Potter Catherine, Tian Yiwei, Walker Gavin, McCoy Colin, Hornsby Peter, Donnelly Conor, Jones David S, Andrews Gavin P
§Department of Chemical and Environmental Science, University of Limerick, Castletroy, Co. Limerick, Ireland.
Mol Pharm. 2015 May 4;12(5):1377-90. doi: 10.1021/mp500644h. Epub 2015 Mar 31.
The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages with respect to improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, while the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterization of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus and polyvinylpyrrolidone K15 using both SFI and HME and characterized for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation, and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers, formulations containing 50% w/w INM, manufactured via SFI, contained the drug in the γ-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method; however, for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained, and for all systems, SFI formulations performed better than similar HME formulations.
将BCS II类药物制成无定形固体分散体已被证明在改善这些化合物的水溶性方面具有优势。虽然热熔挤出（HME）和喷雾干燥（SD）是生产无定形固体分散体（ASD）最常用的方法，但HME通常所需的高温会限制热不稳定药物的加工，而SD过程中使用有毒有机溶剂会影响最终产品的毒性。在本研究中，我们研究了使用二氧化碳的超临界流体浸渍（SFI）作为生产模型难溶性药物吲哚美辛（INM）的ASD的替代工艺的潜力。在此过程中，我们在不使用有机溶剂的情况下且在远低于HME所需温度的条件下制备了ASD。先前的研究集中在使用HME或SFI制备的ASD的表征上，但没有同时考虑这两种工艺。使用两种不同的聚合物Soluplus和聚乙烯吡咯烷酮K15，通过SFI和HME制备分散体，并对药物形态、均匀性、药物 - 聚合物相互作用的存在、玻璃化转变温度、制剂中药物的无定形稳定性以及非漏槽药物释放进行表征，以测量每种制剂产生过饱和药物溶液的能力。使用HME在50% w/w药物载量下以及使用SFI在30% w/w药物载量下成功制备了完全无定形分散体。对于这两种聚合物，通过SFI制备的含有50% w/w INM的制剂中，药物以γ晶型存在。有趣的是，相对于Soluplus，聚乙烯吡咯烷酮分散体中的结晶度水平较低。使用傅里叶变换红外光谱（FTIR）探测两种聚合物体系中药物 - 聚合物相互作用的存在。对于聚乙烯吡咯烷酮体系，这些相互作用的性质取决于加工方法；然而，对于Soluplus制剂，情况并非如此。溶出曲线下面积（AUC）用作维持过饱和浓度时间的度量，对于所有体系，SFI制剂的表现均优于类似的HME制剂。
