Gala Urvi, Miller Dave, Williams Robert O
Molecular Pharmaceutics and Drug Delivery Division, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA.
DisperSol Technologies LLC., 111 W. Cooperative Way, Building 3, Suite 300, Georgetown, TX 78626, USA.
Pharmaceutics. 2020 Apr 14;12(4):357. doi: 10.3390/pharmaceutics12040357.
Abiraterone is a poorly water-soluble drug. It has a high melting point and limited solubility in organic solvents, making it difficult to formulate as an amorphous solid dispersion (ASD) with conventional technologies. KinetiSol is a high-energy, fusion-based, solvent-free technology that can produce ASDs. The aim of this study was to evaluate the application of KinetiSol to make abiraterone ASDs. We developed binary KinetiSol ASDs (KSDs) using both polymers and oligomers. For the first time, we reported that KinetiSol can process hydroxypropyl-β-cyclodextrin (HPBCD), a low molecular-weight oligomer. Upon X-ray diffractometry and modulated differential scanning calorimetry analysis, we found the KSDs to be amorphous. In vitro dissolution analysis revealed that maximum abiraterone dissolution enhancement was achieved using a HPBCD binary KSD. However, the KSD showed significant abiraterone precipitation in fasted state simulated intestinal fluid (FaSSIF) media. Hence, hypromellose acetate succinate (HPMCAS126G) was selected as an abiraterone precipitation inhibitor and an optimized ternary KSD was developed. A pharmacokinetic study revealed that HPBCD based binary and ternary KSDs enhanced abiraterone bioavailability by 12.4-fold and 13.8-fold, respectively, compared to a generic abiraterone acetate tablet. Thus, this study is the first to demonstrate the successful production of an abiraterone ASD that exhibited enhanced dissolution and bioavailability.
阿比特龙是一种水溶性较差的药物。它具有高熔点且在有机溶剂中的溶解度有限，这使得采用传统技术将其制成无定形固体分散体（ASD）变得困难。KinetiSol是一种高能、基于融合且无溶剂的技术，可生产ASD。本研究的目的是评估KinetiSol在制备阿比特龙ASD方面的应用。我们使用聚合物和低聚物开发了二元KinetiSol无定形固体分散体（KSD）。我们首次报道KinetiSol可以处理低分子量低聚物羟丙基-β-环糊精（HPBCD）。通过X射线衍射和调制差示扫描量热法分析，我们发现KSD是无定形的。体外溶出度分析表明，使用HPBCD二元KSD可实现阿比特龙溶出度的最大提高。然而，KSD在禁食状态模拟肠液（FaSSIF）介质中显示出明显的阿比特龙沉淀。因此，选择醋酸羟丙甲纤维素琥珀酸酯（HPMCAS126G）作为阿比特龙沉淀抑制剂，并开发了优化的三元KSD。一项药代动力学研究表明，与普通醋酸阿比特龙片相比，基于HPBCD的二元和三元KSD分别将阿比特龙的生物利用度提高了12.4倍和13.8倍。因此，本研究首次证明成功制备出了溶出度和生物利用度均有所提高的阿比特龙ASD。
