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_max, 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.

中文翻译：

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通过聚合物无定形固体分散体增强了利伐沙班的生物制药性能

利伐沙班（RXB）是活化的丝氨酸蛋白酶因子Xa的口服活性直接抑制剂，在静脉血栓栓塞（VTE）的治疗中作为单一疗法给予。它已在体外表征通过P-gp转运蛋白作为活性，不饱和流出的底物，限制了其高渗透性。因此，研究了抑制P-gp的聚合物通过制备聚合物无定形固体分散体并随后提高溶解度和渗透性来增强RXB的生物药物性能的作用。最初，确定溶解度参数和Flory-Huggins相互作用参数用于药物与聚合物之间的混溶性研究。通过使用喷雾干燥器将药物与聚合物eudragit S100，eudragit L100和soluplus溶解在普通溶剂（5％的v / v水在四氢呋喃中）中来制备二元分散体。通过差示扫描量热法（DSC），显微镜，粉末X射线衍射法（PXRD），傅里叶变换红外光谱（FTIR）对制备的二元分散体进行分析，动态蒸气吸附（DVS）和溶液核磁共振（NMR）光谱。通过对溶解度和溶解度的研究，发现二元分散液的性能优于微粉状活性药物成分。与结晶RXB相比，用soluplus制备的非晶态固体分散体（ASD）的表观溶解度增加了10倍，并且在24小时内保持了过饱和。此外，在动物中进行的药代动力学研究与溶解度数据具有良好的相关性。在AUC和C中观察到增加了5.7和6.7倍 与结晶RXB相比，用soluplus制备的非晶态固体分散体（ASD）的表观溶解度增加了10倍，并且在24小时内保持了过饱和。此外，在动物中进行的药代动力学研究与溶解度数据具有良好的相关性。在AUC和C中观察到增加了5.7和6.7倍 与结晶RXB相比，用soluplus制备的非晶态固体分散体（ASD）的表观溶解度增加了10倍，并且在24小时内保持了过饱和。此外，在动物中进行的药代动力学研究与溶解度数据具有良好的相关性。在AUC和C中观察到增加了5.7和6.7倍与使用结晶RXB的ASD相比，使用soluplus制备的ASD分别为_max。FTIR和NMR光谱揭示了RXB的N–H基团与聚合物的C═O基团在分子间相互作用中的参与。在Caco-2运输研究中，观察到用eudragit S100和soluplus制备的ASD的药物外排率降低，表明RXB的吸收得到改善。因此，本研究证明了使用soluplus作为通过增加溶解度和规避P-gp活性来增强RXB的生物药物性能的有前途的制剂策略的ASD。