Casein Coated CAP Particles for Oral Insulin Delivery

描述（由申请方提供）：胰岛素经皮下途径胃肠外给药是治疗胰岛素依赖型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），需要每日多次注射以管理和维持血糖控制。口服胰岛素将提供一个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的众多且复杂的障碍的阻碍。一种新的输送系统已经出现，可以克服这些障碍。该递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，并导致产生可生物降解的、胰岛素浸渍的、用酪蛋白包覆的磷酸钙/聚乙二醇微粒。粒度和形态的表征、其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，阶段I的目的是利用最新的制造方法制备大量酪蛋白包被的、负载胰岛素的微粒;在粒度、颗粒形态、胰岛素的%负载、胰岛素活性、相对组分组成、水分含量、对消化酶的稳定性、pH依赖性溶解特性和储存稳定性方面对其进行充分表征;并证明啮齿动物中血糖的剂量依赖性降低伴随血清胰岛素水平的增加。此外，将递送系统修饰和适应于另一种经口激发的治疗性蛋白质，如人生长激素，将证明递送系统的一般实用性。本研究的长期目标是开发一种新型、安全、有效、长效的胰岛素口服给药系统，该系统具有剂量依赖性，变异性降低，可能适用于其他治疗相关蛋白质。

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.