Casein Coated CAP Particles for Oral Insulin Delivery

描述(申请人提供)：通过皮下途径非肠道注射胰岛素是治疗胰岛素依赖型糖尿病的唯一商业治疗方法。由于其作用时间相对较短(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个有吸引力的替代方案。然而，口服胰岛素制剂的成功开发一直受到胃肠道固有的众多复杂的蛋白质吸收障碍的阻碍。出现了一种可能克服这些障碍的新型递送系统。这种给药系统的设计包含了对口服胰岛素吸收的复杂障碍的了解，并导致生产出可生物降解的、浸泡在胰岛素中的磷酸钙/聚乙二醇酪蛋白包裹的微粒。颗粒大小和形态的表征、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裹的胰岛素载量微粒；从颗粒大小、颗粒形态、胰岛素载量百分比、胰岛素活性、相对成分组成、水分含量、对消化酶的稳定性、pH依赖的溶出特性和储存稳定性等方面对它们进行全面表征；并证明啮齿类动物的血糖呈剂量依赖性降低，伴随而来的是血清胰岛素水平的升高。此外，将递送系统修改和适应于另一种口服挑战的治疗性蛋白质，例如人类生长激素，将证明递送系统的一般效用。这项研究的长期目标是开发一种新型的、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，降低了变异性，可能适用于其他治疗相关的蛋白质。

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.