口服缓释制剂体内外相关性评价方法研究进展

对近年国内外文献中有关口服缓释制剂体外溶出度测定的试验方法和条件、体内评价的相关方法、体内外相关性研究进行了综述。根据药物的不同性质选择尽可能接近体内环境的试验方法,建立较好的体内外相关性,对口服缓释制剂的研究具有重要意义。     

缓释微球的释放度试验及体内外相关性研究进展

简述了生物可降解的聚乳酸及乳酸-羟基乙酸共聚物微球的体外释放度试验方法及体内外相关性等，指出通过体外释放条件的选择可以获得较好的体内外相关性，并对体外释放通常快于体内的原因进行了探讨。     

难溶性药物口服吸收体内外相关性的研究进展

体内外相关性(in vitro-in vivo correlation,IVIVC)是将药物剂型体外的释药情况与其体内相应的应答关联起来,用数学模型描述药物体外性质(药物溶出的速率或程度)与体内特性(血药浓度或药物吸收量)的关系.它是体外溶出度和体内生物利用度参数的函数.研究某个药物制剂的体内外相关性的目的,在于建立一个可以说明生物利用度的体外质量标准和用作制剂批量生产时的质控指标.水难溶性药物制剂是中国药典规定需要进行生物利用度和溶出度测定的药物类型之一.药物的生物利用度试验操作过程较溶出度试验复杂,在实际工作中,对于具有良好体内外相关性的药物,通过测定体外溶出度来预测难溶性药物的体内生物利用度,进而筛选制剂处方和控制其质量具有重要的意义.一个制剂的改变需要进行一系列生物利用度实验,以证明新制剂与旧制剂具有生物等效性.这过程需要耗费大量的时间和金钱.而具有良好体内外相关性的药物,能很好预测体内释药特征,可以申请豁免生物等效性研究,不仅节约时间,还降低成本.影响药物体内外相关性的因素很多,主要包括体外溶出度研究,体内生物利用度试验研究和拟合模型的数学方法这3个方面.     

缓释制剂的体内外相关性试验及检验

目的：探讨缓释制剂体内外相关试验方法。方法：以植入用缓释依托泊苷为例，根据体内及体外预试验数据，求算对应时间点关联系数K，按中华人民共和国药典要求作对应时间点的点对点相关试验及检验。结果：成功进行植入用缓释依托泊苷的体内外相关试验并实现相关。结论：此法为长效缓释制剂提供了一种体内外相关试验的参考方法。     

纳米给药系统中药物体外释放度测定方法及体内外相关性评价研究进展

目的:为纳米给药系统中药物体外释放度测定方法及体内外相关性评价提供参考。方法:以"纳米给药系统""体外药物释放""体内外相关性""Nanoparticles""Drug release""in vitro-in vivo correlation"等为关键词,在中国知网、维普、PubMed、Elsevier等数据库中组合查询2001年-2018年6月发表的相关文献,从纳米给药系统药物体外释放测定的挑战、药物体外释放度测定的主要方法、体外释放度的数学模型拟合以及体外释放-体内行为相关性研究等3个方面进行归纳和总结。结果与结论:共检索到相关文献4 318篇,其中有效文献41篇。目前纳米给药系统中药物体外释放度研究面临的挑战主要来源于纳米粒径的多样性和不均匀性、体内释放过程的多重性以及在体内易受到各种蛋白的影响等。纳米给药系统中药物体外释放度的主要测定方法有透析法、离心法、流通池法、凝胶法、加压超滤法、扩散池法和原位法等,各有一定的优缺点。目前针对纳米给药系统中药物的体外释放动力学数学模型进行系统研究的文献较少,对其进行体外释放-体内行为相关性研究的文献也较少。今后可通过在药物体外释放测定的介质溶液中引入体内蛋白、在释放测定过程中设计模拟纳米给药系统在体内的分布特性、控制测定装置孔隙大小等方面减小对粒径的影响,使纳米给药系统中药物体外释放度的测定方法更加完善;通过进一步体外释药模型拟合、体内外相关性研究,使纳米给药系统中药物体外释放更好地预测其体内行为。     

流通池法控制制剂释放的应用前景及体内外相关性的探讨

流通池法作为一种新型的溶出度检查方法,有着广阔的应用前景,特别是在药物释放支架、混悬剂、植入剂及微球、脂质体等新剂型中的应用更是具有很大的实用价值,可以很好地弥补传统溶出度方法的不足。在国外,流通池法正逐渐成为溶出度研究的热点。本文系统地介绍了流通池法的历史、现状及应用原理,并对其目前国内外的应用情况做了归纳、总结和前景预测,进一步探讨了流通池法在体内外相关性研究的优越性。     

