聚乳酸-羟基乙酸共聚物载药微球制备工艺研究进展
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摘要
背景:聚乳酸-羟基乙酸共聚物载药微球制作工艺存在缺陷,致使缓释微球内毒性溶剂残留,载药率、包封率低下。目的:综述各种不同工艺方法制备聚乳酸-羟基乙酸共聚物载药微球的原理、优缺点、适用范围、研究现状及进展方向。方法:通过计算机检索CNKI、Pub Med及Google学术数据库中,2012年1月至2017年4月发表的关于聚乳酸-羟基乙酸共聚物载药微球制作、实验、应用研究的文章,分析各种制作工艺原理及优缺点。结果与结论:目前制备聚乳酸-羟基乙酸共聚物载药微球的方法主要有:单/复乳溶剂挥发法、喷雾干燥法、水凝胶模板法、微流体、同轴静电喷涂、相分离法、超临界流体萃取法。这些制作方法都有各自的不足,目前还没有一种方法可兼顾微球的药物包封、释放、溶剂无残留、形态大小及产量。通过对制作工艺的研究和改进,将不同工艺的优点结合起来,有望制作出各种包封率理想、释放平稳的聚乳酸-羟基乙酸共聚物载药微球。
BACKGROUND: Existing flaws have been found in the production process of poly(lactic-co-glycolic acid)(PLGA) copolymer microspheres, which lead to residual solvent, low drug loading rate and low encapsulation efficiency of sustained-release microspheres.OBJECTIVE: To review different methods for preparing PLGA microspheres from the following aspects: basic principles, advantages/disadvantages, indications and future development. METHODS: We retrieved CNKI, Pub Med and Google scholar to access the articles related to the technique process of preparing PLGA microspheres published from January 2012 to April 2017, including experiment and application research on the principles and advantages/disadvantages of the various processes. RESULTS AND CONCLUSION: To date, the main methods to prepare PLGA microspheres include single/re-emulsion solvent evaporation method, spray drying method, hydrogel template method, microfluid, coaxial electrostatic spraying, phase separation method, and supercritical fluid extraction. However, no valid evidences suggest that there is a technique that completely solves all potential problems, such as drug encapsulation and release, residual solvent and appropriate shape and size. Combination and modification of the production processes is expected to develop novel PLGA microspheres with ideal encapsulation efficiency and stable drug release.
BACKGROUND: Existing flaws have been found in the production process of poly(lactic-co-glycolic acid)(PLGA) copolymer microspheres, which lead to residual solvent, low drug loading rate and low encapsulation efficiency of sustained-release microspheres.OBJECTIVE: To review different methods for preparing PLGA microspheres from the following aspects: basic principles, advantages/disadvantages, indications and future development. METHODS: We retrieved CNKI, Pub Med and Google scholar to access the articles related to the technique process of preparing PLGA microspheres published from January 2012 to April 2017, including experiment and application research on the principles and advantages/disadvantages of the various processes. RESULTS AND CONCLUSION: To date, the main methods to prepare PLGA microspheres include single/re-emulsion solvent evaporation method, spray drying method, hydrogel template method, microfluid, coaxial electrostatic spraying, phase separation method, and supercritical fluid extraction. However, no valid evidences suggest that there is a technique that completely solves all potential problems, such as drug encapsulation and release, residual solvent and appropriate shape and size. Combination and modification of the production processes is expected to develop novel PLGA microspheres with ideal encapsulation efficiency and stable drug release.
引文
[1]谭深,宋媛媛,张建安,等.聚乳酸载药微球的制备及改性的应用进展[J].化工新型材料,2015,43(9):231-233.
[2]Sherwood JK,Riley SL,Palazzolo R,et al.A three-dimensional osteochondral composite scaffold for articular cartilage repair.Biomaterials.2002;23(24):4739-4751.
[3]Park TG.Degradation of poly(lactic-co-glycolic acid)microspheres:effect of copolymer composition.Biomaterials.1995;16(15):1123-1130.
[4]李秀娟.乳化-减压溶剂挥发法制备聚合物微球的研究[D].天津大学,2012.
[5]邵文尧,何彩云,冯艳玲,等.乳化-溶剂挥发法制备聚乳酸载药微球[J].功能材料,2015,46(3):3121-3126.
