Ikuta Shotaro, Nakagawa Hidetoshi, Kai Toshiya, Sugano Kiyohiko
Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan; Pharmaceutical Research Laboratories, Pharmaceutical Department, Nipro corporation, 3023, Noji-Cho, Kusatsu, Shiga 525-0055, Japan.
Pharmaceutical Research Laboratories, Pharmaceutical Department, Nipro corporation, 3023, Noji-Cho, Kusatsu, Shiga 525-0055, Japan.
Eur J Pharm Sci. 2023 Jan 1;180:106326. doi: 10.1016/j.ejps.2022.106326. Epub 2022 Nov 5.
The purpose of this study was to develop a bicarbonate buffer flow-through cell (FTC) dissolution test. Mesalazine colon targeting tablets of a generic development product (test formulation, TF; Mesalazine 400 mg tablet) and the original product (reference formulation, RF; Asacol® 400 mg tablet) were used as model formulations. A clinical bioequivalence (BE) study was conducted on 48 healthy male subjects under fasting conditions. The oral absorption time profiles were calculated by point-area deconvolution. The compendial paddle and FTC apparatus were used for dissolution tests. Bicarbonate or phosphate-citrate buffer solutions (McIlvaine buffer) were used as the dissolution media. A floating lid was used to maintain the pH value of the bicarbonate buffer solution in the vessel (paddle) or the reservoir (FTC). In the development of bicarbonate FTC method, the pH changes of bicarbonate buffer solution (pH 5.5-7.5; 5-50 mM bicarbonate) were evaluated. For the evaluation of colon targeting tablets, the dissolution profiles of TF and RF were measured at a pH of 7.5. The TF and RF formulations were exposed to 0.01 HCl (pH 2.0) for 2 h before pH 7.5. In the clinical BE study, drug dissolution started 4-8 h after oral administration and continued slowly more than 10 h. Both the area under the curve (AUC) and maximum plasma concentration (Cmax) of TF were approximately twice as high as those of RF. In the development of the bicarbonate FTC method, the pH change of the bicarbonate buffer solution was suppressed by the floating lid within ∆pH < 0.1 over 10 h. In the dissolution test of McIlvaine buffer solutions, TF and RF showed faster disintegration and higher dissolution than those observed in the clinical BE study. When using the paddle apparatus the dissolution profiles of TF and RF in both buffer solutions were not consistent with those of the clinical result. In bicarbonate FTC, the disintegration time, dissolution rate, and dissolution inequivalence between TF and RF were consistent with the results of the clinical BE study. In conclusion, the bicarbonate FTC method was constructed for the first time in this study. This method is simple and practically useful for predicting in vivo performance of colon targeting tablets during drug development.
本研究的目的是开发一种碳酸氢盐缓冲流通池（FTC）溶出度试验。将一种仿制药开发产品（试验制剂，TF；美沙拉嗪400 mg片剂）和原产品（参比制剂，RF；艾迪莎® 400 mg片剂）的美沙拉嗪结肠靶向片剂用作模型制剂。在48名健康男性受试者空腹条件下进行了临床生物等效性（BE）研究。通过点面积反卷积计算口服吸收时间曲线。采用药典桨法和FTC装置进行溶出度试验。使用碳酸氢盐或磷酸盐 - 柠檬酸盐缓冲溶液（麦克尔维恩缓冲液）作为溶出介质。使用浮动盖维持容器（桨法）或贮液器（FTC）中碳酸氢盐缓冲溶液的pH值。在开发碳酸氢盐FTC方法时，评估了碳酸氢盐缓冲溶液（pH 5.5 - 7.5；5 - 50 mM碳酸氢盐）的pH变化。为评估结肠靶向片剂，在pH 7.5下测量TF和RF的溶出曲线。在pH 7.5之前，将TF和RF制剂暴露于0.01 M HCl（pH 2.0）中2小时。在临床BE研究中，药物溶出在口服给药后4 - 8小时开始，并在超过10小时内缓慢持续。TF的曲线下面积（AUC）和最大血药浓度（Cmax）均约为RF的两倍。在开发碳酸氢盐FTC方法时，浮动盖在10小时内将碳酸氢盐缓冲溶液的pH变化抑制在∆pH < 0.1范围内。在麦克尔维恩缓冲溶液的溶出度试验中，TF和RF表现出比临床BE研究中更快的崩解和更高的溶出度。当使用桨法装置时，TF和RF在两种缓冲溶液中的溶出曲线与临床结果不一致。在碳酸氢盐FTC中，TF和RF之间的崩解时间、溶出速率和溶出不等效性与临床BE研究结果一致。总之，本研究首次构建了碳酸氢盐FTC方法。该方法简单且在药物开发过程中对于预测结肠靶向片剂的体内性能具有实际应用价值。
