HEC Research and Development Center, HEC Pharm Group, Dongguan, 523871, China.
Hunan Provincial Key Laboratory of Xiangnan Rare-Precious Metals Compounds and Applications, College of Chemical Biology and Environmental Engineering, Xiangnan University, Chenzhou, 423043, China.
AAPS PharmSciTech. 2021 Apr 23;22(4):142. doi: 10.1208/s12249-021-02005-x.
Apremilast (APST) is an effective inhibitor of phosphodieasterase 4 (PDE4) which is the first oral drug for the treatment of adult patients with active psoriatic arthritis. However, Apremilasts low solubility restricts its dissolution and bioavailability. In this study, APST solid dispersion with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and Poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA) was developed to improve the dissolution and bioavailability of APST by spray drying. A series of TPGS were synthesized to elucidate the effect of the ratio of monoester to diester on solubilizing capacity. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrophotometry (FT-IR) were used to characterize the solid dispersion, and the results showed that APST was amorphous in solid dispersion. In vitro dissolution study showed that the dissolution rate of solid dispersion in phosphate buffered saline (pH 6.8) was remarkably increased, reaching a release of 90% within 10 min. Moreover, in vivo pharmacokinetics study revealed that the bioavailability of solid dispersion in rats had significant improvement. In particular, its C and AUC were nearly 22- and 12.9-fold greater as compared to APST form B, respectively. In conclusion, APST solid dispersion with TPGS and PVPVA is an alternative drug delivery system to improve the solubility and oral bioavailability of APST.
阿普斯特（APST）是磷酸二酯酶 4（PDE4）的有效抑制剂，是治疗成人活动性银屑病关节炎的第一种口服药物。然而，APST 的低溶解度限制了其溶解和生物利用度。在这项研究中，通过喷雾干燥法开发了 APST 与 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）和聚（1-乙烯基吡咯烷酮-co-醋酸乙烯酯）（PVPVA）的固体分散体，以提高 APST 的溶解和生物利用度。合成了一系列 TPGS，以阐明单酯与二酯的比例对增溶能力的影响。X 射线粉末衍射（XRPD）、差示扫描量热法（DSC）和傅里叶变换红外分光光度法（FT-IR）用于表征固体分散体，结果表明 APST 在固体分散体中为无定形。体外溶解研究表明，固体分散体在磷酸盐缓冲盐水（pH 6.8）中的溶解速率显著提高，在 10 分钟内达到 90%的释放。此外，体内药代动力学研究表明，固体分散体在大鼠体内的生物利用度有显著提高。特别是，与 APST 形式 B 相比，其 C 和 AUC 分别增加了近 22 倍和 12.9 倍。总之，APST 与 TPGS 和 PVPVA 的固体分散体是一种改善 APST 溶解度和口服生物利用度的替代药物传递系统。
