Faculty of Pharmaceutical Science, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Mol Pharm. 2012 May 7;9(5):1489-501. doi: 10.1021/mp300099f. Epub 2012 Apr 18.
The purpose of this study was to characterize the phase separation behavior of fusidic acid (FA) and rifampicin (RIF) in poly(d,l-lactic acid-co-glycolic acid) (PLGA) using a model microsphere formulation. To accomplish this, microspheres containing 20% FA with 0%, 5%, 10%, 20%, and 30% RIF and 20% RIF with 30%, 20% 10%, 5%, and 0% FA were prepared by solvent evaporation. Drug-polymer and drug-drug compatibility and miscibility were characterized using laser confocal microscopy, Raman spectroscopy, XRPD, DSC, and real-time video recordings of single-microsphere formation. The encapsulation of FA and RIF alone, or in combination, results in a liquid-liquid phase separation of solvent-and-drug-rich microdomains that are excluded from the polymer bulk during microsphere hardening, resulting in amorphous spherical drug-rich domains within the polymer bulk and on the microsphere surface. FA and RIF phase separate from PLGA at relative droplet volumes of 0.311 ± 0.014 and 0.194 ± 0.000, respectively, predictive of the incompatibility of each drug and PLGA. When coloaded, FA and RIF phase separate in a single event at the relative droplet volume 0.251 ± 0.002, intermediate between each of the monoloaded formulations and dependent on the relative contribution of FA or RIF. The release of FA and RIF from phase-separated microspheres was characterized exclusively by a burst release and was dependent on the phase exclusion of surface drug-rich domains. Phase separation results in coalescence of drug-rich microdroplets and polymer phase exclusion, and it is dependent on the compatibility between FA and RIF and PLGA. FA and RIF are mutually miscible in all proportions as an amorphous glass, and they phase separate from the polymer as such. These drug-rich domains were excluded to the surface of the microspheres, and subsequent release of both drugs from the microspheres was rapid and reflected this surface location.
本研究旨在通过模型微球制剂来描述游离酸（FA）和利福平（RIF）在聚（DL-丙交酯-共-乙交酯）（PLGA）中的相分离行为。为此，通过溶剂蒸发制备了含有 20% FA 的微球，其中 RIF 的比例分别为 0%、5%、10%、20%和 30%，以及含有 20% RIF 的微球，其中 FA 的比例分别为 30%、20%、10%、5%和 0%。使用激光共聚焦显微镜、拉曼光谱、XRPD、DSC 和单微球形成的实时视频记录，对药物-聚合物和药物-药物的相容性和混溶性进行了表征。FA 和 RIF 单独或组合包封导致溶剂和药物丰富的微域发生液-液相分离，在微球硬化过程中被排除在聚合物本体之外，导致聚合物本体和微球表面形成无定形的球形药物丰富域。FA 和 RIF 与 PLGA 相分离的相对液滴体积分别为 0.311±0.014 和 0.194±0.000，预测了每种药物与 PLGA 的不兼容性。当共载时，FA 和 RIF 在相对液滴体积 0.251±0.002 处发生单一事件的相分离，介于单载制剂之间，取决于 FA 或 RIF 的相对贡献。FA 和 RIF 从相分离微球中的释放仅表现为突释，并且依赖于表面药物丰富域的相排除。相分离导致药物丰富的微滴聚合并排除聚合物相，并且取决于 FA 和 RIF 与 PLGA 之间的相容性。FA 和 RIF 以无定形玻璃的形式在所有比例下都是互溶的，并且它们以这种形式与聚合物相分离。这些药物丰富的域被排斥到微球的表面，随后两种药物从微球中的释放都很快，反映了这种表面位置。
