Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Langmuir. 2012 Feb 7;28(5):2881-9. doi: 10.1021/la203577v. Epub 2012 Jan 26.
This report details the structural characterization and the in vitro drug-release properties of different local anesthetic bupivacaine (BUP)-loaded inverted-type liquid crystalline phases and microemulsions. The effects of variations in the lipid composition and/or BUP concentration on the self-assembled nanostructures were investigated in the presence of the commercial distilled glycerol monooleate Myverol 18-99K (GMO) and medium-chain triglycerides (MCT). Synchrotron small-angle X-ray scattering (SAXS) and rotating dialysis cell model were used to characterize the BUP formulations and to investigate the in vitro BUP release profiles, respectively. The evaluation of SAXS data for the BUP-loaded GMO/MCT formulations indicates the structural transition of inverted-type bicontinuous cubic phase of the symmetry Pn3m → inverted-type hexagonal (H(2)) phase → inverted-type microemulsion (L(2)) with increasing MCT content (0-40 wt %). In the absence of MCT, the solubilization of BUP induces the transition of Pn3m → H(2) at pH 7.4; whereas a transition of Pn3m → (Pn3m + H(2)) is detected as the hydration is achieved at pH 6.0. To mimic the drug release and transport from in situ formed self-assembled systems after subcutaneous administration, the release experiments were performed by injecting low viscous stimulus-responsive precursors to a buffer in the dialysis cell leaving the surface area between the self-assembled system and the release medium variable. Our results suggest that the pH-dependent variations in the lipidic partition coefficient, K(l/w), between the liquid crystalline nanostructures and the surrounding buffer solution are significantly affecting BUP release rates. Thus, a first step toward understanding of the drug-release mechanism of this drug-delivery class has been undertaken tackling the influence of drug ionization as well as the type of the self-assembled nanostructure and its release kinetics under pharmaceutically relevant conditions.
本报告详细介绍了不同局部麻醉布比卡因（BUP）负载的反相液晶相和微乳液的结构特征及其体外药物释放特性。在商业蒸馏甘油单油酸酯 Myverol 18-99K（GMO）和中链甘油三酯（MCT）存在的情况下，研究了脂质组成和/或 BUP 浓度变化对自组装纳米结构的影响。同步加速器小角 X 射线散射（SAXS）和旋转透析池模型分别用于表征 BUP 制剂和研究体外 BUP 释放曲线。BUP 负载 GMO/MCT 制剂的 SAXS 数据分析表明，随着 MCT 含量（0-40wt%）的增加，结构发生转变，从反相双连续立方相（Pn3m）→反相六方（H（2））相→反相微乳液（L（2））。在不存在 MCT 的情况下，pH7.4 时 BUP 的增溶诱导 Pn3m→H（2）的转变；而在 pH6.0 时，当达到水合状态时，检测到 Pn3m→（Pn3m+H（2））的转变。为了模拟皮下给药后原位形成的自组装系统的药物释放和传输，通过将低粘性响应性前体注入透析池中的缓冲液中，在自组装系统和释放介质之间的表面积可变的情况下进行释放实验。我们的结果表明，脂质分配系数 K（l/w）在 pH 依赖性变化显著影响 BUP 释放速率。因此，在理解这种药物传递类别的药物释放机制方面迈出了第一步，解决了药物电离以及自组装纳米结构的类型及其在药学相关条件下的释放动力学的影响。
