阴道黏膜给药系统的研究进展
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摘要
由于不仅可直达病灶部位而发挥局部治疗作用,还可避免肝脏首过效应而发挥全身治疗作用,阴道黏膜给药在阴道炎、宫颈炎等疾病的治疗和避孕等方面越来越受到国内外学者的关注。本文介绍了阴道的生理特点,探讨了影响药物吸收的因素;以美国食品药品监督管理局(FDA),国家食品药品监督管理局(CFDA)药品数据库和2015年版《中国药典》收载的阴道黏膜给药上市制剂为研究对象,对其剂型、适应症等方面的应用情况进行了梳理和分析;查阅了近年来国内外有关阴道黏膜给药系统的相关文献,对其剂型和体内外评价进行了综述;指出了阴道黏膜给药制剂研究中存在的问题:(1)以西药制剂为主,相关的中药制剂开发较少,(2)剂型以片剂、栓剂、胶囊剂等常规剂型居多,(3)开展体内外评价的研究较少。提出阴道黏膜给药系统今后发展可在多种药物联合给药、高黏附性的辅料、脂质体等新技术、新方法的应用方面进行有益的尝试,以期为阴道黏膜给药系统的应用与完善提供参考。
Because it can not only directly reach the lesion site to play a local therapeutic effect,but also avoid the liver first pass effect and play a systemic therapeutic effect,vaginal mucosal administration has attracted more and more attention from domestic and foreign scholars in the treatment of vaginitis,cervicitis and other diseases.This article introduces the physiological characteristics of the vagina and discusses the factors affecting drug absorption.The vaginal mucosal drug-administered preparations,which are contained in the drug database of U.S.Food and Drug Administration(FDA) and China Food and Drug Administration(CFDA),and listed in the 2015 edition of Chinese Pharmacopoeia,are taken as the research objects.And the application of their dosage forms,indications and other aspects were sorted out and analyzed.The related literature on vaginal mucosal drug delivery systems in recent years was reviewed,and the dosages forms and in vitro and in vivo evaluation were summarized.Some problems in the study of vaginal mucosal drug preparations have been pointed out:(1) the western medicine preparations are widely used,and the related Chinese medicine preparations have been developed less;(2)the majority of dosage forms are tablets,suppositories and other conventional dosage forms;(3)there are few studies on the evaluation of vaginal mucosal preparations in vitro and in vivo.It is suggested that the future development of vaginal mucosal drug delivery system can be a useful attempt in the application of new technologies and methods,such as combination of drugs,high adhesion excipients,liposomes,etc;so as to provide reference for the application and improvement of vaginal mucosal drug delivery system.
Because it can not only directly reach the lesion site to play a local therapeutic effect,but also avoid the liver first pass effect and play a systemic therapeutic effect,vaginal mucosal administration has attracted more and more attention from domestic and foreign scholars in the treatment of vaginitis,cervicitis and other diseases.This article introduces the physiological characteristics of the vagina and discusses the factors affecting drug absorption.The vaginal mucosal drug-administered preparations,which are contained in the drug database of U.S.Food and Drug Administration(FDA) and China Food and Drug Administration(CFDA),and listed in the 2015 edition of Chinese Pharmacopoeia,are taken as the research objects.And the application of their dosage forms,indications and other aspects were sorted out and analyzed.The related literature on vaginal mucosal drug delivery systems in recent years was reviewed,and the dosages forms and in vitro and in vivo evaluation were summarized.Some problems in the study of vaginal mucosal drug preparations have been pointed out:(1) the western medicine preparations are widely used,and the related Chinese medicine preparations have been developed less;(2)the majority of dosage forms are tablets,suppositories and other conventional dosage forms;(3)there are few studies on the evaluation of vaginal mucosal preparations in vitro and in vivo.It is suggested that the future development of vaginal mucosal drug delivery system can be a useful attempt in the application of new technologies and methods,such as combination of drugs,high adhesion excipients,liposomes,etc;so as to provide reference for the application and improvement of vaginal mucosal drug delivery system.
