Department of Pharmacy and Biotechnology, University of Bologna, Via S. Donato 19/2, Bologna 40127, Italy.
Department of Applied Science and Technology, Politecnico di Torino, Torino 10129, Italy.
Eur J Pharm Sci. 2024 Jan 1;192:106650. doi: 10.1016/j.ejps.2023.106650. Epub 2023 Nov 22.
This study investigates the correlation between the structural and release properties of solid lipid microparticles (MPs) of tristearin containing 5 % w/w of four different liquid additives used as crystal modifiers: isopropyl myristate (IM), ethyl oleate (EO), oleic acid (OA) and medium chain triglycerides (MCT). All additives accelerated the conversion of the unstable α-form of tristearin, formed after the MPs manufacturing, to the stable β-polymorph and the transformation was completed within 24 h (for IM and EO) or 48 h (for OA and MCT). The kinetic of polymorphic transition at 25 °C was investigated by simultaneous synchrotron SAXS/WAXS and DSC analysis after melting and subsequent cooling of the lipid mixture. After crystallization in the α-phase, additives accelerate the solid-solid phase transformation to β-tristearin. SAXS data showed that two types of structural modifications occurred on MPs during storage: compaction of the crystal packing (slight decrease in lamellar thickness) and crystal growth (increased number of stacked lipid lamellae). The release behavior of a model hydrophilic drug (caffeine) at two different amounts (15 % and 30 %) from MPs was studied in water and biorelevant media simulated the gastric and intestinal environment. It was particularly significant that the introduction of IM, EO and MCT were able to prolong the drug release in water, passing from a diffusion-based Higuchi kinetics to a perfect zero-order kinetic. Moreover, the overall release profiles were higher in biorelevant media, where erosion/digestion of MPs was observed. After 6 months, a moderate but statistically significant change in release profile was observed for the MPs with IM and EO, which can be correlated with the time-dependent structural alterations (i.e. larger average crystallite size) of these formulations; while MPs with OA or MCT displayed stable release profiles. These findings help to understand the correlation between release behavior, polymorphism and supramolecular-level structural modification of lipid formulations containing crystal modifiers.
本研究考察了含有 5wt% 五种不同液体添加剂（作为晶体改性剂的肉豆蔻酸异丙酯（IM）、油酸乙酯（EO）、油酸（OA）和中链甘油三酯（MCT））的三硬脂酸甘油酯（tristearin）固体脂质微球（MPs）的结构和释放性能之间的相关性。所有添加剂都加速了 MPs 制造后形成的不稳定α-型三硬脂酸甘油酯向稳定β-多晶型的转化，并且在 24 小时（对于 IM 和 EO）或 48 小时（对于 OA 和 MCT）内完成了转化。在 25°C 下通过同步同步加速器 SAXS/WAXS 和 DSC 分析研究了熔融和随后冷却脂质混合物后的多晶型转变的动力学。在α-相中结晶后，添加剂加速了β-三硬脂酸甘油酯的固-固相转变。SAXS 数据表明，在储存过程中 MPs 发生了两种类型的结构修饰：晶体堆积的压缩（层状厚度略有减小）和晶体生长（堆叠脂质层的数量增加）。在水和模拟胃和肠环境的生物相关介质中，研究了 MPs 中两种不同量（15%和 30%）模型亲水性药物（咖啡因）的释放行为。特别重要的是，引入 IM、EO 和 MCT 能够延长药物在水中的释放，从基于扩散的 Higuchi 动力学转变为完美的零级动力学。此外，在生物相关介质中观察到 MPs 的侵蚀/消化，整体释放曲线更高。6 个月后，IM 和 EO 中 MPs 的释放曲线发生了适度但具有统计学意义的变化，这与这些制剂的时间依赖性结构变化（即较大的平均微晶尺寸）有关；而含有 OA 或 MCT 的 MPs 则显示出稳定的释放曲线。这些发现有助于理解含有晶体改性剂的脂质制剂的释放行为、多晶型性和超分子水平结构修饰之间的相关性。
