Novel Nanocomposite Formulation for Highly Effective Oral Insulin Delivery

用于高效口服胰岛素输送的新型纳米复合制剂

基本信息

批准号：
7482498
负责人：
Allan E. David
金额：
$ 20万
依托单位：
INDUSTRIAL SCIENCE & TECHNOLOGY NETWORK
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7482498
关键词：
Adsorption Alginates American Animals Applications Grants Biocompatible Biological Availability Blindness Blood Circulation Blood Glucose Cell membrane Cells Chemicals Class Clinical Clinical Management Country Cultured Cells Development Diabetes Mellitus Diagnosis Disease Dose Drug Carriers Drug Controls Drug Delivery Systems Drug Formulations Drug Kinetics Encapsulated Endocytosis Endopeptidases Enteral Enzymes Epithelial Cells Evaluation Expenditure Face Gastrointestinal tract structure Genetic Crossing Over Goals Healthcare Heart Diseases In Vitro Indirect Expenditures Individual Injection of therapeutic agent Insulin Insulin-Dependent Diabetes Mellitus Intestinal Mucosa Intestines Intramuscular Injections Invasive Kidney Failure Life Liposomes Mediating Medical Membrane Methods Non-Insulin-Dependent Diabetes Mellitus Nose Numbers Oral Oral Administration Organ Pathogenesis Pathway interactions Patients Peptide Hydrolases Peptides Pharmacodynamics Phase Physiological Population Process Productivity Protease Inhibitor Proteins Public Health Rate Research Risk Route Safety Silicon Dioxide Small Business Funding Mechanisms Small Business Innovation Research Grant Social Impacts Structure Surface System Technology Tertiary Protein Structure Testing Time Tissues Treatment Protocols United States base compliance behavior concept cost day diabetic diabetic rat in vivo innovation insulin secretion link protein mucosal site nanocomposite nanoparticle non-diabetic novel receptor response social subcutaneous tool type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Approximately 20.8 million Americans are diagnosed with diabetes. Additionally, nearly 54 million people in the U.S. are diagnosed as being pre-diabetic, meaning to suffer from elevated blood glucose levels. Worldwide, the number of people with diabetes has been estimated to increase over 350 million by 2030. Presently, diabetes is treated with insulin injected either intramuscularly or subcutaneously. Because of poor patient compliance, a strong effort has been aimed at developing oral insulin formulations, which also has the potential to mimic physiological insulin secretion seen in non-diabetic individuals. Nevertheless, oral insulin delivery encounters two major barriers: [1] the enzyme barrier that leads to rapid insulin degradation, and [2] the mucosal barrier that limits insulin's bioavailability. Presently, the enzyme barrier has been circumvented to a certain degree by concurrent administration of protease inhibitors or encapsulation of insulin into protective carriers, yet the mucosal barrier remains as a challenge in developing an effective oral insulin delivery system. The recent discovery of a class of cell-penetrating peptides, widely termed as protein transduction domain (PTD) peptides, has provided a tool for finally overcoming the cell membrane barrier. Both cell culture and animal studies demonstrate that by covalently linking PTD to almost any type of cargo, including large proteins (MW >150 kDa), PTD was able to ferry the attached cargo into all types of organ tissues. In this SBIR grant application, we propose an innovative oral insulin delivery approach that could potentially prevail over both the enzyme and mucosal barriers concomitantly. A major component of this system will be a silica-alginate nanocomposite that serves to protect insulin from degradation, target insulin release to the GI tract, and also control drug release rate. Insulin will first be conjugated to LMWP (a proven PTD peptide) by chemical method, and the conjugates will then be encapsulated into a silica-alginate nanocomposite network. Following oral administration, the network structure of the composite would protect entrapped insulin from degradation by proteases in the GI track, whereas the mucoadhesive function of alginate on the surface would provide adsorption of the carriers onto intestinal mucosa. Once accumulated at the mucosal site, the potent cell-penetrating activity of LMWP would allow the released LMWP-insulin conjugates to rapidly cross over the epithelial cell layer, transporting biologically active insulin directly into portal circulation. Promising initial in vitro findings convincingly suggest the plausibility of the proposed system. In this Phase I research, we plan to carry out decisive proof-of-concept animal studies to fully demonstrate the feasibility of this system. Based on the unmatched economical and social impacts of diabetes, the value of the proposed oral insulin delivery technology is far-reaching. PUBLIC HEALTH RELEVANCE: An assessment made by the American Diabetes Association in 2002 indicated that costs attributable to diabetes in that year were approximately $132 billion; including $92 billion in direct medical expenditures and $40 billion in indirect expenditures resulting from lost productivity. Because insulin therapy is required by virtually all patients with type I diabetes, and is also now increasingly used in treating patients with type II diabetes (right now up to 35% of patients with type II diabetes require insulin treatment), effective insulin delivery has become the ultimate goal in clinical management of diabetes. Therefore, the development of this highly effective insulin delivery technology would not only impart tremendous impact on healthcare and social lives but also offer significant benefit to the overall economy of this country.