引文
[1]de Araújo Pereira R R,Bruschi M L.Vaginal mucoadhesive drug delivery systems[J].Drug Dev Ind Pharm,2012,38(6):643-652.
[2]Caramella C M,Rossi S,Ferrari F,et al.Mucoadhesive and thermogelling systems for vaginal drug delivery[J].Adv Drug Deliver Rev,2015,92(17):39-52.
[3]Fatakdawala H,Uhland S A.Hydrogenperoxide mediated transvaginal drug delivery[J].Int J Pharm,2011,409(1/2):121-127.
[4]Woolfson A D,Malcolm R K,Gallagher R.Drug delivery by the intravaginal route[J].Crit Rev Ther Drug Carrier Syst,2000,17(5):509-555.
[5]Sj9berg I,Cajander S,Rylander E.Morphometric characteristics of the vaginal epithelium during the menstrual cycle[J].Gynecol Obstet Invest,1988,26(2):136-144.
[6]Gupta S,Gabrani R,Ali J,et al.Exploring novel approaches to vaginal drug delivery[J].Recent Pat Drug Deliv Formul,2011,5(2):82-94.
[7]das Neves J,Bahia M F.Gels as vaginal drug delivery systems[J].Int J Pharm,2006,318(1/2):1-14.
[8]Richardson J L,Illum L.(D)Routes of delivery:case studies:(8)the vaginal route of peptide and protein drug delivery[J].Adv Drug Deliver Rev,1992,8(2/3):341-366.
[9]YANG S D,CHEN Y F,Ahmadie R,et al.Advancements in the field of intravaginal siRNA delivery[J].J Control Release,2013,167(1):29-39.
[10]Bassi P,Kaur G.Innovations in bioadhesive vaginal drug delivery system[J].Expert Opin Ther Pat,2012,22(9):1019-1032.
[11]LI W Z,ZHAO N,ZHOU Y Q,et al.Post-expansile hydrogel foam aerosol of PG-liposomes:a novel delivery system for vaginal drug delivery applications[J].Eur JPharm Sci,2012,47(1):162-169.
[12]White B A,Creedon D J,Nelson K E,et al.The vaginal microbiome in health and disease[J].Trends Endocrinol Metab,2011,22(10):389-393.
[13]Wong T W,Dhanawat M,Rathbone M J.Vaginal drug delivery:strategies and concerns in polymeric nanoparticle development[J].Expert Opin Drug Del,2014,11(9):1419-1434.
[14]Pruski P,Lewis H V,Lee Y S,et al.Assessment of microbiota:host interactions at the vaginal mucosa interface[J].Methods,2018,149:74-84.
[15]Rohan L C,Sassi A B.Vaginal drug delivery systems for HIV prevention[J].AAPS J,2009,11(1):78-87.
[16]Shaikh R,Singh T R R,Garland M J,et al.Mucoadhesive drug delivery systems[J].J Pharm Bioallied Sci,2011,3(1):89-100.
[17]Hussain A,Ahsan F.The vagina as a route for systemic drug delivery[J].J Control Release,2005,103(2):301-313.
[18]Vermani K,Garg S.The scope andpotential of vaginal drug delivery[J].Pharm Sci Technol Today,2000,3(10):359-364.
[19]Yoo J W,Acharya G,Lee C H.In vivo evaluation of vaginal films for mucosal delivery of nitric oxide[J].Biomaterials,2009,30(23/24):3978-3985.
[20]Mahjabeen S,Hatipoglu M K,Chandra V,et al.Optimization of a vaginal suppository formulation to deliver SHet A2 as a novel treatment for cervical dysplasia[J].J Pharm Sci,2018,107(2):638-646.
[21]张瑞,陈锐,桑佳特,等.复方沙棘籽油栓对6种常见阴道乳杆菌增殖影响的体外研究[J].中国性科学,2014,23(11):33-37.
[22]杨慧丽.金刚藤胶囊联合复方沙棘籽油栓治疗慢性宫颈炎的临床研究[J].现代药物与临床,2017,32(3):477-479.
