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。     

A nanosystem for water-insoluble drugs prepared by a new technology, nanoparticulation using a solid lipid and supercritical fluid

While the number and diversity of lead compounds has increased with the development of science technologies, ca. 90 % of new chemical entities under development have shown low aqueous solubility, classified as class II or IV of the biopharmaceutics classification system (BCS). The low aqueous solubility hinders their clinical translations due to low bioavailability and dissolution-limited absorption of orally-administered drugs. Several technologies have been employed to improve the solubility of poorly water-soluble drugs. In this paper, a new method of nanoparticulation using fat and a supercritical fluid (NUFS) for the formulation of hydrophobic drugs was applied to solve the low solubility problem. A typical BCS class II drug, itraconazole, was selected and formulated with hydroxypropyl methylcellulose, emulsification, and anticoagulating agents for NUFS. The non-spherical itraconazole nanoparticles prepared by NUFS were ~300–500 nm in size with a ~15-fold improved dissolution rate compared to non-nanoparticles of itraconazole (i.e., raw itraconazole). In addition, a high drug content of ~46 % by weight and a drug loading efficiency greater than 85 % were achieved. Therefore, the new technology for nano-platforms could be a promising solution for solubilization of poorly water-soluble drugs, resulting in improved bioavailability.     

Preparation and characterization of solid lipid nanoparticles loaded with alpha-Asarone

This work investigated the potential of solid lipid nanoparticles (SLNs) to improve oral bioavailablity and tissue uptake of a poorly soluble drug, alpha-Asarone. Ultrasonic homogenization method was employed to prepare alpha-Asarone-loaded SLNs (alpha-Asarone-SLNs). Particle size and distribution, pH, viscosity, drug incorporation and zeta potential of the SLNs were investigated. Pharmacokinetic study of oral administration to male rats at 10 mg/Kg suggested that the relative bioavailability of alpha-Asarone was significantly improved in alpha-Asarone-SLN group compared to alpha-Asarone solution group. Comparison of alpha-Asarone-SLN to alpha-Asarone control solution for alpha-Asarone concentrations in rat tissue showed an increased uptake of alpha-Asarone in brain and lung for the ARE-SLN group. These results indicate that alpha-Asarone-SLNs significantly enhance the absorption and tissue distribution of alpha-Asarone. SLNs offer a new approach to improve the oral bioavailability of poorly 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。     

难溶性药物新型速崩片的研究进展

摘 要难溶性药物由于其溶解度低,导致吸收差,生物利用度低,临床应用受到很大局限。运用各种增溶技术,增加难溶性药物的溶解度,进而提高其生物利用度十分必要。然而现有的增溶技术常常会造成增溶后含药量低、粘度高等问题,容易造成服用量的增大以及制剂困难。速崩片可通过局部快速释放达到提高患者顺应性以及增溶的目的。本文针对近年来出现的难溶性药物速崩片增溶技术,综述了固体分散体速崩片、包合物速崩片、乳剂冻干片、自微乳分散片、纳米混悬剂冻干片、微丸速崩片、水分散体冻干片等制剂新技术在增加难溶性药物溶解度、改善生物利用度、提高患者用药依从性等方面的应用。     

Using Physiologically Based Pharmacokinetic (PBPK) Modeling to Evaluate the Impact of Pharmaceutical Excipients on Oral Drug Absorption: Sensitivity Analyses

Drug solubility, effective permeability, and intestinal metabolism and transport are parameters that govern intestinal bioavailability and oral absorption. However, excipients may affect the systemic bioavailability of a drug by altering these parameters. Thus, parameter sensitivity analyses using physiologically based pharmacokinetic (PBPK) models were performed to examine the potential impact of excipients on oral drug absorption of different Biopharmaceutics Classification System (BCS) class drugs. The simulation results showed that changes in solubility had minimal impact on C_max and AUC_0-t of investigated BCS class 1 and 3 drugs. Changes in passive permeability altered C_max more than AUC_0-t for BCS class 1 drugs but were variable and drug-specific across different BCS class 2 and 3 drugs. Depending on the drug compounds for BCS class 1 and 2 drugs, changes in intestinal metabolic activity altered C_max and AUC_0-t. Reducing or increasing influx and efflux transporter activity might likely affect C_max and AUC_0-t of BCS class 2 and 3 drugs, but the magnitude may be drug dependent. Changes in passive permeability and/or transporter activity for BCS class 2 and 3 drugs might also have a significant impact on fraction absorbed and systemic bioavailability while changes in intestinal metabolic activity may have an impact on gut and systemic bioavailability. Overall, we demonstrate that PBPK modeling can be used routinely to examine sensitivity of bioavailability based on physiochemical and physiological factors and subsequently assess whether biowaiver requirements need consideration of excipient effects for immediate release oral solid dosage forms.     

