Box-Behnken响应面法优化索拉非尼PLGA-TPGS聚合物纳米粒的处方与工艺
|
摘要
目的优化索拉非尼聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid),PLGA]-维生素E-聚乙二醇1000琥珀酸酯(D-ɑ-tocopheryl polyethylene glycol 1000succinate,TPGS)聚合物纳米粒的处方与制备工艺。方法采用乳化-溶剂挥发法制备纳米粒,以包封率和载药量为评价指标,采用Box-Behnken响应面法考察索拉非尼与PLGA的质量比、有机相与水相的容积比、乳化剂维生素E-聚乙二醇1000琥珀酸酯(TPGS)的浓度因素对制备的影响,得到最优工艺参数,并对最优处方与工艺下纳米粒药物的体外释放、形态和粒径进行考察。结果最佳处方为:索拉非尼与PLGA的质量比为1∶11.56;有机相与水相的容积比为1∶5.56;乳化剂TPGS的浓度为0.03%。制备的优化纳米粒形态均一,平均粒径为249.6nm,包封率为89.78%,载药量为9.41%。体外索拉非尼在含1%吐温-80的磷酸盐缓冲液(pH 5.0、pH 7.4)中呈二相释放,120h累积释放率分别为80.69%±4.70%和40.67%±3.77%。结论所优选的索拉非尼PLGA-TPGS纳米粒处方与工艺合理可行,体外实验具有明显的缓释作用,可为后期体内、体外研究提供实验基础。
Objective To optimize the prescription and preparation process of sorafenib PLGA-TPGS polymer nanoparticles.Methods Nanoparticles were prepared by the emulsion-solvent evaporation technique.With encapsulation efficiency and drug loading as assessment indices,the Box-Behnken response surface method was used to evaluate the influence of mass ratio of sorafenib to PLGA,volume ratio of organic phase to water phase,and concentration of the emulsifier vitamin E TPGS on preparation and to obtain the optimal processing parameters.The in vitro release,morphology,and particle size of the nanoparticles were observed under the optimal prescription and preparation process.Results The optimal prescription was a mass ratio of sorafenib to PLGA of 1∶11.56,a volume ratio of organic phase to water phase of1∶5.56,and a concentration of TPGS of 0.03%.The optimized nanoparticles had uniform morphology,with an average particle size of 249.6 nm,an average encapsulation efficiency of 89.78%,and an average drug loading rate of 9.41%.In vitro sorafenib was released in two phases in 1%tween-80 phosphate buffer(pH 5.0 and pH 7.4),and the 120-hour cumulative release rates were 80.69%±4.70%and 40.67%±3.77%,respectively.Conclusion The optimized prescription and preparation process of sorafenib PLGATPGS polymer nanoparticles are reasonable and feasible,and in vitro experiments show an obvious sustained-release effect,which provides an experimental basis for future in vivo and in vitro studies.
Objective To optimize the prescription and preparation process of sorafenib PLGA-TPGS polymer nanoparticles.Methods Nanoparticles were prepared by the emulsion-solvent evaporation technique.With encapsulation efficiency and drug loading as assessment indices,the Box-Behnken response surface method was used to evaluate the influence of mass ratio of sorafenib to PLGA,volume ratio of organic phase to water phase,and concentration of the emulsifier vitamin E TPGS on preparation and to obtain the optimal processing parameters.The in vitro release,morphology,and particle size of the nanoparticles were observed under the optimal prescription and preparation process.Results The optimal prescription was a mass ratio of sorafenib to PLGA of 1∶11.56,a volume ratio of organic phase to water phase of1∶5.56,and a concentration of TPGS of 0.03%.The optimized nanoparticles had uniform morphology,with an average particle size of 249.6 nm,an average encapsulation efficiency of 89.78%,and an average drug loading rate of 9.41%.In vitro sorafenib was released in two phases in 1%tween-80 phosphate buffer(pH 5.0 and pH 7.4),and the 120-hour cumulative release rates were 80.69%±4.70%and 40.67%±3.77%,respectively.Conclusion The optimized prescription and preparation process of sorafenib PLGATPGS polymer nanoparticles are reasonable and feasible,and in vitro experiments show an obvious sustained-release effect,which provides an experimental basis for future in vivo and in vitro studies.
