醋酸戈舍瑞林微球的体内外相关性研究
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摘要
本研究的目的是对注射用醋酸戈舍瑞林微球建立体内外相关性(in vitro-in vivo correlation, IVIVC)。制备了3种释放速率不同的注射用醋酸戈舍瑞林微球,并对其物理化学性质进行了表征;采用恒温水浴振荡法测定了3种微球的体外释放度曲线并研究了在该条件下的释放机制;以SD大鼠为动物模型,研究3种微球在体内的药代动力学特性,药代动力学实验方案经山东绿叶制药有限公司动物伦理委员会批准实施;血药浓度-时间曲线经%AUC法处理后得到体内累积释放曲线,并与体外累积释放曲线进行相关性分析。结果表明,本文开发的体外释放度测定方法对不同的醋酸戈舍瑞林微球具有良好的区分能力,醋酸戈舍瑞林微球的体内外相关性良好(r> 0.98),并在SD大鼠体内具有良好的预测能力。
The objective of this paper was to establish a level A in vitro-in vivo correlation(IVIVC) for goserelin acetate extended release microspheres for injection.Three kinds of goserelin acetate microspheres with different release rates were prepared and the critical physicochemical properties,such as drug loading,particle size,glass transition temperature and morphology were characterized.In vitro dissolution test of the prepared goserelin acetate microspheres was performed using sample-and-separate method at 45℃ in 5%(v/v)methanol.The morphology of the microspheres and the molecular weight of poly(lactic-co-glycolic acid)(PLGA)of the prepared goserelin acetate microspheres were investigated to research the release mechanism of microspheres.The plasma concentration of goserelin was detected after intramuscular injection of goserelin acetate microspheres to SD rats,and correlated with the in vitro release profiles after processing by percent AUC method.The pharmacokinetic experimental protocol of goserelin acetate microspheres for injection in SD rats was approved by the Animal Ethics Committee of Shandong Luye Pharmaceutical Co.,Ltd.The results indicated that the developed sample and separate method was able to detect differences in the release characteristics of the prepared goserelin acetate microspheres,and the in vitro-in vivo correlation of goserelin acetate microspheres was excellent(r>0.98) and had good predictive ability in SD rats.
The objective of this paper was to establish a level A in vitro-in vivo correlation(IVIVC) for goserelin acetate extended release microspheres for injection.Three kinds of goserelin acetate microspheres with different release rates were prepared and the critical physicochemical properties,such as drug loading,particle size,glass transition temperature and morphology were characterized.In vitro dissolution test of the prepared goserelin acetate microspheres was performed using sample-and-separate method at 45℃ in 5%(v/v)methanol.The morphology of the microspheres and the molecular weight of poly(lactic-co-glycolic acid)(PLGA)of the prepared goserelin acetate microspheres were investigated to research the release mechanism of microspheres.The plasma concentration of goserelin was detected after intramuscular injection of goserelin acetate microspheres to SD rats,and correlated with the in vitro release profiles after processing by percent AUC method.The pharmacokinetic experimental protocol of goserelin acetate microspheres for injection in SD rats was approved by the Animal Ethics Committee of Shandong Luye Pharmaceutical Co.,Ltd.The results indicated that the developed sample and separate method was able to detect differences in the release characteristics of the prepared goserelin acetate microspheres,and the in vitro-in vivo correlation of goserelin acetate microspheres was excellent(r>0.98) and had good predictive ability in SD rats.
引文
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[16]Chu DF,Fu XQ,Liu WH,et al.Pharmacokinetics and in vitro and in vivo correlation of huperzine A loaded poly(lactic-coglycolic acid)microspheres in dogs[J].Int J Pharm,2006,325:116-123.
[17]Lai HQ,Hu Y,Li XD.The in vitro dissolution of total composi-tion of the tablet of rhizomes of ligusticum chuanxiong compo-nents and in vitro-in vivo correlation by the method of area under the absorbance-wavelength curve[J].Acta Pharm Sin(药学学报),2015,50:788-792.
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[19]Gao KP,Chen QH.Research of method for accelerated in vitro drug release from poly-ester microsphere injection[J].Chin JNew Drugs(中国新药杂志),2009,18:614-617.
