干扰素α-2b缓释微球的制备及影响因素考察

Preparation of IFNα-2b sustained-release microspheres and study on factors influencing microspheres

目的:制备以明胶粉形式固化的干扰素α-2b(IFNα-2b)聚乙二醇/聚对苯二甲酸丁二醇酯共聚物(PEG/PBT)-乳酸-羟基乙酸共聚物(PLGA)缓释微球,并考察微球制备方法,基质材料,IFNα-2b存在形式[包括液态含人血清白蛋白(HSA),固态含HSA及液态不含HSA]及胶粉粒径对微球性质的影响。方法:将IFNα-2b溶于明胶溶液后,冷冻干燥,研磨制备胶粉,然后用S/O/O法、W/O/W法或S/O/W法制备微球;以粒径、包封率及释放为指标,考察微球的制备方法、基质材料、IFNα-2b形式及胶粉粒径对微球性质的影响;采用ELISA法测定IFNα-2b。结果:以液态不含HSA形式的IFNα-2b为原料药,胶粉粒径为14.5μm,以PEG/PBT及PLGA(9∶1)为混合基质材料,S/O/W法制备的微球最为理想,该微球突释约为20%,体外可持续释放19 d以上,累积释放量可达80%以上。结论:微球制备方法、基质材料、IFNα-2b形式及胶粉粒径对微球性质影响很大;将IFNα-2b以胶粉形式固化后制备微球可增加其稳定性,利于其连续释放。本研究为蛋白多肽类药物微球的制备提供了新思路。

Objective： To prepare the PEG/PBT-PLGA sustained-release microspheres of IFNα-2b entrapped in gelatin powders, and investigate the influential factors including manufacturing methods and matrixes of microspheres, IFNα-2b forms（ liquid with HSA, solid with HSA and liquid without HSA） and gelatin powder particle size. Methods： Several kinds of microspheres prepared by different methods and matrixes, different IFNα-2b forms and different sizes of gelatin particles were characterized by evaluating morphology, particle size, encapsulation efficiency and in-vitro release. The levels of IFNα-2b were measured with ELISA. Results： Microspheres prepared by S/O/W with liquid IFNα-2b without HSA had the best characters when PEG/PBT-PLGA （9：1 ） and gelatin powders with average diameter of 14.5 μm were used at the same time. These microspheres had the burst release of about 20% and could sustain releasing IFNα-2b longer than 19 days with the cumulative release above 80%. Conclusion ： The characters of microspheres could be affected by manufacturing method, matrixes of microspheres, forms of IFNα-2b and sizes of gelatin powder particles. It was shown to be a good way to stabilize IFNα-2b in microspheres and to keep sustained-release by encapsulating IFNα-2b in gelatin powder, so the new method of preparing microspheres reported in the paper is promising.