Enabling Oral SN38-Based Chemotherapy with a Combined Lipophilic Prodrug and Self-Microemulsifying Drug Delivery System
Enabling Oral SN38-Based Chemotherapy with a Combined Lipophilic Prodrug and Self-Microemulsifying Drug Delivery System
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DOI：
10.1021/acs.molpharmaceut.6b00591
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发表时间：
2016-10-01
影响因子：
4.9
通讯作者：
Prestidge, Clive A.
中科院分区：
文献类型：
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作者：
Bala, Vaskor;Rao, Shasha;Prestidge, Clive A.
SN38 的口服化疗因其在胃肠道 (GI) 液中的溶解度差和渗透性低而受到限制。在这里，我们报告了通过结合亲脂性前药和基于脂质的制剂策略来口服递送 SN38。将 SN38 的主要亲脂性前药 SN38-十一烷酸酯 (SN38-unde20) 纳入自微乳化药物递送系统 (SMEDDS) 中，以改善体外和体内性能。该配方经过专门设计和优化，采用长链脂质和脂质非离子表面活性剂，以最大限度地提高药物在胃肠道条件下的溶解度，促进跨膜渗透，从而改善口服吸收。在体外脂解和药物溶解研究中，与未配制的药物相比，SN38-unde20-SMEDDS 显着增加（>7 倍）药物在水相中的溶解度。在 Dark Agouti 大鼠模型中进行的口服体内药代动力学研究中，SN38-unde20-SMEDDS 制剂证实了 SN38-unde20 的口服吸收并随后重新转化为 SN38。重要的是，与胃肠外剂量的 SN38-unde20-SMEDDS 和相同剂量 (10 mg/kg) 的 SN38 相比，口服剂量的 SN38-unde20-SMEDDS 的 SN38 总血浆暴露量 (AUC(0 ->无穷大)) 相当。亲脂性前药与最佳递送载体的组合被证明能够有效口服递送传统上通过注射给药的具有挑战性的化疗化合物。
Oral chemotherapy with SN38 is restricted by its poor solubility in gastrointestinal (GI) fluids and low permeability. Here we report the oral delivery of SN38 by a combined lipophilic prodrug and lipid-based formulation strategy. A lead lipophilic prodrug of SN38, SN38-undecanoate (SN38-unde20), was incorporated into a self-microemulsifying drug delivery system (SMEDDS) for improved in vitro and in vivo performance. The formulation was purposefully designed and optimized with long chain lipids and lipid-based nonionic surfactants to maximize drug solubilization in GI conditions, facilitate trans-membrane permeation, and hence improve oral absorption. SN38-unde20-SMEDDS significantly increased (>7 fold) drug solubilization in the aqueous phase compared to unformulated drug during in vitro lipolysis and drug solubilization studies. In an orally dosed in vivo pharmacokinetics study in a Dark Agouti rat model, the SN38-unde20-SMEDDS formulation confirmed oral absorption of SN38-unde20 and subsequent reconversion to SN38. Importantly, the overall plasma exposure of SN38 (AUC(0 ->infinity)) was equivalent for orally dosed SN38-unde20-SMEDDS in comparison with a parenteral dose of SN38-unde20-SMEDDS and SN38 at an identical dose (10 mg/kg). The combination of lipophilic prodrug along with an optimal delivery carrier is demonstrated to enable effective oral delivery of challenging chemotherapeutic compounds that are conventionally dosed by injection.