SPG膜乳化溶剂萃取法制备双羟萘酸曲普瑞林缓释微球的工艺优化

Optimization of the SPG Membrane Emulsification Solvent Extraction Method for Preparation of Triptorelin Pamoate PLGA Microspheres

以双羟萘酸曲普瑞林为模型药物,采用SPG膜乳化溶剂萃取这一简化的方法,制备了聚乳酸-羟基乙酸共聚物(PLGA)长效缓释微球注射剂。采用单因素试验优化了蛋白处理方式和PLGA浓度。扫描电镜和粒度分析显示,优化处方的微球表面光滑,平均粒径为75.67μm,粒度分布均一(多分散系数0.282)。高效液相色谱和气相色谱的定量分析证明,最终产品中双羟萘酸曲普瑞林的包封率为94.99%,而二氯甲烷(DCM,用作PLGA的溶剂)的含量低于限量(6×10^(-4))。体外释放试验显示,双羟萘酸曲普瑞林1 d累积释放率10.23%,33 d累积释放率接近90%,整个释放周期以较均匀的速度持续释放。上述结果说明,SPG膜乳化溶剂萃取法可能是制备多肽药物长效缓释微球注射剂的一个理想而简捷的工艺。

While biodegradable polymer based sustained-release microspheres may substantially reduce the injection frequency and improve patient compliance for peptides, a class of medicines administrated by injection, there are only 9 products available in the market since their birth. This situation is due to the complexity and poor reproducibility of microspheres＇ production engineering, comprising diversified size, burst release, and large dose volume caused by unsteady release （considerable waste）. Clearly, unsatisfied production processes retarded the applications of sustainedrelease microspheres for injection. To address this formulation issue and improve microencapsulation process, we used triptorelin pamoate as a model peptide drug, developed a simplified microsphere production process, SPG membrane aided emulsification and solvent extraction, to prepare poly（lactic-co-glycolic acid） （PLGA） sustained-release microspheres. The protein treatment methods and PLGA concentration during the preparation process were optimized by the single factor test. Scanning electron microscopy （SEM） and laser scattering analysis indicated that the optimized microspheres possessed a smooth surface and narrow size distribution （polydispersity index=0.282） with a mean particle size of 75.67 μm. The quantitative analysis by HPLC and gas chromatography confirmed that the final product of the microspheres encapsulated 94.99% of the added triptorelin pamoate with the dichloromethane （DCM, the solvent for dissolving PLGA） less than 6×10-4. The in vitro release study showed that the peptide released 10.23% of the total load at the first day, followed by a nearly steady release for 32 days, and the cumulative release at 33 d reached about 90%. The results of the present study may lead to a conclusion that SPG membrane aided emulsification and solvent extraction is an ideally simplified method for producing sustained-release microspheres of peptides for injection.