Casein Coated CAP Particles for Oral Insulin Delivery

用于口服胰岛素输送的酪蛋白涂层 CAP 颗粒

• 批准号: 6690466
• 负责人: TULIN MORCOL
• 金额: $ 10万
• 依托单位: BIOSANTE PHARMACEUTICALS, INC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690466
• 关键词: blood glucose; calcium phosphate; caseins; diabetes mellitus therapy; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; gastrointestinal absorption /transport; insulin; insulin dependent diabetes mellitus; laboratory rat; oral administration; pharmacokinetics; polyethylene glycols; somatotropin; surface coating

DESCRIPTION (provided by applicant): Parenteral administration of insulin via the subcutaneous route is the only commercially available therapy to treat insulin-dependent diabetes mellitus. Multiple daily injections are required to manage and maintain blood glucose control due to its relatively short duration of action (4 to 8 hours). Oral insulin would provide an attractive alternative. However, successful development of an oral insulin formulation has been hampered by the numerous and complex barriers to protein absorption inherent to the gastrointestinal tract. A novel delivery system has emerged that may overcome these obstacles. The design of this delivery system incorporates an understanding of the complex barriers to oral insulin absorption and results in the production of biodegradable, insulin-impregnated, calcium phosphate / polyethylene glycol microparticles coated with casein. The characterization of particle size and morphology, their associated physicochemical properties, and the critical factors affecting these parameters will assist in formula optimization and process development. Thus, the aims of Phase I are to prepare a lot of casein coated, insulin-laden microparticles utilizing the most current manufacturing process; to fully characterize them in terms of particle size, particle morphology, % loading of insulin, insulin activity, relative component composition, moisture content, stability against digestive enzymes, pH-dependent dissolution characteristics, and storage stability; and to demonstrate a dose-dependent reduction in blood glucose with concomitant increase in serum insulin levels in rodents. Furthermore, modification and adaptation of the delivery system to another orally challenged therapeutic protein, such as human growth hormone, would demonstrate general utility of the delivery system. The long-range goal of this research is to develop a novel, safe, efficacious, long-acting, oral delivery system for insulin demonstrating a dose dependency with reduced variability that may be applicable to other therapeutically relevant proteins.

描述（由申请人提供）：通过皮下途径肠胃外施用胰岛素是治疗胰岛素依赖性糖尿病的唯一市售疗法。由于其作用持续时间相对较短（4 至 8 小时），因此需要每天多次注射来管理和维持血糖控制。口服胰岛素将提供一种有吸引力的替代方案。然而，口服胰岛素制剂的成功开发受到胃肠道固有的蛋白质吸收众多且复杂的障碍的阻碍。一种新颖的输送系统已经出现，可以克服这些障碍。该输送系统的设计结合了对口服胰岛素吸收的复杂障碍的理解，并导致生产可生物降解的、胰岛素浸渍的、涂有酪蛋白的磷酸钙/聚乙二醇微粒。颗粒尺寸和形态的表征、相关的物理化学性质以及影响这些参数的关键因素将有助于配方优化和工艺开发。因此，第一阶段的目标是利用最新的制造工艺制备大量酪蛋白包覆的、负载胰岛素的微粒；全面表征它们的粒径、颗粒形态、胰岛素负载百分比、胰岛素活性、相关成分组成、水分含量、对消化酶的稳定性、pH依赖性溶出特性和储存稳定性；并证明啮齿类动物的血糖呈剂量依赖性降低，同时血清胰岛素水平增加。此外，针对另一种口服攻击治疗蛋白（例如人生长激素）对递送系统进行修改和适应，将证明该递送系统的通用性。这项研究的长期目标是开发一种新型、安全、有效、长效的口服胰岛素输送系统，该系统显示出剂量依赖性，且变异性降低，可能适用于其他治疗相关的蛋白质。