INJECTABLE CALCIUM SULFATE MICROSPHERES FOR PROTEINS

BIOTEK开发了一种新的工艺，使用硫酸钙制造可注射的可生物降解微球和微胶囊，非常适合于水溶性药物（如肽和蛋白质）的仓库输送。初步试验表明，丁基胆碱酯酶可以以活性形式掺入和释放，最近的改进使常规制备75 - 100微米的可注射微球成为可能。拟议的第一阶段工作将研究组成、加工、装载和疏水处理对溶解和递送的影响。第一阶段的重点将是阐明蛋白质被保持和释放的机制，该项目包括基于两种技术的微球内蛋白质分布研究：银染色结合能量色散X射线光谱和控制表面磨损结合去除材料的蛋白质分析。第二阶段将使用第一阶段的数据开发可注射微球仓库，用于药用蛋白质，如人类生长激素，然后将通过可重复性演示、原型制造、质量评估、稳定性测试、IND提交和初步人体临床研究来进行产品开发。拟议的商业应用：新的多孔硫酸钙微球旨在最终发展成为一种通用的蛋白质仓库输送系统，其中空微球可以在一个工厂生产，然后在温和的加工条件下分发到其他工厂，以装载专有的蛋白质药物，不太可能导致变性或丧失活性。

BIOTEK has developed a new process which uses calcium sulfate to make injectable biodegradable microspheres and microcapsules well suited for depot delivery of water soluble drugs such as peptides and proteins. Preliminary testing has shown that butyrylcholinesterase can be incorporated and released in active form, and recent improvements have made possible routine preparation of injectable 75 - 100 microm microspheres in high yield. The proposed Phase I work will study the effect of variations in composition, processing, loading and hydrophobic treatment on dissolution and delivery. The emphasis in Phase I will be on elucidating the mechanisms by which protein is held and released, and the program includes a study of protein distribution inside microspheres based on two techniques: silver staining combined with Energy Dispersive X- Ray Spectroscopy and controlled surface abrasion combined with protein analysis of the removal material. Phase II will use the data from Phase I to develop an injectable microsphere depot for a medicinal protein such as human growth hormone and will then pursue product development through demonstration of reproducibility, prototype manufacturing, quality assessment, stability testing, IND submission, and an initial human clinical study. PROPOSED COMMERCIAL APPLICATION: The new porous calcium sulfate microspheres are intended for eventual development into a generic protein depot delivery system in which empty microspheres could be manufactured at one facility and then distribute to other facilities for loading with proprietary protein drugs using mild processing conditions unlikely to lead to denaturation or loss of activity.