醋甲唑胺脂质体滴眼剂的研究

【作者】 陈睿；

【导师】 徐群为；

【作者基本信息】 南京医科大学 ， 药理学， 2008， 硕士

【摘要】 乙酰唑胺、醋甲唑胺、双氯非那胺等碳酸酐酶抑制剂自1954年起就被应用于青光眼的降眼压治疗。虽然口服碳酸酐酶抑制剂可以降低眼内压,但是全身性副作用限制了其应用,因此开展了醋甲唑胺脂质体滴眼液的研究。首先建立了醋甲唑胺的紫外测定方法,经方法学验证,该法用于醋甲唑胺体外含量的测定准确可靠;然后用葡聚糖凝胶柱对醋甲唑胺及其脂质体进行洗脱;绘制洗脱曲线并进行洗脱行为的考察,建立了准确可靠的醋甲唑胺脂质体包封率的测定方法,为处方工艺的研究奠定了基础。通过对常用脂质体制备工艺的筛选,确定采用醋酸钙梯度法对醋甲唑胺脂质体进行研制,并在醋酸钙梯度法基本工艺的基础上进行了醋酸钙浓度、磷脂/胆固醇比例、药脂比和温度等影响因素考察,得到了包封率在80%以上的醋甲唑胺脂质体。通过对搅拌速度与粒径关系的研究,得到了具有优良粒径的脂质体,其平均粒径为182.2±31.1nm。建立了醋甲唑胺脂质体体外释放行为的测定方法,对脂质体的释放行为进行考察。在醋甲唑胺脂质体药效学研究中发现,醋甲唑胺脂质体在给药后4h,达到最大降眼压效果为-10.18±4.96mmHg,且降眼压时间持续8h以上。通过1%派立明滴眼液与醋甲唑胺脂质体滴眼液的药效学研究发现,醋甲唑胺脂质体滴眼液有更强的降眼压效果且持续时间更长。房水药物HPLC分析结果证明了本实验研制的醋甲唑胺脂质体滴眼液能有效进入眼內,具有良好的应用前景。更多还原

【Abstract】 Carbonic anhydrase inhibitors (CAIs) were first used to lower intraocular pressure (IOP) in glaucoma in 1954, with the introduction of acetazolamide, methazolamide and diclofenamide were subsequently. Although IOP can be controlled by oral administration of CAIs, systemic side effects severely limit this mode of therapy. Methazolamide liposome eye drops were studied to solve this problem.The UV analysis method of methazolamide was studied and proved to be accurate and reliable for quantitative analysis in vitro through methodology investigation. The encapsulation efficiency (EE%) determination method of methazolamide liposome was created by sephadex column chromatography. It was proved to be accurate and reliable for the detection of encapsulation efficiency of methazolamide liposome through the plot of elution curve and the investigation of elution characteristic.Calcium acetate gradient method was taken as the basic manufacture of methazolamide liposome by comparative selection of different liposome preparationmethod. Proceeded with the calcium acetate gradient method, the concentration of calcium acetate, the phosphatidylcholine cholesterol ratio, drug lipid ratio and temperature were conducted for influential factor investigation, after that the methazolamide liposome with highest EE% (>80%) was obtained. Furthermore, by studying the correlation between stirring rate and particle size, the methazolamide liposome with finest particle size was gained, with mean PCS particle size of 182.2±31.1 nm.In order to realize the releasing behavior of methazolamide liposome, its determination method in vitro was created. Effect of topically administered methazolamide liposomes on the change in IOP in NZW rabbits revealed the maximum IOP reduction reached a value of -10.18±4.96mmHg after 4 hours of topical administration methazolamide liposomes and the IOP reduction was sustained during the time of the experiment (8 hours). Comparing the results of both 1% brinzolamide and methazolamide liposomal formulations, it is obvious that methazolamide liposomes produced a more significant lowering in IOP compared with 1% brinzolamide and showed a more sustained action of IOP reduction. Results of HPLC analysis indicated that the methazolamide liposome eye drops can transfer the corneal barrier and penetrate into the anterior humor. The results demonstrated that this preparation was superior to topical administration.更多还原