Orally bioactive exenatie and insulin for type II diabetes

口服生物活性艾塞那和胰岛素治疗 II 型糖尿病

• 批准号: 8695344
• 负责人: Samir S Mitragotri
• 金额: $ 30.24万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695344
• 关键词: Adhesions; Adhesives; Animal Model; Biological Availability; Blood; Blood Glucose; Caliber; Caprylates; Carbomer-940; Carboxymethylcellulose; Chitosan; Coculture Techniques; Color; Custom; Diabetes Mellitus; Dose; Drug Formulations; Drug Kinetics; Enhancers; Enteral; Enzymes; Evaluation; Exposure to; FDA approved; Face; Foundations; Gastrointestinal tract structure; Glycocholate; Goals; Goblet Cells; Hour; Image; Imagery; In Vitro; Ingestion; Insulin; Intestinal Mucosa; Intestines; Knowledge; Lead; Light; Mind; Miniature Swine; Mucins; Mucous body substance; Nature; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oral Administration; Pathway interactions; Patients; Penetration; Peptide Transport; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Polyethyleneimine; Polymers; Quality of life; Rattus; Rhodamine; Safety; Side; Sodium; Sprague-Dawley Rats; Stomach; Stream; Subcutaneous Injections; System; Technology; Testing; Therapeutic; Thick; Time; Toxic effect; Water; absorption; capsule; clinically relevant; controlled release; design; diabetic patient; exenatide; glucagon-like peptide; human PTCH2 protein; in vivo; interest; millimeter; mimetics; novel; prevent; propylsulfonic acid; public health relevance; time use; type I and type II diabetes

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.

描述（由适用提供）：拟议的项目着重于开发新型的口服递送系统，用于治疗2型糖尿病的胰岛素和胰岛素。艾替尼和胰岛素都遭受胃肠道酶促降解的局限性和较差的口服生物利用度，因此需要通过皮下注射给药。这 拟议中的新型口服递送系统使用多层，毫米大小的粘粘性贴片，这些贴片被封闭在涂层的胶囊中，以防止在摊位中溶解胶囊。进入肠道后，胶囊溶解在肠腔中释放斑块，由于其粘膜性质，斑块粘附在肠粘膜上，并慢慢释放出艾鉴定和胰岛素进入血液。该项目的具体目的的设计如下：1。粘附性斑块的设计和表征：我们将通过压缩粘附性聚合物的最佳混合物来制备粘附性斑块，将粘附性聚合物的最佳混合物压入直径为2-4 mm的圆盘中，并将其涂在30 empers yemermemermemermemermemermemerm and y Impermerm yexter的层上，并将其涂在三个面上，并将其涂在三个面上。斑块将通过诱导高粘膜，单向和持续从张开的面部释放5-6小时的辣椒释放的能力，并保护辣椒免受肠道消化酶的保护。 2。评估肽转运和防止降解的保护：我们将评估斑块在CACO-2和粘液产生的杯状细胞子线HT29-MTX的共同培养物中递送艾替肽和胰岛素的能力。我们还将评估精选渗透增强剂增强整个肠道肽转运的能力。将在体外研究粘附斑块与水溶性肠粘蛋白的相互作用，以了解斑块在口服摄入后承受物理障碍粘附和滥用的物理障碍的能力。斑块的长期稳定性也将进行测试。 3。评估体内药代动力学和药效学的功效，以及大鼠和微型猪的粘膜粘附贴的安全性。我们将使用Sprague Dawley大鼠作为动物模型，我们将评估斑块在直接管道给药后提供治疗剂量的埃纳代剂和胰岛素的能力，以及来自斑块 - 卡赖蛋白胶囊的口服给药。将进行艾鉴化剂和胰岛素递送的药代动力学和药效学分析。斑块的毒性将通过组织学评估评估。经过大鼠的初步研究，我们将测试微型猪中胰岛素和艾替尼的药代动力学特征的优化公式。多剂量后，还将在微型猪中进行毒理学研究。