Quantitative assessment of disintegration rate is important for predicting the oral absorption of solid dosage forms containing poorly soluble weak base drugs
Quantitative assessment of disintegration rate is important for predicting the oral absorption of solid dosage forms containing poorly soluble weak base drugs
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崩解率的定量评估对于预测含有难溶性弱碱性药物的固体剂型的口服吸收具有重要意义
DOI：
10.1016/j.ejpb.2022.09.017
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发表时间：
2022
影响因子：
4.9
通讯作者：
Onoue Satomi
中科院分区：
文献类型：
--
作者：
Nakamura Kohei;Kambayashi Atsushi;Onoue Satomi
本研究旨在开发一种考虑胃内崩解率的新型硅模建模法和模拟法，以预测含有难溶的弱碱性药物、崩解率较慢的口服固体制剂的体内药效。以奥沙米特和盐酸马尼地平为模型药物。首先，在模拟空腹人体胃肠道液体的生物悬浮介质中，使用USP II桨式溶出仪测定茶碱的体外崩解率和溶出度。接下来，使用新的模拟模型预测剂型的口服吸收，不仅包括溶出度，还包括估计的崩解率。由于两种药物在禁食状态模拟胃液中的体外崩解时间均为45min或更长，故认为这两种剂型的崩解速率均为缓释(IR)片。虽然使用新模型预测和观察到的两种药物的药动学曲线具有可比性，但没有考虑崩解步骤的传统模型低估了这两种药物的口服吸收。因此，我们新的模拟模型与体外试验估计的崩解率相结合，有望预测含有难溶的弱碱性药物、崩解率较慢的口服固体制剂的体内药效。
This study aimed to develop a novelin silicomodeling and simulation that considers the disintegration rate in the stomach to predict thein vivoperformance of oral solid dosage forms with slow disintegration rates containing poorly soluble weak base drugs. Oxatomide and manidipine hydrochloride were used as model drugs. First, thein vitrodisintegration rate and dissolution rate were determined in biorelevant media that simulate the gastrointestinal fluids in fasted humans using a USP apparatus II paddle dissolution tester. Next, the oral absorption of the dosage forms was predicted using the novel simulation model coupled with not only the dissolution rate but also the estimated disintegration rate. As thein vitrodisintegration time was 45 min or longer for both drugs in Fasted State Simulated Gastric Fluid, the disintegration rate of these dosage forms was considered slow as immediate release (IR) tablets. While the predicted and observed pharmacokinetic profiles of both drugs were comparable using the new model, the conventional model, which did not consider the disintegration step, underestimated the oral absorption of both drugs. Thus, our novel simulation model coupled with the disintegration rate estimated fromin vitrotests is promising for predicting thein vivoperformance of oral solid dosage forms with slow disintegration rates containing poorly soluble weak base drugs.