Development and validation of discriminating method of dissolution for fosamprenavir tablets based on in vivo data

The aim of this work is to develop and validate a dissolution test for fosamprenavir tablets (Telzir^®) based on in vivo data. The appropriate conditions were determined after testing sink conditions in dissolution medium, rotation speed and stability of the drug. In vivo release profiles were obtained from the literature. The fraction (and percentage) of dose absorbed (FA) was calculated by deconvolution, using the Wagner–Nelson method. For this formulation, the best dissolution conditions were achieved using a USP apparatus 1 900 ml of medium containing HCl 0.01 M at a rotation speed of 75 rpm. Under these conditions a significant linear relationship between fraction of drug absorbed versus dissolved was obtained (R² = 0.984) and a level-A IVIVC was established. The in vitro dissolution samples were analyzed using a HPLC method and the validation was performed according to USP protocol. The method showed accuracy, precision, linearity and specificity within the acceptable range. The discriminatory power of the dissolution method was challenged. The kinetics of dissolution was determined using model-dependent methods. The dissolution profiles were best described by the Hixson–Crowell model. The dissolution test was validated and could be applied to evaluate the dissolution profile of fosamprenavir tablets.     

美洛昔康片溶出度考察及其体内外相关性

目的:考察2种市售美洛昔康片的体外溶出度,评价其质量及其体内外相关性.方法:采用转篮法测定溶出度,计算累积溶出百分率并与体内吸收百分率进行相关性评价;用Weibull分布模型对溶出曲线进行拟合,提取溶出参数并进行统计分析.结果:2种美洛昔康片的溶出参数之间差异有非常显著意义(P＜0.01).t检验表明同一厂家3批产品的参数之间差异有时也有显著性(P＜0.05).2种片剂的体外溶出与体内吸收之间均具有显著相关性.结论:2个厂家产品的溶出度之间存在差异并且体内外具有相关性,提示在临床用药时应加以注意.     

Comparison of two dissolution apparatuses with correlation of in vitro-in vivo data for prednisone and prednisolone tablets

Dissolution profiles in 0.1N hydrochloric acid using both the paddle stirrer apparatus and the spin filter apparatus were obtained for prednisone tablets made by seven different manufacturers and prednisolone tablets made by eight different manufacturers. Dissolution parameters were correlated with results obtained in three human bioavailability trials which were previously reported. Also, results obtained in one apparatus were correlated with those obtained in the other apparatus. Such correlations may be useful in the setting of in vitro dissolution rate specifications for commerical prednisone and prednisolone tablets.     

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     

卡马西平片体外溶出度与体内吸收相关性

目的：考察卡马西平（ＣＢＺ）片溶出度与体内吸收的相关性。方法：应用ＺＲＳ－４溶出度仪测定卡马西平片的溶出度。４名男性健康志愿性ｐｏ单剂量２００ｍｇＣＢＺ用ＴＤｘ分析仪测定血药浓度，并按照Ｗａｇｎｅｒ－Ｎｅｌｓｏｎ公式计算药物吸收分数。结果：体外溶出度与体内药物吸收分数的相关系数ｒ＝０．９２６１，体外溶出度与体内药物吸收分数的相关系数ｒ＝０．９９７７。结论：ＣＢＺ片体外溶出度与体内吸收有较好的相关性     

In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCl

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non-disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus. The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and t_d of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and t_d between 149 and 291 min. The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half-life t_1/2 (7.12 h), while apparent t_1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for C_max and AUC values, and no relationships could be established with the type of formulation. An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p <0.05). In a few cases the Wagner-Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the ‘Levy's plot’ (per cent released versus per cent absorbed) approach and provided further support for the correlation found.     

盐酸氨溴索缓释片体内外相关性研究

目的考察盐酸氨溴索缓释片体外释放度与体内吸收的相关性。方法应用释放度测定法研究盐酸氨溴索缓释片体外释药行为 ,采用HPLC法测定盐酸氨溴索缓释制剂在家犬体内的血药浓度 ,按照Wagner Nelson公式计算药物的吸收分数。 结果 3种自制盐酸氨溴索缓释片与参比制剂生物等效 ,以药物累积吸收百分数 f(t)与相应时刻的体外累积释放百分数F(t)建立的一元线性回归方程 ,参比制剂与 3种自制制剂的体内外相关系数分别为 0 969、0 979、0 970和 0 983。结论盐酸氨溴索缓释片的体外释放度与体内吸收具有显著的相关性。     

