应用纳米技术增加难溶性药物吸收的研究进展

随着高通量筛选等新技术的出现,涌现出许多难溶性的候选药物。利用纳米技术能减小难溶性药物的粒径,增加其溶解度、溶出度和口服生物利用度,减少食物效应的影响。本文介绍了纳米粒的制备方法,商用的专利纳米技术以及应用纳米技术成功上市的药品。纳米技术对改善生物药剂学分类体系（BCS）Ⅱ类药物的吸收具有广阔的前景。     

Stable and Fast-Dissolving Amorphous Drug Composites Preparation via Impregnation of Neusilin® UFL2

A promising approach to increase the aqueous solubility, hence the bioavailability, of poorly water-soluble drugs is to convert them into their amorphous state through impregnation into mesoporous silica. Unfortunately, mesoporous silica is not yet available in bulk quantities due to high manufacturing costs. In this work, feasibility of using a commercially available cost-effective mesoporous fine grade Neusilin^® UFL2 to prepare amorphous drug composites of 2 model poorly soluble drugs, fenofibrate and itraconazole, is established. In contrast to fluidized-bed spray-impregnation, only mixing and drying steps are required. Complimentary assessment using X-ray powder diffraction, differential scanning calorimetry, and Raman spectroscopy confirmed drug within the composites to be amorphous at as high as 30% drug loading both after formation and after 3 months of storage at 40°C and 75% relative humidity. Amorphous drug recrystallization was completely suppressed due to the confinement effect due to the Neusilin^®. The amorphous drug composites resulted in higher apparent solubility and faster dissolution rate of the model drugs as compared to their crystalline counterpart, confirmed by United States Pharmacopeia II dissolution and ultraviolet surface dissolution imaging. Overall, stable, high drug-loaded fast-dissolving amorphous drug composites preparation using Neusilin^® UFL2 is demonstrated as a promising approach to enhance solubility of poorly soluble drugs.     

Enhanced dissolution rate of celecoxib using PVP and/or HPMC-based solid dispersions prepared by spray drying method

Celecoxib with low solubility and high permeability (BCS class II) in water is a non-steroidal anti-inflammatory drug used in the treatment of pain and inflammation, associated with rheumatoid arthritis, and several other inflammatory disorders. Also, it is a selective cyclooxygenase 2 inhibitor with low water solubility and high crystallinity. The objective of this study was to improve dissolution rate of celecoxib which was water-insoluble drug. Solid dispersions were prepared by spray drying as the solvent evaporation method. The dissolution behavior of solid dispersions was compared with Celebrex^® (Pfizer) as a control group in simulated gastric juice (pH 1.2, 0.5 % SLS. The characterization of the prepared solid dispersions is analyzed by scanning electron microscope, powder X-ray diffractometer, Fourier transform infrared spectroscopy and reverse phase-high performance liquid chromatography The best formulation was SD 8 in this study. It was the cumulative release of 97 % at 120 min. This study suggests that the solubility and bioavailability of poorly water-soluble celecoxib improved through the prepared solid dispersions by spray drying method.     

Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system.

Poorly water-soluble drug candidates often emerge from contemporary drug discovery programs, and present formulators with considerable technical challenges. The absorption of such compounds when presented in the crystalline state to the gastrointestinal tract is typically dissolution rate-limited, and the drugs are typically BCS class II or class IV compounds. Class IV compounds, which have low membrane permeability as well as poor aqueous solubility, are often poor candidates for development, unless the dose is expected to be low. The rate and extent of absorption of class II compounds is highly dependent on the performance of the formulated product. These drugs can be successfully formulated for oral administration, but care needs to be taken with formulation design to ensure consistent bioavailability. Essentially the options available involve either reduction of particle size (of crystalline drug) or formulation of the drug in solution, as an amorphous system or lipid formulation. The performance of amorphous or lipid formulations is dependent on their interaction with the contents of the gastrointestinal tract, therefore, a formulation exercise should involve the use of techniques which can predict the influence of gut physiology. A major consideration is the fate of metastable supersaturated solutions of drug, which are formed typically after dispersion of the formulation and its exposure to gastrointestinal digestion. A better understanding of the factors which affect drug crystallization is required, and the introduction of standardised predictive in vitro tests would be valuable. Although many bioavailability studies have been performed with poorly water-soluble drugs, thus far this research field has lacked a systematic approach. The use of a lipid formulation classification system combined with appropriate in vitro tests will help to establish a database for in vitro-in vivo correlation studies.     

