难溶性药物的增溶及其缓/控释制剂研究进展

目前由高通量药物筛选而得的活性物质约有40％是水难溶性的，难溶性药物（poorly water—soluble drug）因其在水中溶解度小，药物难以被机体吸收，体内消除速度较快，血药浓度容易出现峰谷现象，口服制剂生物利用度低，且难以实现剂型的多样化。已报道的增溶技术如固体分散技术、环糊精包合技术、胶束增溶、微乳增溶、超微粉碎等已用于增加难溶性药物的溶解度，提高其口服制剂的生物利用度。缓／控释制剂（sustained or controlled release dosage forms）具有减少用药总剂量和用药次数，避免血浓峰谷现象，降低毒副作用，提高病人顺应性等优点，在临床上的应用日益广泛。目前应用增溶技术和缓／控释技术提高难溶性药物的溶解度和生物利用度，研制难溶性药物的缓／控释制剂以成为药剂学研究的热点方向。本文就难溶性药物的增溶及其缓／控释制剂的研究进展做如下综述。     

将难溶性药物制成单层渗透泵片的中间技术-固体分散体技术

对于难溶性药物而言,不能像水溶性药物一样,按照普通的方法制成释药完全的单层渗透泵片。本论文主要介绍通过固体分散体技术提高难溶性药物的溶解度,再制备成单层渗透泵制剂,进而提高药物的溶解度及其体内生物利用度。     

自微乳化释药系统与液固压缩技术在难溶性中药制剂中的联合应用

药物的难溶性严重影响药物的生物利用度,也严重影响药物制成各类制剂。如何增加中药难溶性成分的溶解度,改善其生物利用度,一直是药剂学研究的重要内容。对于难溶性药物来说,药物只有处于溶解状态下,才能表现出较好的溶出和生物利用度。自微乳化释药系统和液固压缩技术均有很好的增溶作用,而且液固压缩技术使药物以无定形或分子状态给药,两者联合应用,可以显著提高药物的溶出度和生物利用度,为中药增溶领域提供一种新的思路与方法。     

难溶性药物的制剂增溶技术及应用

目的：综述难溶性药物增溶和提高生物利用度的制剂技术及应用。方法：查阅国内外相关文献进行总结、归纳。结果：难溶性药物随着制剂技术的改进及新剂型的应用,可通过环糊精包合或复合、固体分散体、微粉化、加增溶剂或助溶剂、成盐处理等多种途径来提高药物的溶出速率和生物利用度。结论：随着药学领域中新制剂技术的发展、新材料的应用,难溶性药物的吸收差、生物利用度低这一限制已逐渐被克服,难溶性药物也可获得较好的吸收和生物利用度。     

非晶固体分散体技术的研究现状

提高药物的溶解度和生物利用度是制剂研究的重要挑战。非晶固体分散体(ASD)能极大增加药物的溶解度和溶出速度,从而改善其生物利用度,被广泛用于难溶性药物的递送。ASD的成功必须满足两点要求:良好的物理稳定性以及良好的溶出以获得较高的生物利用度。本文主要综述ASD的制备方法,表征技术,物理稳定性以及制剂设计理论,以期为ASD药物递送技术的进一步研究提供参考。     

制剂新技术在水难溶性药物中的应用研究进展

目的:了解制剂新技术在水难溶性药物中的应用研究进展。方法:根据文献,综述了水难溶性药物的增溶新技术、缓/控释制剂新技术、增溶-缓释制剂新技术等方面的研究现状。结果:增溶新技术包括合成水溶性前体药物、主药分子结构中导入亲水基团、合成磷脂复合物、加入嵌段共聚物增溶剂、制成微乳等;缓/控释制剂新技术包括骨架型制剂和渗透泵型制剂;增溶-缓释制剂新技术包括固体分散体制剂、包合物制剂和固体脂质纳米粒制剂。结论:增溶新技术、缓/控释制剂新技术、增溶-缓释制剂新技术的应用较好地改善了水难溶性药物吸收差、生物利用度低的不足,发展前景良好。     

自微乳化释药系统在药物制剂中的应用

很多新活性药物在生物体内溶解度很小,如何增加药物溶解度,提高其生物利用度是药物制剂工作中的一大难题.本文介绍了自微乳化释药系统的基本概述,并对其在难溶性西药制剂中的应用进行综述.     

