Ammar H O, Salama H A, Ghorab M, El-Nahhas S A, Elmotasem H
Department of Pharmaceutical Technology, National Research Centre, Cairo, Egypt.
Curr Drug Deliv. 2006 Jul;3(3):333-41. doi: 10.2174/156720106777731037.
Glipizide is one of the most commonly prescribed drugs for treatment of type 2 diabetes. Oral therapy with glipizide comprises problems of bioavailability fluctuations and may be associated with severe hypoglycaemia and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glipizide. For this purpose, inclusion complexes of the drug in beta-cyclodextrin (beta-CyD), dimethyl-beta-cyclodextrin (DM-beta-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CyD) were prepared. Several percutaneous formulations of the drug and the prepared complexes in different bases (o/w emulsion, polyethylene glycol, carboxymethyl cellulose and Carbopol) were developed. Release studies revealed an improved release of the drug from formulations containing glipizide-CyD complexes. Ex vivo permeation studies through full thickness rat abdominal skin were conducted, whereby the effect of several conventional penetration enhancers (propylene glycol [PG], oleic acid, urea, dimethyl sulfoxide, menthol, limonene and cineole) was monitored. Highest flux was obtained from ointments prepared with Carbopol gel base containing a combination of PG and oleic acid as well as ointments prepared in the same base utilizing glipizide-DM-beta-CyD complex and urea. In vivo studies on diabetic male Wistar rats revealed a marked therapeutic efficacy sustained for about 48 hours. In this respect, two formulations showed best biological performance. In the first formulation, the drug was incorporated in Carbopol gel base in the presence of 20% PG together with 15% oleic acid. The second was prepared by incorporating glipizide-DM-beta-CyD complex in Carbopol gel base in presence of 15% urea. The glucose tolerance test showed suppression of hyperglycaemia induced in glucose-loaded rats. The above-mentioned results might shed a strong beam of light on the feasibility of using glipizide in a transdermal delivery system for treatment of type 2 diabetes with the aim of improving both patient compliance and pathophysiology of the disease.
格列吡嗪是治疗2型糖尿病最常用的处方药之一。口服格列吡嗪治疗存在生物利用度波动的问题，且可能与严重低血糖和胃肠道紊乱有关。作为一种方便、安全且有效的抗糖尿病治疗的潜在方法，本研究的基本原理是开发一种格列吡嗪透皮给药系统。为此，制备了药物与β-环糊精（β-CyD）、二甲基-β-环糊精（DM-β-CyD）、羟丙基-β-环糊精（HP-β-CyD）和羟丙基-γ-环糊精（HP-γ-CyD）的包合物。开发了该药物以及制备的包合物在不同基质（水包油乳液、聚乙二醇、羧甲基纤维素和卡波姆）中的几种经皮制剂。释放研究表明，含格列吡嗪-CyD包合物的制剂中药物的释放有所改善。进行了通过大鼠腹部全层皮肤的体外渗透研究，监测了几种传统渗透促进剂（丙二醇[PG]、油酸、尿素、二甲基亚砜、薄荷醇、柠檬烯和桉叶油素）的效果。含PG和油酸组合的卡波姆凝胶基质制备的软膏以及使用格列吡嗪-DM-β-CyD包合物和尿素在相同基质中制备的软膏获得了最高通量。对糖尿病雄性Wistar大鼠的体内研究显示出持续约48小时的显著治疗效果。在这方面，两种制剂表现出最佳的生物学性能。在第一种制剂中，药物在20% PG和15%油酸存在下被掺入卡波姆凝胶基质中。第二种制剂是通过在15%尿素存在下将格列吡嗪-DM-β-CyD包合物掺入卡波姆凝胶基质中制备的。葡萄糖耐量试验显示，在葡萄糖负荷大鼠中诱导的高血糖得到抑制。上述结果可能为使用格列吡嗪透皮给药系统治疗2型糖尿病以提高患者依从性和改善疾病病理生理学的可行性提供有力的依据。