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

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.KEY WORDS: Bioavailability, Cocrystals, Solubility, Inclusion complexation, Nanoparticles, Self-emulsifying formulations, Proliposomes     

Solubility enhancers for oral drug delivery

With recent progress in high throughput screening of potential therapeutic agents, the number of poorly water-soluble drug candidates has risen sharply and formulating for poorly water-soluble compounds for oral delivery now presents one of the most frequent and greatest challenges to scientists in the pharmaceutical industry. Many new drugs and potential therapeutic compounds under investigation possess high lipophilicity, poor water solubility, and low oral bioavailability. Furthermore, development of improved oral dosage forms for currently marketed drugs can also enhance their therapeutic value. Oral delivery systems designed for poorly water-soluble drugs include micelles with surfactants, microemulsions, self-emulsifying/microemulsifying drug delivery systems (SEDDS/SMEDDS), solid dispersions, microspheres and cyclodextrin inclusion complexes. These delivery systems have been shown to enhance oral bioavailability and therapeutic effects of poorly water-soluble drugs mainly by improving the poor solubility. As a consequence of extensive research, various oral delivery systems for poorly water-soluble agents are being developed in clinical phases worldwide. New formulation technologies and multidisciplinary expertise may lead to development of advanced and effective oral drug delivery systems applicable to a wide range of poorly water-soluble drugs in the near future.     

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate

Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self-microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted of propylene glycol laurate (Lauroglycol FCC) (60 %), macrogol-15-hydroxystearate (Solutol HS 15) (27 %), and diethylene glycol monoethyl ether (Transcutol-P) (13 %). The mean droplet size of the oil phase in the microemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs.     

制剂技术在提高BCSIV类药物生物利用度中的应用及此类药物体内外相关性研究现状

随着组合化学和高通量筛选在药物发现中的广泛应用．别暌选药物不断涌现,其中不乏各种BCSIV类药物,而该类药物凸显的低溶解性／低渗透性极大地阻碍了其进一步的临床开发与应用。因此,如何有效提高该类药物生物利用度,已成为药剂学研究者长期以来广泛关注并致力于解决的课题。分类综述制剂技术在改善BCSIV类药物溶解性／渗透性方面的应用研究,并简介该类药物的体内外相关性研究进展。     

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

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

Formulation and pharmacokinetic evaluation of once-daily sustained-released system of nifedipine with solid dispersion and coating techniques

A novel sustained-release system was developed for poorly water-soluble drugs by applying solid dispersion (SD) technique to improve the solubility. The SD systems composed of polyvinyl pyrrolidone and stearic acid could not control the release of nifedipine. When the above SD granules were coated with ethylcellolulose (EC10, 45 and 100cp), the dissolution rate extended from 16 to 20 h. When the concentration of EC100cp was increased to 4–6 %, the sustained-release formulation F7 and F8 prepared with 4 % EC100cp and 6 % EC100cp, respectively, could control the drug release in a better manner, namely, they could control drug release in the initial hours with a high cumulative amount of drug at 24 h. The mechanism of drug release from F7 and F8 was diffusion coupled with erosion. When immediate-release capsules was orally administered to rabbits, its absorption was very rapid with a short elimination half-life, while a prolonged maintenance of the plasma drug level up to 24 h was obtained for F7 and F8. Furthermore, the oral bioavailability of F7 and F8 was significantly improved. The results suggested that this novel sustained-release system would be a promising system to improve the solubility and sustain the absorption of poorly water-soluble drugs.     

Cryogenic liquids, nanoparticles, and microencapsulation

The biopharmaceutical classification system (BCS) is used to group pharmaceutical actives depending upon the solubility and permeability characteristics of the drug. BCS class II compounds are poorly soluble but highly permeable, exhibiting bioavailability that is limited by dissolution. The dissolution rate of BCS class II drug substances may be accelerated by enhancing the wetting of the bulk powder and by reducing the primary particle size of the drug to increase the surface area. These goals may be achieved by nucleating drug particles from solution in the presence of stabilizing excipients. In the spray freezing into liquid (SFL) process, a drug containing solution is atomized and frozen rapidly to engineer porous amorphous drug/excipient particles with high surface areas and dissolution rates. Aqueous suspensions of nanostructured particles may be produced from organic solutions by evaporative precipitation into aqueous solution (EPAS). The suspensions may be dried by lyophilization. The particle size and morphology may be controlled by the type and level of stabilizers. In vivo studies have shown increased bioavailability of a wide variety of drugs particles formed by SFL or EPAS. For both processes, increased serum levels of danazol (DAN) were observed in mice relative to bulk DAN and the commercial product, Danocrine. Orally dosed itraconazole (ITZ) compositions, formed by SFL, produce higher serum levels of the drug compared to the commercial product, Sporanox oral solution. Additionally, nebulized SFL processed ITZ particles suspended in normal saline have been dosed via the pulmonary route and led to extended survival times for mice inoculated with Aspergillis flavus. SFL and EPAS processes produce amorphous drug particles with increased wetting and dissolution rates, which will subsequently supersaturate biological fluids in vivo, resulting in increased drug bioavailability and efficacy.     