描述（由申请人提供）：大约 2080 万美国人被诊断患有糖尿病。此外，美国有近 5400 万人被诊断为糖尿病前期，即血糖水平升高。据估计，到 2030 年，全球糖尿病患者数量将增加超过 3.5 亿。目前，糖尿病的治疗方法是肌肉注射或皮下注射胰岛素。由于患者依从性差，人们大力致力于开发口服胰岛素制剂，该制剂也有可能模仿非糖尿病个体的生理胰岛素分泌。然而，口服胰岛素输送遇到两个主要障碍：[1]导致胰岛素快速降解的酶屏障，以及[2]限制胰岛素生物利用度的粘膜屏障。目前，通过同时施用蛋白酶抑制剂或将胰岛素封装到保护性载体中已在一定程度上绕过了酶屏障，但粘膜屏障仍然是开发有效的口服胰岛素递送系统的挑战。最近发现的一类细胞穿透肽，广泛称为蛋白质转导域（PTD）肽，为最终克服细胞膜屏障提供了工具。细胞培养和动物研究都表明，通过将 PTD 与几乎任何类型的货物（包括大蛋白（MW > 150 kDa））共价连接，PTD 能够将附着的货物运送到所有类型的器官组织中。在本次 SBIR 拨款申请中，我们提出了一种创新的口服胰岛素输送方法，该方法可能同时克服酶和粘膜屏障。该系统的主要组成部分是二氧化硅-海藻酸盐纳米复合材料，它可以保护胰岛素免于降解，将胰岛素释放到胃肠道，并控制药物释放速率。首先通过化学方法将胰岛素与 LMWP（一种经过验证的 PTD 肽）结合，然后将结合物封装到二氧化硅-海藻酸盐纳米复合网络中。口服给药后，复合材料的网络结构将保护包埋的胰岛素免遭胃肠道中的蛋白酶降解，而表面藻酸盐的粘膜粘附功能将提供载体吸附到肠粘膜上。一旦在粘膜部位积累，LMWP 强大的细胞穿透活性将使释放的 LMWP-胰岛素缀合物快速穿过上皮细胞层，将具有生物活性的胰岛素直接转运到门静脉循环中。有希望的初步体外研究结果令人信服地表明所提出的系统的合理性。在这一阶段的研究中，我们计划进行决定性的概念验证动物研究，以充分证明该系统的可行性。基于糖尿病无与伦比的经济和社会影响，所提出的口服胰岛素输送技术的价值是深远的。公共健康相关性：美国糖尿病协会 2002 年的一项评估表明，当年糖尿病造成的费用约为 1,320 亿美元；其中包括 920 亿美元的直接医疗支出和 400 亿美元的生产力损失造成的间接支出。由于几乎所有 I 型糖尿病患者都需要胰岛素治疗，并且现在也越来越多地用于治疗 II 型糖尿病患者（目前高达 35% 的 II 型糖尿病患者需要胰岛素治疗），因此有效的胰岛素输送已成为糖尿病临床管理的最终目标。因此，开发这种高效的胰岛素输送技术不仅会对医疗保健和社会生活产生巨大影响，而且还会为该国的整体经济带来重大利益。