目的 研究他克莫司眼用微乳-原位凝胶剂,并对其质量和安全性进行评价。方法 以泊洛沙姆407(F127)和泊洛沙姆188(F68)为温敏型凝胶基质,以原位凝胶溶液经模拟泪液(STF)稀释前后的胶凝温度(Tg)为复合指标,通过正交设计试验筛选最佳处方,将他克莫司微乳制备成温敏型凝胶剂。并对该微乳-原位凝胶的外观,粒径,形态,胶凝温度,流变性质、体外释放特性等进行考察。同时,以他克莫司的混悬型滴眼液为对照,考察微乳-原位凝胶剂的在体滞留时间;以生理盐水为对照,根据Draize评分原则和标准,评价所制眼用制剂的单次与多次给药刺激性。结果 含1 mg·mL-1他克莫司的最佳微乳-原位凝胶处方中凝胶基质的组成为140 mg·mL-1 F127和20 mg·mL-1 F68;其眼内外的平均胶凝温度分别为27.1、33.9 ℃,平均粒径为18.70 nm,乳滴在微乳及微乳-原位凝胶中均呈规整椭圆形态均匀分布。体外溶蚀及释放试验表明,他克莫司微乳-原位凝胶符合零级动力学特性。他克莫司微乳-原位凝胶剂的兔眼滞留时间为22.67 min,比其混悬滴眼液和微乳的滞留时间长并具有显著性差异;其刺激性评价结果显示无刺激性。结论 在微乳处方基础上制备他克莫司温度敏感型原位凝胶可行,其制备工艺简便可控,具有良好的温敏性和铺展性,刺激性较小。与他克莫司的混悬滴眼液相比,微乳-原位凝胶可平稳缓慢释药,有望成为疏水性药物的一种优良眼用给药系统。
Abstract
OBJECTIVE To develop the formulation of in-situ ophthalmic microemulsion gel loaded with tacrolimus and evaluate its quality and safety. METHODS The formulation to make tacrolimus microemulsion into thermosensitive in-situ ophthalmic gel was optimized by orthogonal experiment design using poloxamer 407(F127)and poloxamer 188(F68)as the thermosensitive gel matrix and the gelatinization temperature(Tg) of in-situ gel before and after diluting in simulated tear fluid as compounding effect indicator. The appearance, particle size, gelation temperature, morphological characteristics, rheological properties and dissolution behavior of the optimal in situ microemulsion gel were determined. Simultaneously, the residence time of tacrolimus microemulsion and its in-situ gel were examined using tacrolimus suspension eye drops as control. Irritation of these ophthalmic preparations after single and multiple dose administrations were evaluated against normal saline as control by intra-individual self-control method with Draize test criteria. RESULTS The gel matrix of the optimal in-situ microemulsion gel containing 1 mg·mL-1 tacrolimus was composed of 140 mg·mL-1 F127 and 20 mg·mL-1 F68. The oval-shaped emulsion droplets homogenously dispersed in the in-situ emulsion gel with average particle size of 18.70 nm. Its gelation temperatures inside and outside eyes were 27.1 and 33.9 ℃, respectively. In vitro dissolution and release tests showed that its releasing characteristics followed zero-order kinetics. The average residence time of tacrolimus in-situ microemulsion gel in rabbit eyes was 22.67 min,significantly longer than those of the suspension and microemulsion of tacrolimus. No irritation was observed for tacrolimus suspension drops, microemulsion and its in-situ gel. CONCLUSION It would be feasible to prepare tacrolimus temperature-sensitive in-situ gel from microemulsion with a simple preparation process. The gel was of controllable quality, good stability,good temperature sensitivity,and good spreadability, with low eye irritation. Compared with suspension eye drops, in-situ microemulsion gel can be expected to be a superior ophthalmic drug delivery system for hydrophobic drugs due to its steady and sustained release characteristics.
关键词
他克莫司 /
微乳-原位凝胶 /
眼用制剂 /
体外释放 /
刺激性
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Key words
tacrolimus /
in-situ microemulsion gel /
ophthalmic preparation /
in vitro release /
irritation
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中图分类号：
R978
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参考文献
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脚注
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基金
四川省科技创新苗子工程资助培育项目资助(2016053)
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