肠道P-糖蛋白辅料抑制剂的研究进展

位于小肠上皮细胞顶端的P-糖蛋白(P-gp)是一种能量依赖性外排泵，可降低多种底物药物的生物利用度。抑制肠道P-gp以增加药物生物利用度受到越来越多的关注。本文将肠道P-gp辅料抑制剂分为非离子型表面活性剂、聚乙二醇类、 β-环糊精衍生物和壳聚糖硫醇盐，并对其作用机制进行综述。与传统P-gp抑制剂相比，辅料抑制剂的非特异性药理作用极小，因此几乎不产生副作用。辅料抑制剂有望代替传统P-gp抑制剂，广泛用于增加难溶性及低口服吸收药物的肠道吸收，从而增加该类药物的生物利用度。这些辅料抑制P-gp的机制及其临床应用还需更多研究和探讨。     

纳米结构脂质载体用于难溶性药物口服传递的研究进展

纳米结构脂质载体可以提高难溶性药物的口服生物利用度,是一种具有前景的难溶性药物口服传递系统。通过查阅文献,对纳米结构脂质载体常见的制备材料、方法,体外表征和释药,及提高难溶性药物口服生物利用度的机制进行综述。     

In vitro models to evaluate the permeability of poorly soluble drug entities: challenges and perspectives

The application of in vitro models in drug permeability studies represents a useful screening tool for assessing the biopharmaceutical appropriateness of new chemical entities (NCEs). Of note, there remains an ever-increasing number of NCEs which exhibit poor aqueous solubility. However, in their classical configuration, both cellular and non-cellular in vitro models show numerous deficiencies in their ability to accurately model the absorption of such compounds. As a consequence, investigators continue to explore the possibility of modifying different experimental parameters in an attempt to yield a more bio-relevant model system which offers good compatibility with poorly soluble compounds. Moreover, in many instances poorly soluble drugs necessitate the inclusion of excipients to facilitate efficient delivery and to enhance their bioavailability. Thus, there exists an increasing demand for in vitro models which can effectively appraise the effects of excipients on a drug's permeability. Herein, we provide an overview of those models currently in use and discuss their associated benefits and drawbacks. Furthermore, we review the challenges encountered in assaying the permeability of poorly soluble drugs and critically assess those experimental modifications and solutions employed thus far in terms of their capacity to generate results with improved accuracy and precision.     

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).     

新型自乳化给药系统研究进展

自乳化给药系统因可提高药物的吸收速度和程度,增强难溶性药物的溶解能力,提高生物利用度而成为当前药剂研究的一大热点。本综述就近几年国内外关于自乳化给药系统的最新研究进展作一简要介绍。     

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。     

In vitro assessment of oral lipid based formulations

In recent years there has been an increase in interest in the utility of lipid based delivery systems, at least in part as a result of the effective development of lipid based products such as Sandimmun Neoral (cyclosporin), Norvir (ritonavir) and Fortovase (saquinavir). The development pathway for lipid based formulations, however, is still largely empirical, and in vitro models that are predictive of oral bioavailability enhancement are lacking. The use of modified dissolution media, reflecting the bile salt and phospholipid levels in the intestine, has met with some success in terms of the ability to predict the bioavailability of poorly water soluble drugs and the potential bioavailability enhancing effects of food. These approaches, however, do not have the flexibility or complexity to deal with the interactions inherent in the digestion, dispersion and solubilisation of a lipid based formulation and the coincident dissolution profile of a co-administered drug. In this review, the utility of modified dissolution media to predict the impact of food on the absorption of poorly water soluble, lipophilic drugs, is explored. These dissolution based systems are subsequently contrasted with the use of lipid digestion models which have found increasing application in assessment of the interaction of digestible dose forms with the gastrointestinal milieu.     