评价固体制剂的体内外相关性的一种新方法

本文用隔室模型分别来描述药物在体外和体内的过程，并建立了药物在体内、外的动力学方程。通过求算方程中的体内、外港出速度参数Ｒ(ｉｎ)和Ｒ(ｏｕｔ)来评价药物的体内外相关性。采用模型药物盐酸曲马多的体内外数据，根据建立的动力学方程，用自编程序计算在０、２５、１００ｒｐｍ条件下的体外溶出参数Ｒ(ｏｕｔ)的值分别为９.０３±２．０３ｘ１０(－５)ｍＬ．ｍｇ(－２／３)ｍｉｎ(－１)，１.６３±０.９０ｘ１０(－４)ｍＬ·ｍｇ(－２／３)ｍｉｎ(－１)，１８０±０.６５ｘ１０(－４)ｍＬ·ｍｇ(－２／３)·ｍｉｎ(-1)，体内溶出参数Ｒ(ｉｎ)的值为６．２７±０.５２ｘ１０(－５)ｍＬ·ｍｇ(－２／３)·ｍｉｎ(－１)。结果表明，在上述三个不同转数的情况下，体外溶出参数Ｒ(ｏｕｔ)比体内溶出参数Ｒ(ｉｎ)稍大。据此，可以通过调整体外溶出条件进而能更精确地模拟体内溶出情况。     

氯氮平漂浮缓释胶囊体内外相关性评价

目的建立氯氮平漂浮缓释胶囊体内外相关性评价模型 ,评价体内外相关性。方法利用Wanger Nelson方法和卷积模型分别评价氯氮平漂浮缓释胶囊体内外相关性。通过反卷积方法由体外释放数据得到了氯氮平漂浮缓释胶囊的体内输入函数。利用基本卷积模型和扩展卷积模型预测了氯氮平漂浮缓释胶囊体内血药浓度峰值 (Cmax)和血药浓度 时间曲线下面积值 (AUC)。结果Wanger Nelson方法的相关系数为0 9798;反卷积方法得到的体内输入值与体外释药量相关性良好 ,相关系数为 0 996。扩展卷积模型预测的Cmax和AUC值与实验值误差 <6 % ;而基本卷积模型预测值误差 >2 8%。结论氯氮平漂浮缓释胶囊体内外相关性良好。应用扩展的卷积模型能很好的预测氯氮平体内血药浓度 ,预测的体内情况可用来指导处方筛选     

硝苯地平缓释片体内外相关性模型的建立与评估

目的 建立和评价硝苯地平缓释片体内外相关性(IVIVC)的模型. 方法 筛选不同处方片剂的体外释放条件,采用高效液相色谱(HPLC)法测定其累积释放百分率(Fd);液相色谱串联-质谱(LC-MS/MS)法测定健康志愿者单剂量口服两种不同释放速率的硝苯地平缓释片后的血药浓度,利用Wagner-Nelson方程计算累积吸收百分率(Fa). 结果两种制剂体外释放与体内累积吸收相关性均良好,用与硝苯地平控释片生物等效的制剂,创建IVIVC模型： Fa＝0.831 4 Fd＋0.005 2,r＝0.980 8(P<0.01);用另一种制剂对其模型进行外部预测能力的评估：AUC_0～24和 C_max的预测误差分别为3.2%,3.5%. 结论 IVIVC模型具有良好的预测硝苯地平缓释片体内吸收的能力,为硝苯地平缓释片质量标准制订提供依据.     

左乙拉西坦缓释片的制备与体内外相关性研究

目的:研制左乙拉西坦缓释片并考察其体外释放及犬体内药动学。方法:以羟丙甲基纤维素,乙基纤维素为混合骨架材料制备日服一次的缓释片,测定其体外释放度和Beagle犬口服单剂量缓释片后血浆中药物的浓度,推算药动学参数。结果:自制缓释片体外释放符合Higuchi模型。左乙拉西坦普通片,上市缓释片和自制缓释片的有关药动学参数如下:t1/2分别为(2.09±0.45),(5.35±0.76),(7.44±1.48)h,T(peak)分别为(1.184±0.38),(3.87±0.37),(4.07±0.56)h,AUC分别为为(175.40±15.47),(240.93±19.73),(251.47±13.22)μg.h.mL-1。结论:自制缓释片具体良好的缓释特性。体外释放和体内吸收有良好的相关性。     

应用人工神经网络研究红霉素缓释微囊的体内外相关性

以明胶为囊材制备了红霉素缓释微囊，并采用人工神经网络对微囊的体内外相关性进行研究。以体外释放度的数据作为输入、血药浓度数据作为输出训练神经网络系统，通过比较体内血药浓度实测值与预测值的差异考察网络的可靠性，结果表明本网络得到的体内外相关性较好。     