茶碱控释胶囊的体外释放与体内吸收相关性

目的：考察茶碱控释胶囊（ＴＰＣＣ）释放度与体内的相关性。方法：应用ＺＲＳ－４溶出度仪测定ＴＰＣＣ的释放度。采用紫外分光光度法对８名健康受试者单剂量ｐｏＴＰＣＣ４００ｍｇ测定经时血药浓度,并按照Ｗａｇｎｅｒ－Ｎｅｌｓｏｎ公式计算药物吸收分数。结果：体外释放度与体内吸收分数的相关系数为ｒ＝０．９６９．４。结论：ＴＰＣＣ片体外溶出度与体内吸收具有良好相关性。     

卷积法在体内外相关性研究中的应用

本文介绍了体内外相关性和卷积法/反卷积法的概念及原理, 阐述了采用卷积法使用Excel根据制剂的药代动力学数据计算其在体内释放行为的策略及方法, 并用于体内外相关性研究。该法用数学软件对药代动力学数据进行拟合以弥补缺失的数据点, 在假设输入函数基本符合威布尔规律的前提下, 在Excel中根据卷积法原理以试错法的方式确定拟合度最佳的输入函数(威布尔函数)参数, 最后以拟合度最佳的输入函数作为制剂的体内释放行为与体外释放数据进行相关性研究。在实例中不仅详细说明了该法的应用, 并且通过与隔室模型法和反卷积法的比较证明此方法简单有效, 可以作为体内外相关性研究的有力工具。     

In vitro — In vivo correlation of dissolution,a time scaling problem? Transformation of in vitro results to the in vivo situation,using theophylline as a practical example

Summary Two principal approaches to demonstrating the continuous in vivo relevance of an in vitro dissolution test are outlined. The first uses the convolution technique to predict the concentration-time course in vivo; the second uses deconvolution as a mathematical tool to estimate the in vivo dissolution profile. The weighting function must be known to utilise either technique. Defined by the aim of the analysis the dose-normalized response to the oral solution is regarded as the weighting function (Impulse Response). In both cases the essential step is continuous comparison of the predicted time dependent data with actual readings of the same class. To permit the prediction of concentration-time data from in vitro dissolution data the basic equations for the transformation of the time base from in vitro to in vivo conditions are developed. The transformation is essential, since one cannot assume that the time scales for the in vitro and the in vivo experiment are definitely the same. The estimated in vivo dissolution profile using the deconvolution technique gives a hypothetical image of the true in vivo dissolution curve. Comparison with in vitro dissolution test results, using one of the equivalence testing procedures, reveals how closely and for how long the in vitro dissolution test simulates the in vivo dissolution process. For the formulation of theophylline studied, equivalence of the in vitro and the estimated in vivo dissolution profiles was not confirmed for the entire period of observation, but it was demonstrated for approximately the first 5 h. The later inequivalence is not due to possible non-linear or time-dependent kinetics of theophylline. There is a discussion of whether a change in pH, agitation of the formulation, diffusion conditions or the absorption rate constant along the gastrointestinal tract might explain the biphasic linear correlation of the in vitro and in vivo data observed.     

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。     

萘普生钠片溶出度测定及体内外相关性评价

目的:进行萘普生钠片体外溶出度的测定及体内外相关性评价.方法:按USP29版萘普生钠片溶出度测定法测定萘普生钠片体外溶出度,用HPLC法测定萘普生钠片在人体内的血药浓度,并用BAPP2.0程序进行拟合.结果:以体内吸收分数(F)对体外累积溶出率(X)进行线性回归,得方程F=0.330 3X 0.699 8(r=0.991 5),体内吸收分数与体外累积溶出率具有良好的相关性.结论:USP29版萘普生钠片的溶出度方法合理,可以较好反映体内吸收情况.     

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.     

盐酸噻吩诺啡缓释微球的体外释放度及其体内外相关性研究

目的 建立体内外相关性良好的盐酸噻吩诺啡缓释微球的体外释放度测定方法.方法 采用直接释药法和透析释药法测定盐酸嚷吩诺啡缓释微球的体外释放度;采用高效液相色谱法测定盐酸噻吩诺啡缓释微球在大鼠注射部位的残留量,计算微球在体内的释药速度.通过相关性评价确定最佳的体外释放度测定方法.结果 透析释药法和直接释药法均可获得良好的体内外相关性.结论 直接释药法和透析释药法均可用于测定盐酸噻吩诺啡微球的体外释放度.     