引文
[1]WILHELM S M,CARTER C,TANG L Y,et al.BAY 43-9006exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis[J].Cancer research,2004,64(19):7099-7109.
[2]ZHANG J,WANG T,MU S,et al.Biomacromolecule/lipid hybrid nanoparticles for controlled delivery of sorafenib in targeting hepatocellular carcinoma therapy[J].Nanomedicine,2017,12(8):911-925.
[3]CHANG Y S,ADNANE J,TRAIL P A,et al.Sorafenib(BAY 43-9006)inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models[J].Cancer Chemotherapy&Pharmacology,2007,59(5):561.
[4]HASSKARL J.Sorafenib[J].Recent Results Cancer Res,2010,184:61-70.
[5]TAKIMOTO C H,AWADA A.Safety and anti-tumor activity of sorafenib(Nexavar)in combination with other anti-cancer agents:a review of clinical trials[J].Cancer Chemother Pharmacol,2008,61(4):535-548.
[6]WANG X Q,FAN J M,LIU Y O,et al.Bioavailability and pharmacokinetics of sorafenib suspension,nanoparticles and nanomatrix for oral administration to rat[J].International Journal of Pharmaceutics,2011,419(1):339-346.
[7]AL-SHAKARCHI W,ALSURAIFI A,CURTIS A,et al.Dual acting polymeric nano-aggregates for liver cancer therapy[J].Pharmaceutics,2018,10(2):e63[2018-05-26].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027472.DOI:10.3390/pharmaceutics10020063.
[8]GAO D Y,LIN T,SUNG Y C,et al.CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer[J].Biomaterials,2015,67:194-203.
[9]LIN T T,GAO D Y,LIU Y C,et al.Development and characterization of sorafenib-loaded PLGA nanoparticles for the systemic treatment of liver fibrosis[J].Journal of Controlled Release,2015,221:62-70.
[10]ZHANG Z,FENG S S.Nanoparticles of poly(lactide)/vitamin E TPGS copolymer for cancer chemotherapy:synthesis,formulation,characterization and in vitro drug release.[J].Biomaterials,2006,27(2):262-270.
[11]WIN K Y,FENG S S.In vitro and in vivo studies on vitamin E TPGS-emulsified poly(D,L-lactic-co-glycolic acid)nanoparticles for paclitaxel formulation[J].Biomaterials,2006,27(10):2285-2291.
[12]DONG H,WU G,XU H,et al.N-acetylaminogalactosyl-decorated biodegradable PLGA-TPGS copolymer nanoparticles containing emodin for the active targeting therapy of liver cancer[J].Artif Cells Nanomed Biotechnol,2018,19:1-13.
[13]ZHANG H,ZHANG F M,YAN S J.Preparation,in vitro release,and pharmacokinetics in rabbits of lyophilized injection of sorafenib solid lipid nanoparticles[J].International Journal of Nanomedicine,2012,7:2901.
[14]严春临,张季,刘敏,等.星点设计-响应面法优化吴茱萸次碱固体脂质纳米粒处方[J].中草药,2015,46(9):1307-1313.
[15]SIM爦EK S,EROGLU H,KURUM B,et al.Brain targeting of atorvastatin loaded amphiphilic PLGA-bPEG nanoparticles[J].Journal of Microencapsulation,2013,30(1):10-20.
[16]GIGLIO V,VIALE M,BERTONE V,et al.Cyclodextrin polymers as nanocarriers for sorafenib[J].Invest New Drugs,2018,36(3):370-379.
[17]涂颖秋,朱孟夏,刘会,等.优化药物制剂工艺的多种数据处理方法的研究进展[J].中国药学杂志,2013,4(16):1333-1337.
[18]张南生,孙卫军,郭虹,等.Box-Behnken Design效应面法在制剂处方优化中的应用[J].中国医药导报,2015,12(23):34-37.
[19]郝吉福,房信胜,王建筑,等.应用Box-Behnken实验设计优化水飞蓟素固体脂质纳米粒处方研究[J].中草药,2011,42(11):2221-2225.
[20]牛小童,张力中,冯易,等.吴茱萸碱固体脂质纳米粒的制备和抗肿瘤活性[J].中成药,2016,38(10):2149-2156.
[21]张洪,张福明,闫士君.索拉非尼固体脂质纳米粒冻干粉制备及体外释药特性研究[J].中国药学杂志,2013,48(3):196-199.