In Vitro-In Vivo Relationship of Oral Extended-Release Dosage Forms

Purpose. A method to establish the in vitro-in vivo relationship of oral extended-release products is proposed. Methods. The approach utilizes incremental amounts of drug released and absorbed within defined time intervals, to construct a ² distributed variable for testing in vitro-in vivo similarity. Results. A case study is used to demonstrate that the similarities between incremental values of in vivo absorbed and in vitro dissolved fractions are distinguishable for different dissolution profiles despite naturally significant linear correlations between cumulative in vivo absorbed and in vitro dissolved fractions (with different dissolution tests) of an oral extended-release product. Conclusions. The method enables investigators to compare different in vitro dissolution profiles of an oral extended-release product to find an optimized dissolution profile to be the surrogate of the in vivo release process of the product.     

Development of a predictive in vitro dissolution for clarithromycin granular suspension based on in vitro-in vivo correlations

The objective of this study was to evaluate the in vitro behavior of different clarithromycin granular suspensions based on a developed in vitro-in vivo correlation model, using one reference and two test formulations. In vitro release rate data were obtained for each product using the USP apparatus II, operated at 50?rpm under different pH conditions. The dissolution efficiency was used to analyze the dissolution data. In vivo study was performed on six healthy male volunteers under fasting condition. Correlation was made between in vitro release and in vivo absorption. A linear model was developed using percent absorbed data versus percent dissolved data from the three products. Dissolution condition of 0.1N HCl for 1?h and then phosphate buffer at pH 6.8 was found to be the most discriminating dissolution method. Rate of absorption for the reference as estimated by Wagner-Nelson deconvolution was correlated with in vitro release with a correlation coefficient of 0.99. The in vivo results for the two test products were compared to the predicted values using the reference model with a correlation coefficient of 0.94. Furthermore, multiple level C correlations were obtained for some pharmacokinetic parameters with the corresponding in vitro kinetic parameters with correlation coefficients exceeding 0.90. Moreover, the interpretation of the in vitro and in vivo data with reference to formulations was discussed.     

Ethionine toxicity in vitro: the correlation of data from rat hepatocyte suspensions and monolayers with in vivo observations

The hepato-steatogenic compound ethionine has been used to investigate the correlations between in␣vivo and in vitro toxicity data. The aim was to find a suitable model of toxicity in hepatocyte suspensions or monolayers in vitro, which could predict the known toxicity of ethionine in vivo and which could be implemented in screening compounds of unknown toxicity. Thus a variety of markers of cytotoxicity, metabolic competence and liver-specific functions were investigated in rat hepatocyte suspensions and monolayers and compared with in vivo data in the rat. The following markers were measured in the appropriate system: (1) Neutral red uptake; 3-(4,5 dimethyl)thiazol-2-yl,-2,5-diphenyl tetrazolium bromide (MTT) reduction; lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) leakage (cytotoxicity). (2) ATP levels, protein synthesis and glutathione (GSH) levels (metabolic competence). (3) Urea and triglyceride synthesis and β-oxidation (liver specific functions). Ethionine (0–30 mM) did not affect the markers of direct cytotoxicity, except neutral red uptake, which was reduced by 18 and 30 mM ethionine after 20 h in culture. ATP and GSH depletion occurred in hepatocyte suspensions at the highest concentrations of ethionine (20 and 30 mM) after 1 h. In monolayers, GSH levels were reduced after 4 h, but not 20 h. Urea synthesis was increased in hepatocyte suspensions from 1 to 3 h by 10–30 mM ethionine and reduced after 20 h in cultured hepatocytes (18–30 mM). Protein synthesis was reduced and β-oxidation was increased in ethionine-treated hepatocyte suspensions. Unfortunately, there was no measurable effect on triglyceride accumulation within cells (the major biochemical change in␣vivo) in either system. Ethionine treated hepatocytes in suspension showed the same rate of triglyceride synthesis and transportation out of cells as control cells. Thus, hepatocyte suspensions were able to mimic the early biochemical effects of ethionine in vivo (ATP and GSH depletion, inhibition of protein synthesis) and some effects on urea synthesis, but monolayer cultures appeared to be less sensitive to the toxicity of ethionine. However, neither in vitro system was able to model the effects of ethionine on the accumulation of triglycerides in vivo. Received: 16 June 1998 / Accepted: 29 June 1998     

Recent advances in testing of microsphere drug delivery systems

ABSTRACT

Introduction: This review discusses advances in the field of microsphere testing.

