CDDP decreased the number of regenerative crypts, but treatment with MAK attenuated the extent of UFT- or CDDP-induced small intestinal injury. CPA or Iressa plus MAK up-regulated crypt regeneration. The present results indicate that MAK ameliorates the small intestinal injury caused by several anti-cancer drugs, suggesting that MAK is a potential preventive agent against this common adverse effect of chemotherapy.

  16. 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

  17. 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.

  18. 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.

  19. Water-Soluble Metallocene-Containing Polymers.

    PubMed

    Alkan, Arda; Wurm, Frederik R

    2016-09-01

    Metallocenes are organometallic compounds with reversible redox profiles and tunable oxidation and reduction potentials, depending on the metal and substituents at the cyclopentadienyl rings. Metallocenes have been introduced in macromolecules to combine the redox-activity with polymer properties. There are many examples of such hydrophobic polymer materials, but much fewer water-soluble examples are found scattered across the polymer literature. However, in terms of drug delivery and other biological applications, water solubility is essential. For this very reason, all the synthetic routes to water-soluble metallocene containing polymers are collected and discussed here. The focus is on neutral ferrocene- and ruthenocene-containing and charged cobaltocenium-containing macromolecules (i.e., symmetrical sandwich complexes). The synthetic protocols, self-assembly behavior, and other benefits of the obtained materials are discussed.

  20. Percolation theory and the role of maize starch as a disintegrant for a low water-soluble drug.

    PubMed

    Kimura, Go; Puchkov, Maxim; Betz, Gabriele; Leuenberger, Hans

    2007-01-01

    The objective of the present work is to investigate the presence or absence of a critical concentration of maize starch according to the percolation theory for a truly ternary system with respect to a minimum disintegration time. The results of this study show that the application of percolation theory is not limited to the study of binary systems. In this work it is shown how it can be used to analyze the behavior of binary and ternary systems for caffeine and mefenamic acid formulations containing a starch-based disintegrant. The percolation threshold p(c) can be described by the volumetric ratio of the disintegrant to the drug substance being equal to p(c) = 0.2 (v/v) in in which both components have similar average particle sizes. In addition, the behavior of the disintegration time in the neighborhood of the percolation threshold can be mathematically modeled with the basic equation of the percolation theory yielding a critical exponent q = 0.28 +/- 0.06.

  1. 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

    2015-05-07

    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.

  2. 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.

  3. 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

  4. 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.

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

    PubMed

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

    2008-08-07

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

  6. Pfizer donates drug to South Africa's poor.

    PubMed

    This article reports on Pfizer's AIDS drug donation to South Africa. The donated drug, Diflucan, treats cryptococcal meningitis, a lethal brain infection that occurs in one out of 10 HIV patients. Its daily dose in South Africa costs about US$15, far more than poor people can afford. The HIV and AIDS Treatment Action Campaign, an advocacy group, had lobbied New York-based Pfizer for a year to reduce the drug's price. The donation offered hope among activists that other pharmaceutical companies would follow suit and offer HIV- and AIDS-related drugs at a discount or for free. After the announcement of the donation, the group is now lobbying Glaxo Wellcome, maker of Zidovudine. The group is asking to make the drug available for free to reduce the risk of vertical transmission. Glaxo Wellcome, however, has no plans of offering Zidovudine for free, although the drug was offered 75% cheaper in developing nations.

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

    NASA Astrophysics Data System (ADS)

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

    2016-09-01

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

  8. 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.

  9. In Vivo Precipitation of Poorly Soluble Drugs from Lipid-Based Drug Delivery Systems.

    PubMed

    Sassene, P J; Michaelsen, M H; Mosgaard, M D; Jensen, M K; Van Den Broek, E; Wasan, K M; Mu, H; Rades, T; Müllertz, A

    2016-10-03

    Precipitation of poorly water-soluble drugs from lipid-based drug delivery systems (LbDDS) has been studied extensively during in vitro lipolysis but has never been shown in vivo. The aim of this study was therefore to investigate if drug precipitation can occur from LbDDS during transit of the gastrointestinal tract in vivo. Rats were administered 300 μL of either of two LbDDS (LbDDS I and LbDDS II) loaded with danazol or fenofibrate (or paracetamol to assess gastric emptying). The rats were euthanized at various time points after administration of both LbDDS containing either drug, and the contents of the stomach and proximal part of the small intestine were harvested. The contents were analyzed for crystalline drug by X-ray powder diffraction and polarized light microscopy. No drug precipitation was evident in the stomach or the intestine after administration of LbDDS I containing danazol at the tested time points. Fenofibrate precipitation was absent in the stomach initially after administration of LbDDS I, but was evident in the stomach 90 min after dosing. No crystalline fenofibrate was observed in the intestine. Danazol and fenofibrate precipitation was evident in the stomach following administration of LbDDS II containing either drug, but not in the intestine at the tested time point. Drug precipitation from LbDDS was observed in the stomach, but not in the intestine, which is contrary to what in vitro lipolysis data (obtained under human GI conditions) suggests. Thus, precipitation of drugs from LbDDS in vivo in rats is much lower than might be anticipated from in vitro lipolysis data.

  10. Comparison of predictive ability of water solubility QSPR models generated by MLR, PLS and ANN methods.

    PubMed

    Erös, Dániel; Kéri, György; Kövesdi, István; Szántai-Kis, Csaba; Mészáros, György; Orfi, László

    2004-02-01

    ADME/Tox computational screening is one of the most hot topics of modern drug research. About one half of the potential drug candidates fail because of poor ADME/Tox properties. Since the experimental determination of water solubility is time-consuming also, reliable computational predictions are needed for the pre-selection of acceptable "drug-like" compounds from diverse combinatorial libraries. Recently many successful attempts were made for predicting water solubility of compounds. A comprehensive review of previously developed water solubility calculation methods is presented here, followed by the description of the solubility prediction method designed and used in our laboratory. We have selected carefully 1381 compounds from scientific publications in a unified database and used this dataset in the calculations. The externally validated models were based on calculated descriptors only. The aim of model optimization was to improve repeated evaluations statistics of the predictions and effective descriptor scoring functions were used to facilitate quick generation of multiple linear regression analysis (MLR), partial least squares method (PLS) and artificial neural network (ANN) models with optimal predicting ability. Standard error of prediction of the best model generated with ANN (with 39-7-1 network structure) was 0.72 in logS units while the cross validated squared correlation coefficient (Q(2)) was better than 0.85. These values give a good chance for successful pre-selection of screening compounds from virtual libraries, based on the predicted water solubility.

  11. Melt extrusion with poorly soluble drugs.

    PubMed

    Shah, Sejal; Maddineni, Sindhuri; Lu, Jiannan; Repka, Michael A

    2013-08-30

    Melt extrusion (ME) over recent years has found widespread application as a viable drug delivery option in the drug development process. ME applications include taste masking, solid-state stability enhancement, sustained drug release and solubility enhancement. While ME can result in amorphous or crystalline solid dispersions depending upon several factors, solubility enhancement applications are centered around generating amorphous dispersions, primarily because of the free energy benefits they offer. In line with the purview of the current issue, this review assesses the utility of ME as a means of enhancing solubility of poorly soluble drugs/chemicals. The review describes major processing aspects of ME technology, definition and understanding of the amorphous state, manufacturability, analytical characterization and biopharmaceutical performance testing to better understand the strength and weakness of this formulation strategy for poorly soluble drugs. In addition, this paper highlights the potential advantages of employing a fusion of techniques, including pharmaceutical co-crystals and spray drying/solvent evaporation, facilitating the design of formulations of API exhibiting specific physico-chemical characteristics. Finally, the review presents some successful case studies of commercialized ME based products.

  12. Nanoencapsulation of a water soluble drug in biocompatible polyesters. Effect of polyesters melting point and glass transition temperature on drug release behavior.

    PubMed

    Karavelidis, Vassilios; Giliopoulos, Dimitrios; Karavas, Evangelos; Bikiaris, Dimitrios

    2010-12-23

    Five polyesters based on 1,3-propanediol or ethylene glycol and an aliphatic dicarboxylic acid were used for the preparation of Ropinirole HCl-loaded nanoparticles. The advantage of the present study is that the used polyesters - as well as poly(lactic acid) (PLA) - have similar degree of crystallinity but different melting points, varying from 46.7 to 166.4°C. Based on polymer toxicity on HUVEC, the biocompatibility of these aliphatic polyesters was found comparable to that of PLA and thus the studied polyesters could be used as drug carriers. Drug encapsulation in polyesters was performed via emulsification/solvent evaporation method. Particle size of drug-loaded nanoparticles was between 140 and 190 nm, as measured by light scattering. Drug loading content for all the polyesters varies between 10 and 16% and their entrapment efficiency is relatively high (32-48%). WAXD patterns of nanoparticles show that Ropinirole HCl lies in amorphous state within polymer matrices. Drug release diagrams reveal that the higher percentage of Ropinirole HCl is released during the first 6h after its insertion in the dissolution medium. Fast release rates of the drug are attributed to high hydrophilicity of Ropinirole HCl. Melting point (T(m)) and glass transition temperature (T(g)) of the host polymer matrices seem to be important parameters, since higher drug release rates are observed in polyesters with low T(m) and T(g).

  13. 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.

  14. Synthesis of water soluble graphene.

    PubMed

    Si, Yongchao; Samulski, Edward T

    2008-06-01

    A facile and scalable preparation of aqueous solutions of isolated, sparingly sulfonated graphene is reported. (13)C NMR and FTIR spectra indicate that the bulk of the oxygen-containing functional groups was removed from graphene oxide. The electrical conductivity of thin evaporated films of graphene (1250 S/m) relative to similarly prepared graphite (6120 S/m) implies that an extended conjugated sp (2) network is restored in the water soluble graphene.

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

    PubMed

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

    2012-01-01

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

  16. Evaluation of Matrix Tablets Based on Eudragit®E100/Carbopol®971P Combinations for Controlled Release and Improved Compaction Properties of Water Soluble Model Drug Paracetamol.

    PubMed

    Obeidat, Wasfy M; Nokhodchi, Ali; Alkhatib, Hatim

    2015-10-01

    The purpose of this work was to investigate the influence of Eudragit®E100 polymer in modifying the release rates and compaction properties of water soluble model drug paracetamol from Carbopol®971P NF polymer matrix tablets prepared by direct compression. The effects of the ratio of the two polymers, the total polymeric content, and the tablets mechanical strength on paracetamol release rates were investigated. Dissolution studies were conducted using USP XX Π rotating paddle apparatus at 50 rpm and 37°C at three different stages (pH 1.2, 4.8, and 6.8). Results showed that the polymers combination improved significantly the compaction properties of paracetamol tablets as evident by the higher crushing strengths (8.3 ± 0.4 Kp) compared to polymer-free tablets (3.4 ± 0.2 Kp) at intermediate compression pressure of 490 MPa. When combined with Carbopol®971P NF, Eudragit®E100 was found to be capable of extending paracetamol release for more than 12 h compared to 1 h for polymers-free tablets. The combined polymers were able to control paracetamol release in a pH independent pattern. The f2 (similarity factor) analysis showed that the ratio between the polymers and the total polymer concentration exhibited significant impact on drug release rates. In conclusion, Eudragit®E100 when combined with Carbopol®971P NF was capable of improving the compaction and sustained release properties of paracetamol. Korsmeyer-Peppas model was found to be the most suitable for fitting drug release data. The polymer combinations can potentially be used to control the release rates of highly water soluble drugs.

  17. Matrix tablets: the effect of hydroxypropyl methylcellulose/anhydrous dibasic calcium phosphate ratio on the release rate of a water-soluble drug through the gastrointestinal tract I. In vitro tests.

    PubMed

    Mamani, Pseidy L; Ruiz-Caro, Roberto; Veiga, María D

    2012-12-01

    Different hydroxypropyl methylcellulose (HPMC)/anhydrous dibasic calcium phosphate (ADCP) matrix tablets have been developed aiming to evaluate the influence of both components ratio in the control release of a water-soluble drug (theophylline). In order to characterise the matrix tablets, swelling, buoyancy and dissolution studies have been carried out in different aqueous media (demineralised water, progressive pH medium, simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid). The HPMC/ADCP ratio has turned out to be the determinant in the matrix behaviour: the HPMC characteristic swelling behaviour was modulated, in some cases, by the ADCP characteristic acidic dissolution. When the HPMC/ADCP ratio was ≥0.69, buoyancy, continuous swelling and low theophylline dissolution rate from the matrices (H1, H2 and H3) were observed in all dissolution media. Consequently, these formulations could be adequate as gastro-retentive drug delivery systems. Additionally, HPMC/ADCP ratio ≤0.11 (H5 and H6) induces a pH-dependent drug release which could be applied to design control drug release enteric formulations (with a suitable enteric coating). Finally, a HPMC/ADCP ratio between 0.11 and 0.69 (H4) yield a gastrointestinal controlled drug release, due to its time-dependent buoyancy (7 h) and a total drug delivery in 17 h in simulated colonic fluid.

  18. Effect of Explotab on the tabletability of a poorly soluble drug.

    PubMed

    Muñoz, N; Ferrero, C; Muñoz-Ruiz, A; Velasco, M V; Jiménez-Castellanos, M R

    1998-08-01

    The efficiency of a superdisintegrant (Explotab) in a direct-compression formulation containing a poorly water soluble drug (albumin tanate) at high dosage was investigated. An experimental design with two variables, applied pressure and concentration of Explotab, enabled its effects on the tableting and the mechanical properties of the final tablets to be determined. Differential scanning calorimetry was performed to study the interactions between drug and excipients. No incompatibility was found between drug-excipient mixtures prepared in the proportion 1:1 and in the corresponding formulation at room temperature and after 3 weeks at 50 degrees C. The concentration of Explotab has a positive effect on flow properties. Also, the effect of applied pressure and disintegrant content was found to be significant on all compressional parameters. At low applied pressures, the breaking strength was independent on Explotab concentration. However, at higher applied pressures, the maximum densification obtained with 10% Explotab produced a limited breaking strength lower than that at 0% concentration. The response surface shows a certain level of Explotab, around 7%, at which the disintegration time was the shortest. At this level, the surface response was independent of the applied pressure. In our study, the experimental design was a valuable tool used to establish the optimum manufacturing conditions.

  19. 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.

  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. Soluplus® as an effective absorption enhancer of poorly soluble drugs in vitro and in vivo.

    PubMed

    Linn, Michael; Collnot, Eva-Maria; Djuric, Dejan; Hempel, Katja; Fabian, Eric; Kolter, Karl; Lehr, Claus-Michael

    2012-02-14

    As many new active pharmaceutical ingredients are poorly water soluble, solubility enhancers are one possibility to overcome the hurdles of drug dissolution and absorption in oral drug delivery. In the present work a novel solubility enhancing excipient (Soluplus®) was tested for its capability to improve intestinal drug absorption. BCS class II compounds danazol, fenofibrate and itraconazole were tested both in vivo in beagle dogs and in vitro in transport experiments across Caco-2 cell monolayers. Each drug was applied as pure crystalline substance, in a physical mixture with Soluplus®, and as solid solution of the drug in the excipient. In the animal studies a many fold increase in plasma AUC was observed for the solid solutions of drug in Soluplus® compared to the respective pure drug. An effect of Soluplus® in a physical mixture with the drug could be detected for fenofibrate. In vitro transport studies confirm the strong effect of Soluplus® on the absorption behavior of the three tested drugs. Furthermore, the increase of drug flux across Caco-2 monolayer is correlating to the increase in plasma AUC and C(max)in vivo. For these poorly soluble substances Soluplus® has a strong potential to improve oral bioavailability. The applicability of Caco-2 monolayers as tool for predicting the in vivo transport behavior of the model drugs in combination with a solubility enhancing excipient was shown. Also the improvement of a solid dispersion compared to physical mixtures of the drugs and the excipient was correctly reflected by Caco-2 experiments. In the case of fenofibrate the possible improvement by a physical mixture was demonstrated, underscoring the value of the used tool as alternative to animal studies.

  2. Novel Nanoprinting for Oral Delivery of Poorly Soluble Drugs

    PubMed Central

    Yilmaz, Cihan; Sarisozen, Can; Torchilin, Vladimir; Busnaina, Ahmed

    2016-01-01

    Many of the newly developed drugs for cancer, and some of those for cardiovascular disease, are poorly soluble in water and cannot be taken orally. This can be overcome by employing a new and effective delivery system utilizing nanotechnology. We present a new method for oral preparation of poorly soluble drugs that entails assembling (printing) drug-loaded polymeric micelles into sub-100 nm orally acceptable nanorods (NRs). Due to their small size, these NRs will have a high permeability through cells and thus should transport through the intestine to allow for drug delivery in the blood. These NRs drugs are expected to penetrate tumors more efficiently and much faster than individual nanoparticles and may also be useful for drug delivery to atherosclerotic plaque. This should lead to better bioavailability of the drug with reduced toxicity and side effects. Currently used micellar formulations are administered intravenously, which is invasive and could be toxic due to high doses and interaction with normal healthy tissues. Oral drug administration is the easiest and most desirable way to deliver most drugs, including those that are poorly soluble. PMID:27826370

  3. Influence of sodium dodecyl sulfate on swelling, erosion and release behavior of HPMC matrix tablets containing a poorly water-soluble drug.

    PubMed

    Zeng, Aiguo; Yuan, Bingxiang; Fu, Qiang; Wang, Changhe; Zhao, Guilan

    2009-01-01

    The effect of sodium dodecyl sulfate (SDS) on the swelling, erosion and release behavior of HPMC matrix tablets was examined. Swelling and erosion of HPMC matrix tablets were determined by measuring the wet and subsequent dry weights of matrices. The rate of uptake of the dissolution medium by the matrix was quantified using a square root relationship whilst the erosion of the polymer was described using the cube root law. The extent of swelling decreased with increasing SDS concentrations in the dissolution medium but the rate of erosion was found to follow a reverse trend. Such phenomena might have been caused by the attractive hydrophobic interaction between HPMC and SDS as demonstrated by the cloud points of the solutions containing both the surfactant and polymer. Release profiles of nimodipine from HPMC tablets in aqueous media containing different concentrations of SDS were finally studied. Increasing SDS concentrations in the medium was shown to accelerate the release of nimodipine from the tablets, possibly due to increasing nimodipine solubility and increasing rate of erosion by increasing SDS concentrations in the dissolution medium.

  4. 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.

  5. Biosynthesis of A Water-Soluble Lipid I Analogue and A Convenient Assay for Translocase I

    PubMed Central

    Skorupinska-Tudek, Karolina; Swiezewska, Ewa; Kurosu, Michio

    2014-01-01

    Translocase I (MraY/MurX) is an essential enzyme in growth of the vast majority of bacteria that catalyzes the transformation from UDP-MurNAc-pentapeptide (Park’s nucleotide) to prenyl-MurNAc-pentapeptide (lipid I), the first membrane-anchored peptidoglycan precursor. MurX has been received considerable attentions to the development of new TB drugs due to the fact that the MurX inhibitors kill exponentially growing Mycobacterium tuberculosis (Mtb) much faster than clinically used TB drugs. Lipid I isolated from Mtb contains the C50-prenyl unit that shows very poor water-solubility, and thus, this chemical characteristic of lipid I renders MurX enzyme assays impractical for screening and lacks reproducibility of the enzyme assays. We have established a scalable chemical synthesis of Park’s nucleotide-Nε-dansylthiourea 2 that can be used as a MurX enzymatic substrate to form lipid I analogues. In our investigation of minimum structure requirement of the prenyl phosphate in the MraY/MurX-catalyzed lipid I analogue synthesis with 2, we found that neryl phosphate (C10-phosphate) can be recognized by MraY/MurX to generate the water-soluble lipid I analogue in quantitative yield under the optimized conditions. Herein, we report a rapid and robust analytical method for quantifying MraY/MurX inhibitory activity of library molecules. PMID:24939461

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

    PubMed

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

    2011-05-01

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

  7. Encapsulation of poorly soluble basic drugs into enteric microparticles: a novel approach to enhance their oral bioavailability.

    PubMed

    Alhnan, Mohamed A; Murdan, Sudaxshina; Basit, Abdul W

    2011-09-15

    Poorly water soluble basic drugs are very sensitive to pH changes and following dissolution in the acidic stomach environment tend to precipitate upon gastric emptying, which leads to compromised or erratic oral bioavailability. In this work, we show that the oral bioavailability of a model poorly soluble basic drug (cinnarizine) can be improved by drug encapsulation within highly pH-responsive microparticles (Eudragit L). The latter was prepared by emulsion solvent evaporation which yielded discrete spherical microparticles (diameter of 56.4±6.8μm and a span of 1.2±0.3). These Eudragit L (dissolution threshold pH 6.0) microparticles are expected to dissolve and release their drug load at intestinal conditions. Thus, the enteric microparticles inhibited the in vitro release of drug under gastric conditions, despite high cinnarizine solubility in the acidic medium. At intestinal conditions, the particles dissolved rapidly and released the drug which precipitated out in the dissolution vessel. In contrast, cinnarizine powder showed rapid drug dissolution at low pH, followed by precipitation upon pH change. Oral dosing in rats resulted in a greater than double bioavailability of Eudragit L microparticles compared to the drug powder suspension, although C(max) and T(max) were similar. The higher bioavailability with microparticles contradicts the in vitro results. Such an example highlights that although in vitro results are an indispensable tool for formulation development, an early in vivo assessment of formulation behaviour can provide better prediction for oral bioavailability.

