用于阴道黏膜给药的纳米胶束复合温敏水凝胶的制备及性能评价

Preparation and Evaluation of Nano Micelles Composite Thermosensitive Hydrogels for Vaginal Mucosa Administration

宫颈癌的发生与人乳头瘤病毒(HPV)感染密切相关。治疗HPV感染可有效预防宫颈癌。洛匹那韦(LPV)是Food and Drug Administration(FDA)批准的抗艾滋病病毒的治疗药物,研究发现洛匹那韦具有抗HPV病毒的活性。本工作旨在制备一种负载LPV的纳米胶束复合水凝胶载药系统,探究其通过阴道黏膜局部给药的性能。采用两亲性聚合物维生素E聚乙二醇琥珀酸酯(TPGS)和助渗透剂牛磺脱氧胆酸钠(STDC)自组装制备混合载药胶束(TPGS-STDC/LPV),混合胶束分散在温敏凝胶中形成载药纳米胶束复合温敏水凝胶(NMCH)。对TPGS-STDC/LPV的粒径、ZETA电位、形貌、包封率、载药量和释药等进行了检测,还测试了NMCH的黏膜粘附性、药物释放、透皮渗透和抗病毒活性等。实验结果表明,TPGS-STDC/LPV具有高药物包封率、高载药量,累积释放率达(96.82±2.93)%(pH=4.5,72 h),表现出酸响应释放性能;复合水凝胶具有适宜人体的温敏特性,对阴道上皮黏膜具有优异的粘附性,所制备的NMCH的LPV渗透率最好,为(54.05±2.74)%,约为游离LPV的7.4倍;NMCH具有显著的抗HPV病毒活性。该体系适合用于阴道局部给药。

The occurrence of cervical cancer is closely related to infection with human papillomavirus(HPV).Treatment of HPV infection is effective for preventing the development of cervical cancer.Lopinavir(LPV)is an anti-HIV drug approved by FDA,and it was found that LPV has anti-HPV activity.The aim of this study was to develop a nano-micelles composite hydrogel drug delivery system loaded LPV and explore its perfor-mance for local administration through vaginal mucosa.LPV-loaded mixed micelles(TPGS-STDC/LPV)were prepared by the self-assembly of amphiphilic polymer TPGS,penetrant STDC,and LPV,then were dispersed into the thermosensitive hydrogel to form LPV-loaded nano-micelles composite hydrogel(NMCH).The particle size,zeta potential,morphology,entrapment efficiency,drug loading and drug release of TPGS-STDC/LPV were detected.The mucosal adhesion,drug release,transdermal penetration and antiviral activity of NMCH were also tested.The results showed that TPGS-STDC/LPV exhibited high entrapment efficiency and high drug loading,and the cumulative release of LPV achieved(96.82±2.93)%with pH of 4.5 at 72 h,Showing a good acid-response drug release.NMCH had a human temperature sensitive nature and good adhesion to the vaginal epithelial mucosa,and the skin permeation rate of LPV(54.05±2.74)%was observed about 7.4 times that of free LPV,and NMCH displayed good anti-HPV activities.This drug delivery system could be suitable for topical vaginal administration.