Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability
Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability
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DOI：
10.1002/jps.10511
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发表时间：
2003-12-01
影响因子：
3.8
通讯作者：
Hageman, MJ
中科院分区：
文献类型：
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作者：
Gao, P;Rush, BD;Hageman, MJ
采用羟丙基甲基纤维素 (HPMC) 作为沉淀抑制剂，采用传统的 SEDDS 配方，开发了一种新型紫杉醇过饱和自乳化药物递送系统 (S-SEDDS)。 S-SEDDS 制剂的体外稀释导致微乳液的形成，然后静置时紫杉醇缓慢结晶。该结果表明该系统相对于结晶紫杉醇是过饱和的，并且制剂中的HPMC延长了过饱和状态。在没有 HPMC 的情况下，SEDDS 制剂会快速沉淀，产生低浓度的紫杉醇溶液。在雄性 Sprague-Dawley 大鼠中进行了一项药代动力学研究，以评估在含有 (S-SEDDS) 和不含 HPMC 的 SEDDS 制剂中口服 10 mg/kg 紫杉醇剂量后的暴露情况。与口服紫杉醇((R))制剂（F约2.0%）和不含HPMC的SEDDS制剂（F约1%）相比，紫杉醇S-SEDDS制剂显示出相似的最大浓度（C-max）高10倍和口服生物利用度高5倍（F约9.5%）。环孢菌素 A (CsA)（一种 P-糖蛋白和 CYP 3A4 酶的抑制剂）以 5 mg/kg 的剂量与 S-SEDDS 制剂共同给药，进一步增加了口服生物利用度（F 大约为 22.6%）。该评估表明，通过 S-SEDDS 方法可以显着改善口服给药后紫杉醇的全身暴露。 (C) 2003 Wiley-Liss, Inc.
A new, supersaturable self-emulsifying drug delivery system (S-SEDDS) of paclitaxel was developed employing hydroxypropyl methylcellulose (HPMC) as a precipitation inhibitor with a conventional SEDDS formulation. In vitro dilution of the S-SEDDS formulation results in formation of a microemulsion, followed by slow crystallization of paclitaxel on standing. This result indicates that the system is supersaturated with respect to crystalline paclitaxel, and the supersaturated state is prolonged by HPMC in the formulation. In the absence of HPMC the SEDDS formulation undergoes rapid precipitation, yielding a low paclitaxel solution concentration. A pharmacokinetic study was conducted in male Sprague-Dawley rats to assess exposure after an oral paclitaxel dose of 10 mg/kg in the SEDDS formulations with (S-SEDDS) and without HPMC. The paclitaxel S-SEDDS formulation shows similar to10-fold higher maximum concentration (C-max) and five-fold higher oral bioavailability (F approximate to 9.5%) compared with that of the orally dosed Taxol((R)) formulation (F approximate to 2.0%) and the SEDDS formulation without HPMC (F approximate to 1%). Coadministration of cyclosporin A (CsA), an inhibitor of P-glycoprotein and CYP 3A4 enzyme, at a dose of 5 mg/kg with the S-SEDDS formulation further increased the oral bioavailability (F approximate to 22.6%). This assessment demonstrates that the systemic exposure of paclitaxel following oral administration can be substantially improved via the S-SEDDS approach. (C) 2003 Wiley-Liss, Inc.