Orally bioactive exenatie and insulin for type II diabetes

描述(申请人提供)：拟议的项目侧重于开发一种用于治疗2型糖尿病的新型口服艾塞那肽和胰岛素给药系统。埃塞那肽和胰岛素都受到胃肠道酶降解和口服生物利用度低的限制，因此需要通过皮下注射给药。这个 提出的新的埃塞那肽口服给药系统使用多层毫米大小的粘附性贴片，这些贴片被包裹在肠溶胶囊中，以防止胶囊在胃中溶解。进入肠道后，胶囊溶解，释放肠腔内的贴片，由于其粘附性，贴片附着在肠粘膜上，并慢慢将埃塞那肽和胰岛素释放到血流中。该项目的具体目标如下：1.粘附性贴片的设计和表征：我们将通过将最佳的粘附性聚合物混合物压缩成直径2-4 mm、厚度400�m的圆盘，并在其三面涂上一层50�m厚的乙基纤维素层，来制备粘附性贴片。将测试贴片诱导高粘附性、单向性以及多肽从开放表面持续释放5-6小时的能力，以及保护多肽免受肠道消化酶的影响。2.多肽转运的评估和对降解的保护：我们将评估贴片在Caco-2和产生粘液的杯状细胞亚系HT29-MTX的共培养中输送埃塞那肽和胰岛素的能力。我们还将评估选定的渗透促进剂增强多肽在肠道中运输的能力。黏附贴片与水溶性肠粘蛋白的相互作用将在体外进行研究，以了解贴片在口服后抵抗黏附和吸收的生理障碍的能力。还将测试贴片的长期稳定性。3.粘附性贴片在大鼠和小型猪体内的药代动力学、药效学和安全性评价以SD大鼠为动物模型，我们将评估贴剂在直接空肠给药和口服贴片胶囊后给药的治疗剂量艾塞那肽和胰岛素的能力。将进行艾塞那肽和胰岛素释放的药代动力学和药效学分析。贴片的毒性将通过组织学评估进行评估。在对大鼠进行初步研究后，我们将测试胰岛素和埃克塞那肽在小型猪身上的药代动力学曲线的优化配方。毒理学研究也将在多次注射后在小型猪身上进行。

DESCRIPTION (provided by applicant): The proposed project focuses on developing a novel oral delivery system for exenatide and insulin for the treatment of Type 2 Diabetes. Both exenatide and insulin suffer from the limitations of enzymatic degradation in the gastrointestinal tract and poor oral bioavailability, thus requiring administration via subcutaneous injections. The proposed novel oral delivery system for exenatide utilizes multilayered, millimeter-sized mucoadhesive patches, which are enclosed in an enteric-coated capsule so as to prevent dissolution of the capsule in the stomach. Upon entering the intestine, the capsule dissolves to release patches in the intestinal lumen, where the patches adhere to the intestinal mucosa due to their mucoadhesive nature and slowly release exenatide and insulin into the blood stream. The specific aims of the project are designed as follows: 1. Design and Characterization of Mucoadhesive Patches: We will prepare mucoadhesive patches by compressing optimal blends of mucoadhesive polymers into disks of 2-4 mm diameter and 400 �m thickness, and coating them on three sides by a 50 �m thick layer of an impermeable layer comprising ethylcellulose. Patches will be tested for their ability to induce high mucoadhesion, unidirectiona as well as sustained release of peptides from the open face for 5-6 hours, and protection of peptides from the digestive enzymes in the intestine. 2. Assessment of Peptide Transport, and Protection against Degradation: We will assess the ability of patches to deliver exenatide and insulin across co-cultures of Caco-2 and mucus producing goblet cell sub-line HT29-MTX. We will also assess the ability of select penetration enhancers to enhance peptide transport across the intestine. Interactions of mucoadhesive patches with water soluble intestinal mucins will be studied in vitro so as to understand the ability of the patches to withstand the physiological hurdles to adhesion and absorption following oral ingestion. Long-term stability of patches will also be tested. 3. Assessment of In vivo Pharmacokinetic and Pharmacodynamic Efficacy, and Safety of Mucoadhesive Patches in Rats and Miniature Swine. Using Sprague Dawley rats as an animal model, we will assess the ability of patches to deliver therapeutic doses of exenatide and insulin after direct jejunal administration as well as oral administration from a patch-carryin capsule. Pharmacokinetic and pharmacodynamic analysis of exenatide and insulin delivery will be performed. Toxicity of patches will be assessed by histological evaluation. Following initial studies in rats, we will test the optimized formulations for pharmacokinetic profile in miniature swine for insulin as well as exenatide. Toxicological studies will also be performed in miniature swine after multiple doses.