提高难透膜水溶性药物口服生物利用度的方法研究进展

难透膜水溶性药物多为基因工程药物或传统中药中水溶性活性成分,近年来该类药物发展迅速,但由于口服生物利用度低,在临床上往往需要注射给药,开发此类药物的口服制剂是近年来药剂学领域关注的热点和难点问题之一。本文综述了改善此类药物口服吸收的方法,包括利用化学修饰、载体主动转运吸收、吸收促进剂、微粒给药系统、生物黏附给药系统和酶抑制剂等方法。部分药物通过此类方法已经成功进入临床试验,个别药物已经上市。     

Exploring the potential of functional polymer-lipid hybrid nanoparticles for enhanced oral delivery of paclitaxel

Most biopharmaceutics classification system (BCS) class IV drugs, with poor solubility and inferior permeability, are also substrates of P-glycoprotein (P-gp) and cytochrome P450 (CYP450), leading to their low oral bioavailability. The objective of this study is to explore the potential of using functional polymer-lipid hybrid nanoparticles (PLHNs) to enhance the oral absorption of BCS IV drugs. In this paper, taking paclitaxel (PTX) as a drug model, PTX-loaded PLHNs were prepared by a self-assembly method. Chitosan was selected to modify the PLHN to enhance its mucoadhesion and stability. Three P-gp inhibitors (D-α-tocopherol polyethylene glycol 1000 succinate, pluronic P123 and Solutol^Ⓡ HS15) were incorporated into selected PLHNs, and a CYP450 inhibitor (the extract of VBRB, BC0) was utilized to jointly promote the drug absorption. Properties of all the PLHNs were characterized systemically, including particle size, zeta potential, encapsulation efficiency, morphology, stability, in vitro drug release, mucoadhesion, in situ intestinal permeability and in vivo systemic exposure. It was found mucoadhesion of the CS-modified PLHNs was the strongest among all the formulations tested, with absolute bioavailability 21.95%. P-gp and CYP450 inhibitors incorporation further improved the oral bioavailability of PTX to 42.60%, 8-fold increase compared with that of PTX itself (4.75%). Taken together, our study might shed light on constructing multifunctional PLHNs based on drug delivery barriers for better oral absorption, especially for BCS IV drugs.     

Evaluation and prediction of oral drug absorption and bioequivalence with food-druginteraction

This article reviews the impacts on the in vivo prediction of oral bioavailability (BA) and bioequivalence (BE) based on Biopharmaceutical classification systems (BCS) by the food-drug interaction (food effect) and the gastrointestinal (GI) environmental change. Various in vitro and in silico predictive methodologies have been used to expect the BA and BE of the test oral formulation. Food intake changes the GI physiology and environment, which affect oral drug absorption and its BE evaluation. Even though the pHs and bile acids in the GI tract would have significant influence on drug dissolution and, hence, oral drug absorption, those impacts largely depend on the physicochemical properties of oral medicine, active pharmaceutical ingredients (APIs). BCS class I and III drugs are high soluble drugs in the physiological pH range, food-drug interaction may not affect their BA. On the other hand, BCS class II and IV drugs have pH-dependent solubility, and the more bile acid secretion and the pH changes by food intake might affect their BA. In this report, the GI physiological changes between the fasted and fed states are described and the prediction on the oral drug absorption by food-drug interaction have been introduced.     

Mesoporous silica nanoparticles for increasing the oral bioavailability and permeation of poorly water soluble drugs

We investigate the effects of spherical mesoporous silica nanoparticles (MSNs) as an oral drug delivery system to improve the oral bioavailability of the model drug telmisartan (TEL) and examine their cellular uptake and cytotoxicity. Further, we explore the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by MSNs. An investigation of intestinal epithelial cellular binding, association and uptake was carried out by laser scanning confocal microscopy, transmission electron microscopy and fluorescence activated cell sorting. The results show that the cellular uptake is highly time-, concentration- and size-dependent. The model drug permeability studies in the human colon carcinoma (Caco-2) cell lines indicated that MSNs could significantly enhance TEL permeability and reduce rate of drug efflux. After loading TEL into MSNs, its oral bioavailability was compared with that of the marketed product Micardis and TEL-loaded ordered mesoporous silica microparticles (MSMs) in beagle dogs. The relative bioavailability of TEL-loaded MSN formulation and TEL-loaded MSM formulation was 154.4 ± 28.4% and 129.1 ± 15.6%, respectively. MSNs offer the potential to achieve enhanced oral bioavailability of poorly soluble drugs via improved drug dissolution rate and enhanced drug permeability.     

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.     

Controlled Release Systems Containing Solid Dispersions: Strategies and Mechanisms

In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system.