[6]李静涵.复乳溶剂挥发法制备利多卡因-PLGA缓释微球工艺改进[D].天津大学,2015.
[7]王飞.万古霉素局部微球注射治疗耐甲氧西林金黄色葡萄球菌感染性椎间盘炎的实验研究[J].中国骨与关节外科,2013,6(6):519-525.
[8]何胤,杨宗强,王骞,等.复合三联抗结核药聚乳酸-羟基乙酸缓释微球的制备及体外释药特性[J].中国脊柱脊髓杂志,2015,25(5):456-461.
[9]Wan F,Yang M.Design of PLGA-based depot delivery systems for biopharmaceuticals prepared by spray drying.Int J Pharm.2015;498(1-2):82-95.
[10]Sosnik A,Seremeta KP.Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers.Adv Colloid Interface Sci.2015;223:40-54.
[11]张丽梅.异烟肼缓释微球的制备与评价研究[D].北京协和医学院中国医学科学院;北京协和医学院,中国医学科学院,清华大学医学部,2013.
[12]施敏.喷雾干燥法制备P(MMA-BA)、PLA/EC中空微球及其性能研究[D].湖南大学,2012.
[13]Zhu C,Huang Y,Zhang X,et al.Comparative studies on exenatide-loaded poly(D,L-lactic-co-glycolic acid)microparticles prepared by a novel ultra-fine particle processing system and spray drying.Colloids Surf B Biointerfaces.2015;132:103-110.
[14]Malavia N,Reddy L,Szinai I,et al.Biodegradable sustained-release drug delivery systems fabricated using a dissolvable hydrogel template technology for the treatment of ocular indications.Inv Ophthalmol Vis Sci.2015;56(7):1296-1296.
[15]齐献利.伊立替康微球突释效应的影响因素及控制方法[D].河北科技大学,2015.
[16]Lu Y,Sturek M,Park K.Microparticles produced by the hydrogel template method for sustained drug delivery.Int J Pharm.2013;461(1-2):258-269.
[17]魏文浩.单分散微球制备装置的构建及载COL海藻酸钙-壳聚糖复合微球制备的研究[D].中国海洋大学,2015.
[18]Liu P,Zhong Y,Luo Y.Preparation of monodisperse biodegradable magnetic microspheres using a novel T-shaped microchannel reactor.Mater Lett.2014;(117):37-40.
[19]Leon RAL,Somasundar A,Badruddoza AZM,et al.Microfluidic Fabrication of Multi‐Drug‐Loaded Polymeric Microparticles for Topical Glaucoma Therapy.Part Part Syst Char.2015;32(5):567-572.
[20]Xu Q,Hashimoto M,Dang TT,et al.Preparation of Monodisperse Biodegradable Polymer Microparticles Using a Microfluidic Flow-focusing Device for Controlled Drug Delivery.Small.2009;5(13):1575.
[21]Yuan S,Lei F,Liu Z,et al.Coaxial Electrospray of Curcumin-Loaded Microparticles for Sustained Drug Release.PLo S One.2014;10(7):e0132609.
[22]Zhang L,Si T,Fischer AJ,et al.Coaxial Electrospray of Ranibizumab-Loaded Microparticles for Sustained Release of Anti-VEGF Therapies.Plo S One.2015;10(8):e0135608.
[23]Wang Y,Yang X,Liu W,et al.Controlled release behaviour of protein-loaded microparticles prepared via coaxial or emulsion electrospray.J Microencapsul.2013;30(5):490.
[24]Jain RA.The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide)(PLGA)devices.Biomaterials.2001;21(23):2475-2490.
[25]Awwad S,Day RM,Khaw PT,et al.Sustained release ophthalmic dexamethasone:In vitro in vivo correlations derived from the PK-Eye.Int J Pharm.2017;522(1-2):119-127..
[26]郁晓,任杰,任天斌,等.两性霉素B缓释微球的制备及缓释性能研究[J].中国生物医学工程学报,2007,26(3):445-451.
[27]忻娜.超临界CO_2抗溶剂法制备姜黄素及姜黄素-PLGA复合纳米颗粒[D].上海交通大学,2014.
[28]Falco N,Reverchon E,Porta GD.Injectable PLGA/hydrocortisone formulation produced by continuous supercritical emulsion extraction.Int J Pharm.2013;441(1-2):589-597.
