【作者】 刘卫平；

【导师】 贺建功； 王会娟；

【作者基本信息】 河北医科大学 ， 药剂学， 2008， 硕士

【摘要】 传统的眼用制剂往往由于眼部特殊的生理屏障及保护机制使其利用度极低,存在许多缺陷,如药物流失造成药物损失及经鼻泪管流失的药物增加了局部和全身的各种不良反应,需多次给药造成患者使用不便等。眼部药物传递作为控制释放领域的重要分支一直备受人们的关注。眼睛的有效保护机制与高度敏感性促使人们探索开发安全合理的给药系统,同时又限制了许多药剂学手段的应用,为此类剂型的设计带来了极大的困难。眼用即型凝胶(in Situ Forming Eye Gel)是指以溶液状态给药后立即在用药部位发生相转变,形成非化学交联的半固体制剂。该制剂融合了溶液剂与凝胶剂的优点,克服了其缺点,具有很好的应用和发展前景。本文以马来酸噻吗洛尔为模型药物,制备具有适宜渗透压及pH值的离子敏感型眼用即型凝胶,研讨眼用即型凝胶中药物释放规律,给药后的药效,并对药物的体外释放及给药后的药效同此药的滴眼液及国外上市的同类制剂进行了比较研究。离子敏感型眼用即型凝胶具较好的缓释作用,能够显著提高药物的生物利用度,表现出良好的应用前景。目的:以马来酸噻吗洛尔为模型药物,结冷胶为基质,制备离子敏感型眼用即型凝胶;考察其稳定性;研究其体外释放规律;刺激性;比较此眼用即型凝胶和国外同类产品及滴眼液对眼压的降低作用。方法:在参考文献的基础上,对温度敏感型,离子敏感型,pH敏感型的眼用即型凝胶分别进行了制备,从使用方便及适应性考虑确定制备离子敏感型较好。以体外释放及同国外的同类产品比较对处方进行了筛选,从而确定了离子敏感型眼用即型凝胶的最佳处方。采用自制溶出模型,以人工泪液为释放介质,在规定的时间点内取样,考察药物的体外释放,将释放度数据用Higu- chi模型、零级和一级方程进行拟合,研究药物的释放机理。采用高效液相色谱法(HPLC)对眼用即型凝胶中药物含量进行检测,马来酸噻吗洛尔在(20.0~100.0μg/ml)范围内,其浓度和峰面积有良好的线性关系,相关系数r=0.9998。将最佳处方的眼用即型凝胶分别进行强光照射实验、加速实验、长期留样,考察其稳定性。家兔眼部刺激性实验:将受试物滴入到家兔(10只)一侧眼结膜囊中,另一侧作为空白对照。给药后,在规定时间,对多次给药后眼部的刺激症状进行检查、记录,以Draize眼部刺激试验评分标准评价刺激程度。药效实验:以家兔为实验动物,双眼前房注射0.3%的复方卡波姆溶液制作慢性高眼压模型,将造模成功的眼睛分为四组,分别给予自制眼用即型凝胶(实验组),国外上市的Timolol GFS(对照组),自制滴眼液(对照组),不给药(对照组),比较各组对眼压的降低情况。结果:从使用方便、适应性、体外释放等综合考虑,最终确定眼用即型凝胶的最佳处方为:0.5%主药马来酸噻吗洛尔,0.5%结冷胶,4.5%甘露醇,0.2%Tris,0.003%硫柳汞钠,蒸馏水至足量。在该处方下,制剂的体外释放规律符合一级速率方程,可达12小时缓释。稳定性实验:强光照射实验结果发现,马来酸噻吗洛尔眼用即型凝胶在强光4500±500 lx下,外观无显著变化,含量略有下降。在温度60℃下,外观含量均无显著变化。加速和长期留样结果表明在6个月内,制剂的pH值、含量、外观均无明显变化。家兔眼部刺激性实验:多次给药对兔眼均无明显影响,双眼角膜透明,无混浊,虹膜纹理清晰,无水肿、无分泌物,但结膜略有充血。药效实验:兔眼前房注射0.3%复方卡波姆溶液成功的制作成慢性高眼压模型,16只眼睛中有12只眼睛形成高眼压,高眼压持续时间为21~28天,眼压为23.78~38.80 mmHg。将各组眼压测定结果比较,结果表明马来酸噻吗洛尔眼用即型凝胶给药组与马来酸噻吗洛尔滴眼液组之间无显著性差异,自制马来酸噻吗洛尔眼用即型凝胶每天一次给药与马来酸噻吗洛尔滴眼液每天两次给药可达到相同的降眼压效果;马来酸噻吗洛尔眼用即型凝胶给药组与国外上市的Timolol GFS组之间无显著性差异,自制马来酸噻吗洛尔眼用即型凝胶每天一次给药与Timolol GFS每天一次给药可达到相同的降眼压效果。结论:此制剂点眼后即由溶液状态变为凝胶状态,体外释放达12小时。体内外实验表明马来酸噻吗洛尔眼用即型凝胶同其滴眼液相比延长了药物在眼部的滞留时间,眼部刺激性小,具有明显的缓释作用,提高了药物的生物利用度,减少了给药次数,给药方便,易被患者接受,可作为马来酸噻吗洛尔滴眼液的替代品。更多还原

