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: 7739678
• 负责人: STEVEN P. SCHWENDEMAN
• 金额: $ 22.72万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739678
• 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（由申请人提供）：我们的最终目标是开发一种新的和简单的方法，以微胶囊化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，在可生物降解的控释聚合物。目前在聚合物如聚（乳酸-共-乙醇酸）（PLGA）中微囊化的方法存在以下问题：a）蛋白质不稳定性，包括使用蛋白质变性有机溶剂，B）用于囊化每种感兴趣的肽/蛋白质的昂贵的大规模无菌处理，和c）护理点的临床医生或该领域的其他非制剂科学家不能有效地进行囊化。我们将利用我们的新发现，即PLGA孔自发闭合以微囊化蛋白质和肽，通过：创建具有限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，然后使孔网络闭合，例如，通过简单加热到生理温度。与绝大多数微胶囊化方法不同，这些方法在微胶囊化之前或期间将药物与溶解的聚合物接触，这种方法在微胶囊化中创造了一种新的范例，由此最初创建生物材料系统，然后在制备的最后进行微胶囊化。在某种意义上，聚合物孔网络通过“自身”自发地进行微胶囊化，因此称为“自微胶囊化”。“此外，微囊化a）在非变性条件下发生而不需要有机溶剂，B）可以用用于多种肽和/或蛋白质的最终灭菌的多孔PLGA微球廉价地完成，c）将适用于许多聚合物构型和几何形状，例如微球、纳米球、组织工程支架、药物洗脱支架，和d）可以由临床医生和研究者在本领域中进行，因为包封是通过蛋白质和聚合物的简单无菌混合进行的。该方案将验证这样的假设，即包埋高负载的蛋白质或肽类药物的PLGA微球可以通过自微囊化可重复地制备，并且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个具体目的中进行测试：1）确定制剂变量对模型蛋白质的自微囊化的影响，2）研究水性介质中自发孔闭合的机制，和3）测试自囊化以在体外和体内稳定和控制治疗性肽和蛋白质的释放的可行性。 公共卫生关系：该项目测试了一种全新的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，该发现展示了可生物降解的聚合物如何在水中自发地修复其微小的孔和裂缝。微囊化方法不使用有机溶剂，并且可以具有从可注射储库、组织工程支架和药物洗脱支架缓慢递送重要的生物大分子类药物和疫苗抗原的深远应用。