Orally bioactive exenatie and insulin for type II diabetes

描述（由申请人提供）：拟议项目的重点是开发一种用于治疗2型糖尿病的艾塞那肽和胰岛素的新型口服给药系统。艾塞那肽和胰岛素都受到胃肠道中酶降解的限制和较差的口服生物利用度，因此需要通过皮下注射给药。的 所提出的用于艾塞那肽的新的口服递送系统利用多层的毫米大小的粘膜粘附贴片，所述贴片被封装在肠溶包衣胶囊中，以防止胶囊在胃中溶解。在进入肠后，胶囊溶解以在肠腔中释放贴剂，其中贴剂由于其粘膜粘附性质而粘附于肠粘膜并缓慢释放艾塞那肽和胰岛素到血流中。本项目的具体目标设计如下：1.粘膜粘附贴片的设计和表征：我们将通过将粘膜粘附聚合物的最佳共混物压缩成直径为2-4 mm、厚度为400 μ m的圆盘，并在其三面涂上50 μ m厚的包含乙基纤维素的不可渗透层来制备粘膜粘附贴片。将测试贴剂诱导高粘膜粘附、单向性以及肽从开放面持续释放5-6小时的能力，以及保护肽免受肠中消化酶的影响的能力。2.肽转运和抗降解保护的评估：我们将评估贴剂在Caco-2和产生粘液的杯状细胞亚系HT 29-MTX的共培养物中递送依塞那肽和胰岛素的能力。我们还将评估选择的渗透增强剂增强肽转运通过肠道的能力。将在体外研究粘膜粘附贴剂与水溶性肠粘蛋白的相互作用，以了解贴剂耐受口服后粘附和吸收的生理障碍的能力。还将测试贴剂的长期稳定性。3.在大鼠和小型猪中评估粘膜粘附贴片的体内药代动力学和药效学有效性以及安全性。使用Sprague道利大鼠作为动物模型，我们将评估贴剂在直接空肠给药以及从贴剂携带胶囊口服给药后递送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给药的药代动力学和药效学分析。将通过组织学评价评估贴剂的毒性。在大鼠中进行初步研究后，我们将在小型猪中测试胰岛素以及艾塞那肽的药代动力学特征的优化制剂。还将在小型猪中进行多次给药后的毒理学研究。

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.