Development Considerations for Nanocrystal Drug Products

Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date. Over 60% of the submissions were for the oral route of administration. Based on the Biopharmaceutics Classification System (BCS), most nanocrystal drugs submitted to the FDA are class II compounds that possess low aqueous solubility and high intestinal permeability. Impact of food on drug bioavailability was reduced for most nanocrystal formulations as compared with their micronized counterparts. For all routes of administration, dose proportionality was observed for some, but not all, nanocrystal products. Particular emphasis in the development of nanocrystal products was placed on the in-process tests and controls at critical manufacturing steps (such as milling process), mitigation and control of process-related impurities, and the stability of APIs or polymorphic form (s) during manufacturing and upon storage. This emphasis resulted in identifying challenges to the development of these products including accurate determination of particle size (distribution) of drug substance and/or nanocrystal colloidal dispersion, identification of polymorphic form (s), and establishment of drug substance/product specifications.     

Drug precipitation inhibitors in supersaturable formulations

Use of supersaturable formulations has been demonstrated as an effective approach to improve solubility and oral absorption of poorly water-soluble compounds. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when the formulations are exposed to the gastrointestinal fluids and drug might precipitate before being absorbed, resulting in delayed response, and reduced efficacy or compromised bioavailability. Polymer based drug precipitation inhibitors have been used to inhibit or retard such precipitation. In this manner one can maintain a drug in the supersaturated concentration for an extended period of time, leading to significantly improved bioavailability of the poorly water-soluble drugs. This review article discusses different types of precipitation inhibitors, working hypotheses, and case studies with improved oral bioavailability.     

Preparation and characterization of solid dispersions of itraconazole by using aerosol solvent extraction system for improvement in drug solubility and bioavailability

The objective of this study was to elucidate the feasibility to improve the solubility and bioavailability of poorly water-soluble itraconazole via solid dispersions by using supercritical fluid (SCF). Solid dispersions of itraconazole with hydrophilic polymer, HPMC 2910, were prepared by the aerosol solvent extraction system (ASES) under different process conditions of temperature/pressure. The particle size of solid dispersions ranged from 100 to 500 nm. The equilibrium solubility increased with decrease (15 to 10 MPa) in pressure and increase (40 to 60 degrees C) in temperature. The solid dispersions prepared at 45 degrees C/15 MPa showed a slight increase in equilibrium solubility (approximately 27-fold increase) when compared to pure itraconazole, while those prepared at 60 degrees C/10 MPa showed approximately 610-fold increase and no endothermic peaks corresponding to pure itraconazole were observed, indicating that itraconazole might be molecularly dispersed in HPMC 2910 in the amorphous form. The amorphous state of itraconazole was confirmed by DSC/XRD data. The pharmacokinetic parameters of the ASES-processed solid dispersions, such as Tmax, Cmax, and AUC(o-24 h) were almost similar to Sporanox capsule which shows high bioavailability. Hence, it was concluded that the ASES process could be a promising technique to reduce particle size and/or prepare amorphous solid dispersion of drugs in order to improve the solubility and bioavailability of poorly water-soluble drugs.     

