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

• 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
• 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

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）：大约有2080万美国人被诊断出患有糖尿病。此外，在美国，将近5400万人被诊断为糖尿病前期，这意味着血糖水平升高。在全球范围内，到2030年，糖尿病患者的数量估计会增加超过3.5亿。目前，糖尿病是用肌内或皮下注射的胰岛素治疗的。由于患者的依从性差，旨在开发口服胰岛素制剂的努力，这也有可能模仿非糖尿病患者看到的生理胰岛素分泌。然而，口服胰岛素递送遇到了两个主要障碍：[1]导致胰岛素快速降解的酶屏障，[2]限制胰岛素生物可利用性的粘膜屏障。目前，通过同时给予蛋白酶抑制剂或将胰岛素封装到保护性载体中，该酶的屏障已在一定程度上得到了避免，但是粘膜屏障仍然是开发有效的口服胰岛素递送系统的挑战。最近发现一类细胞穿透肽的发现，被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一种工具。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））联系起来，PTD能够将附着的货物运送到所有类型的器官组织中。在此SBIR赠款申请中，我们提出了一种创新的口服胰岛素输送方法，该方法可能同时出现在酶和粘膜壁垒上。该系统的一个主要组成部分将是一种二氧化硅纳米复合材料，可保护胰岛素免受降解，靶向胰岛素释放到GI区域，并控制药物释放速率。胰岛素首先通过化学方法将胰岛素结合到LMWP（一种经过验证的PTD肽），然后将结合物封装在硅胶氧化盐纳米复合网络中。口服给药后，复合材料的网络结构将保护所包裹的胰岛素免受GI轨道中蛋白酶的降解，而藻酸盐在表面上的粘膜粘附功能将提供载体上的吸附到肠粘膜上。一旦积累在粘膜部位，LMWP的有效细胞渗透活性将使释放的LMWP-胰岛素结合物迅速越过上皮细胞层，将生物活性的胰岛素直接运输到门户循环中。有希望的初始体外发现令人信服地表明该系统的合理性。在此阶段I研究中，我们计划进行果断概念证明动物研究，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，拟议的口服胰岛素输送技术的价值是深远的。公共卫生相关性：美国糖尿病协会在2002年进行的评估表明，归因于当年糖尿病的费用约为1320亿美元；包括920亿美元的直接医疗支出和400亿美元的间接支出，导致生产力损失。由于几乎所有I型糖尿病患者都需要胰岛素治疗，并且现在越来越多地用于治疗II型糖尿病患者（目前最多35％的II型糖尿病患者需要胰岛素治疗），因此有效的胰岛素递送已成为糖尿病临床管理中的最终目标。因此，这种高效的胰岛素输送技术的发展不仅会对医疗保健和社会生活产生巨大影响，而且还为该国的整体经济带来了重大利益。