Self-microencapsulation in polymer delivery systems without organic solvents

不含有机溶剂的聚合物输送系统中的自微囊化

• 批准号: 7894812
• 负责人: STEVEN P. SCHWENDEMAN
• 金额: $ 18.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894812
• 关键词: Acids; Biocompatible Materials; Bovine Serum Albumin; Coumarins; Drug Delivery Systems; Drug Formulations; Drug Stability; Encapsulated; Evaluation; Exhibits; Figs - dietary; Glycolates; Goals; Healed; Heating; Hindlimb; Hydration status; In Vitro; Incubated; Injectable; Label; Leuprolide; Leuprolide Acetate; Methodology; Methods; Microencapsulations; Microspheres; Modeling; Molecular Conformation; Mus; Nanosphere; Organic solvent product; Peptides; Performance; Pharmaceutical Preparations; Physiological; Polymers; Preparation; Process; Proteins; Rattus; Research; Research Personnel; Route; Scientist; Solutions; Solvents; Stents; Swelling; System; Temperature; Testing; Testosterone; Therapeutic; Tissue Engineering; Vaccine Antigen; Vascular Endothelial Growth Factors; Water; alpha benzopyrone; aqueous; base; biodegradable polymer; biomaterial preparation; clinically relevant; controlled release; evaporation; healing; in vivo; interest; interfacial; novel; point of care; prevent; public health relevance; scaffold; seal

DESCRIPTION (provided by applicant): Our ultimate goal is to develop a new and simple method to microencapsulate drugs and other bioactive substances, particularly biomacromolecules such as proteins and peptides, in biodegradable controlled-release polymers. Current methods of microencapsulation in polymers such as poly(lactic-co-glycolic acid) (PLGA) suffer from: a) protein instability including use of protein-denaturing organic solvents, b) expensive large-scale, aseptic processing for encapsulation of each peptide/protein of interest, and c) the inability of clinicians at the point-of-care or other non formulation scientists in the field to effectively perform encapsulation. We will exploit our novel finding of spontaneous PLGA pore closing to microencapsulate proteins and peptides by: creating polymer delivery systems with defined pore networks, placing the polymers in the presence of an aqueous drug solution of interest, and then causing the pore network to close, e.g., by simple heating to physiological temperature. Unlike the vast majority of microencapsulation methodologies, which place drug in contact with dissolved polymer before or during microencapsulation, this approach creates a new paradigm in microencapsulation, whereby the biomaterial system is initially created and then microencapsulation is performed at the very end of preparation. In a sense, the polymer pore network microencapsulates by "itself" spontaneously-hence the term, "self-microencapsulation." Moreover, microencapsulation a) takes place under nondenaturing conditions without the need for organic solvent, b) could be done inexpensively with terminally sterilized porous PLGA microspheres for multiple peptides and/or proteins, c) would be applicable to numerous polymer configurations and geometries such as microspheres, nanospheres, tissue engineering scaffolds, drug-eluting stents, and d) could be performed by clinicians and investigators in the field, since encapsulation is by simple aseptic mixing of protein and polymer. This proposal will test the hypothesis that PLGA microspheres entrapping high loading of protein or peptide drugs can be prepared reproducibly by self-microencapsulation, and the resulting polymer will exhibit excellent drug stability and release performance both in vitro and in vivo. This hypothesis will be tested in 3 specific aims: 1) determine the effect of formulation variables on self- microencapsulation of model proteins, 2) investigate the mechanism of spontaneous pore closing in aqueous media, and 3) test the feasibility of self-encapsulation to stabilize and control the release of therapeutic peptides and proteins in vitro and in vivo. PUBLIC HEALTH RELEVANCE: This project tests the feasibility of a brand new method of microencapsulation based on a recent finding from our group demonstrating how biodegradable polymers can heal their tiny holes and cracks spontaneously in water. The microencapsulation method does not use organic solvents and could have far reaching applications to the slow delivery of the important biomacromolecular class of drugs and vaccine antigens from injectable depots, tissue engineering scaffolds, and drug-eluting stents.

描述（申请人提供）：我们的最终目标是开发一种新的、简单的方法，将药物和其他生物活性物质，特别是生物大分子，如蛋白质和肽，微胶囊化在可生物降解的控释聚合物中。目前的聚合物微囊化方法，如聚乳酸-乙醇酸 (PLGA)，存在以下问题：a) 蛋白质不稳定性，包括使用蛋白质变性有机溶剂；b) 封装每种感兴趣的肽/蛋白质需要昂贵的大规模无菌处理；c) 现场护理临床医生或该领域的其他非制剂科学家无法有效地进行封装。我们将通过以下方式利用我们的新发现：自发 PLGA 孔闭合微囊化蛋白质和肽：创建具有确定孔网络的聚合物递送系统，将聚合物置于感兴趣的药物水溶液存在下，然后导致孔网络闭合，例如通过简单加热至生理温度。与绝大多数微胶囊化方法（在微胶囊化之前或微胶囊化过程中将药物与溶解的聚合物接触）不同，这种方法创造了微胶囊化的新范例，首先创建生物材料系统，然后在制备的最后阶段进行微胶囊化。从某种意义上说，聚合物孔网络通过“自身”自发地微囊化——因此术语“自微囊化”。此外，微囊化 a) 在非变性条件下进行，无需有机溶剂，b) 可以使用最终灭菌的多孔 PLGA 微球来廉价地完成多种肽和/或蛋白质，c) 将适用于多种聚合物构型和几何形状，如微球、纳米球、组织工程支架、药物洗脱支架，d) 可以 由临床医生和该领域的研究人员进行，因为封装是通过蛋白质和聚合物的简单无菌混合实现的。该提案将测试这样的假设：包埋高负载蛋白质或肽药物的 PLGA 微球可以通过自微胶囊化重复制备，所得聚合物将在体外和体内表现出优异的药物稳定性和释放性能。该假设将在 3 个具体目标中进行测试：1）确定配方变量对模型蛋白自微囊化的影响，2）研究水介质中自发孔闭合的机制，3）测试自囊化在体外和体内稳定和控制治疗性肽和蛋白质释放的可行性。 公共健康相关性：该项目测试了一种全新微胶囊化方法的可行性，该方法基于我们小组最近的一项发现，展示了可生物降解聚合物如何在水中自发修复其小孔和裂缝。微囊化方法不使用有机溶剂，对​​于从注射剂、组织工程支架和药物洗脱支架中缓慢输送重要的生物大分子药物和疫苗抗原具有深远的应用。