Striking the Optimal Solubility-Permeability Balance in Oral Formulation Development for Lipophilic Drugs: Maximizing Carbamazepine Blood Levels
Striking the Optimal Solubility-Permeability Balance in Oral Formulation Development for Lipophilic Drugs: Maximizing Carbamazepine Blood Levels
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DOI：
10.1021/acs.molpharmaceut.6b00967
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发表时间：
2017-01-01
影响因子：
4.9
通讯作者：
Dahan, Arik
中科院分区：
文献类型：
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作者：
Beig, Avital;Miller, Jonathan M.;Dahan, Arik
本研究的目的是研究基于助溶剂的增溶制剂在亲脂性药物口服给药中的性能，考虑胃肠道（GIT）管腔增溶过程、溶解度渗透性相互作用和整体体内全身吸收。将难溶性抗癫痫药物卡马西平配制在三种基于共溶剂的制剂中：20%、60%和100%PEG-400，并评估了药物在这些制剂中的表观溶解度和大鼠渗透性。使用生物相关pH稀释法评估制剂在动态GIT环境中的性能。然后，研究大鼠经口给药后的总体体内药物暴露。三种制剂显示出显著的溶解度和渗透性差异; 100%PEG-400提供了最高的溶解度增强，20%最差，而从渗透性的角度来看，完全相反。溶出度结果表明，20%PEG-400制剂在口服给药后迅速崩溃，但60%和100%PEG-400制剂均允许在整个GIT样过程中完全溶解剂量。体内表现最好的制剂是60%PEG-400（F-sys > 90%），其次是100%PEG-400（F-sys = 76%）和20%PEG-400制剂（F-sys接近60%）。总之，这项工作证明了亲脂性药物口服给药中的体内溶解度渗透性权衡;当开发溶解度使能制剂时，应靶向最小阈值溶解度，即刚好足以使药物剂量在整个GIT中溶解，同时应避免过量增溶剂。
The purpose of this research was to investigate the performance of cosolvent based solubility-enabling formulations in oral delivery of lipophilic drugs, accounting for the gastrointestinal tract (GIT) luminal solubilization processes, the solubility permeability interplay, and the overall in vivo systemic absorption. The poorly soluble antiepileptic agent carbamazepine was formulated in three cosolvent-based formulations: 20%, 60%, and 100% PEG-400, and the apparent solubility and rat permeability of the drug in these formulations were evaluated. The performance of the formulations in the dynamic GIT environment was assessed utilizing the biorelevant pH-dilution method. Then, the overall in vivo drug exposure was investigated following oral administration to rats. The three formulations showed dramatic solubility and permeability differences; the 100% PEG-400 provided the highest solubility enhancement and the 20% the poorest, while the exact opposite was evident from the permeability point of view. The dissolution results indicated that the 20% PEG-400 formulation crashes quickly following oral administration, but both the 60% and the 100% PEG-400 formulations allowed full solubilization of the dose throughout the entire GIT-like journey. The best in vivo performing formulation was the 60% PEG-400 (F-sys > 90%), followed by the 100% PEG-400 (F-sys = 76%), and the 20% PEG-400 formulation (F-sys approximate to 60%). In conclusion, this work demonstrates the in vivo solubility permeability trade-off in oral delivery of lipophilic drugs; when a solubility-enabling formulation is developed, minimal threshold solubility should be targeted, that is just enough to allow solubilization of the drug dose throughout the GIT, while excess solubilizer should be avoided.