University of Toronto, Department of Chemical Engineering and Applied Chemistry, 200 College Street, Toronto, Ontario M5S 3E5, Canada.
University of Toronto, Faculty of Medicine, Division of Comparative Medicine, Medical Sciences Building, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Int J Pharm. 2021 Dec 15;610:121237. doi: 10.1016/j.ijpharm.2021.121237. Epub 2021 Oct 28.
Lecithin-linker microemulsions have been previously proposed as a platform for designing a fully dilutable self-microemulsifying drug delivery system (SMEDDS). This SMEDDS formulation, composed of ethyl caprate (oil), lecithin (Le), glycerol monooleate (lipophilic linker, LL) and polyglycerol caprylate (hydrophilic linker, HL), produced a ternary phase diagram (TPD) that had a fully dilutable path suitable for oral drug delivery. However, introducing ibuprofen as an active pharmaceutical ingredient (API) resulted in TPD phase boundaries that eliminated the fully dilutable path. The purpose of this work was to understand the origin of the changes in the TPD, use that understanding to restore the fully dilutable path with an ibuprofen-loaded SMEDDS, and finally to evaluate the absorption of ibuprofen in vivo. The effect of ibuprofen on the HLD (hydrophilic-lipophilic difference, interpreted as normalized net interfacial curvature) of the system was evaluated via a polar oil model, showing that ibuprofen played a surfactant-like role, having a characteristic curvature (Cc) value of +5 (highly hydrophobic). The net-average curvature (NAC) framework used the HLD calculated with Le, LL, HL and ibuprofen Cc to generate TPDs in ibuprofen lecithin-linker systems. The HLD-NAC simulations show that restoring full dilutability required a highly hydrophilic linker (HL) with a Cc of -5 or more negative. The fully dilutable path was restored after introducing a hexaglycerol caprylate as HL- (Cc = -6). Plasma concentration profiles obtained with this ibuprofen-loaded SMEDDS showed a more than three-fold increase in the area under the curve (AUC) of rat plasma concentration profiles compared to the same 25 mg/kg ibuprofen dose in suspension.
已提出将磷脂连接体微乳液作为设计完全可稀释自微乳化药物传递系统 (SMEDDS) 的平台。该 SMEDDS 制剂由辛酸乙酯（油）、磷脂（Le）、甘油单油酸酯（亲脂性连接体，LL）和聚甘油辛酸酯（亲水性连接体，HL）组成，产生了具有完全可稀释路径的三元相图 (TPD)，适用于口服药物递送。然而，引入布洛芬作为活性药物成分 (API) 导致 TPD 相边界消除了完全可稀释的路径。这项工作的目的是了解 TPD 变化的起源，利用这种理解用载有布洛芬的 SMEDDS 恢复完全可稀释的路径，并最终评估布洛芬在体内的吸收。通过极性油模型评估了布洛芬对系统 HLD（亲水-亲脂性差异，解释为归一化净界面曲率）的影响，结果表明布洛芬发挥了表面活性剂的作用，具有特征曲率 (Cc) 值为 +5（高度疏水性）。使用 Le、LL、HL 和布洛芬 Cc 计算 HLD 的净平均曲率 (NAC) 框架生成了布洛芬磷脂连接体系统的 TPD。HLD-NAC 模拟表明，恢复完全可稀释性需要具有 -5 或更负 Cc 的高度亲水性连接体 (HL)。在引入十六甘油辛酸酯作为 HL-（Cc=-6）后，恢复了完全可稀释的路径。与混悬剂中相同的 25mg/kg 布洛芬剂量相比，该载有布洛芬的 SMEDDS 的血浆浓度曲线下面积 (AUC) 使大鼠血浆浓度曲线下面积增加了三倍以上。
