多肽微球缓释注射剂中载体辅料丙交酯乙交酯共聚物的关键质量属性分析

目的： 对部分已上市多肽微球注射剂中丙交酯乙交酯共聚物（PLGA）的关键质量属性进行表征和分析，为全面评价该类制剂及其体外释放度加速试验方法研究提供参考。方法： 采用凝胶渗透色谱法（GPC）、核磁共振谱法（¹H NMR）、GPC三联检测器法（GPC-3D）和差示扫描量热分析仪法（DSC），分别测定多肽微球注射剂和多种丙交酯乙交酯共聚物样品的相对重均分子质量（M_w^R）、丙交酯乙交酯摩尔比（L：G）与微球中PLGA含量、绝对重均分子质量（M_w^A）与支化度（g'）、玻璃化转变温度（T_g），分析影响微球注射剂T_g的因素。结果： 5种12个不同规格的多肽微球注射剂中PLGA的M_w^R在12~53 kDa；L：G值有52：48、50：50、53：47、55：45、74：26、75：25和100：0；PLGA含量在55.8%~80.5%；M_w^M_wAR在7~45 kDa，线型载体微球的g'值为0.9~1.0，星型载体微球的G值在0.8左右；T_g值在32.1~47.2℃。11种型号的纯PLGA样品的M_w^R在23~70 kDa；L：G值有50：50、55：45和60：40；M_w^M_wAR在1.5~6.1万道尔顿，线型PLGA的g'值在0.9~1.0，非线型PLGA的g'值随着其结构在0.6~0.8之间变化；T_g值在35.5~44.5℃。结论： 多肽微球注射剂中丙交酯乙交酯共聚物的相对分子质量、L：G值及含量对T_g值的影响呈正相关，且其支化度对T_g值也有一定的影响。本文可为多肽微球缓释注射剂丙交酯乙交酯共聚物的表征及其内在质量的对比研究，以及体外释放度加速试验方法的研究提供参考。

Objective: The critical quality attributes of poly (lactide-co-glycolide)(PLGA) in some polypeptide microsphere injection on the market were characterized and analyzed,which provides a reference for the comprehensive evaluation of both the kind of formulation and the research of the in vitro accelerated release test methods. Methods: The methods of gel permeation chromatography (GPC),magnetic resonance spectroscopy (¹H NMR),GPC triple detector (GPC-3D),and differential scanning calorimetry (DSC) were respectively used to determine the relative weight average molecular weight (M_w^R),the molar ratio of lactide to glycolide (L:G),the content of poly(lactide-co-glycolide)(PLGA) in microsphers,the absolute weight average molecular weight(M_w^M_wAR)and branching degree (g'),the glass transition temperature (T_g) of polypeptide microsphere injections and various PLGA samples. And the factors influencing the T_g of microsphere injections were analyzed. Results: The M_w^R of PLGA in 5 kinds of 12 different specifications of polypeptide microsphere injections were 12-53 kDa;There were 7 kinds of L:G with the ratio value of 52:48,50:50,53:47,55:45,74:26,75:25 and 100:0,respectively;The content of PLGA was 55.8%-80.5%;The M_w^M_wAR were 7-45 kDa,the g' value of linear carrier microspheres was 0.9-1.0,and that of star carrier microspheres was around 0.8. The T_g was 32.1-47.2℃. The M_w^R of 11 kinds of pure PLGA samples were 23-70 kDa;There were 3 kinds of L:G with the ratio value of 50:50,55:45 and 60:40,respectively;The M_w^M_wAR were 15-61 kDa,the g' value of linear PLGA was 0.9-1.0,and the g' value of non-linear PLGA varies with its structure from 0.6 to 0.8;The T_g was 32.1-47.2℃. Conclusions: The molecular weight,L:G value and content of PLGA in polypeptide microsphere injections had a positive correlation with its T_g value,and its branching degree also has some influence on the T_g. This paper can provide a reference for the comprehensive characterization of polypeptide microsphere injection and the comparative study of their internal quality,as well as the study of the in vitro accelerated release test method.

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