【摘要】：他克莫司為23元大環(huán)內(nèi)酯類抗生素,呈強脂溶性。其在治療自身免疫性眼病、眼過敏性疾患及角膜移植術(shù)后的免疫排斥反應(yīng)中發(fā)揮著重要作用。上市和重點研究的他克莫司眼用劑包括混懸滴眼液,乳劑,膠粒等,普遍存在生物利用度低和用藥順應(yīng)性差的缺點,為了改善現(xiàn)有他克莫司眼用制劑的不足,本文設(shè)計的總體思路是利用制劑學(xué)技術(shù),增加脂溶型他克莫司在眼部的作用時間和眼內(nèi)藥物生物利用度。目的:制備他克莫司微乳,繼而開發(fā)他克莫司眼用微乳-原位凝膠給藥系統(tǒng);并對他克莫司微乳劑和微乳-原位凝膠劑進(jìn)行質(zhì)量和安全性評價。方法:(1)他克莫司微乳的制備。采用溶解度試驗與滴定法繪制的偽三元相圖研究各處方成分對微乳形成的影響;以粒徑,PDI和載藥量為評價指標(biāo),采用星點設(shè)計-效應(yīng)面法優(yōu)化微乳處方;通過單因素實驗考察制備工藝對微乳的影響;建立高效液相色譜法測定微乳的載藥量,并考察其理化性質(zhì)。(2)他克莫司微乳-原位凝膠的制備。以PE28和PE8為溫敏型凝膠基質(zhì),以原位凝膠經(jīng)模擬淚液稀釋前后的膠凝溫度為復(fù)合指標(biāo),通過單因素和正交設(shè)計試驗篩選最佳處方,將他克莫司微乳制備成溫敏型凝膠劑;對其外觀,粒徑,形態(tài),膠凝溫度,流變性質(zhì)及體外溶蝕和釋放特性等進(jìn)行考察。(3)以他克莫司混懸型滴眼液為對照,考察他克莫司的微乳劑和微乳-原位凝膠劑的在體滯留時間;以同體自身對照法為給藥模型,以生理鹽水為對照,根據(jù)Draize評分原則和標(biāo)準(zhǔn),評價所制眼用微乳和微乳凝膠劑的單次和多次給藥刺激性。結(jié)果:(1)載藥量為0.1%的他克莫司微乳是以13%Kolliphor EL為乳化劑,5%Labrasol為助乳化劑,2%Labrafil M1944CS為油相,以雙蒸水為水相形成的O/W型微乳;乳滴在微乳中呈橢球形,其平均pH值為7.57,滲透壓為305 mOsm·Kg-1,平均粒徑為15.55 nm。(2)最佳微乳-原位凝膠處方中凝膠基質(zhì)的組成為14%PE28和2%PE8;其眼內(nèi)外的膠凝溫度分別為27.1℃、33.9℃,粒徑為18.70 nm,乳滴在微乳-原位凝膠中呈規(guī)整的橢圓形態(tài)均勻分布。體外溶蝕及釋放試驗表明,他克莫司微乳-原位凝膠符合零級動力學(xué)特性。(3)他克莫司的微乳和微乳-原位凝膠劑兔眼的滯留時間分別為15.33 min和22.67 min,而其混懸滴眼液的滯留時間為15.67min;他克莫司混懸滴眼液,微乳液和微乳-原位凝膠液的刺激性結(jié)果顯示無刺激性。結(jié)論:在微乳處方基礎(chǔ)上制備他克莫司溫度敏感型原位凝膠可行,其制備工藝簡單,質(zhì)量可控,穩(wěn)定性較好,刺激性較小。與他克莫司的混懸滴眼液相比,微乳凝膠可平穩(wěn)緩慢釋藥,有望成為疏水性藥物的一種優(yōu)良眼用給藥系統(tǒng)。
[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，

本文編號：2399954