Effect of biocompatible polymers on the physicochemical and dissolution properties of fenofibrate in nanoparticle system

This study aimed to evaluate the effect of biocompatible polymers on the physicochemical and dissolution properties of poorly water-soluble drugs in nanoparticle systems. Four types of nanoparticles containing poorly water-soluble fenofibrate were prepared using solvent evaporation technique with different biocompatible polymers such as polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), carbopol and ethylcellulose. Their physicochemical properties were investigated using scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. The solubility and dissolution of nanoparticle-entrapped fenofibrate were compared with those of free drug powder. Biocompatible polymers affected the morphology and sizes of fenofibrate nanoparticles. PVP or carbopol-based nanoparticles showed spherical appearance, whereas HPMC or ethylcellulose-based nanoparticles formed aggregates with irregular shape. The particle sizes increased in the order of the nanoparticle prepared with carbopol ≤ PVP < HPMC < ethylcellulose. The size of PVP-based nanoparticles did not significantly differ from that of carbopol-based nanoparticles, showing the mean sizes of ca. 10 μm. As compared to free drug powder, the solubility and dissolution of the drug in nanoparticles increased in the order of PVP > HPMC > carbopol > ethylcellulose. The enhanced solubility and dissolution of poorly water-soluble fenofibrate via nanoparticle system did not depend on particle size but on crystallinity. In conclusion, in nanoparticle development of poorly water-soluble drugs such as fenofibrate, the nature of biocompatible polymers plays an important role in the physicochemical and dissolution of poorly water-soluble drugs in the nanoparticles.     

Development of novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability

To develop a novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability, various itraconazole-loaded solid dispersions were prepared with water, polyvinylpyrroline, poloxamer and citric acid. The effect of carriers on aqueous solubility of itraconazole was investigated. Their physicochemical properties were investigated using SEM, DSC, and powder X-ray diffraction. The dissolution, bioavailability in rats and stability of solid dispersions were evaluated. Unlike conventional solid dispersion system, the itraconazole-loaded solid dispersion with relatively rough surface did not change crystalline form of drug. Our DSC and powder X-ray diffraction results suggested that this solid dispersion was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in conversion of the hydrophobic drug to hydrophilic form. The itraconazole-loaded solid dispersion at the weight ratio of itraconazole/polyvinylpyrroline/poloxamer of 10/2/0.5 gave maximum drug solubility of about 20 μg/mL. It did not change the crystalline form of drug for at least 6 months, indicating that it was physically stable. It gave higher AUC, C_max and T_max compared to itraconazole powder and similar values to the commercial product, suggesting that it was bioequivalent to commercial product in rats. Thus, it would be useful to deliver a poorly water-soluble itraconazole without crystalline change with improved bioavailability.     

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

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

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

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

Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system.

Since its inception in 1995, the biopharmaceutical classification system (BCS) has become an increasingly important tool for regulation of drug products world-wide. Until now, application of the BCS has been partially hindered by the lack of a freely available and accurate database summarising solubility and permeability characteristics of drug substances. In this report, orally administered drugs on the Model list of Essential Medicines of the World Health Organization (WHO) are assigned BCS classifications on the basis of data available in the public domain. Of the 130 orally administered drugs on the WHO list, 61 could be classified with certainty. Twenty-one (84%) of these belong to class I (highly soluble, highly permeable), 10 (17%) to class II (poorly soluble, highly permeable), 24 (39%) to class III (highly soluble, poorly permeable) and 6 (10%) to class IV (poorly soluble, poorly permeable). A further 28 drugs could be provisionally assigned, while for 41 drugs insufficient or conflicting data precluded assignment to a specific BCS class. A total of 32 class I drugs (either certain or provisional classification) were identified. These drugs can be further considered for biowaiver status (drug product approval based on dissolution tests rather than bioequivalence studies in humans).     

Influence of polyvinylpyrrolidone quantity on the solubility,crystallinity and oral bioavailability of fenofibrate in solvent-evaporated microspheres

The objective of this study is to explore the influence of polyvinylpyrrolidone (PVP) quantity on the solubility, crystallinity and oral bioavailability of poorly water-soluble fenofibrate in solvent-evaporated microspheres. Numerous microspheres were prepared with fenofibrate, sodium lauryl sulphate (SLS) and PVP using the spray-drying technique. Their aqueous solubility, dissolution, physicochemical properties and pharmacokinetics in rats were assessed. The drug in the solvent-evaporated microspheres composed of fenofibrate, PVP and SLS at the weight ratio of 1:0.5:0.25 was not entirely changed to the amorphous form and partially in the microcrystalline state. However, the microspheres at the weight ratio of 1:4:0.25 provided the entire conversion to the amorphous form. The latter microspheres, with an improvement of about 115 000-fold in aqueous solubility and 5.6-fold improvement in oral bioavailability compared with the drug powder, gave higher aqueous solubility and oral bioavailability compared with the former. Thus, PVP quantity played an important role in these properties of fenofibrate in the solvent-evaporated microspheres.