[29]Della PG,Falco N,Giordano E,et al.PLGA microspheres by Supercritical Emulsion Extraction:a study on insulin release in myoblast culture.J Biomater Sci Polym Ed.2013;24(16):1831.
[30]Della PG,Campardelli R,Cricchio V,et al.Injectable PLGA/Hydroxyapatite/Chitosan Microcapsules Produced by Supercritical Emulsion Extraction Technology:An In Vitro Study on Teriparatide/Gentamicin Controlled Release.J Pharm Sci.2016;105(7):2164-2172.
[31]安森博,汪龙,胡懿郃.聚乳酸-羟基乙酸共聚物载药微球性质及缓释行为的影响因素[J].中国医院药学杂志,2016,36(13):1140-1144.
[32]王芳,袁健,刘秀秀,等.PLGA基载药复合微球的制备及其释放性能[J].南京林业大学学报(自然科学版),2016,40(2):95-99.
[33]程德林.骨修复聚合物微球/支架的表面形貌构建及其对干细胞影响规律研究[D].华南理工大学,2014.
[34]孙爱平.喷雾干燥法制备聚乳酸载药微球及其药物释放行为研究[D].天津大学,2008.
[35]缪世锋.基于超临界流体技术的银杏黄酮提取和微粒化过程研究[D].浙江大学,2011.
[36]李俊起,朱爱臣,马丽霞,等.聚乳酸在3D打印医疗器械产品中的研究进展[J].生物医学工程研究,2016,35(4):309-312.
[37]贺超良,汤朝晖,田华雨,等.3D打印技术制备生物医用高分子材料的研究进展[J].高分子学报,2013,57(6):722-732.
[38]黄玉,孟令贤,侯一帆,等.小粒径PLGA纳米颗粒的制备[J].平顶山学院学报,2015,30(2):44-49.
[2]Sherwood JK,Riley SL,Palazzolo R,et al.A three-dimensional osteochondral composite scaffold for articular cartilage repair.Biomaterials.2002;23(24):4739-4751.
[3]Park TG.Degradation of poly(lactic-co-glycolic acid)microspheres:effect of copolymer composition.Biomaterials.1995;16(15):1123-1130.
[4]李秀娟.乳化-减压溶剂挥发法制备聚合物微球的研究[D].天津大学,2012.
[5]邵文尧,何彩云,冯艳玲,等.乳化-溶剂挥发法制备聚乳酸载药微球[J].功能材料,2015,46(3):3121-3126.
[6]李静涵.复乳溶剂挥发法制备利多卡因-PLGA缓释微球工艺改进[D].天津大学,2015.
[7]王飞.万古霉素局部微球注射治疗耐甲氧西林金黄色葡萄球菌感染性椎间盘炎的实验研究[J].中国骨与关节外科,2013,6(6):519-525.
[8]何胤,杨宗强,王骞,等.复合三联抗结核药聚乳酸-羟基乙酸缓释微球的制备及体外释药特性[J].中国脊柱脊髓杂志,2015,25(5):456-461.
[9]Wan F,Yang M.Design of PLGA-based depot delivery systems for biopharmaceuticals prepared by spray drying.Int J Pharm.2015;498(1-2):82-95.
[10]Sosnik A,Seremeta KP.Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers.Adv Colloid Interface Sci.2015;223:40-54.
[11]张丽梅.异烟肼缓释微球的制备与评价研究[D].北京协和医学院中国医学科学院;北京协和医学院,中国医学科学院,清华大学医学部,2013.
[12]施敏.喷雾干燥法制备P(MMA-BA)、PLA/EC中空微球及其性能研究[D].湖南大学,2012.
[13]Zhu C,Huang Y,Zhang X,et al.Comparative studies on exenatide-loaded poly(D,L-lactic-co-glycolic acid)microparticles prepared by a novel ultra-fine particle processing system and spray drying.Colloids Surf B Biointerfaces.2015;132:103-110.
[14]Malavia N,Reddy L,Szinai I,et al.Biodegradable sustained-release drug delivery systems fabricated using a dissolvable hydrogel template technology for the treatment of ocular indications.Inv Ophthalmol Vis Sci.2015;56(7):1296-1296.
[15]齐献利.伊立替康微球突释效应的影响因素及控制方法[D].河北科技大学,2015.