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

    PubMed

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

    2016-05-10

    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.

  9. Water-soluble constituents of dill.

    PubMed

    Ishikawa, Toru; Kudo, Masato; Kitajima, Junichi

    2002-04-01

    From the water-soluble portion of the methanol extract of dill (fruit of Anethum graveolens L.), which has been used as a spice and medicine, thirty-three compounds, including a new monoterpenoid, six new monoterpenoid glycosides, a new aromatic compound glucoside and a new alkyl glucoside were obtained. Their structures were clarified by spectral investigation.

  10. 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.

  11. 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.

  12. 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.

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

    PubMed

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

    2017-03-07

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

  14. Theory and practice of supersaturatable formulations for poorly soluble drugs.

    PubMed

    Kawakami, Kohsaku

    2015-03-01

    Candidate compounds with high activity do not always possess adequate physicochemical properties to be developed as commercial products. Notably, the development of candidates with poor aqueous solubility has been a great challenge in the past two decades. Formulations that offer supersaturated state during the dissolution process are considered effective for increasing the oral bioavailability of such candidates. Representative supersaturatable dosage forms include amorphous solid dispersions, nanocrystal formulations and self-(micro)emulsifying drug delivery systems. This review describes the characteristics of these formulations, with emphasis on the suitability of the candidates for each type of formulation, from a physicochemical viewpoint. Influence of developmental strategy on the formulation selection is also discussed. This review aims to provide guidance for selecting formulations for poorly soluble drugs based on both academic and practical backgrounds.

  15. 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

  16. 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

  17. 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.

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

    PubMed

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

    2017-03-02

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

  19. 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

  20. 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.

  1. Water-soluble titanium alkoxide material

    DOEpatents

    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.

  2. 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.

  3. 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

  4. Raman spectroscopy for in-line and off-line quantification of poorly soluble drugs in strip films.

    PubMed

    Zhang, Jun; Ying, Ye; Pielecha-Safira, Barbara; Bilgili, Ecevit; Ramachandran, Rohit; Romañach, Rodolfo; Davé, Rajesh N; Iqbal, Zafar

    2014-11-20

    Raman spectroscopy was used as a process analytical technology (PAT) tool for in-line measurement of active pharmaceutical ingredient (API) content during continuous manufacturing of strip films containing nanoparticles of poorly water-soluble APIs. Fenofibrate and naproxen were used as model APIs, whose concentrations ranged from 3% to 26% (w/w) in the model calibration. For both in-line and off-line measurements, calibration models employed partial least square (PLS) analysis, yielding correlation coefficients (R(2)) greater than 0.9946 and root mean squared error of calibration (RMSEC) of about 0.44%, indicating the validity and accuracy of the calibration. The robustness of Raman spectroscopy as a PAT tool was established by considering three processing parameters after substrate interference correction: sensing location, substrate speed and film thickness. Calibration models for each API were validated using a separate batch of strip films by predicting the API concentrations to within ±1.3%. Principal component analysis (PCA) was used to explain the interactions between processing variables and calibration models, which suggest that besides API concentration, film thickness could also be monitored using Raman spectroscopy. The results demonstrate the potential of Raman spectroscopy as an effective PAT tool for novel strip film manufacturing process, facilitating detection of drug form and concentration in real-time.

  5. 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

  6. 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.

  7. Molecularly designed water soluble, intelligent, nanosize polymeric carriers.

    PubMed

    Pişkin, Erhan

    2004-06-11

    Intelligent polymers, also referred as "stimuli-responsive polymers" undergo strong property changes (in shape, surface characteristics, solubility, etc.) when only small changes in their environment (changes in temperature, pH, ionic strength light, electrical and magnetic field, etc.). They have been used in several novel applications, drug delivery systems, tissue engineering scaffolds, bioseparation, biomimetic actuators, etc. The most popular member of these type of polymers is poly(N-isopropylacrylamide) (poly(NIPA)) which exhibits temperature-sensitive character, in which the polymer chains change from water-soluble coils to water-insoluble globules in aqueous solution as temperature increases above the lower critical solution temperature (LCST) of the polymer. Copolymerization of NIPA with acrylic acid (AAc) allows the synthesis of both pH and temperature-responsive copolymers. This paper summarizes some of our related studies in which NIPA and its copolymers were synthesized and used as intelligent carriers in diverse applications.

  8. 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.

  9. 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

  10. 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.

  11. Non-invasive insight into the release mechanisms of a poorly soluble drug from amorphous solid dispersions by confocal Raman microscopy.

    PubMed

    Punčochová, Kateřina; Vukosavljevic, Branko; Hanuš, Jaroslav; Beránek, Josef; Windbergs, Maike; Štěpánek, František

    2016-04-01

    In this study, we investigated the release mechanism of the poorly water soluble drug aprepitant from different amorphous solid dispersions using confocal Raman microscopy (CRM). Solid dispersions were fabricated based on either Soluplus®, as an amphiphilic copolymer and solubilizer, or on polyvinylpyrrolidone, as a hydrophilic polymer, in order to elucidate the influence of the polymer characteristics on the drug form and dissolution mechanisms. Aprepitant exhibited its amorphous form in both solid dispersions. However, the release differed depending on the polymer. The high complexation effect of Soluplus was shown to be a crucial factor for stabilization of the amorphous drug, resulting in continuous release without any recrystallization of aprepitant. In contrast, solid dispersions based on polyvinylpyrrolidone showed a different mechanism of dissolution; due to the good affinity of PVP and water, the polymer is dissolving fast, leading to phase separation and local recrystallization of the drug. The study highlights the complexity of release processes from solid dispersions and elucidates the influence of the polymer on drug release kinetics.

  12. PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels for drug delivery.

    PubMed

    Cho, Hyunah; Gao, Jieming; Kwon, Glen S

    2016-10-28

    Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles and poly(D,L-lactic-co-glycolic acid)-block-polyethylene glycol)-block-poly(D,L-lactic-co-glycolic acid) (PLGA-b-PEG-b-PLGA) sol-gels have been extensively researched for systemic and localized drug delivery applications, respectively, and they have both progressed into humans for paclitaxel, an important yet poorly water-soluble chemotherapeutic agent. In this review article, preclinical and clinical research on PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels that has focused on paclitaxel will be updated, and recent research on other poorly water-soluble anticancer agents and delivery of drug combinations (i.e. multi-drug delivery) that seeks synergistic anticancer efficacy will be summarized. PEG-b-PLA micelles are a first-generation platform for the systemic multi-delivery of poorly water soluble anticancer agents. PLGA-b-PEG-b-PLGA sol-gels are a first-generation platform for the localized multi-drug delivery of water-soluble and/or poorly water-soluble anticancer agents. In summary, PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels may safely enable pre-clinical evaluation and clinical translation of poorly water-soluble anticancer agents, especially for promising, rapidly emerging anticancer combinations.

  13. Encapsulation of poorly soluble drugs in polymer-drug conjugates: effect of dual-drug nanoformulations on cancer therapy

    PubMed Central

    Senanayake, Thulani H.; Lu, Yaman; Bohling, Anna; Raja, Srikumar; Band, Hamid; Vinogradov, Serguei V.

    2014-01-01

    Purpose Current cancer chemotherapy is gradually shifting to the application of drug combinations that prevent development of drug resistance. Many anticancer drugs have poor solubility and limited oral bioavailability. Using an innovative approach, we developed dual-drug nanoformulations of a polymeric nanogel conjugate with anticancer 5-FU nucleoside analog, floxuridine (FLOX), and the second anticancer drugs, paclitaxel (PCL), or a geldanamycin analog,17-AAG, for combination therapy. Methods PCL or17-AAG had been encapsulated in the cholesteryl-polyvinyl alcohol-floxuridine nanogel (CPVA-FLOX) by simple solution mixing and sonication. Dual nanodrugs formed particles with diameter 180 nm and either drug content (5–20%) that were stable and could be administered orally. Their cytotoxicity in human and mouse cancer cells was determined by MTT assay, and cellular target inhibition – by Western blot analysis. Tumor growth inhibition was evaluated using an orthotopic mouse mammary 4T1 cancer model. Results CPVA-FLOX was more potent than free drug in cancer models including drug-resistant ones; while dual nanodrugs demonstrated a significant synergy(CPVA-FLOX/PCL), or showed no significant synergy (CPVA-FLOX/17-AAG) compared to free drugs (PCL or 17-AAG). Dual nanodrug CPVA-FLOX/17-AAG effect on its cellular target (HSP70) was similar to 17-AAG alone. In animal model, however, both dual nanodrugs effectively inhibited tumor growth compared to CPVA-FLOX after oral administration. Conclusion Oral dual-drug nanoformulations of poorly-soluble drugs proved to be a highly efficient combination anticancer therapy in preclinical studies. PMID:24452808

  14. Water-soluble dopamine-based polymers for photoacoustic imaging.

    PubMed

    Repenko, Tatjana; Fokong, Stanley; De Laporte, Laura; Go, Dennis; Kiessling, Fabian; Lammers, Twan; Kuehne, Alexander J C

    2015-04-11

    Here we present a facile synthetic method yielding a linear form of polydopamine via Kumada-coupling, which can be converted into water-soluble melanin, generating high contrast in photoacoustic imaging.

  15. 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)

  16. Water-soluble pyrrolopyrrole cyanine (PPCy) NIR fluorophores.

    PubMed

    Wiktorowski, Simon; Rosazza, Christelle; Winterhalder, Martin J; Daltrozzo, Ewald; Zumbusch, Andreas

    2014-05-11

    Water-soluble derivatives of pyrrolopyrrole cyanines (PPCys) have been synthesized by a post-synthetic modification route. In highly polar media, these dyes are excellent NIR fluorophores. Labeling experiments show how these novel dyes are internalized into mammalian cells.

  17. Preparation and in vitro evaluation of povidone-sodium cholate-phospholipid mixed micelles for the solubilization of poorly soluble drugs.

    PubMed

    Zhu, Yuan; Yu, Jiangnan; Tong, Shanshan; Wang, Li; Peng, Min; Cao, Xia; Xu, Ximing

    2010-06-01

    Mixed micelles made of polyvinylpyrrolidone (PVP), sodium cholate, and phospholipids were prepared to improve the solubility of poorly water-soluble drugs. Sylibin, a drug used in treating liver diseases, was incorporated into the mixed micelles. The formulation of sylibin containing PVP-sodium cholate-phospholipid mixed micelles with an optimized composition (PVP/sodium cholate/phospholipid/silybin = 3:3:4:1 approximately 2 by weight) was obtained based on the study of pseudoternary phase diagrams. The critical micelle concentration was used to evaluate the micellar stability towards dilution. The results showed that addition of PVP to sodium-cholate-phospholipid mixed micelles increased stability. The solubility of sylibin in PVP-sodium cholate-phospholipid mixed micelles was higher than that in pure water or in sodium cholate-phospholipid mixed micelles. In a stability study, we found that PVP-sodium cholate-phospholipid mixed micelles showed good stability. After 3 months storage at 40 degrees C, just 2.6% sylibin was lost with only minor changes of the particle size when compared to a reference formulation containing sodium cholate and phospholipid mixed micelles. In addition, the developed formulation significantly improved in vitro drug release. The time required to release 50% sylibin (t50%) from sodium cholate and phospholipid mixed micelles was 326 h, while the t50% from PVP-sodium cholate-phospholipid mixed micelles was only 51.1 h. Our results suggest that these mixed micelles might have significant potential application to the biomedical field.

  18. Pharmacological characterization of novel water-soluble cannabinoids.

    PubMed

    Martin, Billy R; Wiley, Jenny L; Beletskaya, Irina; Sim-Selley, Laura J; Smith, Forrest L; Dewey, William L; Cottney, Jean; Adams, Julia; Baker, James; Hill, David; Saha, Bijali; Zerkowski, John; Mahadevan, Anu; Razdan, Raj K

    2006-09-01

    Presently, there are numerous structural classes of cannabinoid receptor agonists, all of which require solubilization for experimental purposes. One strategy for solubilizing water-insoluble tetrahydrocannabinols is conversion of the phenolic hydroxyl to a morpholinobutyryloxy substituent. The hydrochloride salts of these analogs are water-soluble and active in vivo when administered in saline. The present investigation demonstrated that hydrochloride salts of numerous substituted butyryloxy esters are water-soluble and highly potent. The substitutions include piperidine, piperazine, and alkyl-substituted amino moieties. It was also discovered that incorporation of a nitrogenous moiety in the alkyl side chain increased the pharmacological potency of tetrahydrocannabinol. For example, an analog containing a pyrazole in the side chain (O-2545) was found to have high affinity and efficacy at cannabinoid 1 (CB(1)) and CB(2) receptors, and when dissolved in saline, it was highly efficacious when administered either intravenously or intracerebroventricularly to mice. A series of carboxamido and carboxylic acid amide analogs exhibited high pharmacological potency, but their hydrochloride salts were not water-soluble. On the other hand, incorporation of imidazoles into the terminus of the side chain led to water-soluble hydrochloride salts that were highly potent when administered in saline to laboratory animals. It is now possible to conduct cannabinoid research with agonists that are water-soluble and thus obviating the need of solubilizing agents.

  19. Antimalarial activity of new water-soluble dihydroartemisinin derivatives.

    PubMed

    Lin, A J; Klayman, D L; Milhous, W K

    1987-11-01

    The usefulness of sodium artesunate (3), a water-soluble derivative of artemisinin (1), is impaired by its poor stability in aqueous solution. To overcome the ease of hydrolysis of the ester group in 3, a new series of derivatives of dihydroartemisinin (2) was prepared in which the solubilizing moiety, which contains a carboxylate group, is joined to dihydroartemisinin by an ether rather than an ester linkage. The new derivatives were prepared in good yield by treatment of dihydroartemisinin with an appropriate alcohol under boron trifluoride etherate catalysis at room temperature. All major condensation products are the beta isomer. Hydrolysis of the esters with 2.5% KOH/MeOH gave the corresponding potassium salts, which were converted to free acids (8b-d) by acidification. The derivatives were tested in vitro against two clones of human malaria, Plasmodium falciparum D-6 (Sierra Leone clone) and W-2 (Indochina clone). No cross-resistance to the antimalarial agents mefloquine, chloroquine, pyrimethamine, sulfadoxine, and quinine was observed. In general, the new compounds are more effective against the W-2 than the D-6 strain. Esters (5a-d) possess activity comparable to that of the parent compounds 1 and 2; however, conversion of the esters to their corresponding carboxylates (7a-d) or acids (8b-d), with the exception of artelinic acid (8d), drastically decreases the antimalarial activities in both cell lines. Artelinic acid, which is both soluble and stable in 2.5% K2CO3 solution, possesses superior in vivo activity against Plasmodium berghei than artemisinin or artesunic acid.

  20. 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.

  1. Potentiometric analysis of water soluble cutting fluid-metal combinations

    SciTech Connect

    Kelley, E.E.

    1991-12-01

    The results of corrosion studies conducted by the University of Kansas under Contract G257763 for Allied-Signal Inc., Kansas City Division (KCD), are given. These potentiometric studies evaluate the corrosivity of two water soluble cutting fluids at varying concentrations on samples of 304 stainless steel, 6061-T6 aluminum, and beryllium copper. This testing serves two purposes: (1) to develop effective test procedures adaptable to existing KCD corrosion measurement equipment for corrosion analysis of cutting fluid-metals combinations, and (2) to understand the relative corrosiveness of the varying water soluble cutting fluids on different metals. The tests used were adapted from the American Society of Testing Materials (ASTM). Future testing will identify polarization techniques for establishing corrosion rates which will be used in evaluating both water soluble cutting fluids and other aqueous solutions used at KCD.

  2. 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.

  3. Water-Soluble Coenzyme Q10 Reduces Rotenone-Induced Mitochondrial Fission.

    PubMed

    Li, Hai-Ning; Zimmerman, Mary; Milledge, Gaolin Z; Hou, Xiao-Lin; Cheng, Jiang; Wang, Zhen-Hai; Li, P Andy

    2017-02-11

    Parkinson's disease is a neurodegenerative disorder characterized by mitochondrial dysfunction and oxidative stress. It is usually accompanied by an imbalance in mitochondrial dynamics and changes in mitochondrial morphology that are associated with impaired function. The objectives of this study were to identify the effects of rotenone, a drug known to mimic the pathophysiology of Parkinson's disease, on mitochondrial dynamics. Additionally, this study explored the protective effects of water-soluble Coenzyme Q10 (CoQ10) against rotenone-induced cytotoxicity in murine neuronal HT22 cells. Our results demonstrate that rotenone elevates protein expression of mitochondrial fission markers, Drp1 and Fis1, and causes an increase in mitochondrial fragmentation as evidenced through mitochondrial staining and morphological analysis. Water-soluble CoQ10 prevented mitochondrial dynamic imbalance by reducing Drp1 and Fis1 protein expression to pre-rotenone levels, as well as reducing rotenone treatment-associated mitochondrial fragmentation. Hence, water-soluble CoQ10 may have therapeutic potential in treating patients with Parkinson's disease.

  4. 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.

  5. On the mechanism of solubilization of drugs in the presence of poorly soluble additives.

    PubMed

    Boldyrev, V V; Shakhtshneider, T P; Chizhik, S A

    2005-05-13

    A model is proposed which describes the solubilization of a poorly soluble drug in the presence of an insoluble excipient which forms an easily soluble compound with the drug. For sulfathiazole-calcium carbonate system as an example, it is demonstrated using sulfathiazole single crystals and powdered samples that the presence of insoluble additive causes an increase in dissolution rate and solubility of the drug.

  6. Nanosizing of drugs: Effect on dissolution rate.

    PubMed

    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.

  7. 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

  8. 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.

  9. 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...

  10. 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...

  11. Water-soluble constituents of cumin: monoterpenoid glucosides.

    PubMed

    Ishikawa, Toru; Takayanagi, Tomomi; Kitajima, Junichi

    2002-11-01

    From the water-soluble portion of the methanol extract of cumin (fruit of Cuminum cyminum L.), which has been used as a spice and medicine since antiquity, sixteen monoterpenoid glucosides, including twelve new compounds, were isolated. Their structures were clarified by spectral investigation.

  12. Control of pulmonary absorption of water-soluble compounds by various viscous vehicles.

    PubMed

    Yamamoto, Akira; Yamada, Keigo; Muramatsu, Hideaki; Nishinaka, Asako; Okumura, Shigeki; Okada, Naoki; Fujita, Takuya; Muranishi, Shozo

    2004-09-10

    Effects of various viscous vehicles on the pulmonary absorption of water-soluble drugs were examined by an in situ pulmonary absorption experiment. Gelatin, polyvinylacohol (PVA), hydroxypropylcellose (HPC), chondroitin sulfate A sodium salt (CS), polyacrylic acid (PAA), methylcellulose #400 (MC400) and hyaluronic acid sodium salt (HA) were used as models of viscous vehicles. 5(6)-Carboxyfluorescein (CF) and fluorescein isothiocayanate-labeled dextran with an average molecular weight of 4000 (FD4) were used as water-soluble drugs. The plasma concentration of CF was controlled and regulated in the presence of these viscous vehicles, especially gelatin (1-5%) and polyvinyl alcohol (PVA) 1%. In the pharmacokinetic analysis, the Cmax values of CF significantly decreased, and its Tmax values increased in the presence of these viscous vehicles compared with the control. The MRT and MAT values of CF with these vehicles were significantly higher than those without these vehicles. Therefore, these findings indicated that the viscous vehicles were effective to regulate the absorption rate of CF. On the other hand, the pulmonary absorption of FD4 was not so much affected even in the presence of gelatin and PVA, although PVA slightly decreased MRT value, and significantly decreased Tmax value. Furthermore, we examined the release rate of CF from the cellulose tube containing various concentrations of gelatin. The release rate of CF from the cellulose tube with gelatin was inversely related to the viscosity of gelatin. In addition, the release rate of CF was inversely related to DeltaMAT (DeltaMAT = MATgel(MAT with gelatin)-MATsol(MAT without gelatin)) in the presence of varying concentrations of gelatin. These findings indicated that these viscous vehicles were effective to control the pulmonary absorption of CF, a water-soluble drug with low molecular weight and they might be useful to increase the local concentration of drugs in the lung.

  13. 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.

  14. 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.

  15. New water-soluble prodrugs of HIV protease inhibitors based on O-->N intramolecular acyl migration.

    PubMed

    Hamada, Yoshio; Ohtake, Jun; Sohma, Youhei; Kimura, Tooru; Hayashi, Yoshio; Kiso, Yoshiaki

    2002-12-01

    To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-272 and KNI-279 which are potent HIV-1 protease inhibitors consisting of an Apns-Thz core structure (Apns; allophenylnorstatine, Thz; thiazolidine-4-carboxylic acid) as an inhibitory machinery. The prodrugs, which contained an O-acyl peptidomimetic structure with an ionized amino group leading to the increase of water-solubility, were designed to regenerate the corresponding parent drugs based on the O-->N intramolecular acyl migration reaction at the alpha-hydroxy-beta-amino acid residue, that is allophenylnorstatine. The synthetic prodrugs 3, 4, 6, and 7 improved the water-solubility (>300mg/mL) more than 4000-fold in comparison with the parent compounds, which is the practically acceptable value as water-soluble drugs. These prodrugs were stable as an HCl salt and in a strongly acidic solution corresponding to gastric juice (pH 2.0), and could be converted to the parent compounds promptly in the aqueous condition from slightly acidic to basic pH at 37 degrees C, with the suitable migration rate, via a five-membered ring intermediate. Using a similar method, we synthesized a prodrug (12) of ritonavir, a clinically useful HIV-1 protease inhibitor as an anti-AIDS drug. In contrast to the prodrugs 3, 4, 6, and 7, the prodrug 12 was very slowly converted to ritonavir probably through a six-membered ring intermediate, with the t(1/2) value of 32h that may not be suitable for practical use.

