他克莫司眼用微乳-原位凝胶的研究
发布时间：2019-01-04 07:11
【摘要】：他克莫司为23元大环内酯类抗生素,呈强脂溶性。其在治疗自身免疫性眼病、眼过敏性疾患及角膜移植术后的免疫排斥反应中发挥着重要作用。上市和重点研究的他克莫司眼用剂包括混悬滴眼液,乳剂,胶粒等,普遍存在生物利用度低和用药顺应性差的缺点,为了改善现有他克莫司眼用制剂的不足,本文设计的总体思路是利用制剂学技术,增加脂溶型他克莫司在眼部的作用时间和眼内药物生物利用度。目的:制备他克莫司微乳,继而开发他克莫司眼用微乳-原位凝胶给药系统;并对他克莫司微乳剂和微乳-原位凝胶剂进行质量和安全性评价。方法:(1)他克莫司微乳的制备。采用溶解度试验与滴定法绘制的伪三元相图研究各处方成分对微乳形成的影响;以粒径,PDI和载药量为评价指标,采用星点设计-效应面法优化微乳处方;通过单因素实验考察制备工艺对微乳的影响;建立高效液相色谱法测定微乳的载药量,并考察其理化性质。(2)他克莫司微乳-原位凝胶的制备。以PE28和PE8为温敏型凝胶基质,以原位凝胶经模拟泪液稀释前后的胶凝温度为复合指标,通过单因素和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;对其外观,粒径,形态,胶凝温度,流变性质及体外溶蚀和释放特性等进行考察。(3)以他克莫司混悬型滴眼液为对照,考察他克莫司的微乳剂和微乳-原位凝胶剂的在体滞留时间;以同体自身对照法为给药模型,以生理盐水为对照,根据Draize评分原则和标准,评价所制眼用微乳和微乳凝胶剂的单次和多次给药刺激性。结果:(1)载药量为0.1%的他克莫司微乳是以13%Kolliphor EL为乳化剂,5%Labrasol为助乳化剂,2%Labrafil M1944CS为油相,以双蒸水为水相形成的O/W型微乳;乳滴在微乳中呈椭球形,其平均pH值为7.57,渗透压为305 mOsm·Kg-1,平均粒径为15.55 nm。(2)最佳微乳-原位凝胶处方中凝胶基质的组成为14%PE28和2%PE8;其眼内外的胶凝温度分别为27.1℃、33.9℃,粒径为18.70 nm,乳滴在微乳-原位凝胶中呈规整的椭圆形态均匀分布。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。(3)他克莫司的微乳和微乳-原位凝胶剂兔眼的滞留时间分别为15.33 min和22.67 min,而其混悬滴眼液的滞留时间为15.67min;他克莫司混悬滴眼液,微乳液和微乳-原位凝胶液的刺激性结果显示无刺激性。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,其制备工艺简单,质量可控,稳定性较好,刺激性较小。与他克莫司的混悬滴眼液相比,微乳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]:Tacrolimus is a 23-dollar macrolide antibiotic with high fat solubility. It plays an important role in the treatment of autoimmune ophthalmopathy, ocular hypersensitivity and immune rejection after keratoplasty. Topical tacrolimus eye drops, emulsions, colloids, and so on, are commonly found to have the disadvantages of low bioavailability and poor drug compliance, in order to improve the shortcomings of existing tacrolimus ophthalmic preparations. The general idea of this design is to increase the time of action and the bioavailability of intraocular drugs in the eye with lipolytic tacrolimus. Aim: to prepare tacrolimus microemulsion and develop tacrolimus ophthalmic microemulsion-in-situ gel delivery system and evaluate the quality and safety of tacrolimus microemulsion and microemulsion in situ gel. Methods: (1) preparation of tacrolimus microemulsion. The effect of each prescription component on the formation of microemulsion was studied by using pseudo-ternary phase diagram drawn by solubility test and titration, and the formulation of microemulsion was optimized by star design-effect surface method with particle size, PDI and drug loading as evaluation index. The effect of preparation process on microemulsion was investigated by single factor experiment. HPLC was established for the determination of drug loading and physical and chemical properties of microemulsion. (2) preparation of tacrolimus microemulsion-in-situ gel. Using PE28 and PE8 as temperature-sensitive gel matrix, the gelation temperature of in-situ gel before and after simulated tear dilution was taken as the composite index. The best formulation was screened by single factor and orthogonal design test, and the thermo-sensitive gel was prepared from tacrolimus microemulsion. The appearance, particle size, morphology, gelation temperature, rheological properties, dissolution and release characteristics in vitro were investigated. (3) Tacrolimus suspension eye drops were used as control. The in vivo retention time of tacrolimus microemulsion and microemulsion-in-situ gel was investigated. The single and multiple administration stimuli of microemulsion and microemulsion gel were evaluated according to the