Abstract：
The purpose of the present study was to provide the experimental and theoretical basis of bioequivalence (BE) dissolution test criteria for formulation development of high solubility-low permeability drugs. According to the biowaiver scheme based on the biopharmaceutics classification system (BCS), for BCS class III drugs, a test formulation and a reference formulation are predicted to be BE when 85% of the drug dissolves within 15 min (T85% < 15 min) in the compendial dissolution test. However, previous theoretical simulation studies have suggested that this criterion may possibly be relaxed for use in practical formulation development. In the present study, the dissolution profiles of 14 famotidine formulations for which BE has been clinically confirmed were evaluated by the compendial dissolution test at pH 1.2 and 6.8. The plasma concentration-time profiles of famotidine formulations were simulated using the dissolution data. In addition, virtual simulations were performed to estimate the range of dissolution rates to be bioequivalent. The fastest and slowest dissolution rates among the famotidine formulations were T85% = 10 min and T85% = 60 min at pH 6.8, respectively. The virtual simulation BE study suggested that famotidine formulations can be bioequivalent when T85% < 99 min. In the case of BCS III drugs, the rate-limiting step of oral drug absorption is the membrane permeation process rather than the dissolution process. Therefore, a difference in the dissolution process has less effect on BE. These results contribute to a better understanding of the biowaiver approach and would be of great help in the formulation development of BCS class III drugs.
摘要：
本研究的目的是为高溶解度-低渗透性药物的制剂开发提供生物等效性(BE)溶出试验标准的实验和理论依据。根据基于生物制药分类系统(BCS)的生物保护方案，对于BCSIII类药物，在药典溶出试验中,当85%的药物在15分钟内溶解(T85%<15分钟)时,预计试验制剂和参考制剂为BE。然而,先前的理论模拟研究表明，该标准可能会放宽，以用于实际的配方开发。在本研究中,通过在pH1.2和6.8下的药典溶出试验评估了14种已被临床证实为BE的法莫替丁制剂的溶出曲线。使用溶出数据模拟法莫替丁制剂的血浆浓度-时间曲线。此外,进行虚拟模拟以估计生物等效的溶解速率范围.法莫替丁制剂中最快和最慢的溶解速率分别是在pH6.8下T85%=10分钟和T85%=60分钟。虚拟模拟BE研究表明，当T85%<99分钟时，法莫替丁制剂可以是生物等效的。在BCSIII药物的情况下，口服药物吸收的限速步骤是膜渗透过程，而不是溶解过程。因此,溶出过程的差异对BE的影响较小。这些结果有助于更好地理解生物保护剂方法，并将对BCSIII类药物的配方开发有很大帮助。