固体分散体在药剂学中的应用

<正>固体分散技术是指制备制剂时将固体药物,特别是难溶性药物高度分散在另一种固体载体中的新技术。自1961年提出固体分散体(Solid dispersion,SD)概念以来,人们围绕如何利用难溶性药物与水溶性材料制成SD的技术,在提高难溶性药物的溶出度和生物利用度方面展开了大量的研究工作。近年     

尼莫地平微粉化物双层渗透泵控释片的制备

目的 制备尼莫地平微粉化物双层渗透泵控释片。方法 以尼莫地平为模型药物,将微粉化增溶技术应用于控释双层渗透泵剂型中,设计并制备体外控释12 h的尼莫地平双层渗透泵片,采用相似因子法（f₂）对不同处方释药行为的相似性进行评价,并对处方进行优化。结果 成功制备了尼莫地平微粉化物双层渗透泵控释片,零级释放特征明显,符合渗透泵的释药机制。结论 将微粉化增溶技术与控释双层渗透泵技术相结合,显著提高了难溶性药物尼莫地平的体外释放,成功制备了控释制剂。     

难溶性药物增溶研究进展

如何增加难溶性药物的溶解度,改善其生物利用度,一直是药剂学研究的重要内容。该文就近年来应用广泛的纳米混悬剂、渗透泵、自微乳化技术、固体分散体、固体脂质纳米粒、液固压缩技术等一些新方法新技术在增加难溶性药物溶解度及改善生物利用度方面的应用进行综述。     

Preparation and in-vitro evaluation of indomethacin nanoparticles

BACKGROUND AND THE PURPOSE OF THE STUDY: During the last two decades one of the most important problems in drug formulations has been low aqueous solubility of new molecules. However, numerous techniques, such as milling, co-solvent solubilization and solid dispersion have been used conventionally for aqueous solubility enhancement and the rate of solubility. Recently, nanoparticle engineering processes have been developed and reported for pharmaceutical applications to increase the dissolution rate of low-soluble drugs which in turn may leads to substantial increases in bioavailability. In this study, a controlled precipitation method was used to produce indomethacin nano-solid suspension in a polymeric matrix (as a model), in order to increase the solubility and rate of the dissolution of poorly soluble model drug. METHODS: Nano-solid suspension of indomethacin in polyvinyl pyrrolidine (PVP) was prepared by controlled precipitation technique, characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) and evaluated for in vitro solubility and dissolution rate. RESULTS AND MAJOR CONCLUSION: Absence of thermal and diffractional peaks in DSC and XRD studies indicated that indomethacin interacts with PVP in solid phase. The solubility of indomethacin in nano-solid suspension compared to crystalline form was increased to about four-fold. It was found that particle size distribution depend to the polymer MW and drug: polymer ratios. Spectroscopy methods and Transmission Electron Microscopy (TEM) images showed that indomethacin dispersed as amorphous nanosize particles in freeze dried powder. Enhanced solubility and dissolution rate of indomethacin compared to physical mixtures and crystalline form of indomethacin (polymorph I), demonstrated that it interacts with PVP via hydrogen bond and probably forming eutectic mixture.     

Drug release from liquisolid systems: speed it up,slow it down

Introduction: Today, the properties of many new chemical entities have shifted towards higher molecular weights and this in turn increases the lipophilicity hence decreasing aqueous solubility. The low solubility of drugs usually has in vivo consequences such as low bioavailability, increased chance of food effect and incomplete release from the dosage form.

Areas covered: The present review discusses the advantages of the liquisolid technology in formulation design of poorly water soluble drugs for dissolution enhancement and highly water soluble drugs for slow release pattern.

Expert opinion: With the advent of high throughput screening and combinatorial chemistry, it has been shown that most of the new chemical entities have a high lipophilicity and poor aqueous solubility, hence poor bioavailability. In order to improve the bioavailability, the release rate of these drugs should be enhanced. Although there are multiple technologies to tackle this issue, they are not cost effective due to the involvement of sophisticated machinery, advanced preparation techniques and complicated technology. As the liquisolid technology uses a similar production process as the conventional tablets, this technology to improve the release rate of poorly water soluble drugs will be cost effective. This technology also has the capability to slow down drug release and allows preparing sustained release tablets with zero order drug release pattern. The excipients required for this technology are conventional and commonly available in the market. The technology is in the early stages of its development with extensive research currently focused on. It is envisaged that the liquisolid compacts could play a major role in the next generation of tablets.     

Drug release from liquisolid systems: speed it up, slow it down

INTRODUCTION: Today, the properties of many new chemical entities have shifted towards higher molecular weights and this in turn increases the lipophilicity hence decreasing aqueous solubility. The low solubility of drugs usually has in vivo consequences such as low bioavailability, increased chance of food effect and incomplete release from the dosage form. AREAS COVERED: The present review discusses the advantages of the liquisolid technology in formulation design of poorly water soluble drugs for dissolution enhancement and highly water soluble drugs for slow release pattern. EXPERT OPINION: With the advent of high throughput screening and combinatorial chemistry, it has been shown that most of the new chemical entities have a high lipophilicity and poor aqueous solubility, hence poor bioavailability. In order to improve the bioavailability, the release rate of these drugs should be enhanced. Although there are multiple technologies to tackle this issue, they are not cost effective due to the involvement of sophisticated machinery, advanced preparation techniques and complicated technology. As the liquisolid technology uses a similar production process as the conventional tablets, this technology to improve the release rate of poorly water soluble drugs will be cost effective. This technology also has the capability to slow down drug release and allows preparing sustained release tablets with zero order drug release pattern. The excipients required for this technology are conventional and commonly available in the market. The technology is in the early stages of its development with extensive research currently focused on. It is envisaged that the liquisolid compacts could play a major role in the next generation of tablets.     