principle and standard of Draize score with the same body self-control method and physiological saline as control. Results: (1) the 0.1% drug loading tacrolimus microemulsion consisted of 13%Kolliphor EL as emulsifier, 5%Labrasol as co-emulsifier, 2%Labrafil M1944CS as oil phase and double distilled water as water phase. The average pH value and osmotic pressure of emulsion droplets in microemulsion were 7.57 and 15.55 nm. (2) respectively. The composition of gel matrix was 14%PE28 and 2PE8 in the formulation of microemulsion-in-situ gel. The gel temperatures were 27.1 鈩，
本文编号：2399954
[Abstract]:Tacrolimus is a 23-dollar macrolide antibiotic with high fat solubility. It plays an important role in the treatment of autoimmune ophthalmopathy, ocular hypersensitivity and immune rejection after keratoplasty. Topical tacrolimus eye drops, emulsions, colloids, and so on, are commonly found to have the disadvantages of low bioavailability and poor drug compliance, in order to improve the shortcomings of existing tacrolimus ophthalmic preparations. The general idea of this design is to increase the time of action and the bioavailability of intraocular drugs in the eye with lipolytic tacrolimus. Aim: to prepare tacrolimus microemulsion and develop tacrolimus ophthalmic microemulsion-in-situ gel delivery system and evaluate the quality and safety of tacrolimus microemulsion and microemulsion in situ gel. Methods: (1) preparation of tacrolimus microemulsion. The effect of each prescription component on the formation of microemulsion was studied by using pseudo-ternary phase diagram drawn by solubility test and titration, and the formulation of microemulsion was optimized by star design-effect surface method with particle size, PDI and drug loading as evaluation index. The effect of preparation process on microemulsion was investigated by single factor experiment. HPLC was established for the determination of drug loading and physical and chemical properties of microemulsion. (2) preparation of tacrolimus microemulsion-in-situ gel. Using PE28 and PE8 as temperature-sensitive gel matrix, the gelation temperature of in-situ gel before and after simulated tear dilution was taken as the composite index. The best formulation was screened by single factor and orthogonal design test, and the thermo-sensitive gel was prepared from tacrolimus microemulsion. The appearance, particle size, morphology, gelation temperature, rheological properties, dissolution and release characteristics in vitro were investigated. (3) Tacrolimus suspension eye drops were used as control. The in vivo retention time of tacrolimus microemulsion and microemulsion-in-situ gel was investigated. The single and multiple administration stimuli of microemulsion and microemulsion gel were evaluated according to the principle and standard of Draize score with the same body self-control method and physiological saline as control. Results: (1) the 0.1% drug loading tacrolimus microemulsion consisted of 13%Kolliphor EL as emulsifier, 5%Labrasol as co-emulsifier, 2%Labrafil M1944CS as oil phase and double distilled water as water phase. The average pH value and osmotic pressure of emulsion droplets in microemulsion were 7.57 and 15.55 nm. (2) respectively. The composition of gel matrix was 14%PE28 and 2PE8 in the formulation of microemulsion-in-situ gel. The gel temperatures were 27.1 鈩，
本文编号：2399954
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