Chen Yuejie, Liu Chengyu, Chen Zhen, Su Ching, Hageman Michael, Hussain Munir, Haskell Roy, Stefanski Kevin, Qian Feng
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
Mol Pharm. 2015 Feb 2;12(2):576-89. doi: 10.1021/mp500660m. Epub 2015 Jan 12.
The in vitro dissolution mechanism of an amorphous solid dispersion (ASD) remains elusive and highly individualized, yet rational design of ASDs with optimal performance and prediction of their in vitro/in vivo performance are very much desirable in the pharmaceutical industry. To this end, we carried out comprehensive investigation of various ASD systems of griseofulvin, felodipine, and ketoconazole, in PVP-VA or HPMC-AS at different drug loading. Physiochemical properties and processes related to drug-polymer-water interaction, including the drug crystallization tendency in aqueous medium, drug-polymer interaction before and after moisture exposure, supersaturation of drug in the presence of polymer, polymer dissolution kinetics, etc., were characterized and correlated with the dissolution performance of ASDs at different dose and different drug/polymer ratio. It was observed that ketoconazole/HPMC-AS ASD outperformed all other ASDs in various dissolution conditions, which was attributed to the drug's low crystallization tendency, the strong ketoconazole/HPMC-AS interaction and the robustness of this interaction against water disruption, the dissolution rate and the availability of HPMC-AS in solution, and the ability of HPMC-AS in maintaining ketoconazole supersaturation. It was demonstrated that all these properties have implications for the dissolution performance of various ASD systems, and further quantification of them could be used as potential predictors for in vitro dissolution of ASDs. For all ASDs investigated, HPMC-AS systems performed better than, or at least comparably with, their PVP-VA counterparts, regardless of the drug loading or dose. This observation cannot be solely attributed to the ability of HPMC-AS in maintaining drug supersaturation. We also conclude that, for fast crystallizers without strong drug-polymer interaction, the only feasible option to improve dissolution might be to lower the dose and the drug loading in the ASD. In this study, we implemented an ASD/water Flory-Huggins parameter plot, which might assist in revealing the physical nature of the drug-polymer interaction. We also introduced supersaturation parameter and dissolution performance parameter as two quantitative measurements to compare the abilities of polymers in maintaining drug supersaturation, and the dissolution performance of various solid dispersions, respectively.
无定形固体分散体（ASD）的体外溶出机制仍然难以捉摸且高度个体化，然而，在制药行业中，合理设计具有最佳性能的ASD并预测其体外/体内性能是非常必要的。为此，我们对不同载药量下，灰黄霉素、非洛地平、酮康唑在PVP-VA或HPMC-AS中的各种ASD体系进行了全面研究。对与药物-聚合物-水相互作用相关的物理化学性质和过程进行了表征，包括药物在水性介质中的结晶趋势、水分暴露前后的药物-聚合物相互作用、聚合物存在下药物的过饱和度、聚合物溶解动力学等，并将其与不同剂量和不同药物/聚合物比例下ASD的溶出性能相关联。结果发现，酮康唑/HPMC-AS ASD在各种溶出条件下均优于所有其他ASD，这归因于药物的低结晶趋势、酮康唑/HPMC-AS之间的强相互作用以及这种相互作用对水破坏的稳健性、HPMC-AS在溶液中的溶解速率和可用性，以及HPMC-AS维持酮康唑过饱和度的能力。结果表明，所有这些性质都对各种ASD体系的溶出性能有影响，对它们的进一步量化可作为ASD体外溶出的潜在预测指标。对于所有研究的ASD，无论载药量或剂量如何，HPMC-AS体系的性能均优于或至少等同于其PVP-VA对应体系。这一观察结果不能仅仅归因于HPMC-AS维持药物过饱和度的能力。我们还得出结论，对于没有强药物-聚合物相互作用的快速结晶药物，改善溶出的唯一可行选择可能是降低ASD中的剂量和载药量。在本研究中，我们实施了ASD/水的弗洛里-哈金斯参数图，这可能有助于揭示药物-聚合物相互作用的物理本质。我们还引入了过饱和度参数和溶出性能参数作为两种定量测量方法，分别用于比较聚合物维持药物过饱和度的能力以及各种固体分散体的溶出性能。