  16. Sources and light absorption of water-soluble organic carbon aerosols in the outflow from northern China

    NASA Astrophysics Data System (ADS)

    Kirillova, E. N.; Andersson, A.; Han, J.; Lee, M.; Gustafsson, Ö.

    2014-02-01

    High loadings of anthropogenic carbonaceous aerosols in Chinese air influence the air quality for over one billion people and impact the regional climate. A large fraction (17-80%) of this aerosol carbon is water-soluble, promoting cloud formation and thus climate cooling. Recent findings, however, suggest that water-soluble carbonaceous aerosols also absorb sunlight, bringing additional direct and indirect climate warming effects, yet the extent and nature of light absorption by this water-soluble "brown carbon" and its relation to sources is poorly understood. Here, we combine source estimates constrained by dual carbon isotopes with light-absorption measurements of water-soluble organic carbon (WSOC) for a March 2011 campaign at the Korea Climate Observatory at Gosan (KCOG), a receptor station in SE Yellow Sea for the outflow from northern China. The mass absorption cross section at 365 nm (MAC365) of WSOC for air masses from N. China were in general higher (0.8-1.1 m2 g-1), than from other source regions (0.3-0.8 m2 g-1). However, this effect corresponds to only 2-10% of the radiative forcing caused by light absorption by elemental carbon. Radiocarbon constraints show that the WSOC in Chinese outflow had significantly higher fraction fossil sources (30-50%) compared to previous findings in S. Asia, N. America and Europe. Stable carbon (δ13C) measurements were consistent with aging during long-range air mass transport for this large fraction of carbonaceous aerosols.

  17. 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.

  18. 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.

  19. Water-soluble sacrificial layers for surface micromachining.

    PubMed

    Linder, Vincent; Gates, Byron D; Ryan, Declan; Parviz, Babak A; Whitesides, George M

    2005-07-01

    This manuscript describes the use of water-soluble polymers for use as sacrificial layers in surface micromachining. Water-soluble polymers have two attractive characteristics for this application: 1) They can be deposited conveniently by spin-coating, and the solvent removed at a low temperature (95-150 degrees C), and 2) the resulting layer can be dissolved in water; no corrosive reagents or organic solvents are required. This technique is therefore compatible with a number of fragile materials, such as organic polymers, metal oxides and metals-materials that might be damaged during typical surface micromachining processes. The carboxylic acid groups of one polymer-poly(acrylic acid) (PAA)-can be transformed by reversible ion-exchange from water-soluble (Na+ counterion) to water-insoluble (Ca2+ counterion) forms. The use of PAA and dextran polymers as sacrificial materials is a useful technique for the fabrication of microstructures: Examples include metallic structures formed by the electrodeposition of nickel, and freestanding, polymeric structures formed by photolithography.

  20. 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.

  1. [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.

  2. 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...

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

    PubMed

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

    2011-08-07

    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.

  4. 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

  5. Phytoglycogen improves the water solubility and Caco-2 monolayer permeation of quercetin.

    PubMed

    Chen, Hua; Yao, Yuan

    2017-04-15

    The study examined the capability of phytoglycogen (PG) to improve the water solubility of quercetin (QC). PG-QC formulations were prepared by mixing a QC ethanol solution with a PG aqueous solution followed with vacuum drying of the supernatant. PG-QC formulations with various PG to QC ratios were prepared; the solubility of QC reached 241.76μg/mL at PG/QC ratio of 30/1 compared with approximately 4.32μg/mL of QC alone. The X-ray powder diffraction and FTIR analyses showed a significant reduction of QC crystallinity upon formulating with PG that was associated with the intermolecular hydrogen bonding between the hydroxyl groups of QC and PG. The Caco-2 cell monolayer permeation tests showed that PG-QC formulations resulted in substantially enhanced cellular uptake and transepithelial permeation of QC, which was related to the much-enhanced QC solubility. This study showed the potential of using PG to formulate poorly water-soluble ingredients such as QC.

  6. 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

    2016-03-15

    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.

  7. 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

  8. Mineralization of sparsely water-soluble polycyclic aromatic hydrocarbons in a water table fluctuation zone

    SciTech Connect

    Holman, H.Y.N.; Tsang, Y.W.; Holman, W.R.

    1999-06-01

    The mineralization potential of sparsely water-soluble polycyclic aromatic hydrocarbons (PAHs) within a highly diesel-contaminated water table fluctuation zone (WTFZ) was investigated using core-scale column microcosms. Experimental conditions mimicked overall seasonal changes in water and oxygen content at the site. During the first aerobic winter, PAH mineralization rates in the freshly contaminated soil were fastest for contaminant [{sup 14}C]-naphthalene which was the least hydrophobic and most water-soluble. Lowering the water table nearly doubled the mineralization rates of all [{sup 14}C]PAHs studied. During the oxygen-poor summer, all mineralization rates were insignificant and failed to respond to water table changes. Neither a return to water-saturated aerobic (winter) conditions nor lowering the water table under aerobic conditions induced detectable mineralization of [{sup 14}C]-naphthalene, but lowering the water table did markedly hasten the still slow mineralization of [{sup 14}C]phenanthrene and [{sup 14}C]anthracene. The time-dependent mineralization behavior and its response to water table fluctuations were explicable in terms of microbial responses to the changing oxygen content and depleting mineral nutrients.

  9. Correlation of octanol/water solubility ratios and partition coefficients

    SciTech Connect

    Pinsuwan, S.; Li, A.; Yalkowsky, S.H.

    1995-05-01

    The partition coefficient between octanol and water in an important physicochemical parameter for characterizing the lipophilicity or hydrophobicity of a compound and it is used in many fields, especially in the environmental and pharmaceutical sciences. The octanol/water solubility ratio (S{sub o}/S{sub W}) was found to be highly correlated with the octanol/water partition coefficient (K{sub ow}) of 82 pharmaceutically and environmentally relevant compounds. The solubility ratio gives comparable estimates to that of the group contribution (log P(calcd)) method for estimating the partition coefficient of the compounds used in this study.

  10. 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.

  11. Water-soluble constituents from aerial roots of Ficus microcarpa.

    PubMed

    Ouyang, M-A; Kuo, Y-H

    2006-01-01

    Three new water-soluble constituents [ficuscarpanoside B (1), (7E,9Z)-dihydrophaseic acid 3-O-beta-D-glucopyranoside (4) and ficuscarpanic acid (6)] and the natural product 2,2'-dihydroxyl ether (7) have been isolated, together with three known compounds [(7S,8R)-syringoylglycerol (2), (7S,8R)-syringoylglycerol-7-O-beta-D-glucopyranoside (3) and icariside D2 (5)] from the aerial roots of Ficus microcarpa. Identification of their structures was achieved by 1D and 2D NMR experiments, including 1H-1H COSY, NOESY, HMQC and HMBC methods and FAB mass spectral data.

  12. Investigations on the drug releasing mechanism from an asymmetric membrane-coated capsule with an in situ formed delivery orifice.

    PubMed

    Lin, Ying Ku; Ho, Hsiu O

    2003-04-14

    Asymmetric membrane-coated capsules with in situ formation of a delivery orifice were examined for their improved osmotic effects. The release mechanisms were investigated for drugs with both moderate to high water solubility and those with poor water solubility. The capsule wall membrane was produced by a phase-inversion process, in which an asymmetric membrane was formed on stainless steel mold pins by dipping the mold pins into a coating solution containing a polymeric material followed by dipping into a quenching solution. In situ formation of a delivery orifice in the thin membrane was proven by visualization of a jet stream of chlorophyll being released from the capsule. The release mechanism for drugs with moderate to high water solubility was mainly controlled by the osmotic effect, which is a function of the drug's solubility. Permeability across the asymmetric membrane of the capsule was determined to be 4.28 x 10(-6) cm(2)/h-atm at 37 degrees C for drugs with water solubilities in a moderate to high range. Accordingly, the poorly water-soluble drug, nifedipine, was unable to create enough of an osmotic effect to activate drug release. Solubilization either by the addition of the solubility enhancer, SLS, or by a solid dispersion with HPMC could increase the solubility of nifedipine to a sufficient extent to activate drug release. It was found that the suspending ability induced by the viscous nature of HPMC further interacted with SLS to synergistically increase the maximal percent release and the release rate of nifedipine. The osmotic effect of this suspension ability was proposed as the underlying mechanism responsible for the release of poorly water-soluble drugs, i.e. nifedipine, from this system.

  13. In vitro release of a water-soluble agent from low viscosity biodegradable, injectable oligomers.

    PubMed

    Sharifpoor, Soroor; Amsden, Brian

    2007-03-01

    Low-molecular-weight poly(epsilon-caprolactone-co-1,3-trimethylene carbonate) and poly(1,3-trimethylene carbonate) are potential vehicles for the regio-specific delivery of water-soluble agents. In this paper, the characteristics and the mechanism governing the in vitro release of a model water-soluble drug, vitamin B12, from these polymer vehicles were determined. The loading of vitamin B12 was kept to 1 w/w%. The oligomers examined ranged from amorphous, high viscosity to crystalline but low viscosity. The oligomers did not degrade appreciably in vitro. The total fraction of vitamin B12 released increased as the crystallinity of the oligomers decreased, reaching nearly total release only for the completely amorphous oligomers. The rate of release was fastest for the amorphous oligomers and dependent on their viscosity. Inclusion of a more osmotically active agent, trehalose, into the vitamin B12 particles through co-lyophilization resulted in enhanced total fraction released and a faster release rate. The results are consistent with an osmotically driven release mechanism.

  14. Water-soluble derivatives of 25-OCH3-PPD and their anti-proliferative activities.

    PubMed

    Zhou, Wu-Xi; Sun, Yuan-Yuan; Yuan, Wei-Hui; Zhao, Yu-Qing

    2017-03-18

    (20R)-25-Methoxyl-dammarane-3β,12β,20-triol (25-OCH3-PPD, AD-1) is a dammarane-type sapogenin showing anti-tumor potential. In the search for new anti-tumor agents with higher potency than our previously identified compound 25-OCH3-PPD, 11 novel sulfamic acid and diacid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 25-OCH3-PPD, compounds 1, 4, and 5 exhibited higher cytotoxic activity on almost all cell lines, together with lower toxicity in the normal cell. In particular, compound 1 exhibited the best anti-tumor activity in the in vitro assays. The water solubility of 25-OCH3-PPD and its derivatives was tested and the results showed that the solubility of 25-OCH3-PPD sulfamic acid and diacid derivatives were better than that of 25-OCH3-PPD in water, which may provide valuable data for the research and development of new anti-tumor agents.

  15. Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury

    PubMed Central

    Liu, Hui; Yang, Lei; Wu, Hui-Jun; Chen, Kui-Hao; Lin, Feng; Li, Gang; Sun, Hai-Ying; Xiao, Guo-Sheng; Wang, Yan; Li, Gui-Rong

    2016-01-01

    The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome. PMID:27819271

  16. Water-soluble prodrugs of dipeptide HIV protease inhibitors based on O-->N intramolecular acyl migration: Design, synthesis and kinetic study.

    PubMed

    Hamada, Yoshio; Matsumoto, Hikaru; Yamaguchi, Satoshi; Kimura, Tooru; Hayashi, Yoshio; Kiso, Yoshiaki

    2004-01-02

    To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-727, a potent small-sized dipeptide-type HIV-1 protease inhibitor consisting of an Apns-Dmt core (Apns; allophenylnorstatine, Dmt; (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid) as inhibitory machinery. These prodrugs contained an O-acyl peptidomimetic structure with an ionized amino group leading to an increase in water-solubility, and were designed to regenerate the corresponding parent drugs based on the O-->N intramolecular acyl migration reaction via a five-membered ring intermediate at the alpha-hydroxy-beta-amino acid residue, that is Apns. The synthetic prodrug 3a improved the water-solubility (13 mg/mL) more than 8000-fold in comparison with the parent compound, which is the practically acceptable value as water-soluble drug. Furthermore, to understand the structural effects of the O-acyl moiety on the migration rate, we evaluated several phenylacetyl-type and benzoyl-type prodrugs. These prodrugs were stable as an HCl salt and in a strongly acidic solution corresponding to gastric juice (pH 2.0), and could be converted to the parent compounds promptly under aqueous conditions from slightly acidic to basic pH at 37 degrees C.

  17. Novel water soluble NIR dyes: does charge matter?

    NASA Astrophysics Data System (ADS)

    Patonay, Gabor; Henary, Maged; Beckford, Garfield; Daube, Alison

    2012-03-01

    Near-Infrared (NIR) dyes are used as reporters, probes or markers in the biological and medical field. NIR dyes can be useful for investigating and characterizing biomolecular interactions or imaging which is possible because biological mammalian tissue has a low absorption window in the NIR region. Biomolecules such as proteins are known to bind to NIR dyes. Upon binding NIR dyes often exhibit spectral changes that can be used for characterizing the binding event. Serum albumins may be responsible for in vivo transport of NIR dyes. Studying this binding event can be useful when correlated to in vivo behavior of the NIR dye. The studies presented here use spectroscopic methods to investigate how NIR dyes that may be used in imaging, biological or bioanalytical applications bind to proteins, such as serum albumins. Our research group systematically synthesized several NIR dyes that have varying hydrophobicity, chromophore size and charge. During these investigations we developed novel NIR cyanine fluorophores having varying aqueous solubility and a variety of net charges. The binding properties of the carbocyanines change when charged or hydrophobic moieties are systematically varied. One of the properties we put a special emphasis on is what we call residual hydrophobicity of the NIR dye molecule which is defined as the unmasked (by the charged moieties) hydrophobicity of the molecule. Residual hydrophobicity may be responsible for binding the otherwise highly water soluble NIR dye to hydrophobic pockets of biomolecules. High residual hydrophobicity of a highly water soluble dye can be disadvantageous during biological, medical or similar applications.

  18. Water-soluble vitamin levels in extended hours hemodialysis.

    PubMed

    Coveney, Natalie; Polkinghorne, Kevan R; Linehan, Leanne; Corradini, AnnMarie; Kerr, Peter G

    2011-01-01

    Patients on extended hours (>15 h/week) hemodialysis may be at a higher risk of deficiency of water-soluble vitamins than conventional (≤15 h/week) hemodialysis patients due to their increased weekly hours of dialysis. We compared serum levels of the water-soluble vitamins in a group of extended and conventional hours hemodialysis patients. Predialysis serum levels of vitamin C, vitamin B12, thiamine, pyridoxine, and folate were measured in 52 patients: 26 extended group and 26 conventional group. Information on patient's intake of vitamin supplements and dialysis regimen was obtained. Data were log transformed due to the skewed distribution of the results. Median vitamin C levels were significantly lower in the extended group (0.30 vs. 1.14 mg/dL, P<0.001), with 7 patients having a level <0.18 mg/dL. Thiamine levels were also lower in the extended group (median 211 vs. 438.5 nmol/L, P=0.0005). However, extended patients had higher levels of pyridoxine (23.2 vs. 11.1 ng/mL, P=0.03). Vitamin B12 and folate levels were not significantly different between the groups. There was significant variability in vitamin supplement prescription in both groups, and dietary data were not obtained. This study showed a high incidence of vitamin C deficiency in extended hours hemodialysis patients, suggesting that supplementation is warranted. It also supports an ongoing role for multivitamin supplementation in conventional hemodialysis patients.

  19. 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.

  20. 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.

  1. Nanoparticle Formulation Increases Oral Bioavailability of Poorly Soluble Drugs: Approaches Experimental Evidences and Theory

    PubMed Central

    Jia, Lee

    2009-01-01

    The increasing frequency at which poorly soluble new chemical entities are being discovered raises concerns in the pharmaceutical industry about drugability associated with erratic dissolution and low bioavailability of these hydrophobic compounds. Nanonization provides a plausible pharmaceutical basis for enhancing oral bioavailability and therapeutic effectiveness of these compounds by increasing their surface area. This paper surveys methods available to pharmaceutical manufacturing nanoparticles, including wet chemical processes, media milling, high pressure homogenization, gas-phase synthesis, and form-in-place processes, and elaborates physicochemical rational and gastrointestinal physiological basis upon which nano-drugs can be readily absorbed. Relevant examples are illustrated to show that nano-drugs permeate Caco-2 cell monolayer fast and are well absorbed into animal systemic circulation with high Tmax and AUC, resulting in oral bioavailability higher than their counterpart micro-drugs. The size-dependent permeability and bioavailability should be given particular consideration in the development of potent and selective drug candidates with poor aqueous solubility. PMID:19865587

  2. Identifying possible reasons why female street sex workers have poor drug treatment outcomes: a qualitative study

    PubMed Central

    Jeal, Nikki; Macleod, John; Salisbury, Chris; Turner, Katrina

    2017-01-01

    Aims To explore street sex workers (SSWs) views and experiences of drug treatment, in order to understand why this population tend to experience poor drug treatment outcomes. Design In-depth interviews. Setting Bristol, UK. Participants 24 current and exited SSWs with current or previous experience of problematic use of heroin and/or crack cocaine. Findings Participants described how feeling unable to discuss their sex work in drug treatment groups undermined their engagement in the treatment process. They outlined how disclosure of sex work resulted in stigma from male and female service users as well as adverse interactions with male service users. Participants highlighted that non-disclosure meant they could not discuss unresolved trauma issues which were common and which emerged or increased when they reduced their drug use. As trauma experiences had usually involved men as perpetrators participants said it was not appropriate to discuss them in mixed treatment groups. SSWs in recovery described how persistent trauma-related symptoms still affected their lives many years after stopping sex work and drug use. Participants suggested SSW-only services and female staff as essential to effective care and highlighted that recent service changes were resulting in loss of trusted staff and SSW-only treatment services. This was reported to be reducing the likelihood of SSWs engaging in drug services, with the resultant loss of continuity of care and reduced time with staff acting as barriers to an effective therapeutic relationship. Conclusions SSWs face many barriers to effective drug treatment. SSW-only treatment groups, continuity of care with treatment staff and contact with female staff, particularly individuals who have had similar lived experience, could improve the extent to which SSWs engage and benefit from drug treatment services. Service engagement and outcomes may also be improved by drug services that include identification and treatment of trauma

  3. Application of melt granulation technology to enhance tabletting properties of poorly compactible high-dose drugs.

    PubMed

    Lakshman, Jay P; Kowalski, James; Vasanthavada, Madhav; Tong, Wei-Qin; Joshi, Yatindra M; Serajuddin, Abu T M

    2011-04-01

    Using metformin HCl as the model drug and hydroxypropylcellulose (HPC) as the polymeric excipient, a melt granulation (MG) process that employs a twin-screw extruder has been developed to enhance compactibility of poorly compactible high-dose drug substances. A high (90%) drug-load tablet formulation, containing 1025 mg of active pharmaceutical ingredients and 109 mg of excipients, was produced. Drug-polymer-powder mixtures were melt granulated at a temperature above glass transition of HPC (130°C) but below melting point of metformin HCl (224°C). MG was compared with modified wet granulation (WG) and solvent granulation (SG) processes. Under identical compression force, the hardness of tablets produced was MG>SG>WG and the friability was MGdrugs and combination products by decreasing the need for relatively large amounts of excipients generally used to overcome physicochemical limitations of drug substances. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1553-1565, 2011.

  4. Planar microdevices for enhanced in vivo retention and oral bioavailability of poorly permeable drugs.

    PubMed

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

    2014-10-01

    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.

  5. Oil-cyclodextrin based beads for oral delivery of poorly-soluble drugs.

    PubMed

    Hamoudi, M C; Bochot, A

    2014-01-01

    The main interest of cyclodextrins results from their ability to form inclusion complexes with hydrophobic molecules. This property is employed in pharmaceutical industry to facilitate the formulation of poorly-soluble and/or fragile drugs. Cyclodextrins are also used to form or stabilise dispersed systems. An original multiparticulate system named "beads" is obtained thanks to the interactions occurring between the molecules of α cyclodextrin and the triglycerides of vegetable oils. Beads are prepared by a simple process involving the external shaking of a mixture of an aqueous solution of α cyclodextrin with soybean oil. This is done without any organic solvent or surface-active agent. Once freezedried, beads have a diameter of 1.6 mm and a high lipid content. They consist in a partially crystalline matrix of cyclodextrin surrounding microdomains of oil. The coating of beads with a layer of α cyclodextrin improves their resistance in gastro- intestinal fluids and prolongs the release of drugs. Beads can also be manufactured from mineral oils with α cyclodextrin and from silicone oils with γ cyclodextrin. Poorly-soluble drugs which do not form inclusion complexes with α cyclodextrin are encapsulated in beads with high efficiency and drug loading. In rats, the oral bioavailability of isotretinoin is twofold enhanced with uncoated beads as compared to the lipid content of a soft capsule. The relative oral bioavailability of indomethacin is improved with both coated and uncoated beads versus a commercial hard capsule. Beads demonstrate an important potential for the encapsulation of poorly-soluble and/or fragile compounds and their delivery by oral route.

  6. 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.

  7. 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

  8. Synthesis of new water-soluble metal-binding polymers: Combinatorial chemistry approach. 1997 mid-year progress report

    SciTech Connect

    Smith, B.F.

