醋酸亮丙瑞林植入剂体外释药模型的建立及释药动力学行为与热力学特征  

Establishment of a drug release model of leuprorelin acetate implant in vitro and release kinetic behavior and thermodynamic characteristics

作　　者：朱柏儒 唐海 孙嘉慧 王小文 李朴超 刘全礼[1] Zhu Boru;Tang Hai;Sun Jiahui;Wang Xiaowen;Li Puchao;Liu Quanli(Baotou Medical College,Baotou 014060,Inner Mongolia Autonomous Region,China;Jiangsu Tasly Diyi Pharmaceutical Co.,Ltd.,Huaian 223003,Jiangsu Province,China)

机构地区：[1]包头医学院,内蒙古自治区包头市014060 [2]江苏天士力帝益药业有限公司,江苏省淮安市223003

出　　处：《中国组织工程研究》2023年第12期1892-1899,共8页Chinese Journal of Tissue Engineering Research

摘　　要：背景:目前,中国尚未对皮下给药制剂的体外溶出做出明确指导,且由于以聚乳酸-乙醇酸共聚物为载体的缓控释制剂释放周期一般较长,因此开发一个能较好模拟体内吸收的体外释放方法至关重要。目的:制备醋酸亮丙瑞林皮下植入剂,开发与体内相关性良好的体外释放方法,建立体外加速释放模型,考察药物释放动力学和热力学的相关性,阐述释药机制。方法:以聚乳酸-乙醇酸共聚物为载体,利用热熔挤出技术制备醋酸亮丙瑞林植入剂,对其在成型过程中的物理化学性质进行表征;根据开发的体外释药方法进行体外释药实验,以释放度为指标,筛选释放周期为1个月的处方。以成年雄性SD大鼠为动物模型,皮下植入释放周期为1个月的醋酸亮丙瑞林植入剂,于设定的时间点眼眶取血,采用液相色谱-串联质谱法检测血浆中亮丙瑞林的浓度,分析体内、外药物释放相关性。取释放周期为1个月的醋酸亮丙瑞林植入剂,以温度为单变量进行体外加速实验,拟合释放动力学方程,同时扫描电镜下观察植入剂的微观形态。结果与结论:①实验设置了5种配方的植入剂,体外释药实验显示第5种配方植入剂(醋酸亮丙瑞林的投料比为25%、载体投料比为75%,其中载体中分子质量10 kD与30 kD的聚乳酸-乙醇酸共聚物质量比为1∶1)的释药周期为30 d,符合要求,用于后续实验;②建立的体外释放方法与体内释药性相关性良好(y=0.945x-5.58618,R^(2)=0.9454);③体外累计释放曲线符合S型三相模式:突释期、迟滞期和零级快速释放期;在升温过程中,以312.15 K的零级释药速率为基准,热力学与药物释放动力学速率符合方程,r=7.76825E-30×e(k/4.78745)+0.88303;④结果表明开发的体外释放方法能较好阐述药物在体内的释放动态信息,体外释药呈S型释放曲线,释药机制为扩散与溶蚀相结合,且零级快速释药期药物释放动力学和热力学BACKGROUND:At present,China has not made clear guidance on the in vitro dissolution of subcutaneous preparations.Because the release cycle of slowrelease and controlled-release preparations with poly(lactic-co-glycolic acid)copolymer as carrier is generally long,it is very important to develop an in vitro release method that can better simulate in vivo absorption.OBJECTIVE:To prepare leuprorelin acetate subcutaneous implant,develop an in vitro release method with good correlation with in vivo,establish an in vitro accelerated release model,investigate the correlation between drug release kinetics and thermodynamics,and elaborate the release mechanism.METHODS:Poly(lactic-co-glycolic acid)was used as a carrier.Leuprolide acetate implants were synthesized by hot-melt extrusion technology,and its physicochemical properties were characterized during the molding process.According to the developed in vitro drug release method,the in vitro drug release test was carried out.Taking the release degree as the index,the formulation with a release cycle of 1 month was screened.Adult male SD rats were used as animal models and subcutaneously implanted with leuprolide acetate implants with a release cycle of 1 month.Blood was obtained from the orbit at the set time point.The concentration of leuprorelin in plasma was determined by liquid chromatography-tandem mass spectrometry to analyze the correlation between in vivo and in vitro drug release.The leuprolide acetate implant was taken with a release cycle of 1 month.The in vitro accelerated test was carried out with temperature as a single variable to fit the release kinetic equation.Simultaneously,the microscopic morphology of the implants was observed under scanning electron microscope.RESULTS AND CONCLUSION:(1)The experiment set up five kinds of implants.The in vitro drug release experiment demonstrated that the release cycle of the 5^(th) formula implant(the feeding ratio of leuprolide acetate was 25%;the feeding ratio of the carrier was 75%;and the mass ratio of poly(lactic

关 键 词：聚乳酸-乙醇酸共聚物 醋酸亮丙瑞林 皮下植入剂 体外释放方法 释药机制 

分 类 号：R459.9[医药卫生—治疗学] R318[医药卫生—临床医学] R944