Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, USA.
Teva Pharmaceuticals Inc., 223 Quaker Rd, Pomona, New York, 10970, USA.
AAPS J. 2016 Sep;18(5):1131-1143. doi: 10.1208/s12248-016-9939-5. Epub 2016 Jun 14.
In a solid dispersion (SD), the drug is generally dispersed either molecularly or in the amorphous state in polymeric carriers, and the addition of a surfactant is often important to ensure drug release from such a system. The objective of this investigation was to screen systematically polymer-surfactant and polymer-drug-surfactant miscibility by using the film casting method. Miscibility of the crystalline solid surfactant, poloxamer 188, with two commonly used amorphous polymeric carriers, Soluplus® and HPMCAS, was first studied. Then, polymer-drug-surfactant miscibility was determined using itraconazole as the model drug, and ternary phase diagrams were constructed. The casted films were examined by DSC, PXRD and polarized light microscopy for any crystallization or phase separation of surfactant, drug or both in freshly prepared films and after exposure to 40°C/75% RH for 7, 14, and 30 days. The miscibility of poloxamer 188 with Soluplus® was <10% w/w, while its miscibility with HPMCAS was at least 30% w/w. Although itraconazole by itself was miscible with Soluplus® up to 40% w/w, the presence of poloxamer drastically reduced its miscibility to <10%. In contrast, poloxamer 188 had minimal impact on HPMCAS-itraconazole miscibility. For example, the phase diagram showed amorphous miscibility of HPMCAS, itraconazole, and poloxamer 188 at 54, 23, and 23% w/w, respectively, even after exposure to 40°C/75% RH for 1 month. Thus, a relatively simple and practical method of screening miscibility of different components and ultimately physical stability of SD is provided. The results also identify the HPMCAS-poloxamer 188 mixture as an optimal surface-active carrier system for SD.
在固体分散体（SD）中，药物通常以分子或无定形态分散在聚合物载体中，添加表面活性剂通常很重要，以确保此类系统中的药物释放。本研究的目的是通过使用薄膜铸造法系统地筛选聚合物-表面活性剂和聚合物-药物-表面活性剂的混溶性。首先研究了结晶固体表面活性剂泊洛沙姆 188 与两种常用的无定形聚合物载体 Soluplus®和 HPMCAS 的混溶性。然后，使用伊曲康唑作为模型药物，确定聚合物-药物-表面活性剂的混溶性，并构建三元相图。用 DSC、PXRD 和偏光显微镜检查刚制备的薄膜和暴露于 40°C/75%RH 7、14 和 30 天后的薄膜，以检查表面活性剂、药物或两者是否结晶或相分离。泊洛沙姆 188 与 Soluplus®的混溶性<10%w/w，而其与 HPMCAS 的混溶性至少为 30%w/w。尽管伊曲康唑本身与 Soluplus®的混溶性高达 40%w/w，但泊洛沙姆的存在使其混溶性急剧降低至<10%w/w。相比之下，泊洛沙姆 188 对 HPMCAS-伊曲康唑的混溶性影响最小。例如，相图显示 HPMCAS、伊曲康唑和泊洛沙姆 188 的无定形混溶性分别为 54%、23%和 23%w/w，即使在暴露于 40°C/75%RH 1 个月后也是如此。因此，提供了一种相对简单实用的筛选不同成分混溶性并最终筛选 SD 物理稳定性的方法。结果还确定了 HPMCAS-泊洛沙姆 188 混合物作为 SD 的最佳表面活性载体系统。