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.     

胆酸钠/磷脂混合胶团对环孢素A的增溶作用研究

目的研究胆酸钠/磷脂混合胶团对难溶性多肽环孢素A(CyA)的增溶作用.方法采用共沉淀法制备胆酸钠/磷脂混合胶团,并对影响增溶作用的处方及工艺进行考查.结果相同胆酸钠浓度条件下,混合胶团对CyA的增溶能力远大于胆酸钠胶团,增大混合胶团中的磷脂用量或者降低胆酸钠/磷脂(摩尔比)均有利于提高混合胶团对药物的增溶能力.升高水合温度,增加水合介质的离子强度,加入抗氧化剂维生素E(VE)及胆固醇,均不同程度的降低了混合胶团的增溶能力.通过优化各个影响因素可获得最大的增溶量(＞5mg/mL),增加CyA溶解度100倍以上.结论胆酸钠/磷脂混合胶团可以成为CyA等难溶性多肽药物的一种新型增溶载体.     

In sight into tadalafil - block copolymer binary solid dispersion: Mechanistic investigation of dissolution enhancement

Tadalafil is a phosphodiesterase-5 inhibitor that is characterized by low solubility and high permeability. Solid dispersion approach represents a promising carrier system for effective enhancement of dissolution and oral bioavailability of poorly soluble drugs. In the present work, novel tadalafil-loaded solid dispersions employing various block copolymers (Pluronics(?)) were prepared through fusion technique. Their solubility and dissolution properties were compared to the drug alone. In order to elucidate the mechanism of dissolution enhancement, solid state characteristics were investigated using scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction. Furthermore, contact angle measurements were carried out. The sign and magnitude of the thermodynamic parameters indicated spontaneity of solubilization process. The phase solubility studies revealed A(L) type of curves for the carriers. Unlike traditional solid dispersion systems, the crystal form of drug in the formulated systems could not be converted to amorphous form. Most of the studied grades showed dissolution improvement vis-à-vis pure drug, with Pluronic F-127 as the most promising carrier. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model. Thus, the results demonstrated that tadalafil/Pluronic F-127 solid dispersion system is a direct and feasible technology which represents a potential candidate for delivering a poorly water-soluble drug with enhanced solubility and dissolution.     

Recent advances and patents in solid dispersion technology

High lipophilicity and high lattice energy of drugs, which result in poor solubility are major real challenges in the pharmaceutical industry for the successful development and commercialization of suitable dosage forms. Therefore various formulation strategies like complexation, lipid based systems, micronization, nanonization, co-crystals, solid dispersions, solubilization etc. have been investigated to resolve the problems associated with solubility related oral bioavailability of poorly water soluble drugs. This article focuses on solid dispersions which is used as one of the formulation strategies to improve the solubility and bioavailability of BCS class II drugs. The present review discusses the fundamentals of solid dispersions, their formulation techniques including various carriers used, their applications, limitations as well as provide an insight into the various alternative approaches to overcome problems associated with solid dispersions. This review also discusses some important aspects of solid dispersion like phase transition, importance of Tg for solid dispersion, controlled release formulations, IVIVC, and the prospect of innovative solid dispersions. Furthermore, the different patents highlighting the applications of solid dispersions have also been comprehensively discussed in the present review.     

纳米载体提高难溶性药物口服生物利用度的研究进展

纳米载体是药剂学备受关注的研究领域,作为一类新型给药系统,它能显著提高难溶性药物的溶解度、生物利用度和稳定性,且具有明显的缓释作用,因此得到了广泛的应用。目前常用于提高难溶性药物口服生物利用度的纳米载体有纳米脂质体、固体脂质纳米粒、纳米胶束、和纳米结晶等,它们的粒径、表面性质及其释药环境等是影响纳米载体药物口服吸收的主要因素。本文对纳米载体提高难溶性药物口服生物利用度的研究进展作一综述。     

Lipid - An emerging platform for oral delivery of drugs with poor bioavailability

The sole objective of pharmaceutical science is to design successful dosage forms which fulfill the therapeutic needs of the patients effectively. Development of new drug entities is posing real challenge to formulators, particularly due to their poor aqueous solubility which in turn is also a major factor responsible for their poor oral bioavailability. Lipids as carriers, in their various forms, have the potential of providing endless opportunities in the area of drug delivery due to their ability to enhance gastrointestinal solubilization and absorption via selective lymphatic uptake of poorly bioavailable drugs. These properties can be harvested to improve the therapeutic efficacy of the drugs with low bioavailability, as well as to reduce their effective dose requirement. The present communication embodies an in-depth discussion on the role of lipids (both endogenous and exogenous) in bioavailability enhancement of poorly soluble drugs, mechanisms involved therein, approaches in the design of lipid-based oral drug delivery systems with particular emphasis on solid dosage forms, understanding of morphological characteristics of lipids upon digestion, in vitro lipid digestion models, in vivo studies and in vitro-in vivo correlation.     

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