【Abstract】 The poor bioavailability exhibited by conventional ophthalmic formulation due to the physiological constraints imposed by the protective mechanisms of the eye. The conventional ophthalmic formulation has many drawbacks, such as the drainage of drugs results in the reduction of the drug. Due to tear drainage, most of the administered dose passes via naso-lacrimal duct leads to side-effects and systemic effects. Rapid elimination of the eye drops administered often results in a short duration of the therapeutic effect making a frequent dosing regimen necessary. Frequent dosing regimen cause inconvenience to patients. As one of the important fields of controlled release, ophthalmic drug delivery has always received extensive interests. The sensitivity and protection mechanisms of the eye promote more effective drug delivery systems with better compliancy to be developed, however, the applications of numerous pharmaceutical methods are limited simultaneously, which presents great challenge in designing ophthalmic dosage forms. In situ forming eye gels refer to the polymer solutions can be administrated as liquid, which undergo a phase transition to a non-cross linked semisolid gel upon exposure to physiological environments. It showed great potential in ophthalmic application for its convenient administration combined with the favorable of solution and gels. In this thesis, Timolol maleate was selected as the model drug, and a series of relative researches were carried out, including development of in situ forming eye gels with modulated osmolality and pH, drug release, pharmacodynamics after the in situ forming eye gels applied topically, comparison with eye drops and such agents marketed abroad in pharmacodynamics and drug release.The in situ forming eye gels produced sustained drug release, substantially increased the bioavailability of the drug, and showed great potential in ophthalmic application.Objective: Timolol maleate was selected as the model drug, Gelrite was used as the gelling agent, to develop an ion-activated in situ forming eye gels. The formulation was evaluated for stability, in vitro release behavior, irritant, comparing the intraocular pressure reduction.Methods: On the basis of scientific literatures, temperature- dependent, ion-activity and pH-triggered in situ forming eye gels were prepared respectively. Ion-activity in situ forming eye gels was selected for its convenience and compliance.The formulation screening was performed by comparing in vitro release with such agents abroad, in which the best formulation of ion-activity in situ forming eye gels was determined.The in vitro release of timolol maleate in situ forming eye gels was studied with dissolution model. The release medium was simulated tears and samples were obtained at set time. The release data were analyzed with three models: Higuchi equation, Zero Order equation, First Order equation.The content of timolol maleate in the gel was determined by HPLC. The linear range of timolol maleate is 20.0~100.0μg/ml, r=0.9998. The chemical and physical stability of optimal formula was investigated in strong light test, accelerative test and long-term test.Ocular irritation studies were performed according to Draize technique on ten albino rabbits. Multiple dosing eye stimulation were observed, recorded and evaluated. The in situ forming eye gels was topically administered to the left eyes of ten rabbits and the right eyes have no drug administered as the blank group. Evaluation was done as per Draize technique.Pharmacodynamics: Rabbits were selected as laboratory animals. The ocular hypertension model was induced by injecting 0.3% carbopol into anterior chamber of the two eyes of each rabbit. The successful ocular hypertension model eyes were divided randomly into four groups: in situ forming eye gels, in situ forming eye gels marketed aboard, eye drops and blank were administered respectively. Reduction of intraocular pressure was compared within the four groups.Results: From the convenience, compliance and in vitro release considerations, the best formulation of in situ forming gels was 0.5%timolol maleate, 0.5%Gelrite, 4.5%Mannitol, 0.2%Tris, 0.003% Merthiolate sodium and H2O to enough. In this formulation, the accumulative release profile of the drug in vitro could be distributed by First Order equation and provided sustained release of the drug over a 12-hour period in vitro.Study of stability: Result showed that the formulation was stable to heat,unstable to light. Result of accelerative test and long-term test indicate that pH, content and appearance of in situ forming eye gels have not changed obviously.Ocular irritation studies: Multiple dosing had no markedly influences on tested rabbit eyes, both corneas are transparent without turbidness, and iris clarity, no edema and no discharge, but have conjunctival congestion.Pharmacodynamics: The establishment of stable ocular hypertension model was successful by injection of 0.3% carbopol into anterior chamber of rabbit. Experimental glaucoma occurred in twelve of sixteen eyes and ocular hypertension lasted from 21 to 28 days. The levels of intraocular pressure were 23.78~38.80 mmHg. The formulations demonstrated the same therapeutic efficacy when compared with conventional eyedrops and in situ forming eye gels marketed aboard.Conclusion: The formulation underwent gelation in the cul-de-sac upon instillation as drops into the eye. The gel formed in vitro produced sustained drug release over 12-h period. This new formulation was a viable alternative to conventional eye drops by virtue of its ability to enhance bioavailability through its sustained drug release and longer pre-corneal and reduced frequency of administration resulting in better patient acceptance.更多还原