Development and In Vitro-In Vivo Evaluation of Polymeric Implants for Continuous Systemic Delivery of Curcumin
Development and In Vitro-In Vivo Evaluation of Polymeric Implants for Continuous Systemic Delivery of Curcumin
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DOI：
10.1007/s11095-011-0375-z
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发表时间：
2011-05-01
影响因子：
3.7
通讯作者：
Gupta, Ramesh C.
中科院分区：
文献类型：
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作者：
Bansal, Shyam S.;Vadhanam, Manicka V.;Gupta, Ramesh C.
姜黄素的水溶性低和生物利用度差阻碍了其进入临床。为了克服这些限制，我们开发了使用聚（ε-己内酯）作为聚合物基质的姜黄素植入物。植入物通过熔融挤出方法制备；针对聚合物组成、载药量、表面积和水溶性添加剂的影响，优化了体外药物释放。还在体内条件下测试了植入物的累积姜黄素释放情况，肝脏浓度与其调节选定的异生素代谢酶（CYP1A1 和 GSTM）的功效相关。植入物的药物释放遵循 Higuchi 动力学的双相释放模式，并且与植入物的表面积成正比。药物释放按比例从 2% (w/w) 药物负载增加到 10% (w/w)，并且掺入 10% (w/w) 水溶性添加剂（F-68、PEG 8000 和环糊精）不会显着改变药物释放。发现体内药物释放比体外释放高 1.8 倍。植入四天后，在肝脏中检测到姜黄素浓度为 60 +/- 20 ng/g，并且在长达 35 天内几乎保持恒定（8-15 ng/g）。姜黄素水平随时间的下降是由于 CYP1A1 和 GSTM (mu) 酶的诱导导致姜黄素代谢增加。我们的数据表明，这些植入物能够长时间释放姜黄素并调节肝脏 I 相和 II 相酶，证明姜黄素通过该递送系统传递的生物功效。
The introduction of curcumin into clinics is hindered by its low water solubility and poor bioavailability. To overcome these limitations, we developed curcumin implants using poly (epsilon-caprolactone) as the polymeric matrix.Implants were prepared by melt-extrusion method; in vitro drug release was optimized for effects of polymer composition, drug load, surface area and water-soluble additives. Implants were also tested under in vivo conditions for cumulative curcumin release, and liver concentration was correlated with its efficacy to modulate selected xenobiotic-metabolizing enzymes (CYP1A1 and GSTM).Drug release from implants followed biphasic release pattern with Higuchi kinetics and was proportional to the surface area of implants. Drug release increased proportionately from 2 to 10% (w/w) drug load, and incorporation of 10% (w/w) of water-soluble additives (F-68, PEG 8000 and cyclodextrin) did not significantly alter the drug release. In vivo drug release was found to be similar to 1.8 times higher than in vitro release. Curcumin was detected at 60 +/- 20 ng/g in the liver after four days of implantation and was almost constant (8-15 ng/g) for up to 35 days. This time-dependent drop in curcumin level was found to be due to induction of CYP1A1 and GSTM (mu) enzymes which led to increased metabolism of curcumin.Our data showed that these implants were able to release curcumin for long duration and to modulate liver phase I and phase II enzymes, demonstrating curcumin's biological efficacy delivered via this delivery system.