Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar 160062, Punjab, India.
Mol Pharm. 2018 Feb 5;15(2):652-668. doi: 10.1021/acs.molpharmaceut.7b01027. Epub 2018 Jan 16.
Rivaroxaban (RXB) is an orally active direct inhibitor of the activated serine protease Factor Xa, given as monotherapy in the treatment of venous thromboembolism (VTE). It has been characterized in vitro as a substrate for the active, nonsaturable efflux via P-gp transporter, limiting its high permeability. Therefore, the role of P-gp inhibiting polymers in enhancing the biopharmaceutical performance of RXB by preparing polymeric amorphous solid dispersion and subsequent improvement in solubility and permeability was investigated. Initially, solubility parameter and Flory-Huggins interaction parameter were determined for miscibility studies between drug and polymers. Binary dispersions were prepared by dissolving drug with polymers eudragit S100, eudragit L100, and soluplus in common solvent (5% v/v water in tetrahydrofuran) using spray dryer. Prepared binary dispersions were analyzed by differential scanning calorimetry (DSC), microscopy, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR), dynamic vapor sorption (DVS), and solution nuclear magnetic resonance (NMR) spectroscopy. Superior performance of binary dispersions was observed upon dissolution and solubility studies over micronized active pharmaceutical ingredient. Amorphous solid dispersion (ASD) prepared with soluplus showed 10-fold increase in apparent solubility and maintenance of supersaturation for 24 h compared to the crystalline RXB. Further, pharmacokinetic study performed in animals was in good correlation with the solubility data. Increases of 5.7- and 6.7-fold were observed in AUC and C, respectively, for ASDs prepared with soluplus compared to those with crystalline RXB. FTIR and NMR spectroscopy unveiled the involvement of N-H group of RXB with C═O group of polymers in intermolecular interactions. The decreased drug efflux ratio was observed for ASDs prepared with eudragit S100 and soluplus in Caco-2 transport study suggesting improvement in the absorption of RXB. Hence, the present study demonstrates ASD using soluplus as a promising formulation strategy for enhancing the biopharmaceutical performance of RXB by increasing the solubility and circumventing the P-gp activity.
利伐沙班（RXB）是一种口服活性的因子 Xa 激活丝氨酸蛋白酶直接抑制剂，作为单一疗法用于治疗静脉血栓栓塞症（VTE）。它在体外表现为通过 P-糖蛋白转运体进行主动、非饱和的外排的底物，限制了其高通透性。因此，通过制备聚合物无定形固体分散体并随后提高溶解度和通透性，研究了 P-糖蛋白抑制聚合物在增强 RXB 的生物制药性能中的作用。最初，确定了药物与聚合物之间混合研究的溶解度参数和 Flory-Huggins 相互作用参数。通过将药物与聚合物 Eudragit S100、Eudragit L100 和 Soluplus 溶解在共同溶剂（5%v/v 水在四氢呋喃中）中，使用喷雾干燥器制备二元分散体。通过差示扫描量热法（DSC）、显微镜、粉末 X 射线衍射（PXRD）、傅里叶变换红外光谱（FTIR）、动态蒸汽吸附（DVS）和溶液核磁共振（NMR）光谱分析制备的二元分散体。与微米化原料药相比，在溶解和溶解度研究中观察到二元分散体的优异性能。与结晶 RXB 相比，用 Soluplus 制备的无定形固体分散体（ASD）显示出 10 倍的表观溶解度增加和 24 小时的过饱和度维持。此外，在动物中的药代动力学研究与溶解度数据具有良好的相关性。与用结晶 RXB 制备的 ASD 相比，用 Soluplus 制备的 ASD 的 AUC 和 C 分别增加了 5.7 倍和 6.7 倍。FTIR 和 NMR 光谱揭示了 RXB 的 N-H 基团与聚合物的 C═O 基团之间的分子间相互作用。在 Caco-2 转运研究中，用 Eudragit S100 和 Soluplus 制备的 ASD 观察到药物外排率降低，表明 RXB 的吸收得到改善。因此，本研究表明，使用 Soluplus 的 ASD 是一种有前途的制剂策略，可通过提高溶解度和避免 P-糖蛋白活性来增强 RXB 的生物制药性能。
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