    1997-06-01

    'The first objective of this research is to develop rapid discovery and optimization approaches to new water-soluble chelating polymers. A byproduct of the development approach will be the new, selective, and efficient metal-binding agents. The second objective is to evaluate the concept of using water and organic soluble polymers as new solid supports for combinatorial synthesis. The technology under development, Polymer Filtration (PF), is a technique to selectively remove or recover hazardous and valuable metal ions and radionuclides from various dilute aqueous streams. Not only can this technology be used to remediate contaminated soils and solid surfaces and treat aqueous wastes, it can also be incorporated into facilities as a pollution prevention and waste minimization technology. Polymer Filtration uses water-soluble metal-binding polymers to sequester metal ions in dilute solution. The water-soluble polymers have a sufficiently large molecular size that they can be separated and concentrated using commercial ultrafiltration technology. Water, small organic molecules, and unbound metals pass freely through the ultrafiltration membrane while concentrating the metal-binding polymer. The polymers can then be reused by changing the solution conditions to release the metal ions. The metal-ions are recovered in concentrated form for recycle or disposal using a diafiltration process. The water-soluble polymer can be recycled for further aqueous-stream processing. To advance Polymer Filtration technology to the selectivity levels required for DOE needs. fixture directions in Polymer Filtration must include rapid development, testing, and characterization of new metal-binding polymers. The development of new chelating molecules can be equated to the process of new drugs or new materials discovery. Thus, the authors want to build upon and adapt the combinatorial chemistry approaches developed for rapid molecule generation for the drug industry to the rapid

  9. Wood-plastic composite using water soluble monomer

    NASA Astrophysics Data System (ADS)

    Khan, Mubarak A.; Ali, K. M. Idriss

    Wood-plastic composite (WPC) has been prepared with simul using acrylamide (AM), a water soluble monomer, in place of styrene (ST) and butylmethacrylate (BA). The highest polymer loading (PL) is achieved with AM along with the highest tensile strengths (TS) among the three bulk monomers studied. Effect of urea, NVP and TMPTA has been investigated in these systems. Co-additive (urea) has played a significant role in presence of NVP and TMPTA with AM compared to ST and BA systems. Methanol, water and water/methanol mixtures have been used as swelling agents in order to study their effect on PL and T f values. TS loss due to the weathering effect is minimum with the WPC, particularly if prepared with swelling agent methanol.

  10. Self-assembly of water-soluble nanocrystals

    DOEpatents

    Fan, Hongyou [Albuquerque, NM; Brinker, C Jeffrey [Albuquerque, NM; Lopez, Gabriel P [Albuquerque, NM

    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.

  11. 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.

  12. Encapsulation of β-carotene within ferritin nanocages greatly increases its water-solubility and thermal stability.

    PubMed

    Chen, Lingli; Bai, Guangling; Yang, Rui; Zang, Jiachen; Zhou, Ting; Zhao, Guanghua

    2014-04-15

    Carotenoids may play a number of potential health benefits for human. However, their use in food industry is limited mostly because of their poor water-solubility and low thermal stability. Ferritins are widely distributed in nature with a shell-like structure which offers a great opportunity to improve the water-solubility and thermal stability of the carotenoids by encapsulation. In this work, recombinant human H-chain ferritin (rHuHF) was prepared and used to encapsulate β-carotene, a typical compound among carotenoids, by taking advantage of the reversible dissociation and reassembly characteristic of apoferritin in different pH environments. Results from high-performance liquid chromatography (HPLC), UV/Vis spectroscopy and transmission electron microscope (TEM) indicated that β-carotene molecules were successfully encapsulated within protein cages with a β-carotene/protein molar ratio of 12.4-1. Upon such encapsulation, these β-carotene-containing apoferritin nanocomposites were water-soluble. Interestingly, the thermal stability of the β-carotene encapsulated within apoferritin nanocages was markedly improved as compared to free β-carotene. These new properties might be favourable to the utilisation of β-carotene in food industry.

  13. 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.

  14. Water-soluble antioxidants improve the antioxidant and anticancer activity of low concentrations of curcumin in human leukemia cells.

    PubMed

    Chen, Jie; Wanming, Da; Zhang, Dawei; Liu, Qing; Kang, Jiuhong

    2005-01-01

    Curcumin (Cur) is a promising antioxidant and anticancer drug, but several recent studies indicate that Cur exerts its anticancer activity through promoting reactive oxygen species (ROS) generation. In the present study, concentration-dependent regulation of Cur on cell proliferation, viability and ROS generation, and effect of water-soluble antioxidants ascorbic acid (ASA), N-acetyl-cysteine (NAC) and reduced glutathione (GSH) on the antioxidant and anticancer activity of Cur were investigated in human myeloid leukemia cells (HL-60 cells). We found that although Cur concentration- and time-dependently decreased the proliferation and viability of cells, its effect on ROS generation (as indicated by the level of malondialdehyde, MDA) varied with its concentrations. I.e., low concentrations of Cur diminished the ROS generation, while high Cur promoted it. Combined with the opposite effect of 50 microM H2O2 on low or high Cur-induced MDA alteration, cell proliferation arrest and cell death, these results proved that low Cur exerted its anticancer activity through diminishing ROS generation in HL-60 cells, while high Cur through promoting ROS generation. Further studies showed that all water-soluble antioxidants ASA, NAC and GSH significantly enhanced both the antioxidant and the anticancer activity of low Cur. Considering that the extra accumulation of ROS is harmful to normal cells, the data presented here indicate that instead of using high doses, combining low doses of Cur with water-soluble antioxidants is a better strategy for us to improve the anticancer activity of Cur.

  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. 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.

  17. Determination of the design space of the HPLC analysis of water-soluble vitamins.

    PubMed

    Wagdy, Hebatallah A; Hanafi, Rasha S; El-Nashar, Rasha M; Aboul-Enein, Hassan Y

    2013-06-01

    Analysis of water-soluble vitamins has been tremendously approached through the last decades. A multitude of HPLC methods have been reported with a variety of advantages/shortcomings, yet, the design space of HPLC analysis of these vitamins was not defined in any of these reports. As per the food and drug administration (FDA), implementing the quality by design approach for the analysis of commercially available mixtures is hypothesized to enhance the pharmaceutical industry via facilitating the process of analytical method development and approval. This work illustrates a multifactorial optimization of three measured plus seven calculated influential HPLC parameters on the analysis of a mixture containing seven common water-soluble vitamins (B1, B2, B6, B12, C, PABA, and PP). These three measured parameters are gradient time, temperature, and ternary eluent composition (B1/B2) and the seven calculated parameters are flow rate, column length, column internal diameter, dwell volume, extracolumn volume, %B (start), and %B (end). The design is based on 12 experiments in which, examining of the multifactorial effects of these 3 + 7 parameters on the critical resolution and selectivity, was carried out by systematical variation of all these parameters simultaneously. The 12 basic runs were based on two different gradient time each at two different temperatures, repeated at three different ternary eluent compositions (methanol or acetonitrile or a mixture of both). Multidimensional robust regions of high critical R(s) were defined and graphically verified. The optimum method was selected based on the best resolution separation in the shortest run time for a synthetic mixture, followed by application on two pharmaceutical preparations available in the market. The predicted retention times of all peaks were found to be in good match with the virtual ones. In conclusion, the presented report offers an accurate determination of the design space for critical resolution in the

  18. [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.

  19. Lipid-soluble and water-soluble beta-blockers. Comparison of the central nervous system depressant effect.

    PubMed

    Gengo, F M; Huntoon, L; McHugh, W B

    1987-01-01

    The sedative effects of a relatively lipid-soluble and a water-soluble beta-blocker were compared in 20 male hypertensives, 30 to 60 years old. In a blinded, randomized, crossover study, critical flash fusion frequency and computerized Stroop Word Test were used to assess psychomotor function parameters during a drug-free control day and then following 14 days of either metoprolol, 150 mg daily, or atenolol, 100 mg daily, treatment. Both drugs caused subtle but significant reductions in both parameters of sedation (critical flash fusion frequency and computerized Stroop Word Testing). Sedation was significantly related to serum concentrations of both drugs. The maximum drug-induced change was 17.2% +/- 9% for metoprolol and 19.6% +/- 3% for atenolol. The duration of effect was six hours after atenolol and two hours after metoprolol. Blood pressure control for all patients was similar during both treatment phases. These results demonstrate that relative lipid solubility does not reliably predict the neurologic effects of beta-blockers. The intensity of drug-induced sedation was similar, but the water-soluble agent produced a longer duration of sedative activity.

  20. 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

  1. Water-soluble adjuvant obtained from Bacterionema matruchotii.

    PubMed Central

    Nitta, T; Okumura, S; Tanabe, M J; Nakano, M

    1978-01-01

    The adjuvant effect of a butanol-extracted water-soluble adjuvant (bu-WSA) obtained from Bacterionemia matruchotii, a gram-positive oral bacteria, was studied on the antibody response at the plaque-forming cell (PFC) level in murine spleens. Intraperitoneal injection of Bu-WSA caused significant increase in direct PFC numbers in spleens 1 to 3 days after the antigenic stimulation with sheep erythrocytes (SRBC). Injection of 100 to 800 microgram of Bu-WSA was effective, and 400 microgram of Bu-WSA seemed to be the optimum for induction of the adjuvant effect. The adjuvant effect was strongest when Bu-WSA was injected at the same time as the SRBC, but some effect was still observed when Bu-WSA was injected 7 days before or 1 day after the immunization. The adjuvant effect of Bu-WSA was greatest at high dose of antigen. The mice injected with Bu-WSA at the time of priming SRBC and then immunized with trinitrophenylated SRBC showed greater anti-trinitrophenyl PFC response than controls without the injection of Bu-WSA. These findings suggest that a part of the adjuvant effect of Bu-WSA depends on thymic cell function and another part does not. PMID:352955

  2. 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.

  3. 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.

  4. 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...

  5. 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.

  6. Role of Molecular Interactions for Synergistic Precipitation Inhibition of Poorly Soluble Drug in Supersaturated Drug-Polymer-Polymer Ternary Solution.

    PubMed

    Prasad, Dev; Chauhan, Harsh; Atef, Eman

    2016-03-07

    We are reporting a synergistic effect of combined Eudragit E100 and PVP K90 in precipitation inhibition of indomethacin (IND) in solutions at low polymer concentration, a phenomenon that has significant implications on the usefulness of developing novel ternary solid dispersion of poorly soluble drugs. The IND supersaturation was created by cosolvent technique, and the precipitation studies were performed in the absence and the presence of individual and combined PVP K90 and Eudragit E100. The studies were also done with PEG 8000 as a noninteracting control polymer. A continuous UV recording of the IND absorption was used to observe changes in the drug concentration over time. The polymorphic form and morphology of precipitated IND were characterized by Raman spectroscopy and scanning electron microscopy. The change in the chemical shift in solution (1)H NMR was used as novel approach to probe IND-polymer interactions. Molecular modeling was used for calculating binding energy between IND-polymer as another indication of IND-polymer interaction. Spontaneous IND precipitation was observed in the absence of polymers. Eudragit E100 showed significant inhibitory effect on nuclei formation due to stronger interaction as reflected in higher binding energy and greater change in chemical shift by NMR. PVP K90 led to significant crystal growth inhibition due to adsorption on growing IND crystals as confirmed by modified crystal habit of precipitate in the presence of PVP K90. Combination of polymers resulted in a synergistic precipitation inhibition and extended supersaturation. The NMR confirmed interaction between IND-Eudragit E100 and IND-PVP K90 in solution. The combination of polymers showed similar peak shift albeit using lower polymer concentration indicating stronger interactions. The results established the significant synergistic precipitation inhibition effect upon combining Eudragit E100 and PVP K90 due to drug-polymer interaction.

  7. Amorphous solid dispersion technique for improved drug delivery: basics to clinical applications.

    PubMed

    Mishra, Dinesh Kumar; Dhote, Vinod; Bhargava, Arpit; Jain, Dinesh Kumar; Mishra, Pradyumna Kumar

    2015-12-01

    Solid dispersion has emerged as a method of choice and has been extensively investigated to ascertain the in vivo improved performance of many drug formulations. It generally involves dispersion of drug in amorphous particles (clusters) or in crystalline particles. Comparatively, in the last decade, amorphous drug-polymer solid dispersion has evolved into a platform technology for delivering poorly water-soluble small molecules. However, the success of this technique in the pharmaceutical industry mainly relies on different drug-polymer attributes like physico-chemical stability, bioavailability and manufacturability. The present review showcases the efficacy of amorphous solid dispersion technique in the research and evolution of different drug formulations particularly for those with poor water soluble properties. Apart from the numerous mechanisms of action involved, a comprehensive summary of different key parameters required for the solubility enhancement and their translational efficacy to clinics is also emphasized.

  8. Aggregation of phospholipid vesicles by water-soluble polymers.

    PubMed Central

    Meyuhas, D; Nir, S; Lichtenberg, D

    1996-01-01

    Water-soluble polymers such as dextran and polyethylene glycol are known to induce aggregation and size growth of phospholipid vesicles. The present study addresses the dependence of these processes on vesicle size and concentration, polymer molecular weight, temperature, and compartmentalization of the vesicles and polymers, using static and dynamic light scattering. Increasing the molecular weight of the polymers resulted in a reduction of the concentration of polymer needed for induction of aggregation of small unilamellar vesicles. The aggregation was fully reversible (by dilution), within a few seconds, up to a polymer concentration of at least 20 wt %. At relatively low phosphatidylcholine (PC) concentrations (up to approximately 1 mM), increasing the PC concentration resulted in faster kinetics of aggregation and reduced the threshold concentration of polymer required for rapid aggregation (CA). At higher PC concentrations, CA was only slightly dependent on the concentration of PC and was approximately equal to the overlapping concentration of the polymer (C*). The extent of aggregation was similar at 37 and 4 degrees C. Aggregation of large unilamellar vesicles required a lower polymer concentration, probably because aggregation occurs in a secondary minimum (without surface contact). In contrast to experiments in which the polymers were added directly to the vesicles, dialysis of the vesicles against polymer-containing solutions did not induce aggregation. Based on this result, it appears that exclusion of polymer from the hydration sphere of vesicles and the consequent depletion of polymer molecules from clusters of aggregated vesicles play the central role in the induction of reversible vesicle aggregation. The results of all the other experiments are consistent with this conclusion. PMID:8913598

  9. Water soluble vitamin E (TMG) as a radioprotector.

    PubMed

    Nair, Cherupally Krishnan K; Devi, Pathirissery Uma; Shimanskaya, R; Kunugita, N; Murase, Hironobu; Gu, Yeun-Hwa; Kagiya, Tsutomu V

    2003-12-01

    Tocopherol monoglucoside (TMG), a water soluble derivative of vitamin E offers protection against deleterious effects of ionizing radiation, both under in vivo and in vitro conditions, to biological systems. TMG was found to be a potent antioxidant and an effective free radical scavenger. It forms a phenoxyl radical similar to trolox upon reaction with various one-electron oxidants. TMG protected DNA from radiation-induced strand breaks. It also protected thymine glycol formation induced by gamma-radiation. Gamma-radiation-induced loss of viability of EL-tumor cells and peroxidation of lipids in microsomal and mitochondrial membranes were prevented by TMG. TMG was nontoxic to mice when administered orally up to 7.0 g/kg body weight. The LD50 dose of TMG for ip administration in mice was 1.15 g/kg body wt. In rats, following oral and ip administration of TMG, the absorption (distribution) half lives were 5.8 and 3.0 min respectively and elimination half lives were 6.7 and 3.1 min respectively. Embryonic mortality resulting from exposure of pregnant mice to ionizing radiation (2 Gy) was reduced by 75% by ip administration of TMG (0.6 g/kg, body wt) prior to irradiation. TMG offered protection to mice against whole body gamma-radiation-induced lethality and weight loss. The LD50(30) of mice increased from 6 to 6.72 Gy upon post irradiation administration of a single dose of TMG (0.6 g/kg, body wt) by ip.

  10. [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.

  11. Interaction of Sulfadiazine with Model Water Soluble Proteins: A Combined Fluorescence Spectroscopic and Molecular Modeling Approach.

    PubMed

    Islam, Mullah Muhaiminul; Moyon, N Shaemningwar; Gashnga, Pynsakhiat Miki; Mitra, Sivaprasad

    2014-03-01

    The binding behavior of antibacterial drug sulfadiazine (SDZ) with water soluble globular proteins like bovine as well as human serum albumin (BSA and HSA, respectively) and lysozyme (LYS) was monitored by fluorescence titration and molecular docking calculations. The experimental data reveal that the quenching of the intrinsic protein fluorescence in presence of SDZ is due to the strong interaction in the drug binding site of the respective proteins. The Stern-Volmer plot shows positive deviation at higher quencher concentration for all the proteins and was explained in terms of a sphere of action model. The calculated fluorophore-quencher distances vary within 4 ~ 11 Å in different cases. Fluorescence experiments at different temperature indicate thermodynamically favorable binding of SDZ with the proteins with apparently strong association constant (~10(4)-10(5) M(-1)) and negative free energy of interaction within the range of -26.0 ~ -36.8 kJ mol(-1). The experimental findings are in good agreement with the respective parameters obtained from best energy ranked molecular docking calculation results of SDZ with all the three proteins.

  12. Poor Prescription: The Costs of Imprisoning Drug Offenders in the United States. Policy Report.

    ERIC Educational Resources Information Center

    Schiraldi, Vincent; Holman, Barry; Beatty, Phillip

    Using data from the National Corrections Reporting Program, this study examined trends in imprisoning drug offenders in the United States, focusing on the numbers of incarcerated drug offenders and the relationship between incarceration for drug use and rates of drug use. Overall, the increase in drug admissions to prison from 1986 to 1996 is…

  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. 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

  15. 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

  16. [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.

  17. Sources and light absorption of water-soluble brown carbon aerosols in the outflow from northern China

    NASA Astrophysics Data System (ADS)

    Kirillova, E. N.; Andersson, A.; Han, J.; Lee, M.; Gustafsson, Ö.

    2013-07-01

    High loadings of anthropogenic carbonaceous aerosols in Chinese air influence the air quality for over 1 billion people and impact the regional climate. A large fraction (17-80%) of this aerosol carbon is water soluble, promoting cloud formation and thus climate cooling. Recent findings, however, suggest that water-soluble carbonaceous aerosols also absorb sunlight, bringing additional direct and indirect climate warming effects, yet the extent and nature of light absorption by this water-soluble brown carbon (WS-BrC) and its relation to sources is poorly understood. Here, we combine source estimates constrained by dual-carbon-isotope with light absorption measurements of WS-BrC for a March 2011 campaign at the Korea Climate Observatory at Gosan (KCOG), a receptor station in SE Yellow Sea for the outflow from N. China. The mass absorption cross-section (MAC) of WS-BrC for air masses from N. China were in general higher (0.8-1.1 m2 g-1), than from other source regions (0.3-0.8 m2 g-1). We estimate that this effect corresponds to 13-49% of the radiative forcing caused by light absorption by black carbon. Radiocarbon constraints show that the WS-BrC in Chinese outflow had significantly higher amounts of fossil sources (30-50%) compared to previous findings in S. Asia, N. America and Europe. Stable carbon (δ13C) measurements indicated influence of aging during air mass transport. These results indicate the importance of incorporating WS-BrC in climate models and the need to constrain climate effects by emission source sector.

  18. Optimization of Amide-Based Inhibitors of Soluble Epoxide Hydrolase with Improved Water Solubility

    PubMed Central

    Kim, In-Hae; Heirtzler, Fenton R.; Morisseau, Christophe; Nishi, Kosuke; Tsai, Hsing-Ju; Hammock, Bruce D.

