响应面法优化西罗莫司胶束及其促小肠吸收作用  

Optimization of Sirolimus Micelles by Response Surface Methodology and Its Effect on Small Intestinal Absorption

作　　者：陈燕[1] 张雅雯 周云琍 陈晓晓[1] 王胜浩 尹丽娜 CHEN Yan;ZHANG Yawen;ZHOU Yunli;CHEN Xiaoxiao;WANG Shenghao;YIN Lina(College of Pharmaceutical Science,Zhejiang Chinese Medical University,Hangzhou 310053,China;Institute of Materia Medica,Hangzhou Medical College,Hangzhou 310013,China;Zhejiang Peptide Company,Hangzhou 310018,China)

机构地区：[1]浙江中医药大学药学院,杭州310053 [2]杭州医学院药物研究所,杭州310013 [3]浙江中肽生化有限公司,杭州310018

出　　处：《中国现代应用药学》2020年第8期939-944,共6页Chinese Journal of Modern Applied Pharmacy

基　　金：浙江省自然科学基金项目(LQY18H300002)。

摘　　要：目的制备和优化西罗莫司(sirolimus,SRL)聚合物胶束,考察其对大鼠在体肠吸收动力学的影响。方法以去氧胆酸修饰的壳聚糖(deoxycholic acid grafted chitosan,CS-DCA)为载体,采用溶剂蒸发法制备SRL CS-DCA胶束。以包封率、载药量、粒径和电位作为考察指标,结合星点设计-效应面法优化处方。建立大鼠在体单向肠灌流模型,并通过肠腔有效吸收系数(Peff)、吸收速率常数(Ka)和药物吸收剂量分数(fa)研究不同浓度SRL CS-DCA的肠吸收特性。结果 SRL CS-DCA最优处方:载体浓度(CS-DCA)为10 mg·mL^-1,药物与载体质量比为20%,该条件下制备得到的SRL CS-DCA带正电荷(37.0±2.7)mV,粒径(182.2±5.7)nm,包封率>90%,载药量(15.8±0.5)%。SRL CS-DCA经大鼠全肠后,反映药物肠吸收程度的评价指标P_(eff)、K_a和f_a均较SRL有显著提高(P<0.05);不同浓度的SRL CS-DCA在大鼠全肠段的Peff、Ka、fa值无显著性差异,提示胶束在10~100μg·mL^-1吸收无浓度抑制,吸收特征为被动转运的线性动力学过程,推测其可能的吸收机制为被动扩散。结论 SRL制备成聚合物胶束后,对其在大鼠小肠的吸收具有明显的促进作用,从侧面证明SRL CS-DCA能有效改善SRL口服生物利用度。OBJECTIVE To prepare sirolimus(SRL)polymer micelles and investigate its effects on the absorption kinetics of rat intestine.METHODS The SRL CS-DCA micelles were prepared by solvent evaporation using deoxycholic acid grafted chitosan(CS-DCA)as carrier.The encapsulation efficiency,drug loading,particle size and potential were taken as the evaluation indexes,and the formulation was optimized by the central composite design-response surface optimization method.In situ single pass perfusion model of rat was set up to investigate intestinal absorption characteristics of SRL CS-DCA micelles with different concentrations.Meanwhile,the intestinal absorption coefficient(Peff),absorption rate constant(Ka)and the dose fraction(fa)were used to evaluate drug absorption.RESULTS The optimum formulation of SRL CS-DCA micelles was as follows:the concentration of CS-DCA was 10 mg·mL^-1,and the mass ratio of drug to carrier was 20%.Under this condition,the system had the positive charge of(37.0±2.7)mV,particle size of(182.2±5.7)nm,the encapsulation efficiency greater than 90%,and the drug loading of(15.80±0.5)%.After the SRL CS-DCA micelles passed through the rat intestine,the Peff,Ka and fa were significantly higher than those of SRL(P<0.05).There was no significant difference in the Peff,Ka and fa values of SRL CS-DCA micelles with different concentration in the whole intestine of rats,suggesting that the micelles had no concentration inhibition at 10-100μg·mL^-1,and the absorption characteristics were linear dynamics of passive transport.It was speculated that its possible absorption mechanism was passive diffusion.CONCLUSION The SRL CS-DCA micelles can enhance effect on intestine absorption of SRL monomer,which proves that SRL CS-DCA can effectively improve the oral bioavailability of sirolimus.

关 键 词：西罗莫司 壳聚糖 聚合物胶束 星点设计-效应面法 在体单向肠灌流 

分 类 号：R944.4[医药卫生—药剂学]