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快速膜乳化法制备载生长激素释放肽-6聚(乳酸-乙醇酸)微球的研究
Alternative TitleStudy on preparation of growth hormone-releasing peptide-6 loaded PLGA microspheres by premix membra
何帆
Subtype硕士
Thesis Advisor苏志国 ; 吴颉
2013-05-01
Degree Grantor中国科学院研究生院
Degree Discipline生物化工
Keyword快速膜乳化   聚(乳酸-乙醇酸)微球   粒径均一   生长激素释放肽-6   体外释放
Abstract生长激素释放肽-6(GHRP-6)能强力诱导生长激素的合成与分泌,被FDA批准用于治疗侏儒症;此外,它的广谱促生长活性使其也能用于促进动物生长。但是GHRP-6半衰期短,需要频繁注射给药,带来了一系列诸如操作、成本等方面的问题。多肽缓释微球能够显著降低给药频率,增加多肽稳定性,可是传统的微球制备方法制备的微球粒径均一性较差,影响了生物利用度和批次间重复性。针对上述问题,本论文采用聚(乳酸-乙醇酸)共聚物(PLGA)为膜材,结合快速膜乳化法与复乳溶剂挥发法包埋GHRP-6,旨在制备粒径均一性好、药物包埋率高的长效缓释微球,实现多肽缓释微球制剂的快速简便的制备。 本论文分为三个部分。第一部分采用快速膜乳化技术结合单乳溶剂蒸发法制备PLGA空白微球。作为长效缓释制剂的微球需要较大粒径(20 μm以上),以实现较长的缓释周期。而快速膜乳化技术多用于制备从纳米到数微米粒径范围内的微球,很少用于制备较大粒径范围(20 μm以上)的微球。本论文通过对过膜压力、油水相体积比、水相PVA浓度、油相PLGA浓度的优化,成功采用快速膜乳化技术制备出粒径均一(span值低于0.7)、平均粒径在24 μm左右的PLGA微球。 第二部分采用快速膜乳化技术结合复乳溶剂蒸发法制备载药微球。为制得高包埋率的载药微球,针对GHRP-6分子量很小,容易在制备过程中扩散到外水相使包埋率降低的特点,系统优化了膜材分子量、内水相体积、油相PLGA浓度、油相乳化剂浓度、外水相盐浓度等因素,优化条件下制得载药微球的包埋率超过80%,且药物活性不受影响。 第三部分研究了载药微球的体外释放行为。结果发现对于不同初乳方式制备的微球而言,超声法制备初乳的载药微球释放时突释低,但后期的释放很缓慢,释放不完全。均质法制备初乳的载药微球释放时突释较大,但释放更完全。并且对体外释放曲线进行了数学拟合,拟合效果较好(R2均高于于0.98)。 研究表明,采用快速膜乳化法与复乳法相结合的工艺制备粒径均一的PLGA载药微球,是一种简便可行的缓释微球制剂制备方法。
Other AbstractGrowth hormone releasing peptide-6 (GHRP-6) is capable of powerfully inducing the synthesis and secretion of growth hormone and was approved by the FDA for the treatment of dwarfism, later as a veterinary drug used to promote animal growth due to its broad spectrum of growth-promoting activity. However, owing to the short half-life of GHRP-6, frequent injections are required, which has brought about a series of problems. Peptide sustained release microspheres are able to significantly reduce the frequency of administration as well as to improve the stability of peptide. However microspheres prepared by general techniques show broad particle size distribution, which would affect the bioavailability and reproducibility. Therefore, the overall goal of this research is to prepare PLGA microspheres with narrow size distribution by premix membrane emulsification technique combined with double emulsion method for sustained release of GHRP-6. The dissertation is divided into three parts. The first part focused on the preparation of PLGA microspheres by combining premix membrane emulsification technique with single emulsion method. As a long-term sustained release microsphere formulation, a relatively larger particle size (above 20 μm) is required, in order to achieve a certain sustained release period. Yet premix membrane emulsification technique usually used for the preparation of microspheres from nanometers to several micrometers size range, is seldom utilized in the preparation for microspheres of relatively larger particle sizes (above 20 μm). Through optimization of the transmembrane pressure, volume ratios of oil to water, concentration of PVA and PLGA, we are able to prepare uniform-sized microspheres (span value of below 0.7), with the average particle size of 24 μm. In the second part, GHRP-6 loaded PLGA microspheres were prepared by combining premix membrane emulsification technique and double emulsion method. The research systematically optimized a serious of parameters including molecular weight of PLGA, concentration of Arlacel 83, PLGA concentration of oil phase, volume of inner aqueous phase in order to acquire high encapsulation efficiency. Moreover, the activity of GHRP-6 is retained after encapsulated. The third part investigated the in vitro release profiles of GHRP-6 loaded microspheres. Microspheres prepared by ultrasonication technique showed low burst release as well as incomplete cumulative drug release while microspheres prepared by homogenization technique exhibited increased burst release and constant drug release. Furthermore, mathematical models were adopted to simulate in-vitro release, presenting rather good fitting results (R2>0.98). In conclusion, the premix membrane emulsification technique, combined with W/O/W double emulsion method, is a convenient and promising technique to prepare sustained release microspheres loading bioactive peptide.
Pages80
Language中文
Document Type学位论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/8272
Collection研究所(批量导入)
Recommended Citation
GB/T 7714
何帆. 快速膜乳化法制备载生长激素释放肽-6聚(乳酸-乙醇酸)微球的研究[D]. 中国科学院研究生院,2013.
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