School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Department of Pharmaceutics and Biopharmaceutics, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland.
Eur J Pharm Sci. 2010 Apr 16;40(1):38-47. doi: 10.1016/j.ejps.2010.02.006. Epub 2010 Feb 23.
Lyophilisation is a common procedure to increase the long-term stability of pharmaceutical formulations. Its applicability to polymeric micelles is usually an issue because of the aggregation of materials during freeze-drying steps. The feasibility of this process was studied on polymeric micelles based on methoxy poly(ethylene glycol)-poly(hexyl-lactide) (MPEG-hexPLA) with and without Cyclosporin A, in order to increase the stability of these pharmaceutical formulations. Freeze-thawing tests were carried out to determine the protective effect of various excipients on the freezing step. Mannitol, trehalose, glucose and sucrose showed the best effectiveness in micelle protection. The lyophilisation process was optimised by thermal analysis (DSC) on excipients to determine the glass transition temperature of the cryoconcentrate solutions (T(g)') and their glass transition temperature (T(g)). The freeze-dried powders were characterized in terms of morphology (SEM) and of moisture content (Karl Fisher titration). The reconstituted micelle formulations were analysed for size by DLS with and without goniometer, for morphology by TEM, for drug loading by HPLC. The formulation presenting the best characteristics before and after reconstitution contained 10% (w/v) sucrose in phosphate buffer. This lyophilised formulation was constituted of a brittle and white cake, with a residual water content of around 2% and it was easily reconstituted in a transparent and clear solution giving back a colloidal system with spherical micelles in the submicron range (<250 nm). The drug loading was not affected by the freeze-drying procedure. This study showed that the MPEG-hexPLA micelles can be efficiently lyophilised and this process can be usefully applied to increase the pharmaceutical stability of these pharmaceutical micelle formulations.
冷冻干燥是提高药物制剂长期稳定性的常用方法。由于在冷冻干燥过程中材料会聚集，因此通常会出现基于甲氧基聚乙二醇-聚己内酯（MPEG-hexPLA）的聚合物胶束的适用性问题。为了提高这些药物制剂的稳定性，研究了载有环孢菌素 A 的和不含环孢菌素 A 的聚合物胶束的这种方法的可行性。进行了冻融试验以确定各种赋形剂对冷冻步骤的保护作用。甘露醇、海藻糖、葡萄糖和蔗糖对胶束的保护效果最佳。通过对赋形剂进行热分析（DSC）优化了冷冻干燥过程，以确定共浓缩物溶液的玻璃化转变温度（T(g)’）及其玻璃化转变温度（T(g)）。通过扫描电子显微镜（SEM）和卡尔费休滴定法（Karl Fisher titration）对冷冻干燥粉末的形态和水分含量进行了表征。使用和不使用折射计通过动态光散射（DLS）分析了再构建胶束制剂的粒径，通过透射电子显微镜（TEM）分析了形态，通过高效液相色谱法（HPLC）分析了药物载量。在再构建前后具有最佳特性的制剂配方含有 10%（w/v）的磷酸盐缓冲液中的蔗糖。这种冻干制剂由易碎的白色蛋糕组成，残余水分含量约为 2%，可轻松再溶解在透明清澈的溶液中，重新形成亚微米范围内（<250nm）的球形胶束胶体体系。药物载量不受冷冻干燥过程的影响。本研究表明，MPEG-hexPLA 胶束可以有效地冷冻干燥，并且该过程可有效地用于提高这些药物胶束制剂的药物稳定性。