    2006-01-01

    Soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. 1,3-Disubstituted ureas with a polar group located on the fifth atom from the carbonyl group of urea function are active inhibitors of sEH both in vitro and in vivo. However, their limited solubility in water and relatively high melting point lead to difficulties in formulating the compounds and poor in vivo efficacy. To improve these physical properties, the effect of structural modification of the urea pharmacophore on the inhibition potencies, water solubilities, octanol/water partition coefficients (log P), and melting points of a series of compounds was evaluated. For murine sEH, no loss of inhibition potency was observed when the urea pharmacophore was modified to an amide function, while for human sEH 2.5-fold decreased inhibition was obtained in the amide compounds. In addition, a NH group on the right side of carbonyl group of the amide pharmacophore substituted with an adamantyl group (such as compound 14) and a methylene carbon present between the adamantyl and amide groups were essential to produce potent inhibition of sEH. The resulting amide inhibitors have 10–30-fold better solubility and lower melting point than the corresponding urea compounds. These findings will facilitate synthesis of sEH inhibitors that are easier to formulate and more bioavailable. PMID:15887969

  19. Ethanol effects on apparent solubility of poorly soluble drugs in simulated intestinal fluid.

    PubMed

    Fagerberg, Jonas H; Al-Tikriti, Yassir; Ragnarsson, Gert; Bergström, Christel A S

    2012-07-02

    Ethanol intake can lead to an unexpected and possibly problematic increase in the bioavailability of druglike compounds. In this work we investigated the effect of ethanol on the apparent solubility and dissolution rate of poorly soluble compounds in simulated intestinal fluid representing a preprandial state. A series of 22 structurally diverse, poorly soluble compounds were measured for apparent solubility and intrinsic dissolution rate (37 °C) in phosphate buffer pH 6.5 (PhB6.5) and fasted state simulated intestinal fluid (FaSSIF, pH 6.5) with and without ethanol at 5% v/v or 20% v/v. The obtained data were used to understand for which molecules ethanol results in an increased apparent solubility and, therefore, may increase the amount of drug absorbed. In FaSSIF20%ethanol 59% of the compounds displayed >3-fold higher apparent solubility than in pure FaSSIF, whereas the effects of 5% ethanol on solubility, in most cases, were negligible. Acidic and neutral compounds were more solubilized by the addition of ethanol than by lecithin/taurocholate aggregates, whereas bases showed a more substance-specific response to the additives in the buffer. The stronger solubilizing capacity of ethanol as compared to the mixed lipid aggregates in FaSSIF was further identified through Spearman rank analyses, which showed a stronger relationship between FaSSIF20%ethanol and PhB6.5,20%ethanol (rS of 0.97) than FaSSIF20%ethanol and FaSSIF (rS of 0.86). No relationships were found between solubility changes in media containing ethanol and single physicochemical properties, but multivariate data analysis showed that inclusion of ethanol significantly reduced the negative effect of compound lipophilicity on solubility. For this data set the higher concentration of ethanol gave a dose number (Do) <1 for 30% of the compounds that showed incomplete dissolution in FaSSIF. Significant differences were shown in the melting point, lipophilicity, and dose profiles between the compounds

  20. Moisture sorption kinetics for water-soluble substances. IV: Studies with mixtures of solids.

    PubMed

    Kontny, M J; Zografi, G

    1985-02-01

    This paper extends earlier work from this laboratory concerning the sorption kinetics of water vapor on deliquescent water-soluble substances to mixtures of these solids. A theoretical model, based on heat transport control, excellently predicted a priori the rate of water uptake by a variety of binary mixtures of alkali halides and sugars. The rates for mixtures containing highly water-soluble quaternary ammonium salts, as either one or both of the components, were less successfully predicted as the combined water solubilities of the two components increased. It is concluded that water-soluble deliquescent substances, normally encountered in pharmaceutical dosage forms, rapidly form saturated aqueous solutions in the aqueous film formed as water vapor uptake proceeds, and that the water uptake rate can be predicted a priori from known and experimentally determinable parameters using the heat transport model.

  1. Polyoxometalate-directed assembly of water-soluble AgCl nanocubes.

    PubMed

    Neyman, Alevtina; Wang, Yifeng; Sharet, Shelly; Varsano, Neta; Botar, Bogdan; Kögerler, Paul; Meshi, Louisa; Weinstock, Ira A

    2012-02-21

    "Out-of-pocket" association of Ag(+) to the tetradentate defect site of mono-vacant Keggin and Wells-Dawson polyoxometalate (POM) cluster-anions is used to direct the formation of water-soluble AgCl nanocubes.

  2. Water-soluble and fluorescent dendritic perylene bisimides for live-cell imaging.

    PubMed

    Gao, Baoxiang; Li, Hongxia; Liu, Hongmei; Zhang, Licui; Bai, Qianqian; Ba, Xinwu

    2011-04-07

    We prepared dendritic perylene bisimide probes with triblock structures: perylene bisimides fluorescence cores, branched oligo(glutamic acid)s and polyethylene glycol chains. These probes showed good water solubility, low cytotoxicity and strong fluorescence in live cells.

  3. Manipulating In-House Designed Drug Databases For The Prediction of pH-Dependent Aqueous Drug Solubility

    PubMed Central

    D’Souza, Malcolm J.; AlAbed, Ghada J.; Earley, Melissa; Roberts, Natalia; Gerges, Fady J.

    2014-01-01

    Chemical, pharmacokinetic, and pharmacodynamics properties are available in the package inserts of every Food and Drug Administration (FDA) approved prescription drug, including all available chemotherapy drugs. These inserts follow a specific format imposed by the FDA. Whether chemotherapy drugs are administered via the parenteral route or alimentary tract, a significant factor affecting their bioavailability, elimination and consequently the drug’s effectiveness and potency, is its state of aqueous solubility. Water solubility has always lent itself poorly to the different predictive and experimental measures employed in the determination of a useful quantitative assessment. In this project, we first built a chemical structure based searchable database for 85 FDA approved chemotherapy drugs and then used Bio-Rad’s KnowItAll® Informatics suite to focus on the drugs pH-dependent water solubility prediction. We compared the predicted values for water solubility to the available values reported in the drug inserts, testing the practical utility and the predictive ability of our model in reporting such a clinically relevant, underreported pharmacokinetic parameter. A relational cancer drug database (MySQL) was created to further facilitate analysis and/or prediction of a chemotherapy compound’s missing pharmacokinetic properties. PMID:24478935

  4. Efficacious Treatment of Experimental Leishmaniasis with Amphotericin B-Arabinogalactan Water-Soluble Derivatives

    PubMed Central

    Golenser, Jacob; Frankenburg, Shoshana; Ehrenfreund, Tirtsa; Domb, Abraham J.

    1999-01-01

    In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED50s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 μg/ml, respectively, for Leishmania major promastigotes and 0.17 and 0.31 μg/ml, respectively, for amastigotes. The effect on Leishmania infantum-infected macrophages was more marked, with ED50s of 0.035 μg/ml for rAmB-AG and 0.027 μg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections. PMID:10471566

  5. 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.

  6. Water-soluble co-polyelectrolytes by selective modification of cellulose esters.

    PubMed

    Liu, Shu; Edgar, Kevin J

    2017-04-15

    Cellulose-based materials are well-suited for biomedical uses, because of their abundance, renewable nature, biodegradability, and relatively low cost. However, the set of commercially available cellulose esters and ethers is limited in number and diversity, and contains no cationically charged cellulose esters. Herein we report a simple, efficient strategy for synthesizing cationic, water-soluble co-polyelectrolytes from commercial, hydrophobic, renewable-based cellulose esters. Cellulose acetate (degree of substitution (DS) 1.78, CA320S), was the exemplary starting material for preparing these cationic polyelectrolytes by a reaction sequence of phosphine-catalyzed bromination and subsequent displacement by an aromatic amine, affording high reaction conversions. We show that these modification techniques can be carried out with essentially complete regio- and chemoselectivity, proceeding in the presence of multiple ester groups, yet preserving those groups. Availability of these novel polysaccharide-based electrolytes starting from uncharged, commercial, inexpensive cellulose esters may open up multiple new application areas, including in several aspects of gene or drug delivery.

  7. Preparation, characterization, and DNA binding studies of water-soluble quercetin--molybdenum(VI) complex.

    PubMed

    Ahmadi, Seyed Mojtaba; Dehghan, Gholamreza; Hosseinpourfeizi, Muhammad Ali; Dolatabadi, Jafar Ezzati Nazhad; Kashanian, Soheila

    2011-07-01

    DNA binding studies of flavonoids are needed to understand the reaction mechanism and improve drugs that target DNA. Quercetin (Q) is one of the most common flavonoids that can chelate metal ions and interact with double-stranded DNA. In the present work, UV absorption spectrophotometry, viscosimetry, circular dichroism, and fluorescence spectroscopic techniques were employed to study the interaction of water-soluble quercetin--molybdenum(VI) complex [Q-Mo(VI)] with calf thymus DNA. The binding constants (K(b)) for the complex with DNA were estimated to be 2.9 × 10(3) through spectroscopic titrations. Upon addition of the complex, significant decreases were observed in the viscosity of calf thymus DNA. Circular dichroic spectra indicated that there are certain detectable conformational changes in the DNA double helix when complex was added. Further, competitive methylene blue binding studies with fluorescence spectroscopy have shown that the complex can bind to DNA through nonintercalative mode. The experimental results suggest that Q-Mo(VI) binds to DNA via an outside binding mode.

  8. 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.

  9. Synthesis, in vitro evaluation, and antileishmanial activity of water-soluble prodrugs of buparvaquone.

    PubMed

    Mäntylä, Antti; Garnier, Tracy; Rautio, Jarkko; Nevalainen, Tapio; Vepsälainen, Jouko; Koskinen, Ari; Croft, Simon L; Järvinen, Tomi

    2004-01-01

    Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successful prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethyl-buparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (drug in human skin homogenate and, therefore, is a promising prodrug candidate to deliver buparvaquone through the skin for the treatment of cutaneous leishmaniasis.

  10. 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.

  11. Instrumentation of Flow-Through USP IV Dissolution Apparatus to Assess Poorly Soluble Basic Drug Products: a Technical Note.

    PubMed

    Paprskářová, Alice; Možná, Petra; Oga, Enoche F; Elhissi, Abdelbary; Alhnan, Mohamed A

    2016-10-01

    Supersaturation and precipitation are common limitations encountered especially with poorly soluble basic drugs. The aims of this work were to explore the pattern of dissolution and precipitation of poorly soluble basic drugs using a United States Pharmacopoeia (USP) IV dissolution apparatus and to compare it to the widely used USP II dissolution apparatus. In order to investigate the influence of gastric emptying time on bioavailability, tables of two model drugs (dipyridamole 100 mg and cinnarizine 15 mg) were investigated and pH change from 1.2 to 6.8 were achieved after 10, 20 or 30 min using USP II or USP IV dissolution apparatuses. Using USP II, dipyridamole and cinnarizine concentrations dropped instantly as a result of drug precipitation with drug crystals evident in the dissolution vessel. At pH change times of 10, 20 and 30 min, the total amount of dissolved drug was dependent on pH change time. Using USP IV, at a flow rate of 8 ml/min, it was possible to have comparable release to agitation at 50 rpm using USP II suggesting that comparable hydrodynamic forces are possible. No drop in drug percentage occurs as the dissolved fraction was readily emptied from the flow cell, preventing drug accumulation in the dissolution medium. However, a negligible percentage of drug release took place following pH change. In conclusion, the use of the flow-through cell dissolution provided laminar flow, use of realistic fluid volumes and avoided precipitation of dissolved drug fraction in the gastric phase as it is discharged before pH change.

  12. Nanosuspension: An approach to enhance solubility of drugs.

    PubMed

    Patel, Vishal R; Agrawal, Y K

    2011-04-01

    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.

  13. 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

  14. A novel water-soluble benzothiazole derivative BD926 triggers ROS-mediated B lymphoma cell apoptosis via mitochondrial and endoplasmic reticulum signaling pathways.

    PubMed

    Li, Min-Hui; Yang, Ping; Yang, Tai; Zhang, Kun; Liu, Yang; Liu, Jin; Li, Li-Mei; Luo, Xing-Yan; Yang, Shu-Xia; Zou, Qiang; Zhang, Chong-Jie

    2016-11-01

    Benzothiazole derivatives are known for various biological activities, and their potency in cancer therapy have received considerable attention in recent years. However, the poor water solubility of most benzothiazole derivatives has limited their clinical application. We developed BD926, a novel water-soluble benzothiazole derivative and showed here that it could inhibit the proliferation and induce apoptosis of human Ramos B-lymphoma cells. We further showed that BD926 triggered apoptosis through both mitochondria and endoplasmic reticulum pathways. Moreover, BD926 caused cell cycle arrest at G0/G1 stage. Furthermore, accumulation of reactive oxygen species (ROS) were observed after BD926 treatment and ROS inhibitor was able to attenuate BD926-induced apoptosis, which suggested that BD926-induced apoptosis may be due to over-producing ROS. These results demonstrate the anticancer effects of BD926 in cell models and raise the possibility for the application of BD926 in cancer therapy.

  15. Prodrug approaches for enhancing the bioavailability of drugs with low solubility.

    PubMed

    Müller, Christa E

    2009-11-01

    Low water solubility and low bioavailability are frequent problems in drug development, particularly in the area of central nervous system (CNS) drugs. This short review describes selected prodrug approaches which have been developed to enhance the bioavailability of drugs, especially that of poorly soluble drugs. Some of the most successful drugs on the market are prodrugs. With a better understanding of active-transport processes at cell membranes in the gut as well as at the blood-brain barrier, the importance of prodrug approaches will further increase in the future. Prodrug approaches will already be considered in the early phase of drug discovery.

  16. Polyamidoamine dendrimers as novel potential absorption enhancers for improving the small intestinal absorption of poorly absorbable drugs in rats.

    PubMed

    Lin, Yulian; Fujimori, Takeo; Kawaguchi, Naoko; Tsujimoto, Yuiko; Nishimi, Mariko; Dong, Zhengqi; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

    2011-01-05

    Effects of polyamidoamine (PAMAM) dendrimers on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF), fluorescein isothiocyanate-dextrans (FDs) with various molecular weights, calcitonin and insulin were used as model drugs of poorly absorbable drugs. The absorption of CF, FD4 and calcitonin from the rat small intestine was significantly enhanced in the presence of PAMAM dendrimers. The absorption-enhancing effects of PAMAM dendrimers for improving the small intestinal absorption of CF were concentration and generation dependent and a maximal absorption-enhancing effect was observed in the presence of 0.5% (w/v) G2 PAMAM dendrimer. However, G2 PAMAM dendrimer had almost no absorption-enhancing effect on the small intestinal absorption of macromolecular drugs including FD10 and insulin. Overall, the absorption-enhancing effects of G2 PAMAM dendrimer in the small intestine decreased as the molecular weights of drug increased. However, G2 PAMAM dendrimer did not enhance the intestinal absorption of these drugs with different molecular weights in the large intestine. Furthermore, we evaluated the intestinal membrane damage with or without G2 PAMAM dendrimer. G2 PAMAM dendrimer (0.5% (w/v)) significantly increased the activities of lactate dehydrogenase (LDH) and the amounts of protein released from the intestinal membranes, but the activities and amounts of these toxic markers were less than those in the presence of 3% Triton X-100 used as a positive control. Moreover, G2 PAMAM dendrimer at concentrations of 0.05% (w/v) and 0.1% (w/v) did not increase the activities and amounts of these toxic markers. These findings suggested that PAMAM dendrimers at lower concentrations might be potential and safe absorption enhancers for improving absorption of poorly absorbable drugs from the small intestine.

  17. 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.

  18. 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.

  19. Water-soluble platinum phthalocyanines as potential antitumor agents.

    PubMed

    Bologna, Giuseppina; Lanuti, Paola; D'Ambrosio, Primiano; Tonucci, Lucia; Pierdomenico, Laura; D'Emilio, Carlo; Celli, Nicola; Marchisio, Marco; d'Alessandro, Nicola; Santavenere, Eugenio; Bressan, Mario; Miscia, Sebastiano

    2014-06-01

    Breast cancer represents the second cause of death in the European female population. The lack of specific therapies together with its high invasive potential are the major problems associated to such a tumor. In the last three decades platinum-based drugs have been considered essential constituents of many therapeutic strategies, even though with side effects and frequent generation of drug resistance. These drugs have been the guide for the research, in last years, of novel platinum and ruthenium based compounds, able to overcome these limitations. In this work, ruthenium and platinum based phthalocyanines were synthesized through conventional techniques and their antiproliferative and/or cytotoxic actions were tested. Normal mammary gland (MCF10A) and several models of mammarian carcinoma at different degrees of invasiveness (BT474, MCF-7 and MDA-MB-231) were used. Cells were treated with different concentrations (5-100 μM) of the above reported compounds, to evaluate toxic concentration and to underline possible dose-response effects. The study included growth curves made by trypan blue exclusion test and scratch assay to study cellular motility and its possible negative modulation by phthalocyanine. Moreover, we investigated cell cycle and apoptosis through flow cytometry and AMNIS Image Stream cytometer. Among all the tested drugs, tetrasulfonated phthalocyanine of platinum resulted to be the molecule with the best cytostatic action on neoplastic cell lines at the concentration of 30 μM. Interestingly, platinum tetrasulfophtalocyanine, at low doses, had no antiproliferative effects on normal cells. Therefore, such platinum complex, appears to be a promising drug for mammarian carcinoma treatment.

  20. Structural data and immunomodulatory properties of a water-soluble heteroglycan extracted from the mycelium of an Italian isolate of Ganoderma lucidum.

    PubMed

    Carrieri, Raffaele; Manco, Rosanna; Sapio, Daniela; Iannaccone, Marco; Fulgione, Andrea; Papaianni, Marina; de Falco, Bruna; Grauso, Laura; Tarantino, Paola; Ianniello, Flora; Lanzotti, Virginia; Lahoz, Ernesto; Capparelli, Rosanna

    2017-01-20

    Mushrooms produce a wide range of bioactive polysaccharides, different from each other in chemical structure and biological effects. In the last years, the idea to develop functional foods or drugs containing fungal polysaccharides is attracting great attention. Fruiting bodies of Basidiomycetes Ganoderma lucidum are commonly used in Oriental medicine to treat several disorders. G. lucidum polysaccharides - mainly β-glucans and heteroglycans - have numerous biological properties such as antitumour and immunomodulatory activities. This report shows, by gene expression analyses and bioenergetic assays, immunomodulatory properties and capacity to improve glucose metabolism of a water-soluble heteroglycan extracted from mycelium of an Italian isolate of G. lucidum. The findings suggest the use of the heteroglycan as probiotic or ingredient in functional foods, being easy to produce and disperse in a food matrix thanks to its water-solubility. Heteroglycan could exert protective effects in pro-inflammatory conditions and benefits for people characterised by suppressed immune response.

  1. 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.

  2. Fabrication and Mechanical Characterization of Water-Soluble Resin-Coated Natural Fiber Green Composites

    NASA Astrophysics Data System (ADS)

    Manabe, Ken-Ichi; Hayakawa, Tomoyuki

    In this study, water-soluble biodegradable resin was introduced as a coating agent to improve the interfacial strength and then to fabricate a high-performance green composite with polylactic acid (PLA) and hemp yarn. Dip coating was carried out for hemp yarn and the green composites were fabricated by hot processing. The coated green composite achieves a high tensile strength of 117 MPa even though the fiber volume fraction is less than 30%. Interfacial shear strength (IFSS) was measured by a single fiber pull-out test, and the effect of water-soluble resin on the tensile properties of the composites was evaluated. As a result, when using coated natural bundles, the IFSS value is smaller than when using noncoated natural bundles. On the basis of observations of the fractured surface of composites and initial yarns using a scanning electron microscope (SEM), the effect of the impregnation of water-soluble resin into the natural bundles on the tensile strength is discussed in detail. It is found that water-soluble resin is effective in improving the mechanical properties of the composite, although the interfacial strength between PLA and water-soluble resin was decreased, and as a result, the tensile strength of green composites increases by almost 20%.

  3. 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.

  4. Drugs of abuse in pregnancy, poor neonatal development, and future neurodegeneration. Is oxidative stress the culprit?

    PubMed

    Neri, Margherita; Bello, Stefania; Turillazzi, Emanuela; Riezzo, Irene

    2015-01-01

    The abuse of licit and illicit drugs is a worldwide issue that is a cause for concern in pregnant women. It may lead to complications in pregnancy that may affect the mother, fetus, and /or neonate. The effects of any substance on the developing embryo and fetus are dependent upon dosing, timing, duration of drug exposure, and the extent of drug distribution. Teratogenic effects have been described when exposure takes place during the embryonic stage; however drugs have subtle effects, including abnormal growth and/or maturation, alterations in neurotransmitters and their receptors, and brain organization. The mechanisms by which intrauterine exposure to many substances may result in neuronal injury have not been completely elucidated. Oxidative stress and epigenetic changes have been recently implicated in the pathogenesis of long - term adverse health sequelae, and neuro-developmental impairment in the offspring of addicted mothers. Transgenerational epigenetics may also explain the alarming datum that developmental abnormalities, impairment in learning and memory, and attention deficit can occur even in the absence of direct fetal exposure, when drugs are consumed prior to conception. There is a growing body of evidence demonstrating a link between redox state unbalance, epigenetic markers, developmental anomalies, and neurodegeneration. The reviewed literature data uphold redox homeostasis disruption as an important factor in the pathogenesis of drug of abuse- induced neurodegeneration, and highlight the potential for new therapies that could prevent neurodegeneration through antioxidant and epigenetic modulatory mechanisms. This therefore reveals important targets for novel neuroprotective strategies.

  5. [Relationship of resistance to diseases and water-soluble amino acids in Konjac leaves].

    PubMed

    Chen, Yongbo; Jiang, Qiaolong

    2008-05-01

    Reversed-phase high performance liquid chromatography was used to analyze water-soluble amino acids in the normal Amorphophallus Konjac, Amorphophallus albus, Amorphophallus bulbifer, and the soft rot Amorphophallus Konjac, to determine the relationship of the different soft-rot resistant Konjac varieties and the proportion and content of the multiple water-soluble amino acids. The results showed that there are remarkable differences in the content and proportion of water-soluble amino acids in different resistant varieties and the same variety of normal and diseased leaves of Amorphophallus. In this study, the bank of fingerprint 15 chromatogram was established and can be used to analyze the related characteristic peaks and the resistance of Amorphophallus.

  6. 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.

  7. Improving the water solubility and antimicrobial activity of silymarin by nanoencapsulation.

    PubMed

    Lee, Ji-Soo; Hong, Da Young; Kim, Eun Suh; Lee, Hyeon Gyu

    2017-03-08

    The aims of this study were to improve the water solubility and antimicrobial activity of milk thistle silymarin by nanoencapsulation and to assess the functions of silymarin nanoparticle-containing film as an antimicrobial food-packaging agent. Silymarin nanoparticles were prepared using water-soluble chitosan (WCS) and poly-γ-glutamic acid (γ-PGA). As the WCS and silymarin concentrations increased, particle size and polydispersity index (PDI) significantly increased. Nanoencapsulation significantly improved the water solubility of silymarin 7.7-fold. Antimicrobial activity of silymarin was effectively improved when silymarin was entrapped within the nanocapsule compared to when it was not entrapped. Films incorporating silymarin nanoparticles had better antimicrobial activity than films incorporating free silymarin. The results suggest that silymarin nanoparticles have applications in antimicrobial food additives and food packing.