[23]Pallavi B,Gurpreet K.Polymeric films as a promising carrier for bioadhesive drug delivery:development,characterization and optimization[J].Saudi Pharm J,2017,25(1):32-43.
[24]Chatterjee A,Bhowmik B B,Thakur Y S.Formulation,in vitro and in vivo pharmacokinetics of anti-HIV vaginal bioadhesive gel[J].J Young Pharm,2011,3(2):83-89.
[25]Akil A,Agashe H,Dezzutti C S,et al.Formulation and characterization of polymeric films containing combinations of antiretrovirals(ARVs)for HIVprevention[J].Pharm Res,2015,32(2):458-468.
[26]Ren9ber S,Karavana S Y,爦enyig(it Z A,et al.Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole:formulation,preparation,and in vitro/in vivo evaluation[J].Pharm Dev Technol,2017,22(4):551-561.
[27]都君君.黄体酮不同给药途径对子宫内膜孕激素水平的影响[J].北方药学,2018,15(4):160-161.
[28]汪平.桂芍四妙汤联合苦参凝胶治疗霉菌性阴道炎疗效观察[J].中医学报,2018,33(9):1790-1793.
[29]Hassan A S,Soliman G M,Ali M F,et al.Mucoadhesive tablets for the vaginal delivery of progesterone:in vitro evaluation and pharmacokinetics/pharmacodynamics in female rabbits[J].Drug Dev Ind Pharm,2018,44(2):224-232.
[30]贾梦.妇必舒阴道泡腾片联合氯喹那多普罗雌烯阴道片治疗细菌性阴道病(湿热型)的临床研究[D].太原:山西中医学院,2016.
[31]Mehnert W,Mder K.Solid lipid nanoparticles:production,characterization and applications[J].Adv Drug Deliver Rev,2012,64(2/3):165-196.
[32]da Silva P B,Ramos M A,Bonifácio B V,et al.Nanotechnological strategies for vaginal administration of drugs-a review[J].J Biomed Nanotechnol,2014,10(9):2218-2243.
[33]van der Straten A,Stadler J,Montgomery E,et al.Women's experiences with oral and vaginal pre-exposure prophylaxis:the VOICE-C qualitative study in johannesburg,South Africa[J].PLo S One,2014,9(2):e89118.
[34]Krogstad E A,Ramanathan R,Nhan C,et al.Nanoparticle-releasing nanofiber composites for enhanced in vivo vaginal retention[J].Biomaterials,2017,144:1-16.
[35]Albertini B,Passerini N,Sabatino M D,et al.Polymerlipid based mucoadhesive microspheres prepared by spray-congealing for the vaginal delivery of econazole nitrate[J].Eur J Pharm Sci,2009,36(4/5):591-601.
[36]Maestrelli F,Jug M,Cirri M,et al.Characterization and microbiological evaluation of chitosan-alginate microspheres for cefixime vaginal administration[J].Carbohyd Polym,2018,192:176-183.
[37]Allen T M,Cullis P R.Liposomal drug delivery systems:from concept to clinical applications[J].Adv Drug Deliver Rev,2013,65(1):36-48.
[38]WANG L,Sassi A B,Patton D,et al.Development of a liposome microbicide formulation for vaginal delivery of octylglycerol for HIV prevention[J].Drug Dev Ind Pharm,2012,38(8):995-1007.
[39]董平.鬼臼毒素脂质体壳聚糖涂膜剂的制备及动物实验研究[D].广州:中国人民解放军第一军医大学,2003.
[40]段晓颖,高卫芳,闫艳仓.中药生物黏附制剂研究进展[J].中国实验方剂学杂志,2010,16(12):209-211.
[41]Alves M C,de Almeida P A,Polonini H C,et al.Taxifolin:evaluation through ex vivo permeations on human skin and porcine vaginal mucosa[J].Curr Drug Deliv,2018,15(8):1123-1134.
[42]Bachhav Y G,Patravale V B.Microemulsion based vaginal gel of fluconazole:formulation,in vitro and in vivo evaluation[J].Int J Pharm,2009,365(1/2):175-179.