[16]Lu Y,Sturek M,Park K.Microparticles produced by the hydrogel template method for sustained drug delivery.Int J Pharm.2013;461(1-2):258-269.
[17]魏文浩.单分散微球制备装置的构建及载COL海藻酸钙-壳聚糖复合微球制备的研究[D].中国海洋大学,2015.
[18]Liu P,Zhong Y,Luo Y.Preparation of monodisperse biodegradable magnetic microspheres using a novel T-shaped microchannel reactor.Mater Lett.2014;(117):37-40.
[19]Leon RAL,Somasundar A,Badruddoza AZM,et al.Microfluidic Fabrication of Multi‐Drug‐Loaded Polymeric Microparticles for Topical Glaucoma Therapy.Part Part Syst Char.2015;32(5):567-572.
[20]Xu Q,Hashimoto M,Dang TT,et al.Preparation of Monodisperse Biodegradable Polymer Microparticles Using a Microfluidic Flow-focusing Device for Controlled Drug Delivery.Small.2009;5(13):1575.
[21]Yuan S,Lei F,Liu Z,et al.Coaxial Electrospray of Curcumin-Loaded Microparticles for Sustained Drug Release.PLo S One.2014;10(7):e0132609.
[22]Zhang L,Si T,Fischer AJ,et al.Coaxial Electrospray of Ranibizumab-Loaded Microparticles for Sustained Release of Anti-VEGF Therapies.Plo S One.2015;10(8):e0135608.
[23]Wang Y,Yang X,Liu W,et al.Controlled release behaviour of protein-loaded microparticles prepared via coaxial or emulsion electrospray.J Microencapsul.2013;30(5):490.
[24]Jain RA.The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide)(PLGA)devices.Biomaterials.2001;21(23):2475-2490.
[25]Awwad S,Day RM,Khaw PT,et al.Sustained release ophthalmic dexamethasone:In vitro in vivo correlations derived from the PK-Eye.Int J Pharm.2017;522(1-2):119-127..
[26]郁晓,任杰,任天斌,等.两性霉素B缓释微球的制备及缓释性能研究[J].中国生物医学工程学报,2007,26(3):445-451.
[27]忻娜.超临界CO_2抗溶剂法制备姜黄素及姜黄素-PLGA复合纳米颗粒[D].上海交通大学,2014.
[28]Falco N,Reverchon E,Porta GD.Injectable PLGA/hydrocortisone formulation produced by continuous supercritical emulsion extraction.Int J Pharm.2013;441(1-2):589-597.
[29]Della PG,Falco N,Giordano E,et al.PLGA microspheres by Supercritical Emulsion Extraction:a study on insulin release in myoblast culture.J Biomater Sci Polym Ed.2013;24(16):1831.
[30]Della PG,Campardelli R,Cricchio V,et al.Injectable PLGA/Hydroxyapatite/Chitosan Microcapsules Produced by Supercritical Emulsion Extraction Technology:An In Vitro Study on Teriparatide/Gentamicin Controlled Release.J Pharm Sci.2016;105(7):2164-2172.
[31]安森博,汪龙,胡懿郃.聚乳酸-羟基乙酸共聚物载药微球性质及缓释行为的影响因素[J].中国医院药学杂志,2016,36(13):1140-1144.
[32]王芳,袁健,刘秀秀,等.PLGA基载药复合微球的制备及其释放性能[J].南京林业大学学报(自然科学版),2016,40(2):95-99.
[33]程德林.骨修复聚合物微球/支架的表面形貌构建及其对干细胞影响规律研究[D].华南理工大学,2014.
[34]孙爱平.喷雾干燥法制备聚乳酸载药微球及其药物释放行为研究[D].天津大学,2008.
[35]缪世锋.基于超临界流体技术的银杏黄酮提取和微粒化过程研究[D].浙江大学,2011.
[36]李俊起,朱爱臣,马丽霞,等.聚乳酸在3D打印医疗器械产品中的研究进展[J].生物医学工程研究,2016,35(4):309-312.
[37]贺超良,汤朝晖,田华雨,等.3D打印技术制备生物医用高分子材料的研究进展[J].高分子学报,2013,57(6):722-732.
[38]黄玉,孟令贤,侯一帆,等.小粒径PLGA纳米颗粒的制备[J].平顶山学院学报,2015,30(2):44-49.
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