  8. 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.

  9. 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.

  10. Separation of three water-soluble vitamins by poly(dimethylsiloxane) microchannel electrophoresis with electrochemical detection.

    PubMed

    Li, Xiang-Yun; Zhang, Qian-Li; Lian, Hong-Zhen; Xu, Jing-Juan; Chen, Hong-Yuan

    2007-09-01

    A method for rapid separation and sensitive determination of three water-soluble vitamins, pyridoxine, ascorbic acid (VC), and p-aminobenzoic acid (PABA) has been developed by PDMS microchannel electrophoresis integrated with amperometric detection. After treatment of the microchip with oxygen plasma, the peak shapes of the three analytes were essentially improved. Pyridoxine, VC, and PABA were well separated within only 80 s in a running buffer of 20 mM borate solution (pH 8.5). Good linearity was obtained within the concentration range of 2-200 microM for the three water-soluble vitamins. The detection limits were 1.0 microM for pyridoxine and VC, and 1.5 microM for PABA. The proposed method has been successfully applied to real human urine sample, without solid phase extraction, with recoveries of 80-122% for the three water-soluble vitamins.

  11. Water-soluble pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines as human A₃ adenosine receptor antagonists.

    PubMed

    Baraldi, Pier Giovanni; Saponaro, Giulia; Romagnoli, Romeo; Aghazadeh Tabrizi, Mojgan; Baraldi, Stefania; Moorman, Allan R; Cosconati, Sandro; Di Maro, Salvatore; Marinelli, Luciana; Gessi, Stefania; Merighi, Stefania; Varani, Katia; Borea, Pier Andrea; Preti, Delia

    2012-06-14

    A relevant problem of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C(5) position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K(i)(hA(3)) = 9.7 nM, IC(50)(hA(3)) = 30 nM, K(i)(hA(1)/hA(3)) = 351, K(i)(hA(2A)/hA(3)) > 515, IC(50)(hA(2B)) > 5 μM) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands.

  12. Synthesis of water-soluble luminescent LaVO4:Ln3+ porous nanoparticles

    NASA Astrophysics Data System (ADS)

    Ansari, Anees A.; Labis, Joselito P.; Alrokayan, Salman A. H.

    2012-08-01

    Water-soluble luminescent Eu3+ and Tb3+-doped LaVO4 porous nanoparticles were synthesized by co-precipitation method. X-ray diffraction (XRD), Field emission-transmission electron microscopy (FE-TEM), energy dispersive X-ray analysis, Fourier transform infrared spectroscopy, UV/Vis absorption, and photoluminescence spectroscopic techniques were employed to characterize the structure and morphology of as-prepared products. The results of the XRD confirm the formation of well-crystallized LaVO4 phase with a tetragonal zircon structure. The TEM images illustrate that the as-formed Eu3+ and Tb3+-doped LaVO4 nanoparticles have irregular spherical shape, hairy nanoporous structures with an average particle size 50-130 nm. These nanoparticles were well-dispersed in polar and non-polar organic solvents to form clear colloidal solutions. The colloidal solutions of Eu3+ and Tb3+-doped zircon-type LaVO4 nanoparticles show the most dominant characteristic emissions (hypersensitive transitions) of Eu3+ at 615 nm (5 D 0 → 7 F 2) and Tb3+ at 543 nm (5 D 4 → 7 F 5), respectively, as the result of an energy transfer from the VO4 3- to luminescent metal ions activators. Compared with other-shape nanocrystals, the luminescence intensity of the irregular hairy spherical porous-like nanoparticles are obviously enhanced. It therefore, suggests that we could obtain function-improved materials by tailoring the size and shape of the LaVO4:Ln3+ nanostructures that are very suitable for use in biological applications, such as protein-labeling, drug delivery, and fluorescent bioprobes.

  13. Synthesis of reduced carbon nitride at the reduction by hydroquinone of water-soluble carbon nitride oxide (g-C{sub 3}N{sub 4})O

    SciTech Connect

    Kharlamov, Alexey; Bondarenko, Marina; Kharlamova, Ganna; Fomenko, Veniamin

    2016-09-15

    For the first time at the reduction by hydroquinone of water-soluble carbon nitride oxide (g-C{sub 3}N{sub 4})O reduced carbon nitride (or reduced multi-layer azagraphene) is obtained. It is differed from usually synthesized carbon nitride by a significantly large (on 0.09 nm) interplanar distance is. At the same time, the chemical bonds between atoms in a heteroatomic plane of reduced carbon nitride correspond to the bonds in a synthesized g-C{sub 3}N{sub 4}. The samples of water-soluble carbon nitride oxide were synthesized under the special reactionary conditions of a pyrolysis of melamine and urea. We believe that reduced carbon nitride consists of weakly connected carbon-nitrogen monosheets (azagraphene sheets) as well as reduced (from graphene oxide) graphene contains weakly connected graphene sheets. - Graphical abstract: XRD pattern and schematic atomic model of one layer of reduced carbon nitride, carbon nitride oxide and synthesized carbon nitride. For the first time at the reduction by hydroquinone of the water-soluble carbon nitride oxide (g-C{sub 3}N{sub 4})O is obtained the reduced carbon nitride (or reduced multi-layer azagraphene). Display Omitted - Highlights: • First the reduced carbon nitride (RCN) at the reduction of the carbon nitride oxide was obtained. • Water-soluble carbon nitride oxide was reduced by hydroquinone. • The chemical bonds in a heteroatomic plane of RCN correspond to the bonds in a synthesized g-C{sub 3}N{sub 4}. • Reduced carbon nitride consists of poorly connected heteroatomic azagraphene layers.

  14. Determination of water-soluble ions in soils from the dry valleys of Antarctica

    NASA Astrophysics Data System (ADS)

    Bustin, R.

    1981-08-01

    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.

  15. 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.

  16. Water Soluble Single-Walled Carbon Nanotubes Inhibit Stimulated Endocytosis in Neurons

    PubMed Central

    Malarkey, Erik B.; Reyes, Reno C.; Zhao, Bin; Haddon, Robert C.; Parpura, Vladimir

    2009-01-01

    We report the use of chemically-functionalized water soluble single-walled carbon nanotube (SWNT) graft copolymers to inhibit endocytosis. The graft copolymers were prepared by the functionalization of SWNTs with poly-ethylene glycol. When added to the culturing medium, these functionalized water soluble SWNTs were able to increase the length of various neuronal processes, neurites, as previously reported. Here we have determined that SWNTs are able to block stimulated membrane endocytosis in neurons, which could then explain the previously noted extended neurite length. PMID:18759491

  17. Evidence of carcinogenicity in humans of water-soluble nickel salts

    PubMed Central

    2010-01-01

    Background Increased risks of nasal cancer and lung cancer in nickel refiners have been investigated scientifically and discussed since they were detected in the 1930s. Nickel compounds are considered to be the main cause of the cancer excess. Parts of the nickel producing industry and their consultants oppose the classification of water-soluble nickel salts as human carcinogens, and argue that the risk in exposed workers should be ascribed to other occupational exposures and smoking. Discussion Respiratory cancer risks in Welsh, Finnish, and Norwegian nickel refiners add to the evidence of carcinogenicity of water-soluble nickel. In Norwegian refiners, the first epidemiological study in 1973 identified high risks of lung cancer and nasal cancer among long-term electrolysis workers. Risk analyses based on exposure estimates developed in the 1980s supported the view that water-soluble nickel compounds were central in the development of cancer. Recently, new exposure estimates were worked out for the same cohort based on personal monitoring of total nickel and chemical determination of four forms of nickel. Additional data have been collected on life-time smoking habits, and on exposure to arsenic, asbestos, sulphuric acid mists, cobalt, and occupational lung carcinogens outside the refinery. After adjustment for these potential confounding exposures in case-control analyses, the risk pattern added to the evidence of an important role of water-soluble nickel compounds as causes of lung cancer. These Norwegian cancer studies rely on national Cancer Registry data, considered close to complete from 1953 onwards; and on National Population Register data continuously updated with mortality and emigration. Canadian mortality studies--perceived to offer the strongest support to the industry position not to recognise carcinogenicity of water-soluble nickel--appear to suffer from limitations in follow-up time, loss to follow-up, absence of risk analysis with individual

  18. 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.

  19. Water-soluble hydrophobically associating polymers for improved oil recovery: A literature review

    SciTech Connect

    Taylor, K.C.; Nasr-El-Din, H.A.

    1995-11-01

    Water-soluble hydrophobically associating polymers are reviewed with particular emphasis on their application in improved oil recovery (IOR). These polymers are very similar to conventional water-soluble polymers used in IOR, except that they have a small number of hydrophobic groups incorporated into the polymer backbone. At levels of incorporation of less than 1 mol%, these hydrophobic groups can significantly change polymer performance. These polymers have potential for use in mobility control, drilling fluids and profile modification. This review includes synthesis, characterization, stability, rheology and flow in porous media of associating polymers in IOR are also examined. 100 refs., 2 tabs.

  20. 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.

  1. Nanosuspension for improving the bioavailability of a poorly soluble drug and screening of stabilizing agents to inhibit crystal growth.

    PubMed

    Ghosh, Indrajit; Bose, Sonali; Vippagunta, Radha; Harmon, Ferris

    2011-05-16

    The purpose of this study was to develop a nanosuspension of a poorly soluble drug by nanomilling process using wet media milling to achieve superior in vitro dissolution and high in vivo exposure in pharmacokinetic studies. A promising nanosuspension was developed with Vitamin E TPGS based formulation with particle size in the nano range. Although the formulation showed significant improvement during in vitro dissolution and in vivo plasma level, probably due to the strong hydrophobic interaction between Vitamin TPGS and the drug molecule, crystal growth was observed during stability studies. A systematic study was done with different combinations of solubilizer/stabilizer system in order to obtain a more stable nanosuspension. Hydroxypropyl methylcellulose (HPMC 3 cps) was found to stabilize the nanosuspension by better surface coverage due to stronger interaction with the drug as compared to other stabilizers used in this study.

  2. 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.

  3. 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

  4. 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

  5. Nanoparticulate strategies for effective delivery of poorly soluble therapeutics.

    PubMed

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

    2010-07-01

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

  6. Effect of lipolysis on drug release from self-microemulsifying drug delivery systems (SMEDDS) with different core/shell drug location.

    PubMed

    Zhang, Jianbin; Lv, Yan; Zhao, Shan; Wang, Bing; Tan, Mingqian; Xie, Hongguo; Lv, Guojun; Ma, Xiaojun

    2014-06-01

    The objective of this study is to investigate the effect of lipolysis on the release of poorly water-soluble drug from SMEDDS in the perspective of drug core/shell location. For this purpose, four SMEDDS formulations with various core/shell properties were developed based on long-chain lipid or medium-chain lipid as well as different surfactant/oil ratios. Poorly water-soluble drugs, hymecromone and resveratrol, were significantly solubilized in all SMEDDS formulations and the diluted microemulsions. Fluorescence spectra analysis indicated that hymecromone was mainly located in the shell of microemulsions, while resveratrol was located in the core. The effect of lipolysis on the release rates of drugs with different core/shell locations were investigated by a modified in vitro drug release model. For the drug located in the shell, hymecromone, the release profiles were not affected during the lipolysis process and no significant differences were observed among four formulations. For the drug located in the core, resveratrol, the release rates were increased to various degrees depending on the extent of digestion. In conclusion, the drug core/shell location plays an important role for determining the effect of lipolysis on drug release from SMEDDS formulation.

  7. 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.

  8. Improved dissolution rate of poorly soluble drug by incorporation of buffers.

    PubMed

    Preechagoon, D; Udomprateep, A; Manwiwattanagul, G

    2000-08-01

    This study focused on comparing dissolution rates of indomethacin after co-compressing with three different buffers (calcium carbonate, sodium carbonate, and sodium citrate) at pH 2 and 7. Factors affecting the dissolution rate were also examined, such as type and particle size of buffer and weight-to-weight ratio of drug to buffer. It was found that, at pH 7, the release rates of indomethacin with sodium carbonate (< 74 microns, all proportions) and sodium citrate (< 74 microns, 75% loading) at a 20-min test time were about 10-fold and 6-fold greater, respectively, than that of indomethacin alone. When the drug and buffer were compressed into tablets using a tableting machine, the release rates of indomethacin for the control, sodium carbonate incorporated (25% and 75% buffer loading), and sodium citrate incorporated (75% buffer loading) at a 15-min test time were 50%, 90%, 66%, and 67%, respectively.

  9. Chemical characteristics of water-soluble organic compounds (WSOC) in PM2.5 in Beijing, China: 2011-2012

    NASA Astrophysics Data System (ADS)

    Xiang, Ping; Zhou, Xueming; Duan, Jinchun; Tan, Jihua; He, Kebin; Yuan, Cheng; Ma, Yongliang; Zhang, Yuanxun

    2017-01-01

    PM2.5 filter sampling was conducted on a daily basis for one year from 2011 to 2012 at an urban site in Beijing. One-third of the samples were subjected to chemical analysis, including water-soluble inorganic ions, organic carbon (OC), elemental carbon (EC) and water-soluble organic carbon (WSOC). The results show that OM (Organic Matter = OC × 1.6; average 50.8% of PM2.5) was the most abundant species, followed by SNA (SO42 - + NO3- + NH4+; average 35%); however, SNA contributed more to PM2.5 in summer and OM contributed more in other seasons. The concentrations of nitrate were higher in summer and autumn than that in winter, suggesting that nitrate had formed in acidic and ammonium-poor environments in summer. WSOC accounted for 26.6% of OC and 8.1% of PM2.5 and exhibited distinct seasonal variations: the lowest concentration occurred in spring (3.90 ± 1.78 μg/m3) and the highest in autumn (5.82 ± 3.73 μg/m3). The higher WSOC/OC ratio in summer suggests that OC was more aged, oxidized and hygroscopic during this season. The seasonal trend of SOC (Secondary Organic Carbon) was the opposite of WSOC/OC, which may indicate that the OC/EC minimum ratio method was not suitable for estimating SOC in this study. Correlations between WSOC and K+, EC and inorganic ions indicated that WSOC was dominated by secondary formation, except that biomass burning was an important source in autumn. Aqueous chemical processes may play an important role in the formation of WSOC in winter. Meteorological conditions had an important influence on WSOC: positive correlations were observed between WSOC and relative humidity, but there was a negative correlation when humidity was higher than 80% in summer.

  10. 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.

  11. 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...

  12. 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.

  13. Purification of water-soluble bone-inductive protein from bovine demineralized bone matrix.

    PubMed

    Yoshimura, Y; Hirano, A; Nishida, M; Kawada, J; Horisaka, Y; Okamoto, Y; Matsumoto, N; Yamashita, K; Takagi, T

    1993-05-01

    The water-soluble fraction containing bone-inductive activity was purified from guanidine-hydrochloride extracts of bovine demineralized bone. The purification steps include ultrafiltration, dialysis, affinity chromatography on heparin-Sepharose and gel chromatography on Sephacryl S-200. Combination of these steps was proven to be an effective and rapid method for the purification of this protein. Subcutaneous implantation of the water-soluble protein with type I collagen was carried out in the thorax of rats. When alkaline phosphatase activity and calcium content in implants were used as indices for purification, the water-soluble bone-inductive protein was purified > 600-fold according to the enzyme activity and 64-fold according to the calcium content. A morphological examination revealed that many chondrocyte and osteoblast cells were seen in the location of the implanted material. Sodium dodecyl sulfate/gel electrophoresis of the protein produced in this way under non-reducing conditions revealed four protein bands of 18, 16, 14 and 11 kDa. None of the separated bands had any biological activity. This result suggests that the water-soluble bone-inductive activity depends on an associated form of various proteins in the range of 18 to 11 kDa.

  14. CORAL: QSPR model of water solubility based on local and global SMILES attributes.

    PubMed

    Toropov, Andrey A; Toropova, Alla P; Benfenati, Emilio; Gini, Giuseppina; Leszczynska, Danuta; Leszczynski, Jerzy

    2013-01-01

    Water solubility is an important characteristic of a chemical in many aspects. However experimental definition of the endpoint for all substances is impossible. In this study quantitative structure-property relationships (QSPRs) for negative logarithm of water solubility-logS (mol L(-1)) are built up for five random splits into the sub-training set (≈55%), the calibration set (≈25%), and the test set (≈20%). Simplified molecular input-line entry system (SMILES) is used as the representation of the molecular structure. Optimal SMILES-based descriptors are calculated by means of the Monte Carlo method using the CORAL software (http://www.insilico.eu/coral). These one-variable models for water solubility are characterized by the following average values of the statistical characteristics: n(sub_train)=725-763; n(calib)=312-343; n(test)=231-261; r(sub_train)(2)=0.9211±0.0028; r(calib)(2)=0.9555±0.0045; r(test)(2)=0.9365±0.0073; s(sub_train)=0.561±0.0086; s(calib)=0.453±0.0209; s(test)=0.520±0.0205. Thus, the reproducibility of statistical quality of suggested models for water solubility confirmed for five various splits.

  15. Water-soluble inhibitor on microbiologically influenced corrosion in diesel pipeline.

    PubMed

    Muthukumar, N; Maruthamuthu, S; Palaniswamy, N

    2006-12-01

    The effect of water-soluble corrosion inhibitor on the growth of bacteria and its corrosion inhibition efficiency were investigated. Corrosion inhibition efficiency was studied by rotating cage test and flow loop techniques. The nature of biodegradation of corrosion inhibitor was also analyzed by using Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (NMR) and Gas chromatography and mass spectrometer (GC-MS). The bacterial isolates (Serratia marcescens ACE2, Bacillus cereus ACE4) have the capacity to degrade the aromatic and aliphatic hydrocarbon present in the corrosion inhibitor. The degraded products of corrosion inhibitor and bacterial activity determine the electrochemical behaviour of API 5LX steel. The influence of bacterial activity on degradation of corrosion inhibitor and its influence on corrosion of API 5LX have been evaluated by employing weight loss techniques and electrochemical studies. The main finding of this paper is that the water-soluble corrosion inhibitor is consumed by the microbial action, which contributes to the decrease in inhibitor efficiency. The present study also emphasis the importance of evaluation of water-soluble corrosion inhibitor in stagnant model (flow loop test) and discusses the demerits of the water-soluble corrosion inhibitors in petroleum product pipeline.

  16. 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...

  17. 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.

  18. Inactivation of Enterobacter sakazakii by Water-soluble Muscadine Seed Extracts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hot and cold water-soluble muscadine (Vitis rotundifolia) seed extracts and their polar and polyphenol fractions from two Muscadine cultivars (‘Ison’, purple and ‘Carlos’, bronze) were investigated for their inhibition of Enterobacter sakazakii. The heat treatment on each seed extract not only incre...

  19. Water-soluble vitamin deficiencies in complicated peptic ulcer patients soon after ulcer onset in Japan.

    PubMed

    Miyake, Kazumasa; Akimoto, Teppei; Kusakabe, Makoto; Sato, Wataru; Yamada, Akiyoshi; Yamawaki, Hiroshi; Kodaka, Yasuhiro; Shinpuku, Mayumi; Nagoya, Hiroyuki; Shindo, Tomotaka; Ueki, Nobue; Kusunoki, Masafumi; Kawagoe, Tetsuro; Futagami, Seiji; Tsukui, Taku; Sakamoto, Choitsu

    2013-01-01

    We investigated over time whether contemporary Japanese patients with complicated peptic ulcers have any water-soluble vitamin deficiencies soon after the onset of the complicated peptic ulcers. In this prospective cohort study, fasting serum levels of water-soluble vitamins (vitamins B1, B2, B6, B12, C, and folic acid) and homocysteine were measured at 3 time points (at admission, hospital discharge, and 3 mo after hospital discharge). Among the 20 patients who were enrolled in the study, 10 consecutive patients who completed measurements at all 3 time points were analyzed. The proportion of patients in whom any of the serum water-soluble vitamins that we examined were deficient was as high as 80% at admission, and remained at 70% at discharge. The proportion of patients with vitamin B6 deficiency was significantly higher at admission and discharge (50% and 60%, respectively, p<0.05) than at 3 mo after discharge (10%). In conclusion, most patients with complicated peptic ulcers may have a deficiency of one or more water-soluble vitamins in the early phase of the disease after the onset of ulcer complications, even in a contemporary Japanese population.

  20. 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.

  1. One-Step Synthesis of Highly Water-Soluble Magnetite ColloidalNanosrystals

    SciTech Connect

    Ge, J.P.; Hu, Y.X.; Biasini, M.; Dong, C.L.; Guo, J.-H.; Beyermann, W.P.; Yin, Y.