[2]ZHANG J,WANG T,MU S,et al.Biomacromolecule/lipid hybrid nanoparticles for controlled delivery of sorafenib in targeting hepatocellular carcinoma therapy[J].Nanomedicine,2017,12(8):911-925.
[3]CHANG Y S,ADNANE J,TRAIL P A,et al.Sorafenib(BAY 43-9006)inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models[J].Cancer Chemotherapy&Pharmacology,2007,59(5):561.
[4]HASSKARL J.Sorafenib[J].Recent Results Cancer Res,2010,184:61-70.
[5]TAKIMOTO C H,AWADA A.Safety and anti-tumor activity of sorafenib(Nexavar)in combination with other anti-cancer agents:a review of clinical trials[J].Cancer Chemother Pharmacol,2008,61(4):535-548.
[6]WANG X Q,FAN J M,LIU Y O,et al.Bioavailability and pharmacokinetics of sorafenib suspension,nanoparticles and nanomatrix for oral administration to rat[J].International Journal of Pharmaceutics,2011,419(1):339-346.
[7]AL-SHAKARCHI W,ALSURAIFI A,CURTIS A,et al.Dual acting polymeric nano-aggregates for liver cancer therapy[J].Pharmaceutics,2018,10(2):e63[2018-05-26].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027472.DOI:10.3390/pharmaceutics10020063.
[8]GAO D Y,LIN T,SUNG Y C,et al.CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer[J].Biomaterials,2015,67:194-203.
[9]LIN T T,GAO D Y,LIU Y C,et al.Development and characterization of sorafenib-loaded PLGA nanoparticles for the systemic treatment of liver fibrosis[J].Journal of Controlled Release,2015,221:62-70.
[10]ZHANG Z,FENG S S.Nanoparticles of poly(lactide)/vitamin E TPGS copolymer for cancer chemotherapy:synthesis,formulation,characterization and in vitro drug release.[J].Biomaterials,2006,27(2):262-270.
[11]WIN K Y,FENG S S.In vitro and in vivo studies on vitamin E TPGS-emulsified poly(D,L-lactic-co-glycolic acid)nanoparticles for paclitaxel formulation[J].Biomaterials,2006,27(10):2285-2291.
[12]DONG H,WU G,XU H,et al.N-acetylaminogalactosyl-decorated biodegradable PLGA-TPGS copolymer nanoparticles containing emodin for the active targeting therapy of liver cancer[J].Artif Cells Nanomed Biotechnol,2018,19:1-13.
[13]ZHANG H,ZHANG F M,YAN S J.Preparation,in vitro release,and pharmacokinetics in rabbits of lyophilized injection of sorafenib solid lipid nanoparticles[J].International Journal of Nanomedicine,2012,7:2901.
[14]严春临,张季,刘敏,等.星点设计-响应面法优化吴茱萸次碱固体脂质纳米粒处方[J].中草药,2015,46(9):1307-1313.
[15]SIM爦EK S,EROGLU H,KURUM B,et al.Brain targeting of atorvastatin loaded amphiphilic PLGA-bPEG nanoparticles[J].Journal of Microencapsulation,2013,30(1):10-20.
[16]GIGLIO V,VIALE M,BERTONE V,et al.Cyclodextrin polymers as nanocarriers for sorafenib[J].Invest New Drugs,2018,36(3):370-379.
[17]涂颖秋,朱孟夏,刘会,等.优化药物制剂工艺的多种数据处理方法的研究进展[J].中国药学杂志,2013,4(16):1333-1337.
[18]张南生,孙卫军,郭虹,等.Box-Behnken Design效应面法在制剂处方优化中的应用[J].中国医药导报,2015,12(23):34-37.
[19]郝吉福,房信胜,王建筑,等.应用Box-Behnken实验设计优化水飞蓟素固体脂质纳米粒处方研究[J].中草药,2011,42(11):2221-2225.
[20]牛小童,张力中,冯易,等.吴茱萸碱固体脂质纳米粒的制备和抗肿瘤活性[J].中成药,2016,38(10):2149-2156.
[21]张洪,张福明,闫士君.索拉非尼固体脂质纳米粒冻干粉制备及体外释药特性研究[J].中国药学杂志,2013,48(3):196-199.