Department of Pharmaceutical Engineering, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan 31116, South Korea.
College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, South Korea.
Mol Pharm. 2023 Aug 7;20(8):4153-4164. doi: 10.1021/acs.molpharmaceut.3c00281. Epub 2023 Jul 11.
This study aimed to develop microspheres using water-soluble carriers and surfactants to improve the solubility, dissolution, and oral bioavailability of rivaroxaban (RXB). RXB-loaded microspheres with optimal carrier (poly(vinylpyrrolidone) K30, PVP) and surfactant (sodium lauryl sulfate (SLS)) ratios were prepared. H NMR and Fourier transform infrared (FTIR) analyses showed that drug-excipient and excipient-excipient interactions affected RXB solubility, dissolution, and oral absorption. Therefore, molecular interactions between RXB, PVP, and SLS played an important role in improving RXB solubility, dissolution, and oral bioavailability. Formulations IV and VIII, containing optimized RXB/PVP/SLS ratios (1:0.25:2 and 1:1:2, w/w/w), had significantly improved solubility by approximately 160- and 86-fold, respectively, compared to RXB powder, with the final dissolution rates improved by approximately 4.5- and 3.4-fold, respectively, compared to those of RXB powder at 120 min. Moreover, the oral bioavailability of RXB was improved by 2.4- and 1.7-fold, respectively, compared to that of RXB powder. Formulation IV showed the highest improvement in oral bioavailability compared to RXB powder (AUC, 2400.8 ± 237.1 vs 1002.0 ± 82.3 h·ng/mL). Finally, the microspheres developed in this study successfully improved the solubility, dissolution rate, and bioavailability of RXB, suggesting that formulation optimization with the optimal drug-to-excipient ratio can lead to successful formulation development.
本研究旨在开发使用水溶性载体和表面活性剂的微球，以提高利伐沙班（RXB）的溶解度、溶解速率和口服生物利用度。制备了载有最优载体（聚乙烯吡咯烷酮 K30，PVP）和表面活性剂（十二烷基硫酸钠（SLS））比例的 RXB 载药微球。1 H NMR 和傅里叶变换红外（FTIR）分析表明，药物-赋形剂和赋形剂-赋形剂相互作用影响 RXB 的溶解度、溶解速率和口服吸收。因此，RXB、PVP 和 SLS 之间的分子相互作用在提高 RXB 的溶解度、溶解速率和口服生物利用度方面发挥了重要作用。载药比为 1:0.25:2（IV 号）和 1:1:2（VIII 号）的配方 IV 和 VIII 与 RXB 粉末相比，溶解度分别显著提高了约 160 倍和 86 倍，最终的溶解速率分别提高了约 4.5 倍和 3.4 倍，分别与 RXB 粉末在 120 分钟时相比。此外，与 RXB 粉末相比，RXB 的口服生物利用度分别提高了 2.4 倍和 1.7 倍。与 RXB 粉末相比，配方 IV 显示出最高的口服生物利用度改善（AUC，2400.8 ± 237.1 比 1002.0 ± 82.3 h·ng/mL）。总之，本研究中开发的微球成功提高了 RXB 的溶解度、溶解速率和生物利用度，表明通过优化药物与赋形剂的比例进行制剂优化可以成功开发制剂。