    2007-03-05

    A high-temperature solution-phase hydrolysis approach has been developed for the synthesis of colloidal magnetite nanocrystals with well-controlled size and size distribution, high crystallinity, and high water solubility. The synthesis was accomplished by the hydrolysis and reduction of iron(III) cations in diethylene glycol with a rapidly injected solution of sodium hydroxide at an elevated temperature. The high reaction temperature allows for control over size and size distribution and yields highly crystalline products. The superior water solubility is achieved by using a polyelectrolyte, that is, poly(acrylic acid) as the capping agent, the carboxylate groups of which partially bind to the nanocrystal surface and partially extend into the surrounding water. The direct synthesis of water-soluble nanocrystals eliminates the need for additional surface modification steps which are usually required for treating hydrophobic nanocrystals produced in nonpolar solvents through the widely recognized pyrolysis route. The abundant carboxylate groups on the nanocrystal surface allow further modifications, such as bioconjugation, as demonstrated by linking cysteamine to the particle surface. The monodisperse, highly water-soluble, superparamagnetic, and biocompatible magnetite nanocrystals should find immediate important biomedical applications.

  2. Wax encapsulation of water-soluble compounds for application in foods.

    PubMed

    Mellema, M; Van Benthum, W A J; Boer, B; Von Harras, J; Visser, A

    2006-11-01

    Water-soluble ingredients have been successfully encapsulated in wax using two preparation techniques. The first technique ('solid preparation') leads to relatively large wax particles. The second technique ('liquid preparation') leads to relatively small wax particles immersed in vegetable oil. On the first technique: stable encapsulation of water-soluble colourants (dissolved at low concentration in water) has been achieved making use of beeswax and PGPR. The leakage from the capsules, for instance of size 2 mm, is about 30% after 16 weeks storage in water at room temperature. To form such capsules a minimum wax mass of 40% relative to the total mass is needed. High amounts of salt or acids at the inside water phase causes more leaking, probably because of the osmotic pressure difference. Osmotic matching of inner and outer phase can lead to a dramatic reduction in leakage. Fat capsules are less suitable to incorporate water soluble colourants. The reason for this could be a difference in crystal structure (fat is less ductile and more brittle). On the second technique: stable encapsulation of water-soluble colourants (encapsulated in solid wax particles) has been achieved making use of carnauba wax. The leakage from the capsules, for instance of size 250 mm, is about 40% after 1 weeks storage in water at room temperature.

  3. 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.

  4. 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.

  5. Improvement of drug delivery with a breath actuated pressurised aerosol for patients with poor inhaler technique.

    PubMed Central

    Newman, S P; Weisz, A W; Talaee, N; Clarke, S W

    1991-01-01

    BACKGROUND The metered dose inhaler is difficult to use correctly, synchronising actuation with inhalation being the most important problem. A breath actuated pressurised inhaler, designed to help patients with poor inhaler technique, was compared with a conventional metered dose inhaler in terms of aerosol deposition and bronchodilator response. METHODS Radioaerosol deposition and bronchodilator response to 100 micrograms salbutamol were measured in 18 asthmatic patients, who inhaled from a conventional metered dose inhaler by their own chosen metered dose inhaler technique, from a conventional metered dose inhaler by a taught metered dose inhaler technique, and from a breath actuated pressured inhaler (Autohaler). RESULTS In the 10 patients who could coordinate actuation and inhalation of the inhaler on their own deposition of aerosol in the lungs and bronchodilator response were equivalent on the three study days. By contrast, in the eight patients who could not coordinate the mean (SEM) percentage of the dose deposited in the lungs with their own inhaler technique (7.2% (3.4%] was substantial lower than those attained by the taught metered dose inhaler technique (22.8% (2.5%] and by Autohaler (20.8% (1.7%]. CONCLUSION Although of little additional benefit to asthmatic patients with good coordination, the Autohaler is potentially a valuable aid to those with poor coordination, and should be considered in preference to a conventional metered dose inhaler in any patient whose inhaler technique is not known to be satisfactory. Images PMID:1750017

  6. Prevalence of poor and rapid metabolizers of drugs metabolized by CYP2B6 in North Indian population residing in Indian national capital territory.

    PubMed

    Varshney, Ekta; Saha, Nilanjan; Tandon, Monika; Shrivastava, Vikesh; Ali, Shakir

    2012-01-01

    Identification of poor and rapid metabolizers for the category of drugs metabolized by cytochrome P450 2B6 (CYP2B6) is important for understanding the differences in clinical responses of drugs metabolized by this enzyme. This study reports the prevalence of poor and rapid metabolizers in North Indian population residing in the National Capital Territory. The prevalence of poor and rapid metabolizers was determined in the target population for the category of drugs metabolized by CYP2B6 by measuring plasma bupropion, a drug metabolized by CYP2B6, and its metabolite. Bupropion (75 mg) was administered to 107 volunteers, and the drug (bupropion) and its metabolite (hydroxybupropion) were determined simultaneously by LCMS/MS in the plasma. CYP2B6 activity was measured as hydroxybupropion/bupropion ratio, and volunteers were categorized as rapid or poor metabolizers on the basis of cutoff value of log (hydroxybupropion/bupropion). Significant differences were observed between the mean metabolite/drug ratio of rapid metabolizers (Mean = 0.59) and poor metabolizers (Mean = 0.26) with p<0.0001. Results indicate that 20.56% individuals in the target population were poor metabolizers for the category of drugs metabolized by CYP2B6. Cutoff value defined in this study can be used as a tool for evaluating the status of CYP2B6 using bupropion as a probe drug. The baseline information would be clinically useful before administering the drugs metabolized by this isoform.

  7. 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

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

    PubMed

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

    2016-04-01

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

  9. Oral fast-dissolving drug delivery membranes prepared from electrospun polyvinylpyrrolidone ultrafine fibers

    NASA Astrophysics Data System (ADS)

    Yu, Deng-Guang; Shen, Xia-Xia; Branford-White, Chris; White, Kenneth; Zhu, Li-Min; Bligh, S. W. Annie

    2009-02-01

    Oral fast-dissolving drug delivery membranes (FDMs) for poorly water-soluble drugs were prepared via electrospinning technology with ibuprofen as the model drug and polyvinylpyrrolidone (PVP) K30 as the filament-forming polymer and drug carrier. Results from differential scanning calorimetry, x-ray diffraction, and morphological observations demonstrated that ibuprofen was distributed in the ultrafine fibers in the form of nanosolid dispersions and the physical status of drug was an amorphous or molecular form, different from that of the pure drug and a physical mixture of PVP and ibuprofen. Fourier-transform infrared spectroscopy results illustrated that the main interactions between PVP and ibuprofen were mediated through hydrogen bonding. Pharmacotechnical tests showed that FDMs with different drug contents had almost the same wetting and disintegrating times, about 15 and 8 s, respectively, but significantly different drug dissolution rates due to the different physical status of the drug and the different drug-release-controlled mechanisms. 84.9% and 58.7% of ibuprofen was released in the first 20 s for FDMs with a drug-to-PVP ratio of 1:4 and 1:2, respectively. Electrospun ultrafine fibers have the potential to be used as solid dispersions to improve the dissolution profiles of poorly water-soluble drugs or as oral fast disintegrating drug delivery systems.

  10. [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)

  11. Scopulariopsis, a Poorly Known Opportunistic Fungus: Spectrum of Species in Clinical Samples and In Vitro Responses to Antifungal Drugs

    PubMed Central

    Sandoval-Denis, Marcelo; Sutton, Deanna A.; Fothergill, Annette W.; Cano-Lira, Josep; Gené, Josepa; Decock, C. A.; de Hoog, G. S.

    2013-01-01

    Ninety-nine isolates of clinical origin, tentatively identified as Scopulariopsis or Microascus, were morphologically and molecularly characterized by a combined analysis of the D1/D2 domains of the 28S rRNA gene and a fragment of the elongation factor 1-α gene (EF1-α) sequences. The most prevalent species was Scopulariopsis brevicaulis (49.4%), followed by Scopulariopsis gracilis (14.4%), Scopulariopsis brumptii (7.2%), Microascus cinereus (5.2%), the Scopulariopsis candida species complex (3.1%), and Microascus cirrosus (2.1%). The most common anatomic sites of isolation were the respiratory tract (61.6%), superficial tissue (19.2%), and deep tissue or fluid samples (19.2%). The antifungal susceptibilities of the isolates to eight drugs were tested in vitro, with all the drugs generally showing poor activity. PMID:24025910

  12. Evaluation of drug load and polymer by using a 96-well plate vacuum dry system for amorphous solid dispersion drug delivery.

    PubMed

    Chiang, Po-Chang; Ran, Yingqing; Chou, Kang-Jye; Cui, Yong; Sambrone, Amy; Chan, Connie; Hart, Ryan

    2012-06-01

    It is well recognized that poor dissolution rate and solubility of drug candidates are key limiting factors for oral bioavailability. While numerous technologies have been developed to enhance solubility of the drug candidates, poor water solubility continuously remains a challenge for drug delivery. Among those technologies, amorphous solid dispersions (SD) have been successfully employed to enhance both dissolution rate and solubility of poorly water-soluble drugs. This research reports a high-throughput screening technology developed by utilizing a 96-well plate system to identify optimal drug load and polymer using a solvent casting approach. A minimal amount of drug was required to evaluate optimal drug load in three different polymers with respect to solubility improvement and solid-state stability of the amorphous drug-polymer system. Validation of this method was demonstrated with three marketed drugs as well as with one internal compound. Scale up of the internal compound SD by spray drying further confirmed the validity of this method, and its quality was comparable to a larger scale process. Here, we demonstrate that our system is highly efficient, cost-effective, and robust to evaluate the feasibility of spray drying technology to produce amorphous solid dispersions.

  13. Absorption-enhancing effects of gemini surfactant on the intestinal absorption of poorly absorbed hydrophilic drugs including peptide and protein drugs in rats.

    PubMed

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

    2016-02-29

    In general, the intestinal absorption of small hydrophilic molecules and macromolecules like peptides, after oral administration is very poor. Absorption enhancers are considered to be one of the most promising agents to enhance the intestinal absorption of drugs. In this research, we focused on a gemini surfactant, a new type of absorption enhancer. The intestinal absorption of drugs, with or without sodium dilauramidoglutamide lysine (SLG-30), a gemini surfactant, was examined by an in situ closed-loop method in rats. The intestinal absorption of 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-dextrans (FDs) was significantly enhanced in the presence of SLG-30, such effect being reversible. Furthermore, the calcium levels in the plasma significantly decreased when calcitonin was co-administered with SLG-30, suggestive of the increased intestinal absorption of calcitonin. In addition, no significant increase in the of lactate dehydrogenase (LDH) activity or in protein release from the intestinal epithelium was observed in the presence of SLG-30, suggestive of the safety of this compound. These findings indicate that SLG-30 is an effective absorption-enhancer for improving the intestinal absorption of poorly absorbed drugs, without causing serious damage to the intestinal epithelium.

  14. Development of an enteric coating formulation and process for tablets primarily composed of a highly water-soluble, organic acid.

    PubMed

    Crotts, G; Sheth, A; Twist, J; Ghebre-Sellassie, I

    2001-01-01

    The purpose of this study was to define coating conditions for the enteric coating of a highly water soluble, acidic tablet core. Acidic tablet cores containing a marker drug were separated into three groups and seal coated to coverage levels of 0% (uncoated, white), 1% (yellow), and 3% (tan) weight gains. By employing a 'color coding' scheme, the different seal coated tablets could be coated simultaneously to reduce the number of experiments and eliminate potential differences that may exist during separate coating processes. In addition, an allotment of each coded tablet type was sequentially numbered with a marker pen, weighed, and recorded in order to identify the precise level of enteric coating as well as to monitor the variability of a given coating operation. The tablets were coated with five Eudragit((R)) L30D-based enteric formulations containing different amounts of plasticizer (10-20 parts) and talc (10-50 parts). During each enteric coating process, a predetermined amount of labeled tablets were removed after attaining 6, 8, and 10% weight gains. The labeled tablets were re-weighed, sorted, and then tested using USP disintegration and dissolution methods. Weight gain measurements of individual tablets indicated low coating variability (6.2% RSD) during the enteric coating processes. Dissolution results revealed that all enteric coat formulations inhibited drug release for 2 h in 0.1 N HCl. In contrast, it was found that tablets without a seal coat failed the USP disintegration test. In addition, seal coated tablets exhibited ca. 1.5-5 fold greater drug release at most intermediate sampling time points in phosphate buffer, pH 6.8, than tablets without a seal coat, suggesting that the dissolution of the latter was delayed by the generation of an acidic microenvironment at the interface of the enteric coat/acidic tablet core. Prior to enteric coating an acidic, highly water soluble substrate, a seal coat barrier should be applied to prevent retardation in

  15. 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.

  16. 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

  17. Biorelevant solubility of poorly soluble drugs: rivaroxaban, furosemide, papaverine and niflumic acid.

    PubMed

    Takács-Novák, Krisztina; Szőke, Vera; Völgyi, Gergely; Horváth, Péter; Ambrus, Rita; Szabó-Révész, Piroska

    2013-09-01

    In this work the biorelevant solubility of four drugs representing different acid-base property, wide range of lipohilicity and low aqueous solubility was studied. The equilibrium solubility of rivaroxaban (non-ionizable), furosemide (acid), papaverine (base) and niflumic acid (ampholyte) was determined in simulated gastric fluid (SGF pH 1.2), in simulated intestinal fluid fasted state (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0) and their corresponding blank buffers at a temperature of 37 °C using saturation shake-flask method. The concentration was measured by optimized HPLC analysis. The solubilizing effect of bile acid/lipid micelles as additive components of biorelevent media (BRM) is expressed with the solubility ratio (SR: SBRM/Sblank buffer) and the food effect was estimated from SFeSSIF/SFaSSIF coefficient. It was revealed that ionization plays primarily role in solubility of compounds which undergo ionization in BRM. The solubilizing effect in FaSSIF was marginal for the neutral compound (rivaroxaban) and for molecules are anionic at pH 6.5 (furosemide and niflumic acid). The higher concentration of solubilizing agents in FeSSIF improved the solubility of papaverine carrying positive charge and niflumic acid being partially zwitterionic at pH 5.0.

  18. A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin.

    PubMed

    Schoemaker, N E; van Kesteren, C; Rosing, H; Jansen, S; Swart, M; Lieverst, J; Fraier, D; Breda, M; Pellizzoni, C; Spinelli, R; Grazia Porro, M; Beijnen, J H; Schellens, J H M; ten Bokkel Huinink, W W

    2002-09-09

    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.

  19. The referral pathway of presumptive drug-resistant tuberculosis in an urban poor setting, The Philippines

    PubMed Central

    Yoshimatsu, S.; Querri, A.; Coprada, L.; Bermejo, J.; Paulino, M. R.; Medina, A.; Garfin, A. M. C.; Ohkado, A.

    2016-01-01

    Setting: Socio-economically underprivileged urban areas in the Philippines. Objectives: To identify gaps in the referral pathway of presumptive drug-resistant tuberculosis (DR-TB) patients from initial consultation until initiation of treatment. Design: A retrospective study in which a masterlist of presumptive multidrug-resistant TB (MDR-TB) patients registered in 18 DOTS facilities in Tondo, Manila and Payatas, Quezon City, from October 2012 to September 2013, was analysed and reviewed. Results: Among 378 presumptive DR-TB patients identified and listed in the masterlist, 97% (368/378) were referred, of whom 90% (333/368) were screened at an MDR-TB treatment centre. Of the 368 patients, 35 (9.5%) were not screened, mainly due to loss to follow-up. Among those screened, 86.4% (288/333) were recommended for anti-tuberculosis treatment, of whom 98.2% (283/288) initiated treatment. The time between sample collection and examination was significantly longer at the laboratories of non-government organisations (NGOs) than at local government units (LGUs) (1 day vs. 0 day; P < 0.001). The time to the release of smear examination results to patients was significantly shorter at the NGOs than at the LGUs (4 days vs. 6 days; P = 0.009). Conclusion: The development of the presumptive MDR-TB masterlist facilitated tracking of patients for diagnosis and treatment. The NGOs should reduce delays in diagnosis and the LGUs should intensify patient follow-up to ensure early initiation of treatment. PMID:28123960

  20. The referral pathway of presumptive drug-resistant tuberculosis in an urban poor setting, The Philippines.

    PubMed

    Lopez, E; Yoshimatsu, S; Querri, A; Coprada, L; Bermejo, J; Paulino, M R; Medina, A; Garfin, A M C; Ohkado, A

    2016-12-21

    Setting: Socio-economically underprivileged urban areas in the Philippines. Objectives: To identify gaps in the referral pathway of presumptive drug-resistant tuberculosis (DR-TB) patients from initial consultation until initiation of treatment. Design: A retrospective study in which a masterlist of presumptive multidrug-resistant TB (MDR-TB) patients registered in 18 DOTS facilities in Tondo, Manila and Payatas, Quezon City, from October 2012 to September 2013, was analysed and reviewed. Results: Among 378 presumptive DR-TB patients identified and listed in the masterlist, 97% (368/378) were referred, of whom 90% (333/368) were screened at an MDR-TB treatment centre. Of the 368 patients, 35 (9.5%) were not screened, mainly due to loss to follow-up. Among those screened, 86.4% (288/333) were recommended for anti-tuberculosis treatment, of whom 98.2% (283/288) initiated treatment. The time between sample collection and examination was significantly longer at the laboratories of non-government organisations (NGOs) than at local government units (LGUs) (1 day vs. 0 day; P < 0.001). The time to the release of smear examination results to patients was significantly shorter at the NGOs than at the LGUs (4 days vs. 6 days; P = 0.009). Conclusion: The development of the presumptive MDR-TB masterlist facilitated tracking of patients for diagnosis and treatment. The NGOs should reduce delays in diagnosis and the LGUs should intensify patient follow-up to ensure early initiation of treatment.

  1. 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

  2. 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.

  3. 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.

  4. Characterization of water-soluble dark-brown pigment from Antarctic bacterium, Lysobacter oligotrophicus.

    PubMed

    Kimura, Tomomi; Fukuda, Wakao; Sanada, Tomoe; Imanaka, Tadayuki

    2015-07-01

    Lysobacter oligotrophicus strain 107-E2(T) isolated from Antarctica produces dark-brown colored water-soluble pigment, in addition to hydrolases and lytic enzymes. The production of pigment is a common characteristic among members of the genus Lysobacter, but the identity of the pigments has been unknown. In this study, we identified the pigment from L. oligotrophicus as melanin pigment (Lo-melanin) by chemical and spectroscopic analyses. Although melanin is generally insoluble in both aqueous and organic solvents, the results in this study revealed that Lo-melanin shows water-solubility by means of the added polysaccharide chain. Lo-melanin production of L. oligotrophicus was increased by ultraviolet (UV) exposure, and survival rate of Escherichia coli under UV-irradiated condition was increased by the addition of Lo-melanin to the medium.

  5. Rapid screening of water soluble arsenic species in edible oils using dispersive liquid-liquid microextraction.

    PubMed

    López-García, Ignacio; Briceño, Marisol; Vicente-Martínez, Yesica; Hernández-Córdoba, Manuel

    2015-01-15

    A methodology for the non-chromatographic screening of the main arsenic species present in edible oils is discussed. Reverse dispersive liquid-liquid microextraction was used to extract water soluble arsenic compounds (inorganic arsenic, methylarsonate, dimethylarsinate and arsenobetaine) from the edible oils into a slightly acidic aqueous medium. The total arsenic content was measured in the extracts by electrothermal atomic absorption spectrometry using palladium as the chemical modifier. By repeating the measurement using cerium instead of palladium, the sum of inorganic arsenic and methylarsonate was obtained. The detection limit was 0.03 ng As per gram of oil. Data for the total and water-soluble arsenic levels of 29 samples of different origin are presented. Inorganic arsenic was not found in any of the samples marketed as edible oils.

  6. Synthesis and characterization of a hyper-branched water-soluble β-cyclodextrin polymer

    PubMed Central

    Caldera, Fabrizio; Cavalli, Roberta; Mele, Andrea; Punta, Carlo; Melone, Lucio; Castiglione, Franca; Rossi, Barbara; Ferro, Monica; Crupi, Vincenza; Majolino, Domenico; Venuti, Valentina

    2014-01-01

    Summary 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

  7. 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.

  8. Characteristics of the behavior of the water-soluble fraction of oil in model experiments

    SciTech Connect

    Mikhailova, L.V.

    1987-01-01

    In connection with the characteristics of the behavior of petroleum products in water, when conducting toxicological investigations, the highly sensitive radiotracer technique is used which permits judging the concentration of hydrocarbons based on radioactivity (RA) in a small volume of water. A method of labeling water-soluble components of oil with radioactive iodine-131 is discussed. The authors extracted the water-soluble fraction of crude oil (WSFO) with chloroform and labeled it with radioactive iodine-131, obtaining (/sup 131/I)WSFO, which was then introduced into a vessel with water and into the bottom sediments for conducting model experiments. The RA was determined sixfold. The dynamics of petroleum hydrocarbons in the water-WSFO system are discussed, as well as in the water-sediment-WSFO system and in the water-sediment-animals-WSFO system.

  9. Copper ions interfere with the reduction of the water-soluble tetrazolium salt-8.

    PubMed

    Semisch, Annetta; Hartwig, Andrea

    2014-02-17

    Metabolic activity as a measure of cell viability is frequently determined using the water-soluble tetrazolium salt 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt (WST-8), commercially available as CCK-8 reagent. In this study, CCK-8 was investigated with respect to its suitability for investigating nano- and microscale copper oxide (CuO NP and CuO MP) as well as water-soluble copper chloride (CuCl2). The results were compared to cell number and colony forming ability. Our data demonstrate that the CCK-8 assay overestimates the loss of metabolic activity by CuCl2 and CuO NP, because of interference by copper ions with the reduction of the dye.

  10. 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.