Comparison of in vitro and in vivo release characteristics of acetaminophen from gradient matrix systems

An effort was made to correlate the in vivo and in vitro release data of acetaminophen from two formulations of a recently developed controlled-release system, the Gradient Matrix System (GMS-1 and GMS-2). The in vivo release curves, obtained by deconvolution of the plasma concentration time plots, showed a small inter-subject variability. GMS-1 with fastest in vitro release also showed fastest in vivo release. A good relationship was only found after time-scaling of the release data.     

Dissolution testing for sustained or controlled release oral dosage forms and correlation with in vivo data: Challenges and opportunities

Despite the fact that dissolution tests were first introduced to characterise the release profile of low solubility (< 1%) drugs in aqueous media, the emphasis is now to adopt dissolution tests in monographs of almost all oral solid dosage forms in most pharmacopoeias. This is attributable mainly to the growing demand by both regulatory authorities and pharmaceutical industries of more in vivo predictability of the release and absorption behaviours of drug(s) from the dosage form by means of in vitro tests, i.e. in vitro-in vivo correlation. Dissolution testing is also essential in various stages of formulation development for screening and proper assessment of different formulations. Although dissolution tests have been successfully implemented on conventional dosage forms, there are enormous difficulties in establishing proper dissolution test conditions and parameters for testing sustained or controlled release oral dosage forms because of prolonged gastrointestinal residence of the dosage form and variabilities in physiological conditions of the gastrointestinal tract. This review focuses on the challenges faced by formulation scientists and regulatory authorities in generalising the dissolution test conditions and parameters for testing sustained or controlled release dosage forms, and describes some recent trends and progress in overcoming some of these challenges.     

美斯地浓缓释片体外释放与体内吸收的相关性

目的:研究美斯地浓缓释片体外释放与体内吸收的相关性。方法:以水为溶出介质,测定美斯地浓缓释片的体外释放度,采用高效液相色谱法测定兔口服美斯地浓缓释片后的血药浓度,按照Loo-Riegelman公式计算药物的吸收分数,并对体内外相关性进行评价。结果:不同时间点的体内吸收百分数与体外累计释放百分数相关系数良好(r=0.997),相关性方程为Y=1.667 7 X+0.563。结论:美斯地浓缓释片体外释放累积百分数与体内吸收百分数具有显著的体内外相关性。     

脱卷积法进行自制尼群地平缓释制剂体内外相关性研究

目的用脱卷积法进行自制尼群地平缓释制剂体内外相关性的研究。方法以自制尼群地平口服溶液剂的犬体内血药浓度数据为权函数，根据3种自制尼群地平缓释制剂试验犬体内血药浓度数据，采用脱卷积法计算体内释药特性，与相应的体外释药特性进行比较，考察体内外相关性。结果用脱卷积法计算3种尼群地平缓释制剂的体内外释药相关性良好。结论脱卷积法适用于自制尼群地平缓释制剂的体内外相关性研究。     

盐酸尼卡地平缓释微丸人体内外相关性的研究

目的考察盐酸尼卡地平缓释微丸体外释放和人体内吸收的相关性。方法体外溶出试验采用转篮法。人体内血药浓度测定采用反相HPLC。该法以安定为内标,其线性范围为5.0～200.0ng/ml,峰面积比值R对药物浓度C的回归方程为R=0.05893+0.01237C(r=0.9996,n=6),最低检测浓度为2.5ng/ml,日内、日间相对标准偏差分别为5.35%和7.27%(n=3),平均回收率为96.94%。结果将体外释放百分率F(%)对人体吸收百分率f(%)进行线性回归,得方程f=-6.1403+1.2780F(r=0.9681,P＜0.01)。结论盐酸尼卡地平缓释微丸体内吸收百分率与体外释放百分率间存在良好的相关关系。     

茶碱缓释片体内外试验的相关性

目的：评价茶碱缓释片的体外释放与体内吸收的相关性,为其质量控制提供实验依据。方法：用反相高效液相色谱法测定血浆中的茶碱浓度,按Ｗａｇｎｅｒ－Ｎｅｌｓｏｎ公式计算一定时间内２种茶碱缓释片的体内吸收百分率。在３种不同ｐＨ的介质中进行体外释放度试验,。计算相应时间内的累积释放百分率。结果：介质的ｐＨ变化对茶碱缓释片的体外释放度无明显影响。结论;茶碱缓释片的体内吸收百分率与体外释放百分率间存在良好的相关关