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目的制备Nifeviroc微乳热敏原位凝胶(NFVR/ME-TISG),并对其体内外毒性进行评价。方法纳米粒度仪检测微乳的平均粒径和PDI,流变仪检测微乳凝胶在不同温度(10~45℃)下复数粘度的变化。四甲基偶氮唑盐(MTT)法检测不同浓度NFVR/ME-TISG和Nifeviroc热敏原位凝胶(NFVR-TISG)对阴道上皮细胞系VK2/E6E7的细胞活性影响。16只SD大鼠分成NFVR/ME-TISG和NFVR-TISG组,分别给药0.2 ml(次/d,10 d),第11天麻醉处死,取阴道组织进行苏木素-伊红(HE)染色,根据WHO公认的Eckstein评价标准,对阴道粘膜进行评分。结果在4℃条件下,12个月内微乳的平均粒径和PDI无明显变化;从10℃升至29℃时,NFVR/ME-TISG复数粘度随温度指数性升高,发生相转变;MTT结果显示NFVR/ME-TISG对VK2/E6E7细胞活性影响低于NFVR-TISG;大鼠阴道组织病理结果显示NFVR/METISG组和NFVR-TISG组阴道组织评分小于2,差异无统计学意义(P=0.118)。结论微乳体系稳定,制成的凝胶具有热敏性,低温下为牛顿流体,高温下呈现剪切变稀的假塑流体特征,微乳凝胶制剂与普通凝胶制剂相比对阴道上皮细胞具有一定的保护作用,阴道刺激性评分在临床可接受范围。
Objective To prepare Nifeviroc microemulsion thermosensitive in situ gels (NFVR / ME-TISG) and to evaluate its in vitro and in vivo toxicity. Methods The average particle diameter and PDI of microemulsion were measured by nano-particle size analyzer. The viscosities of microemulsion gel at different temperatures (10-45 ℃) were measured by rheometer. The effect of NFVR / ME-TISG and Nifeviroc thermal in situ gels (NFVR-TISG) on the cell viability of vaginal epithelial cell line VK2 / E6E7 was detected by MTT assay. Sixteen SD rats were divided into two groups: NFVR / ME-TISG and NFVR-TISG group. The rats were administered 0.2 ml once daily for 10 days. The rats were sacrificed on the 11th day. The vaginal tissues were harvested for hematoxylin and eosin (HE) Vaginal mucosa was scored according to WHO’s accepted Eckstein criteria. Results At 4 ℃, the average particle size and PDI of microemulsion did not change significantly within 12 months. The complex viscosity of NFVR / ME-TISG increased exponentially with phase transition from 10 ℃ to 29 ℃. MTT results showed that NFVR / ME-TISG had less effect on VK2 / E6E7 cell activity than NFVR-TISG; vaginal histopathology showed that the score of vaginal tissue in NFVR / METISG group and NFVR-TISG group was less than 2 = 0.118). Conclusions The microemulsion system is stable, the prepared gel is heat-sensitive, Newtonian fluid at low temperature, showing pseudoplastic fluid characteristics of shear thinning at high temperature. The microemulsion gel preparation has the following advantages over vaginal epithelial cells A certain degree of protection, vaginal irritation score in the clinically acceptable range.