  11. Synthesis and Antibacterial Evaluation of Novel Water-Soluble Organic Peroxides

    PubMed Central

    Liu, Wenqiu; Liu, Xuejun; Knaebel, David; Luck, Linda; Li, Yuzhou

    1998-01-01

    A set of new water-soluble organic peroxides has been synthesized and evaluated for in vitro antibacterial activity as part of an effort to develop new antibacterial agents for the treatment of acne vulgaris. The water solubility of these new dialkyl peroxides and peroxyesters was achieved by incorporating either a quaternary ammonium group or a polyethylene glycol moiety. These peroxides are effective against both gram-positive and gram-negative bacteria and have a prolonged activity compared to that of benzoyl peroxide and other peroxide-type antiseptic agents. Among them 4-[[(tert-butylperoxy)carbonyl]benzyl]triethylammonium chloride and [10-(tert-butylperoxy)decyl]trimethylammonium bromide have the broadest antimicrobial spectrums. We have shown that the oxidizing properties of the dioxy group of these compounds are responsible for their antibacterial activities. PMID:9559807

  12. 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.

  13. 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.

  14. Compositional studies on succinoglycan-like extracellular water-soluble Rhizobium polysaccharides.

    PubMed

    Ghai, S K

    1981-01-01

    This study reports structural information on extracellular, water-soluble polysaccharides from 5 different strains of Rhizobium, viz. R. trifolii J60, R. meliloti J1017, 202, 204 and 207. All the 5 polysaccharides had glucose and galactose in approximate molar ratio of 7:1. Methylation analysis revealed that the polysaccharides contained (1 leads to 3), (1 leads to 6), (1 leads to 4), (1 leads to 4, 1 leads to 6)-linked D-glucose residues, (1 leads to 3)-linked D-galactose and non-reducing terminal D-glucose attached to pyruvate. This structure was found to be exactly the same as that of succinoglycan, a succinic acid containing water-soluble polysaccharide elaborated by Alcaligenes faecalis var. myxogenes 10C3. The similarity of the structure of polysaccharides of two different Rhizobium species and also to the polysaccharide produced by Alcaligenes are discussed in terms of host specificity.

  15. New water-soluble metal working fluids additives from phosphonic acid derivatives for aluminum alloy materials.

    PubMed

    Kohara, Ichitaro; Tomoda, Hideyuki; Watanabe, Shoji

    2007-01-01

    Water-soluble metal working fluids are used for processing of aluminum alloy materials. This short paper describes properties of new additives for water-soluble cutting fluids for aluminum alloy materials. Some alkyldiphosphonic acids were prepared with known method. Amine salts of these phosphonic acids showed anti-corrosion property for aluminum alloy materials. However, they have no hard water tolerance. Monoesters of octylphosphonic acid were prepared by the reaction of octylphosphonic acid dichloride with various alcohols in the presence of triethylamine. Amine salts of monoester of octylphosphonic acid with diethyleneglycol monomethyl ether, ethyleneglycol monomethyl ether and triethyleneglycol monomethyl ether showed both of a good anti-corrosion property for aluminum alloy materials and hard water tolerance.

  16. 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

  17. Afterglow Study of ZnS:Cu,Co Water-soluble Nanoparticles and Potential Applications

    NASA Astrophysics Data System (ADS)

    Ma, Lun; Chen, Wei

    2011-03-01

    ZnS:Cu,Co water-soluble afterglow particles with average size of 4 nm have been prepared by using simple wet chemistry method. The X-ray diffraction pattern of the nanoparticles shows a cubic zinc blende structure as the synthesis temperature is low comparing with solid state reactions. The nanoparticles have two photoluminescence emission peaks. The blue emission is from sulfur defects (vacancies), while the green emission is from Cu 2+ luminescent center which also contributes to the particle's afterglow. The presence of co-dopant Co 2+ is critical to perform the afterglow of these nanoparticles. The afterglow intensity and decay vary on different Cu 2+ and Co 2+ doping levels. Further conjugation of ZnS:Cu,Co nanoparticles and photosensitizers presents a new method for deep cancer treatment in photodynamic therapy. The successful afterglow observation from water-soluble nanoparticles may find many new applications in biological imaging, detection and treatment.

  18. 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

  19. Phosphated cyclodextrins as water-soluble chiral NMR solvating agents for cationic compounds

    PubMed Central

    Puentes, Cira Mollings

    2017-01-01

    The utility of phosphated α-, β- and γ-cyclodextrins as water-soluble chiral NMR solvating agents for cationic substrates is described. Two sets of phosphated cyclodextrins, one with degrees of substitution in the 2–6 range, the other with degrees of substitution in the 6–10 range, are examined. Results with 33 water-soluble cationic substrates are reported. We also explored the possibility that the addition of paramagnetic lanthanide ions such as praseodymium(III) and ytterbium(III) further enhances the enantiomeric differentiation in the NMR spectra. The chiral differentiation with the phosphated cyclodextrins is compared to prior results obtained with anionic carboxymethylated cyclodextrins. There are a number of examples where a larger differentiation is observed with the phosphated cyclodextrins. PMID:28179947

  20. Water-soluble polymer exfoliated graphene: as catalyst support and sensor.

    PubMed

    Wang, Haibo; Xia, Baoyu; Yan, Ya; Li, Nan; Wang, Jing-Yuan; Wang, Xin

    2013-05-09

    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.

  1. 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.

  2. Interaction of multi-walled carbon nanotubes with water-soluble proteins: effect of sidewall carboxylation.

    PubMed

    Takada, Tomoya; Kurosaki, Rei; Konno, Yuji; Abe, Shigeaki

    2014-04-01

    Effect of sidewall carboxylation on protein adsorption behavior of multi-walled carbon nanotubes (MWCNTs) was studied. Two water-soluble proteins, bovine serum albumin (BSA) and egg white lysozyme (LYS), were employed in this work. Carboxylation of MWCNTs suppressed adsorption of BSA, whereas adsorption of LYS was enhanced by the carboxylation. These behaviors are explained by the difference in the dominance of hydrophobic interaction and ionic interaction between MWCNTs and the proteins.

  3. Structural features of a water soluble gum polysaccharide from Murraya paniculata fruits.

    PubMed

    Mondal, S K; Ray, B; Ghosal, P K; Teleman, A; Vuorinen, T

    2001-10-22

    A water soluble gum polysaccharide was isolated from Murraya paniculata fruits. Hydrolytic experiments, methylation analysis, periodate oxidation studies and NMR data revealed that the polysaccharide was extensively branched and it consisted of 1,3-, and 1,3,6-linked beta-D-galactopyranosyl units, terminal beta-D-galactopyranosyl units and terminal alpha-D-glucopyranosyl 1,4-beta-D-galactopyranosyl units. Small amounts of 4-O-methylglucuronic acid residues were also present.

  4. New water-soluble Mn-porphyrin with catalytic activity for superoxide dismutation and peroxynitrite decomposition.

    PubMed

    Asayama, Shoichiro; Nakajima, Takumi; Kawakami, Hiroyoshi

    2011-07-01

    We have synthesized a new water-soluble cationic Mn-porphyrin with catalytic activity for both superoxide dismutation and peroxynitrite decomposition. The resulting Mn-porphyrin also showed higher stability for reactive oxygen species such as hydrogen peroxide and lower cytotoxicity, when compared with a control normal Mn-porphyrin. Furthermore, the new porphyrin recovered the viability of lipopolysaccharide-stimulated macrophage RAW 264.7 cells but the control Mn-porphyrin did not.

  5. 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)

  6. Enhanced water-solubility, antibacterial activity and biocompatibility upon introducing sulfobetaine and quaternary ammonium to chitosan.

    PubMed

    Chen, Yuxiang; Li, Jianna; Li, Qingqing; Shen, Yuanyuan; Ge, Zaochuan; Zhang, Wenwen; Chen, Shiguo

    2016-06-05

    Chitosan (CS) has attracted much attention due to its good antibacterial activity and biocompatibility. However, CS is insoluble in neutral and alkaline aqueous solution, limiting its biomedical application to some extent. To circumvent this drawback, we have synthesized a novel N-quaternary ammonium-O-sulfobetaine-chitosan (Q3BCS) by introducing quaternary ammonium compound (QAC) and sulfobetaine, and its water-solubility, antibacterial activity and biocompatibility were evaluated compare to N-quaternary ammonium chitosan and native CS. The results showed that by introducing QAC, antibacterial activities and water-solubilities increase with degrees of substitution. The largest diameter zone of inhibition (DIZ) was improved from 0 (CS) to 15mm (N-Q3CS). And the water solution became completely transparent from pH 6.5 to pH 11; the maximal waters-solubility was improved from almost 0% (CS) to 113% at pH 7 (N-Q3CS). More importantly, by further introducing sulfobetaine, cell survival rate of Q3BCS increased from 30% (N-Q3CS) to 85% at 2000μg/ml, which is even greater than that of native CS. Furthermore, hemolysis of Q3BCS was dropped sharply from 4.07% (N-Q3CS) to 0.06%, while the water-solution and antibacterial activity were further improved significantly. This work proposes an efficient strategy to prepare CS derivatives with enhanced antibacterial activity, biocompatibility and water-solubility. Additionally, these properties can be finely tailored by changing the feed ratio of CS, glycidyl trimethylammonium chloride and NCO-sulfobetaine.

  7. Irreversible Catalyst Activation Enables Hyperpolarization and Water Solubility for NMR Signal Amplification by Reversible Exchange

    DTIC Science & Technology

    2016-09-12

    Irreversible Catalyst Activation Enables Hyperpolarization and Water Solubility for NMR Signal Amplification by Reversible Exchange Milton L. Truong...Supporting Information ABSTRACT: Activation of a catalyst [IrCl(COD)(IMes)] (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene; COD = cyclooctadiene...for signal amplification by reversible exchange (SABRE) was monitored by in situ hyperpolarized proton NMR at 9.4 T. During the catalyst -activation

  8. Water-soluble phenylpropanoid constituents from aerial roots of Ficus microcarpa.

    PubMed

    Ouyang, Ming-An; Chen, Pei-Qing; Wang, Si-Bing

    2007-07-20

    New water-soluble phenylpropanoid constituents, ficuscarpanoside A, guaiacylglycerol 9-O-beta-D-glucopyranoside, and erythro-guaiacylglycerol 9-O-beta-D-glucopyranoside, along with known guaiacylglycerol, erythro-guaiacylglycerol, 4-methoxy guaiacylglycerol 7-O-beta-D-glucopyranoside, and 3-(4-hydroxy-3-methoxy phenyl) propan-1,2-diol, have been isolated from the aerial roots of Ficus microcarpa. Their structures were elucidated on the basis of 1D and 2D NMR experiments.

  9. Synthesis and Size Dependent Reflectance Study of Water Soluble SnS Nanoparticles

    PubMed Central

    Xu, Ying; Al-Salim, Najeh; Tilley, Richard D.

    2012-01-01

    Near-monodispersed water soluble SnS nanoparticles in the diameter range of 3–6 nm are synthesized by a facile, solution based one-step approach using ethanolamine ligands. The optimal amount of triethanolamine is investigated. The effect of further heat treatment on the size of these SnS nanoparticles is discussed. Diffuse reflectance study of SnS nanoparticles agrees with predictions from quantum confinement model.

  10. 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.

  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. Synthesis of water-soluble camptothecin-polyoxetane conjugates via click chemistry.

    PubMed

    Zolotarskaya, Olga Yu; Wagner, Alison F; Beckta, Jason M; Valerie, Kristoffer; Wynne, Kenneth J; Yang, Hu

    2012-11-05

    Water-soluble camptothecin (CPT)-polyoxetane conjugates were synthesized using a clickable polymeric platform P(EAMO) that was made by polymerization of acetylene-functionalized 3-ethyl-3-(hydroxymethyl)oxetane (i.e., EAMO). CPT was first modified with a linker 6-azidohexanoic acid via an ester linkage to yield CPT-azide. CPT-azide was then click coupled to P(EAMO) in dichloromethane using bromotris(triphenylphosphine)copper(I)/N,N-diisopropylethylamine. For water solubility and cytocompatibility improvement, methoxypolyethylene glycol azide (mPEG-azide) was synthesized from mPEG 750 g mol(-1) and click grafted using copper(II) sulfate and sodium ascorbate to P(EAMO)-g-CPT. (1)H NMR spectroscopy confirmed synthesis of all intermediates and the final product P(EAMO)-g-CPT/PEG. CPT was found to retain its therapeutically active lactone form. The resulting P(EAMO)-g-CPT/PEG conjugates were water-soluble and produced dose-dependent cytotoxicity to human glioma cells and increased γ-H2AX foci formation, indicating extensive cell cycle-dependent DNA damage. Altogether, we have synthesized CPT-polymer conjugates able to induce controlled toxicity to human cancer cells.

  13. Biodesulfurization of water-soluble coal-derived material by Rhodococcus rhodochrous IGTS8

    SciTech Connect

    Kilbane, J.J. II; Jackowski, K.

    1991-12-31

    Rhodococcus rhodochrous IGTS8 was previously isolated because of its ability to use coal as its sole source of sulfur for growth. Subsequent growth studies have revealed that IGTS8 is capable of using a variety of organosulfur compounds as sources of sulfur but not carbon. In this paper, the ability of IGTS8 to selectively remove organic sulfur from water-soluble coal-derived material is investigated. The microbial removal of organic sulfur from coal requires microorganisms capable of cleaving carbonsulfur bonds and the accessibility of these bonds to microorganisms. The use of water-soluble coal-derived material effectively overcomes the problem of accessibility and allows the ability of microorganisms to cleave carbonsulfur bonds present in coal-derived material to be assessed directly. Three coals, two coal solubilization procedures, and two methods of biodesulfurization were examined. The results of these experiments reveal that the microbial removal of significant amounts of organic sulfur from watersoluble coal-derived material with treatment times as brief as 24 hours is possible. Moreover, the carbon content and calorific value of biotreated products are largely unaffected. Biotreatment does, however, result in increases in the hydrogen and nitrogen content and a decreased oxygen content of the coal-derived material. The aqueous supernatant obtained from biodesulfurization experiments does not contain sulfate, sulfite, or other forms of soluble sulfur at increased concentrations in comparison with control samples. Sulfur removed from water-soluble coal-derived material appears to be incorporated into biomass.

  14. 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.

  15. A novel injectable water-soluble amphotericin B-arabinogalactan conjugate.

    PubMed

    Falk, R; Domb, A J; Polacheck, I

    1999-08-01

    New, stable, highly water-soluble, nontoxic polysaccharide conjugates of amphotericin B (AmB) are described. AmB was conjugated by a Schiff-base reaction with oxidized arabinogalactan (AG). AG is a highly branched natural polysaccharide with unusual water solubility (70% in water). A high yield of active AmB was obtained with the conjugates which were similarly highly water soluble and which could be appropriately formulated for injection. They showed comparable MICs for Candida albicans and Cryptococcus neoformans (MICs, 0.1 to 0.2 microg/ml). The reduced AmB conjugate, which was synthesized at pH 11 for 48 h at 37 degrees C, was nonhemolytic and was much safer than conventional micellar AmB-deoxycholate. It was the least toxic AmB-AG conjugate among those tested with mice (maximal tolerated dose, 50 mg/kg of body weight), and histopathology indicated no damage to the liver or kidneys. This conjugate, similarly to the liposomal formulation (AmBisome), was more effective than AmB-deoxycholate in prolonging survival. It was more effective than both the liposomal and the deoxycholate formulations in eradicating yeast cells from target organs. The overall results suggest that after further development of the AmB-AG conjugate, it may be a potent agent in the treatment of fungal infections.

  16. Poly(ether ester) Ionomers as Water-Soluble Polymers for Material Extrusion Additive Manufacturing Processes.

    PubMed

    Pekkanen, Allison M; Zawaski, Callie; Stevenson, André T; Dickerman, Ross; Whittington, Abby R; Williams, Christopher B; Long, Timothy E

    2017-04-12

    Water-soluble polymers as sacrificial supports for additive manufacturing (AM) facilitate complex features in printed objects. Few water-soluble polymers beyond poly(vinyl alcohol) enable material extrusion AM. In this work, charged poly(ether ester)s with tailored rheological and mechanical properties serve as novel materials for extrusion-based AM at low temperatures. Melt transesterification of poly(ethylene glycol) (PEG, 8k) and dimethyl 5-sulfoisophthalate afforded poly(ether ester)s of sufficient molecular weight to impart mechanical integrity. Quantitative ion exchange provided a library of poly(ether ester)s with varying counterions, including both monovalent and divalent cations. Dynamic mechanical and tensile analysis revealed an insignificant difference in mechanical properties for these polymers below the melting temperature, suggesting an insignificant change in final part properties. Rheological analysis, however, revealed the advantageous effect of divalent countercations (Ca(2+), Mg(2+), and Zn(2+)) in the melt state and exhibited an increase in viscosity of two orders of magnitude. Furthermore, time-temperature superposition identified an elevation in modulus, melt viscosity, and flow activation energy, suggesting intramolecular interactions between polymer chains and a higher apparent molecular weight. In particular, extrusion of poly(PEG8k-co-CaSIP) revealed vast opportunities for extrusion AM of well-defined parts. The unique melt rheological properties highlighted these poly(ether ester) ionomers as ideal candidates for low-temperature material extrusion additive manufacturing of water-soluble parts.

  17. Enhanced water-solubility and antibacterial activity of novel chitosan derivatives modified with quaternary phosphonium salt.

    PubMed

    Zhu, Dan; Cheng, Honghao; Li, Jianna; Zhang, Wenwen; Shen, Yuanyuan; Chen, Shaojun; Ge, Zaochuan; Chen, Shiguo

    2016-04-01

    Chitosan (CS) has been widely recognized as an important biomaterial due to its good antimicrobial activity, biocompatibility and biodegradability. However, CS is insoluble in water in neutral and alkaline aqueous solution due to the linear aggregation of chain molecules and the formation of crystallinity. This is one of the key factors that limit its practical applications. Therefore, improving the solubility of CS in neutral and alkaline aqueous solution is a primary research direction for biomedical applications. In this paper, a reactive antibacterial compound (4-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-benzyl)-triphenyl-phosphonium bromide (NHS-QPS) was synthesized for chemical modification of CS, and a series of novel polymeric antimicrobial agents, N-quaternary phosphonium chitosan derivatives (N-QPCSxy, x=1-2,y=1-4) were obtained. The water solubilities and antibacterial activities of N-QPCSxy against Escherichia coli and Staphylococcus aureus were evaluated compare to CS. The water solubility of N-QPCSxy was all better than that of CS at neutral pH aqueous solution, particularly, N-QPCS14 can be soluble in water over the pH range of 3 to 12. The antibacterial activities of CS derivatives were improved by introducing quaternary phosphonium salt, and antibacterial activity of N-QPCSxy increases with degree of substitution. Overall, N-QPCS14 represents a novel antibacterial polymer material with good antibacterial activity, waters solubility and low cytotoxicity.

  18. Synthesis of water soluble glycosides of pentacyclic dihydroxytriterpene carboxylic acids as inhibitors of α-glucosidase.

    PubMed

    Xu, Jiancong; Nie, Xuliang; Hong, Yanping; Jiang, Yan; Wu, Guoqiang; Yin, Xiaoli; Wang, Chunrong; Wang, Xiaoqiang

    2016-04-07

    A series of compounds were synthesized by glycosylation of maslinic acid (MA) and corosolic acid (CA) with monosaccharides and disaccharides, and the structures of the derivatives were elucidated by standard spectroscopic methods including (1)H NMR, (13)C NMR and HRMS. The α-glucosidase inhibitory activities of all the novel compounds were evaluated in vitro. The solubility and inhibitory activity of α-glucosidase assays showed that the bis-disaccharide glycosides of triterpene acids possessed higher water solubility and α-glucosidase inhibitory activities than the bis-monosaccharide glycosides. Among these compounds, maslinic acid bis-lactoside (8e, IC50 = 684 µM) and corosolic acid bis-lactoside (9e, IC50 = 428 µM) had the best water solubility, and 9e exhibited a better inhibitory activity than acarbose (IC50 = 478 µM). However, most of glycosylated derivatives possessed lower inhibitory activities than the parent compounds, although their water solubility was enhanced obviously. Moreover, the kinetic inhibition studies indicated that 9e was a non-competitive inhibitor, and structure-activity relationships of the derivatives are also discussed.

  19. A Novel Injectable Water-Soluble Amphotericin B-Arabinogalactan Conjugate

    PubMed Central

    Falk, Rama; Domb, Abraham J.; Polacheck, Itzhack

    1999-01-01

    New, stable, highly water-soluble, nontoxic polysaccharide conjugates of amphotericin B (AmB) are described. AmB was conjugated by a Schiff-base reaction with oxidized arabinogalactan (AG). AG is a highly branched natural polysaccharide with unusual water solubility (70% in water). A high yield of active AmB was obtained with the conjugates which were similarly highly water soluble and which could be appropriately formulated for injection. They showed comparable MICs for Candida albicans and Cryptococcus neoformans (MICs, 0.1 to 0.2 μg/ml). The reduced AmB conjugate, which was synthesized at pH 11 for 48 h at 37°C, was nonhemolytic and was much safer than conventional micellar AmB-deoxycholate. It was the least toxic AmB-AG conjugate among those tested with mice (maximal tolerated dose, 50 mg/kg of body weight), and histopathology indicated no damage to the liver or kidneys. This conjugate, similarly to the liposomal formulation (AmBisome), was more effective than AmB-deoxycholate in prolonging survival. It was more e