Correlations between in vitro dissolution rate and bioavailability of alaproclate tablets

In two different absorption studies, quantitative correlations between the in vitro dissolution rate and the bioavailability have been shown after single administration of various tablet compositions of alaproclate hydrochloride to healthy subjects. Both statistical moment analysis and the use of empirical single value parameters were tested. For conventional tablets a linear relationship was obtained between mean dissolution time in vitro and in vivo. A similar relationship was obtained between the mean dissolution time in vitro and the mean residence time for controlled release tablets of the matrix type. It was also possible to establish an in vitro--in vivo correlation for these latter tablets by using the single point estimate of maximum plasma concentration as in vivo parameter. When comparing the mean dissolution time in vitro to the total area under the plasma drug concentration-time curve attained after different types of tablets, it is obvious that the extent of bioavailability of alaproclate will not fall below 80% of the value found for an aqueous solution until the mean dissolution time in vitro exceeds approximately 3 hr. Statistical moment analysis seems to have a broader applicability than the use of empirical point estimates, and it seems to be useful both for conventionally dissolving tablets and controlled release tablets.     

A dissolution rate apparatus for the prediction of initial drug absorption patterns in beagles: Tolbutamide tablets

An apparatus utilizing liquid turbulence to simulate hydrodynamic conditions generated by gastrointestinal peristalsis was designed to estimate drug release from solid oral dosage forms. This turbulence was achieved through special arrangement of a pipetting pump to a dissolution chamber. By adjusting the flow rate of the pump to deliver and withdraw a fixed volume of dissolution medium per minute, a correlation was developed between dissolution rates and absorption patterns in beagles of two commercial tolbutamide tablets, A and B, and a micronized tolbutamide suspension. On the basis of this relationship, it was possible to predict the initial absorption patterns of two misformulated tablets, C and D.     

Correlation betweenin vitro andin vivo drug metabolism rate: Oxidation of ethoxybenzamide in rat

In vitroand in vivocorrelations of the microsomal oxidation of drugs were examined, using ethoxybenzamide as a model drug. Ethoxybenzamide disappearance time course from rat plasma in vivowas analyzed by a two-compartment model assuming a Michaelis-Menten type elimination process. Ethoxybenazmide oxidation in vitrowas measured by the appearance rate of salicylamide in rat liver microsomal suspension. Parameters obtained were V_max=3.46 and 3.77 moles/min/kg body weight and K_m=0.378 and 0.192mM, in vitroand in vivo,respectively.     

Investigating relationships betweenin vivo andin vitro pharmacological variables for the purpose of prediction

Consistency of effect in vivois an important characteristic of a drug product, and great variation from lot to lot or between manufacturers is not desirable. The variation usually arises when some lots fail to meet minimum standards. It may then be necessary to develop a procedure for detecting and screening out these defective lots. A new, heuristic approach is presented for evaluating procedures in which screening is to be based on in vitromeasurements rather than more costly in vivomeasures. A quantification of risks is defined from which a minimum (in a certain sense) risk procedure may be selected from a set of candidate procedures. This approach is shown to be more appropriate than those based on correlational techniques.The views expressed herein are those of the author and not necessarily those of the Food and Drug Administration. This article was originally presented at the Thirty-first Annual Princeton Conference on Applied Statistics, Princeton, New Jersey, December 1975.     

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。     

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。     

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.     

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.     

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。     

药物代谢清除率体外预测模型研究进展与问题分析

本文介绍了药物代谢清除率临床前预测的相关理论和数学模型，从而将所得的体外代谢清除率数据用于肝清除率的推算，并根据国内外学者对该预测方法准确度评估及体内体外相关性考察，指出该研究领域中出现的难点和可能的改进方案；以期使体内代谢行为的预测更加准确，并对尽早确定创新药物在人体内药物代谢动力学行为是否适合进行进一步研究开发具有重要的指导意义，并为今后创新药物的研发提供新的思路。     

具有区分力的罗红霉素片体外溶出度方法研究

目的 研究罗红霉素片的溶出行为,确定有区分力的溶出度检查方法。方法 考察罗红霉素在不同pH溶液中的稳定性及溶解度,测定不同处方自研制剂与参比制剂在4种不同溶出介质中的溶出度,绘制溶出曲线,用相似因子法进行拟合。结果 罗红霉素在pH6.8和7.4磷酸盐缓冲液中8 h内稳定性较好,自研制剂A与参比制剂在4种溶出介质中的溶出曲线均具有较好的相似性,自研制剂B与参比制剂在pH 6.8磷酸盐缓冲液中的溶出曲线不相似。结论 以pH 6.8磷酸盐缓冲液为溶出介质,采用浆法测定,75 r/min对本品溶出具有较好的区分力,可为本品的质量控制和一致性评价提供参考。     

伐昔洛韦缓释片体外释放速率与人体内吸收速率的相关性

目的:研究伐昔洛韦缓释片体外释放速率与人体内吸收速率的相关性。方法:以水为释放介质,测定伐昔洛韦缓释片的体外释放速率;采用Wagner-Nelson法计算单剂量口服缓释片后体内吸收分数,考察吸收相体内吸收与体外释放的相关性。结果:伐昔洛韦缓释片体内吸收分数(f_a)与体外释放速率(f_r)的关系为:f_a=2.11f_r -20.12,r=0.994 0(n=5)。结论:伐昔洛韦缓释片人体内外相关性良好(P<0.001)。     

