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。     

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.     

纳米晶体技术在水难溶性药物口服制剂中应用的研究进展

目的综述水难溶性药物纳米晶体的制备方法,稳定剂在纳米晶体形成过程中的主要应用原理及产品物理性质的表征,为改善水难溶性药物溶解度或口服生物利用度提供理论依据。方法查阅国内外相关文献27篇,回顾纳米晶体技术的发展历程,提供药物纳米晶体技术的最新研究进展。结果药物纳米晶体不仅制备工艺简单,性质考察方便;还能够提高难溶性药物在胃肠道中的溶解度,改善难溶性药物的口服生物利用度。结论药物纳米晶体技术具有实际生产意义和广阔的应用前景。     

Drug delivery strategies for poorly water-soluble drugs: the industrial perspective

Introduction: For poorly soluble compounds, a good bioavailability is typically needed to assess the therapeutic index and the suitability of the compound for technical development. In industry, the selection of the delivery technology is not only driven by technical targets, but also by constraints, such as production costs, time required for development and the intellectual property situation.

Areas covered: This review covers current developments in parenteral and oral delivery technologies and products for poorly water-soluble compounds, such as nano-suspensions, solid dispersions and liposomes. In addition, the use of biorelevant dissolution media to assess dissolution and solubility properties is described. Suggestions are also included to systematically address development hurdles typical of poorly water-soluble compounds intended for parenteral or oral administration.

Expert opinion: A holistic assessment is recommended to select the appropriate delivery technology by taking into account technical as well as intellectual property considerations. Therefore, first and foremost, a comprehensive physico-chemical characterization of poorly water-soluble compounds can provide the key for a successful selection and development outcome. In this context, the identified physical form of the compound in the formulation is used as a guide for a risk–benefit assessment of the selected oral delivery technology. The potential of nano-suspensions for intravenous administration is unclear. In the case of oral administration, nano-suspensions are mainly used to improve the oral absorption characteristics of micronized formulations. The development of an in situ instantaneous solubilization method, based on stable, standardized liposomes with low toxicity, opens new avenues to solubilize poorly water-soluble compounds.     

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

Introduction: In the past two decades, there has been a spiraling increase in the complexity and specificity of drug–receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends.

Areas covered: Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends.

Expert opinion: Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.     

Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs

Nanocrystals, a carrier-free colloidal delivery system in nano-sized range, is an interesting approach for poorly soluble drugs. Nanocrystals provide special features including enhancement of saturation solubility, dissolution velocity and adhesiveness to surface/cell membranes. Several strategies are applied for nanocrystals production including precipitation, milling, high pressure homogenization and combination methods such as NanoEdge™, SmartCrystal and Precipitation-lyophilization-homogenization (PLH) technology. For oral administration, many publications reported useful advantages of nanocrystals to improve in vivo performances i.e. pharmacokinetics, pharmacodynamics, safety and targeted delivery which were discussed in this review. Additionally, transformation of nanocrystals to final formulations and future trends of nanocrystals were also described.     

有序介孔硅胶提高难溶性药物白藜芦醇的溶出速率

本研究的目的是制备有序介孔硅胶并考察其作为难溶性药物载体的体外药物释放特点。以十六烷基三甲基溴化铵为模板合成了有序介孔硅胶, 以白藜芦醇为模型药物, 采用扫描电镜、透射电镜、N₂吸附-脱附、X-射线衍射和红外光谱对载药前后的有序介孔硅胶进行表征, 并考察药物体外释放行为。结果表明, 合成的有序介孔硅胶比表面积大、粒度均匀, 具有有序六方孔道结构, 载药后药物以无定形态或分子态存在, 释放速率明显提高。有序介孔硅胶有望成为新型的难溶性药物载体。     

Microcrystals for dissolution rate enhancement of poorly water-soluble drugs

Slight dissolution rates related to poor water-solubility are one of the well-known difficulties to be covered during the development of new drug substances. The poorly water-soluble drug ECU-01, a low molecular enzyme-inhibitor with anti-inflammatory properties for oral administration, shows a poor dissolution rate. This study is intended to enhance the drug dissolution rate by using microcrystals. The common way for micronization is the milling of previously formed larger crystals. However, milling shows several disadvantages as the newly created surfaces are thermodynamically activated due to the high energy input and not naturally grown. In this study microcrystals were not produced using any cutting up techniques, but only by association. Naturally grown microcrystals were prepared by a precipitation method in the presence of stabilizing agents (e.g. gelatin, chitosan, different types of cellulose ethers) followed by spray-drying of the formed dispersion. First the drug was dissolved in acetone and then precipitated by rapid pouring an aqueous solution of the stabilizer into the drug solution. Particularly, cellulose ethers were able to form stable and homogeneous dispersions of microcrystals (mean particle size = 1 microm) showing a tight particle size distribution. By spray-drying, the drug powder was obtained. The dissolution rate is significantly enhanced (common drug: 4% after 20 min/microcrystals 93% after 20 min) due to the large surface, which is hydrophilized by adsorbed stabilizers as shown by the decreased contact angle (65 and 30 degrees, respectively).     