Areas covered: In vitro release-testing methods such as sample and separate, dialysis membrane sacs and USP apparatus IV have been used for microspheres. Based on comparisons of these methods, USP apparatus IV is currently the method of choice. Accelerated in vitro release tests have been developed to shorten the testing time for quality control purposes. In vitro-in vivo correlations using real-time and accelerated release data have been developed, to minimize the need to conduct in vivo performance evaluation. Storage stability studies have been conducted to investigate the influence of various environmental factors on microsphere quality throughout the product shelf life. New tests such as the floating test and the in vitro wash-off test have been developed along with advancement in characterization techniques for other physico-chemical parameters such as particle size, drug content, and thermal properties.

Expert opinion: Although significant developments have been made in microsphere release testing, there is still a lack of guidance in this area. Microsphere storage stability studies should be extended to include microspheres containing large molecules. An agreement needs to be reached on the use of particle sizing techniques to avoid inconsistent data. An approach needs to be developed to determine total moisture content of microspheres.     

In vitro-in vivo correlations for drugs eliminated by glucuronidation: investigations with the model substrate zidovudine

AIMS: To investigate the effects of incubation conditions on the kinetic constants for zidovudine (AZT) glucuronidation by human liver microsomes, and whether microsomal intrinsic clearance (CLint) derived for the various conditions predicted hepatic AZT clearance by glucuronidation (CLH) in vivo. METHODS: The effects of incubation constituents, particularly buffer type (phosphate, Tris) and activators (Brij58, alamethacin, UDP-N-acetylglucosamine (UDP-NAcG)), on the kinetics of AZT glucuronidation by human liver microsomes was investigated. AZT glucuronide (AZTG) formation by microsomal incubations was quantified by h.p.l.c. Microsomal CLint values determined for the various experimental conditions were extrapolated to a whole organ CLint and these data were used to calculate in vivo CLH using the well-stirred, parallel tube and dispersion models. RESULTS: Mean CLint values for Brij58 activated microsomes in both phosphate (3.66 +/- 1.40 micro l min-1 mg-1, 95% CI 1.92, 5.39) and Tris (3.79 +/- 0.74 micro l min-1 mg-1, 95% CI 2.87, 4.71) buffers were higher (P < 0.05) than the respective values for native microsomes (1.04 +/- 0.42, 95% CI 0.53, 1.56 and 1.37 +/- 0.30 micro l min-1 mg-1, 95% CI 1.00, 1.73). Extrapolation of the microsomal data to a whole organ CLint and substitution of these values in the expressions for the well-stirred, parallel tube and dispersion models underestimated the known in vivo blood AZT clearance by glucuronidation by 6.5- to 23-fold (3.61-12.71 l h-1vs 82 l h-1). There was no significant difference in the CLH predicted by each of the models for each set of conditions. A wide range of incubation constituents and conditions were subsequently investigated to assess their effects on GAZT formation, including alamethacin, UDP-NAcG, MgCl2, d-saccharic acid 1,4-lactone, ATP, GTP, and buffer pH and ionic strength. Of these, only decreasing the phosphate buffer concentration from 0.1 m to 0.02 m for Brij58 activated microsomes substantially increased the rate of GAZT formation, but the extrapolated CLH determined for this condition still underestimated known AZT glucuronidation clearance by more than 4-fold. AZT was shown not to bind nonspecifically to microsomes. Analysis of published data for other glucuronidated drugs confirmed a trend for microsomal CLint to underestimate in vivo CLH. CONCLUSIONS: AZT glucuronidation kinetics by human liver microsomes are markedly dependent on incubation conditions, and there is a need for interlaboratory standardization. Extrapolation of in vitro CLint underestimates in vivo hepatic clearance of drugs eliminated by glucuronidation.     

格列吡嗪控释片体外药物释放特征和体内外相关性研究

目的考察格列吡嗪控释片体外药物释放特征和体内外相关性。方法分别采用3种不同pH值的缓冲溶液作为释放介质,并对pH6．8的释放介质分别采用3种不同的转速来测定格列吡嗪控释片的体外药物释放度,考察释放介质pH值和转速对释放度的影响。用Loo-Riegelman法计算格列吡嗪控释片在健康男性受试者体内吸收百分数,并与相应时间体外累积释放度线性回归,进行体内外相关性考察。结果格列吡嗪控释片在不同pH值释放介质中的释放度一致,均符合零级动力学,且不受转速影响。将体内累积吸收百分数y与相应时间在pH6．8释放介质中的体外释放百分数x进行线性回归（n=7）,回归方程为y=0．6904x＋22．941,r=0．9528。结论格列吡嗪控释片的释放度不受释放介质pH值和转速的影响,释药恒速。体外释放累积百分数与体内吸收百分数呈A级相关,具有良好的体内外相关性。