[20]Somayaji MR,Das D,Przekwas A.A new level a type IVIVCfor the rational design of clinical trials toward regulatory approval of generic polymeric long-acting injectables[J].Clin Pharmaco-kinet,2016,55:1179-1190.
[2]D'Souza SS,Deluca PP.Development of a dialysis in vitro release method for biodegradable microspheres[J].AAPSPharmSciTech,2005,6:E323-E328.
[3]Andhariya JV,Shen J,Choi S,et al.Development of in vitroin vivo correlation of parenteral naltrexone loaded polymeric microspheres[J].J Control Release,2017,255:27-35.
[4]Rawat A,Bhardwaj U,Burgess DJ.Comparison of in vitroin vivo release of Risperdal?Consta?microspheres[J].Int JPharm,2012,434:115-121.
[5]Shen J,Burgess DJ.Accelerated in-vitro release testing methods for extended-release parenteral dosage forms[J].J Pharm Phar-macol,2012,64:986-996.
[6]Shen J,Choi S,Qu W,et al.In vitro-in vivo correlation of paren-teral risperidone polymeric microspheres[J].J Control Release,2015,218:2-12.
[7]Burgess DJ,Crommelin DJ,Hussain AS,et al.Assuring quality and performance of sustained and controlled released parenterals[J].Eur J Pharm Sci,2004,21:679-690.
[8]Zhao YQ,Zhou SH,Liu WJ,et al.Discussion of development and validation of dissolution methods for solid oral dosage forms[J].Acta Pharm Sin(药学学报),2018,53:202-209.
[9]FDA:guidance for industry extended release oral dosage forms:development,evaluation,and application of in vitro/in vivo correlation[EB/OL].US:Department of Human Health and Human Services,Food and Drug Administration,1997[2018-08-30].http://www.fda.gov/cder/guidance/index.htm.
[10]Shen J,Burgess DJ.In vitro-in vivo correlation for complex nonoral drug products:where do we stand?[J].J Control Release,2015,219:644-651.
[11]Suarez-Sharp S,Li M,Duan J,et al.Regulatory experience with in vivo-in vitro,correlations(IVIVC)in new drug applications[J].AAPS J,2016,18:1379-1390.
[12]Roudier B,Davit BM,Beyssac E,et al.In vitro-in vivo correla-tion's dissolution limits setting[J].Pharm Res,2014,31:2529-2538.
[13]Zolnik BS,Burgess DJ.Evaluation of in vivo-in vitro release of dexamethasone from PLGA microspheres[J].J Control Release,2008,127:137-145.
[14]Zhang S,Han JB,Leng GY,et al.An LC-MS/MS method for the simultaneous determination of goserelin and testosterone in rat plasma for pharmacokinetic and pharmacodynamic studies[J].JChromatogr B,2014,965:183-189.
[15]D'Souza S,Faraj JA,Giovagnoli S,et al.IVIVC from long acting olanzapine microspheres[J].Int J Biomater,2014,2014:407065.
[16]Chu DF,Fu XQ,Liu WH,et al.Pharmacokinetics and in vitro and in vivo correlation of huperzine A loaded poly(lactic-coglycolic acid)microspheres in dogs[J].Int J Pharm,2006,325:116-123.
[17]Lai HQ,Hu Y,Li XD.The in vitro dissolution of total composi-tion of the tablet of rhizomes of ligusticum chuanxiong compo-nents and in vitro-in vivo correlation by the method of area under the absorbance-wavelength curve[J].Acta Pharm Sin(药学学报),2015,50:788-792.
[18]Trelstar?:depot,clinical pharmacology and biopharmaceutics review for NDA[EB/OL].US:Department of Human Health and Human Services,Food and Drug Administration,2000[2018-08-30].https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20-715_Trelstar_biopharmr_P1.pdf.
[19]Gao KP,Chen QH.Research of method for accelerated in vitro drug release from poly-ester microsphere injection[J].Chin JNew Drugs(中国新药杂志),2009,18:614-617.
[20]Somayaji MR,Das D,Przekwas A.A new level a type IVIVCfor the rational design of clinical trials toward regulatory approval of generic polymeric long-acting injectables[J].Clin Pharmaco-kinet,2016,55:1179-1190.