纳米给药系统在难溶性药物制剂研究中的应用

近年来,难溶性药物给药系统一直是制剂学研究的重点和难点之一。纳米载体由于其良好的生物相容性及可装载大量难溶性药物等特点而被广泛应用于难溶性药物给药系统的研究,该类载体主要包括纳米粒、脂质体、纳米乳、聚合物胶束、纳米混悬剂等。本文结合近几年国内外文献报道,对纳米给药系统在难溶性药物制剂研究中的最新进展进行概述。     

固体分散体在提高难溶性药物口服生物利用度中的应用

固体分散体在提高难溶性药物溶出度和口服生物利用度中的应用引起了药学工作者的关注,本文综述了固体分散体常用载体、常用的溶剂、提高难溶性药物溶出速率的机制和制备方法以及其他替代的方法,以期将难溶性药物制备为固体分散体提供参考。     

Liquisolid technology for dissolution rate enhancement or sustained release

Importance of the field: Most of the drugs that have been invented are of BCS Class II. Therefore, dissolution rate enhancement is the key aspect for absorption of these drugs. Liquisolid technology is very efficient in the dissolution rate enhancement of these drugs. Moreover, use of other polymers such as Eudragit and hydroxypropyl methylcellulose in the liquisolid approach can cause sustained release of drugs. This review focuses on the formulation approaches of liquisolid tablets or compacts along with its fundamental principles.

Areas covered in this review: The review focuses on the developments in liquisolid technology from 1998 to 2009 with in vitro and in vivo performance of the dosage forms prepared using this technology.

What the reader will gain: Benefits of this review include a concise evaluation of this technology by focusing on the scope of future developments to be done using this technique.

Take home message: Liquisolid technology, the next generation of powder solution technology, can be helpful for enhancing dissolution rates of poorly water-soluble drugs as well as effective at sustaining drug release.     

Improved dissolution behavior of lipophilic drugs by solid dispersions: the production process as starting point for formulation considerations

Introduction: Many new drug substances have low aqueous solubility which can cause poor bioavailability after oral administration. The application of solid dispersions is a useful method to increase the dissolution rate of these drugs and thereby improve their bioavailability. So far, several methods have been developed to prepare solid dispersions. To obtain a product with the desired attributes, both the formulation and production processes should be considered.

Areas covered: The most currently used methods to produce solid dispersions, such as the fusion method, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation, are reviewed in this paper. In addition, the physicochemical characteristics of the obtained solid dispersions are discussed.

Expert opinion: Solid dispersions can be successfully prepared by simple fusion, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation. Hot melt extrusion, spray drying and freeze drying are processes that can be applied for large scale production. The simple fusion method is not very suitable for large scale production, but is particularly suitable for screening formulations. The most recent method to produce sold dispersions is supercritical fluid precipitation. The process conditions of this method need extensive investigation, in particular in relationship with the selection of the type of carrier and/or solvent. Both processes and formulation aspects strongly affect the characteristics of solid dispersion products. Furthermore, application of crystalline solid dispersions is gaining increasing interest because they are thermodynamically more stable than amorphous solid dispersions.     

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

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.     

改善难溶性药物功效的一种新型给药系统——干酏剂的研究进展

干酏剂是一种将乙醇和药物同时包裹入水溶性聚合物壳内的固态微囊.乙醇的潜溶剂作用及喷雾干燥工艺可能产生的无定形药物,有利于包裹于干酏剂中的水难溶性药物快速分散并溶解于水性介质中,从而提高其溶出速率和生物利用度.本文综合近年来干酏剂研究的主要文献,从干酏剂的制剂成型工艺及机制、对难溶性药物体外溶出、体内吸收及生物利用度的影响,以及基于干酏剂的剂型设计及应用做一综述.     

Lipid-based formulations for oral administration of poorly water-soluble drugs

Lipid-based drug delivery systems have shown great potentials in oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Pre-dissolving drugs in lipids, surfactants, or mixtures of lipids and surfactants omits the dissolving/dissolution step, which is a potential rate limiting factor for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect on the biopharmaceutical aspects of drug absorption and distribution both in vitro and in vivo. The aim of this review is to provide an overview of the different lipid-based dosage forms from a biopharmaceutical point of view and to describe effects of lipid dosage forms and lipid excipients on drug solubility, absorption and distribution.     

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

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 ¹H-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 ¹³C-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.     

提高难溶性药物尼群地平溶出率和口服生物利用度的研究

目的通过制剂手段提高难溶性药物尼群地平的体外溶出率和家犬体内的相对生物利用度。方法用共研磨法制备研磨混合物,并用差热分析法、X射线衍射法、显微镜法鉴别药物在共研磨混合物中的存在状态,在此基础上采用直接压片法制备口腔速崩片,测定体外溶出速率,所有试验均以物理混合物为参照进行比较;用HPLC法测定3只健康家犬分别口服尼群地平口腔速崩片(受试制剂)、市售普通片(参比制剂)后不同时间血浆中尼群地平的浓度,计算药物代谢动力学参数及相对生物利用度。结果共研磨混合物中尼群地平的粒径远小于物理混合物,并以微晶状态存在;以共研磨混合物制备的口腔速崩片的溶出速度和程度均大于以物理混合物制备的口腔速崩片;在家犬体内受试制剂和参比制剂的tmax分别为1.5 h和4.25 h,ρmax分别为176.54μg.L-1和111.12μg.L-1,AUC0-t分别为903.78μg.h.L-1和651.99μg.h.L-1,AUC0-∞分别为1 030.46μg.h.L-1和903.68μg.h.L-1,受试制剂的相对生物利用度为138.5%;受试制剂的体内吸收和体外溶出速率均高于参比制剂。结论通过制备共研磨混合物和口腔速崩片的方法,提高了尼群地平的体外溶出度和家犬体内的相对生物利用度。     

纳米结构脂质载体促进难溶性药物口服吸收机制的研究进展

纳米结构脂质载体（NLC）是药剂学备受关注的研究领域,作为一种性能优良的新型药物传递系统,能促进难溶性药物的口服吸收。探讨并总结纳米结构脂质载体促进难溶性药物口服吸收的机制。     

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.     

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

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