[2]Caramella C M,Rossi S,Ferrari F,et al.Mucoadhesive and thermogelling systems for vaginal drug delivery[J].Adv Drug Deliver Rev,2015,92(17):39-52.
[3]Fatakdawala H,Uhland S A.Hydrogenperoxide mediated transvaginal drug delivery[J].Int J Pharm,2011,409(1/2):121-127.
[4]Woolfson A D,Malcolm R K,Gallagher R.Drug delivery by the intravaginal route[J].Crit Rev Ther Drug Carrier Syst,2000,17(5):509-555.
[5]Sj9berg I,Cajander S,Rylander E.Morphometric characteristics of the vaginal epithelium during the menstrual cycle[J].Gynecol Obstet Invest,1988,26(2):136-144.
[6]Gupta S,Gabrani R,Ali J,et al.Exploring novel approaches to vaginal drug delivery[J].Recent Pat Drug Deliv Formul,2011,5(2):82-94.
[7]das Neves J,Bahia M F.Gels as vaginal drug delivery systems[J].Int J Pharm,2006,318(1/2):1-14.
[8]Richardson J L,Illum L.(D)Routes of delivery:case studies:(8)the vaginal route of peptide and protein drug delivery[J].Adv Drug Deliver Rev,1992,8(2/3):341-366.
[9]YANG S D,CHEN Y F,Ahmadie R,et al.Advancements in the field of intravaginal siRNA delivery[J].J Control Release,2013,167(1):29-39.
[10]Bassi P,Kaur G.Innovations in bioadhesive vaginal drug delivery system[J].Expert Opin Ther Pat,2012,22(9):1019-1032.
[11]LI W Z,ZHAO N,ZHOU Y Q,et al.Post-expansile hydrogel foam aerosol of PG-liposomes:a novel delivery system for vaginal drug delivery applications[J].Eur JPharm Sci,2012,47(1):162-169.
[12]White B A,Creedon D J,Nelson K E,et al.The vaginal microbiome in health and disease[J].Trends Endocrinol Metab,2011,22(10):389-393.
[13]Wong T W,Dhanawat M,Rathbone M J.Vaginal drug delivery:strategies and concerns in polymeric nanoparticle development[J].Expert Opin Drug Del,2014,11(9):1419-1434.
[14]Pruski P,Lewis H V,Lee Y S,et al.Assessment of microbiota:host interactions at the vaginal mucosa interface[J].Methods,2018,149:74-84.
[15]Rohan L C,Sassi A B.Vaginal drug delivery systems for HIV prevention[J].AAPS J,2009,11(1):78-87.
[16]Shaikh R,Singh T R R,Garland M J,et al.Mucoadhesive drug delivery systems[J].J Pharm Bioallied Sci,2011,3(1):89-100.
[17]Hussain A,Ahsan F.The vagina as a route for systemic drug delivery[J].J Control Release,2005,103(2):301-313.
[18]Vermani K,Garg S.The scope andpotential of vaginal drug delivery[J].Pharm Sci Technol Today,2000,3(10):359-364.
[19]Yoo J W,Acharya G,Lee C H.In vivo evaluation of vaginal films for mucosal delivery of nitric oxide[J].Biomaterials,2009,30(23/24):3978-3985.
[20]Mahjabeen S,Hatipoglu M K,Chandra V,et al.Optimization of a vaginal suppository formulation to deliver SHet A2 as a novel treatment for cervical dysplasia[J].J Pharm Sci,2018,107(2):638-646.
[21]张瑞,陈锐,桑佳特,等.复方沙棘籽油栓对6种常见阴道乳杆菌增殖影响的体外研究[J].中国性科学,2014,23(11):33-37.
[22]杨慧丽.金刚藤胶囊联合复方沙棘籽油栓治疗慢性宫颈炎的临床研究[J].现代药物与临床,2017,32(3):477-479.