异烟肼片体外溶出度测定方法的建立及溶出曲线评价

目的 建立异烟肼片体外溶出度HPLC检测方法及溶出曲线评价。方法 溶出度试验采用桨法,转速50 r/min;以pH1.2盐酸缓冲液、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液、水900 mL为溶出介质;HPLC法测定溶出量。结果 异烟肼在0.198 1~0.990 4 μg线性良好（r=0.999 3）,平均回收率为100.2%;精密度、重复性、专属性均良好。在测定的16家企业中,有4家企业水中溶出曲线与参比制剂山德士异烟肼片不相似。结论 HPLC测定方法简单方便,提高了异烟肼溶出量测定的准确性和专属性;溶出方法具有较强的区分力,该溶出度测定方法可用于异烟肼片溶出曲线的测定。     

两相溶出系统及其在难溶性药物制剂评价中的应用

两相溶出系统由水相和有机相组成,是一个同时测定药物溶出和分配的体外溶出方法,具有模拟体内吸收、克服表面活性剂对溶出的影响等优点,在评价难溶性药物的体外溶出方面具有良好的应用前景.本文综合近年来该领域的相关研究,对两相溶出系统的发展历史、溶出装置、理论模型及应用作简要综述,并对研究前景进行了总结与展望.     

反卷积分法研究长春西汀推拉式渗透泵控释片体内外相关性

目的：采用反卷积分法评价长春西汀渗透泵控释片的体外释放与Beagle犬体内吸收相关性。方法：以0．5％SDS水溶液为溶出介质，测定长春西汀的体外释放度；高效液相色谱测定犬体内血药浓度，选择长春西汀普通片为参比制剂，应用反卷积分法评价长春西汀推拉式渗透泵体内体外相关性。结果：体外累计释放度（Y）与输入函数（R）回归方程为iY=237．99R-13．544（r=0．9763），表明长春西汀推拉式渗透泵体内体外相关性良好。结论：反卷积分法适合自制长春西汀推拉式渗透泵控释片体内外相关性研究。     

Effect of pomegranate pretreatment on the oral bioavailability of buspirone in male albino rabbits

BACK GROUND AND THE PURPOSE OF STUDY: Many drug substances and variety of naturally occurring dietary or herbal components are capable of interaction with the CYP enzyme system. The aim of the study was to investigate the effect of pomegranate juice pretreatment on the bioavailability of buspirone in rabbits. METHODS: White New Zealand rabbits weighing 2.1±0.13 Kg were selected for study. The bioavailability of buspirone after pre-treatment with pomegranate juice (10 ml Kg(-1) for seven days) was compared with an oral solution of 10 mg kg(-1) of buspirone in distilled water. Animals were allowed free access to food and water, until night prior to dosing and were fasted for 10 hrs. In the first phase oral solution (10 mg kg(-1)) was administered through feeding tube followed by rinsing with 10 ml of water. In the second phase, the group was pretreated with pomegranate juice for 7 days and study was conducted after 15 days of washout period. RESULTS AND CONCLUSION: The results showed that there was a significant (p<0.05) difference in the bioavailability of buspirone after pre-treatment with pomegranate juice.This increase in bioavailability might be due to inhibition of CYP3A4. Further studies are required to prove this mechanism in humans.     

不同粉碎度野生西洋参人参皂苷Rb1的体外溶出度研究

目的 采用体外溶出法考察野生西洋参细粉、极细粉与超微粉人参皂苷Rb₁的溶出速率与溶出度。方法 按2010年版《中国药典》规定进行不同粉碎度野生西洋参粉体外溶出度试验,绘制溶出曲线,考察不同粉碎度粉末的体外溶出行为及释药机制。结果 前10 min,野生西洋参中人参皂苷Rb₁的溶出速率为极细粉>细粉>超微粉,10 min后超微粉的溶出率最大,极细粉的溶出次之,而细粉溶出最慢。结论 野生西洋参粉中人参皂苷Rb₁的溶出速率与粉末本身的粒径和浸润有关,在粉末浸润后,超微粉的溶出最快。     

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     

阿昔莫司缓释片的体外释放度与犬体内吸收相关性

目的:研究阿昔莫司缓释片的体外释放度与其在家犬体内吸收的相关性。方法:以水为溶出介质,测定阿昔莫司缓释片的体外释放度。采用高效液相色谱法测定家犬单剂量口服阿昔莫司胶囊和缓释片后的血药浓度,用非隔室模型对阿昔莫司的体内过程进行拟合,以反卷积分法求算积分方程中的输入函数。以输入函数与同时间点体外累积释放度回归求得相关系数并与相关系数临界值进行比较。结果:以累积释放度Y与输入函数R建立的回归方程为:Y=18.118R+35.717(r=0.9309),相关系数临界值r4,0.05=0.811,r>r4,0.05,表明回归方程显著。结论:自制阿昔莫司缓释片体内外相关性良好。     

Unique approach for calculation of first-order absorption rate constants from blood or urine data

Several methods are employed to estimate an apparent first-order rate constant for absorption in a one-compartment model. A method for calculation of the absorption rate constant (K _a )has been derived based on the area under the concentration-time curve for blood data or the area under the excretion rate-time curve for urine data between the observed time of maximum concentration or rate (t _max )and the maximum concentration (C _max )or maximum rate of excretion (X _umax ).The method obviates the need for large numbers of samples in the absorptive phase. The method also avoids extensive calculations and is less influenced by errors in data points prior to C_max or X_{u max},where the rate of change is rapid and error is likely. The methods have been tested on theoretical data with and without error generated using a range of values for K_a and elimination rate constants (K _E ).Errors in the estimate of K_a are proportional to error in the data. The method compares favorably with nonlinear regression analysis.