多替拉韦自微乳化释药系统的制备与大鼠药动学评价  

Preparation and pharmacokinetic evaluation of dolutegravir self-microemulsifying drug delivery systems in rats

作　　者：黄四周 赖世忠 HUANG Sizhou;LAI Shizhong(Wei Sheng Yuan(Xiamen)Biotechnology Co.,LTD,Xiamen,Fujian 361028,China)

机构地区：[1]维生原(厦门)生物科技有限公司,福建厦门361028

出　　处：《安徽医药》2023年第12期2371-2377,共7页Anhui Medical and Pharmaceutical Journal

摘　　要：目的制备多替拉韦自微乳化释药系统(DTG-SMEDDSs),并对其在大鼠体内的药动学行为进行评价。方法2021年6月至2023年3月通过测定多替拉韦(DTG)在不同种类油、乳化剂和助乳化剂中的平衡溶解度、辅料配伍相容性实验来确定DTG-SMEDDSs的处方组成,根据伪三元相图初步确定各辅料的用量范围,评价DTG-SMEDDSs的热力学稳定性以及在不同稀释倍速中的稳定性,通过透射电镜观察到DTG-SMEDDSs形成乳液的微观形态,考察DTG-SMEDDSs的体外药物溶出速率,通过大鼠口服给药比较DTG混悬剂与DTG-SMEDDSs的大鼠体内药动学特征。结果平衡溶解度和辅料配伍相容性实验确定选择单亚油酸甘油酯(Maisine)作为油相,吐温80作为乳化剂,二乙二醇单乙基醚(Transcutol HP)作为助乳化剂,其配比为30∶35∶35,制备的DTG-SMEDDSs具有良好的热力学稳定性及稀释稳定性,其自乳化形成的微乳呈类球形;DTG-SMEDDSs中的药物在10 min内基本完全溶出,其溶出速率显著快于DTG原料药;大鼠体内药动学结果显示,大鼠口服DTG-SMEDDSs后的达峰浓度(Cmax)是DTG混悬剂的2.46倍,血药浓度-时间曲线下面积(AUC(0-∞))是DTG混悬剂液的2.52倍,说明DTG-SMEDDSs可显著提高药物的达峰浓度,增加药物口服生物利用度。结论多替拉韦自微乳化释药系统,有助于药物快速溶出,显著提高了多替拉韦的口服生物利用度。Objective To prepare dolutegravir self-microemulsification drug delivery systems(DTG-SMEDDSs)and evaluate their pharmacokinetic behavior in rats.Methods The formulation composition of DTG-SMEDDSs was determined by measuring the equilibrium solubility of dolutegravir(DTG)in different kinds of oils,emulsifiers and coemulsifiers and excipient pairing compatibility experiments from June 2021 to March 2023.The dosage range of each excipient was preliminarily determined according to the pseudoternary phase diagram,and the thermodynamic stability of DTG-SMEDDSs was evaluated as well as the stability in different dilution multiplicities.The microscopic morphology of emulsion formation by DTG-SMEDDSs was observed by transmission electron microscopy.The dissolution rate of DTG-SMEDDSs in vitro was investigated.The pharmacokinetic characteristics of DTG suspension and the DTGSMEDDSs in rats were compared in vivo by oral administration to rats.Results Equilibrium solubility and excipient compatibility experiments to confirm the selection of glycerol monooleate(maisine)as the oil phase,Tween 80 as the emulsifier,and diethylene glycol monoethyl ether(Transcutol HP)as a coemulsifier,with a ratio of 30∶35∶35.The prepared DTG-SMEDDSs showed good thermodynamic and dilutional stability,and the microemulsion formed by self-emulsification was spherical.The drug in DTG-SMEDDSs was almost completely dissolved within 10 min,and the dissolution rate was significantly faster than that of DTG API.The in vivo pharmacokinetic results in rats showed that the Cmax of DTG-SMEDDSs was 2.46 times higher than that of the DTG suspension,and the AUC(0-∞)was 2.52 times higher than that of the DTG suspension,indicating that the peak concentration of the drug could be significantly increased and that the oral bioavailability of the drug could be increased by DTG-SMEDDSs.Conclusion The self-microemulsifying drug delivery system for dolutegravir facilitated rapid drug dissolution and significantly improved the oral bioavailability of the drug.

关 键 词：工艺学 制药 多替拉韦 自微乳化释药系统 溶出速率 药动学 生物利用度 

分 类 号：R943[医药卫生—药剂学] R965[医药卫生—药学]