[23]Pallavi B,Gurpreet K.Polymeric films as a promising carrier for bioadhesive drug delivery:development,characterization and optimization[J].Saudi Pharm J,2017,25(1):32-43.
[24]Chatterjee A,Bhowmik B B,Thakur Y S.Formulation,in vitro and in vivo pharmacokinetics of anti-HIV vaginal bioadhesive gel[J].J Young Pharm,2011,3(2):83-89.
[25]Akil A,Agashe H,Dezzutti C S,et al.Formulation and characterization of polymeric films containing combinations of antiretrovirals(ARVs)for HIVprevention[J].Pharm Res,2015,32(2):458-468.
[26]Ren9ber S,Karavana S Y,爦enyig(it Z A,et al.Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole:formulation,preparation,and in vitro/in vivo evaluation[J].Pharm Dev Technol,2017,22(4):551-561.
[27]都君君.黄体酮不同给药途径对子宫内膜孕激素水平的影响[J].北方药学,2018,15(4):160-161.
[28]汪平.桂芍四妙汤联合苦参凝胶治疗霉菌性阴道炎疗效观察[J].中医学报,2018,33(9):1790-1793.
[29]Hassan A S,Soliman G M,Ali M F,et al.Mucoadhesive tablets for the vaginal delivery of progesterone:in vitro evaluation and pharmacokinetics/pharmacodynamics in female rabbits[J].Drug Dev Ind Pharm,2018,44(2):224-232.
[30]贾梦.妇必舒阴道泡腾片联合氯喹那多普罗雌烯阴道片治疗细菌性阴道病(湿热型)的临床研究[D].太原:山西中医学院,2016.
[31]Mehnert W,Mder K.Solid lipid nanoparticles:production,characterization and applications[J].Adv Drug Deliver Rev,2012,64(2/3):165-196.
[32]da Silva P B,Ramos M A,Bonifácio B V,et al.Nanotechnological strategies for vaginal administration of drugs-a review[J].J Biomed Nanotechnol,2014,10(9):2218-2243.
[33]van der Straten A,Stadler J,Montgomery E,et al.Women's experiences with oral and vaginal pre-exposure prophylaxis:the VOICE-C qualitative study in johannesburg,South Africa[J].PLo S One,2014,9(2):e89118.
[34]Krogstad E A,Ramanathan R,Nhan C,et al.Nanoparticle-releasing nanofiber composites for enhanced in vivo vaginal retention[J].Biomaterials,2017,144:1-16.
[35]Albertini B,Passerini N,Sabatino M D,et al.Polymerlipid based mucoadhesive microspheres prepared by spray-congealing for the vaginal delivery of econazole nitrate[J].Eur J Pharm Sci,2009,36(4/5):591-601.
[36]Maestrelli F,Jug M,Cirri M,et al.Characterization and microbiological evaluation of chitosan-alginate microspheres for cefixime vaginal administration[J].Carbohyd Polym,2018,192:176-183.
[37]Allen T M,Cullis P R.Liposomal drug delivery systems:from concept to clinical applications[J].Adv Drug Deliver Rev,2013,65(1):36-48.
[38]WANG L,Sassi A B,Patton D,et al.Development of a liposome microbicide formulation for vaginal delivery of octylglycerol for HIV prevention[J].Drug Dev Ind Pharm,2012,38(8):995-1007.
[39]董平.鬼臼毒素脂质体壳聚糖涂膜剂的制备及动物实验研究[D].广州:中国人民解放军第一军医大学,2003.
[40]段晓颖,高卫芳,闫艳仓.中药生物黏附制剂研究进展[J].中国实验方剂学杂志,2010,16(12):209-211.
[41]Alves M C,de Almeida P A,Polonini H C,et al.Taxifolin:evaluation through ex vivo permeations on human skin and porcine vaginal mucosa[J].Curr Drug Deliv,2018,15(8):1123-1134.
[42]Bachhav Y G,Patravale V B.Microemulsion based vaginal gel of fluconazole:formulation,in vitro and in vivo evaluation[J].Int J Pharm,2009,365(1/2):175-179.