Cyclosporine a-loaded UniORV?: Pharmacokinetic and safety characterization
Cyclosporine a-loaded UniORV?: Pharmacokinetic and safety characterization
复制标题
负载环孢素 a 的 UniORV？：药代动力学和安全性表征
DOI：
10.1016/j.ijpharm.2019.118630
复制
发表时间：
2019
影响因子：
5.8
通讯作者：
Onoue Satomi
中科院分区：
文献类型：
--
作者：
Iyama Yosuke;Mineda Misuzu;Sei Shunsuke;Hirasawa Wataru;Matahira Yoshiharu;Seto Yoshiki;Sato Hideyuki;Onoue Satomi
本研究旨在通过UniORV®方法改善环孢素A（CsA）的药代动力学行为并降低安全性问题，这是一种新的固体分散体制剂平台。制备了CsA负载的UniORV®（UO/CsA），并根据液滴尺寸分布和溶出度评价了其物理化学性质。在大鼠中评估口服给药CsA样品（10 mg-CsA/kg）的药代动力学行为和肾毒性潜力。UO/CsA在水中再分散后，观察到细小液滴，计算出液滴的平均直径为45 nm。与无定形CsA在水中相比，UniORV®方法显著改善了溶解行为。大鼠口服无定形CsA、Neoral®和UO/CsA后，UO/CsA的最大浓度比Neoral®低32%，平均滞留时间比Neoral®长5.1 h。CsA制剂的口服吸收高于无定形CsA;特别是UO/CsA的口服生物利用度是无定形CsA的71倍。Neoral®引起肾毒性，血浆肌酐水平为1.29 mg/dL;然而，Neoral®诱导的肾毒性在UO/CsA中减弱，如UO/CsA的血浆肌酐水平比Neoral®低15%所证明的。从这些发现来看，UO/CsA可能是一种具有改善CsA生物药剂学性质的有前途的剂型。
This study aimed to improve pharmacokinetic behavior and reduce safety concern of cyclosporine A (CsA) by UniORV® approach, a new platform for solid dispersion formulation. CsA-loaded UniORV® (UO/CsA) was prepared, and its physicochemical properties were evaluated in terms of droplet size distribution and dissolution. The pharmacokinetic behavior and nephrotoxic potential of orally-dosed CsA samples (10 mg-CsA/kg) were assessed in rats. After re-dispersion of UO/CsA in water, fine droplets were observed, and the mean diameter of droplets was calculated to be 45 nm. The UniORV® approach markedly improved the dissolution behavior compared with amorphous CsA in water. After oral administration of amorphous CsA, Neoral®, and UO/CsA in rats, UO/CsA exhibited a 32% lower maximum concentration and 5.1 h longer mean residence time than those of Neoral®. The oral absorption of CsA formulations was higher compared with amorphous CsA; in particular, the oral bioavailability of UO/CsA was 71-fold higher than that of amorphous CsA. Neoral® elicited nephrotoxicity with plasma creatinine level of 1.29 mg/dL; however, Neoral®-induced nephrotoxicity was attenuated in UO/CsA, as evidenced by a 15% lower plasma creatinine level of UO/CsA than that of Neoral®. From these findings, UO/CsA might be a promising dosage form with improved biopharmaceutical properties of CsA.