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简单方法，以在可生物降解的受控释放聚合物中微封装药物和其他生物活性物质，尤其是蛋白质和肽等生物大分子。当前在聚合物（例如聚（乳酸 - 乙醇酸）（PLGA）等聚合物中的微囊泡方法）受到以下：a）蛋白质不稳定性，包括使用蛋白质污染有机溶剂，b）昂贵的大规模的无菌处理，用于对每种肽/蛋白质的封装，以及对临床的表现，或者对临床的表现不佳。我们将通过以下方式利用自发的PLGA孔封闭到微囊蛋白和肽的新发现，通过：创建具有定义的孔网络的聚合物输送系统，将聚合物放置在感兴趣的水溶液溶液中，然后使孔网络闭合，例如，通过简单的热量加热到生理学温度。与绝大多数微囊化方法论不同，在微囊化之前或过程中，将药物与溶解聚合物接触，这种方法在微囊化中产生了新的范式，最初会产生生物材料系统，然后在制备结束时进行微囊泡。从某种意义上说，聚合物孔网络通过“自发自发”术语“自我微囊化”。 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由于封装是通过蛋白质和聚合物的简单混合封装的，因此由临床医生和研究人员进行。该提案将检验以下假设：PLGA微球可以通过自我微囊化来重现蛋白质或肽药物的高负载，并且所得聚合物将在体外和体内表现出出色的药物稳定性和释放性能。该假设将在3个具体目的中进行检验：1）确定配方变量对模型蛋白的自微囊化的影响，2）研究水性培养基中自发性孔隙关闭的机制，以及3）测试自我结合的可行性，可自我封闭，以稳定和控制Intros和Vivo的疗法蛋白质稳定和控制。 公共卫生相关性：该项目基于我们小组的最新发现，证明了可生物降解的聚合物如何治愈其微小的孔和在水中自发破解，因此该项目测试了全新的微型塑料方法的可行性。微囊化方法不使用有机溶剂，并且可能在较慢的生物焦分子类药物和疫苗抗原从可注射仓，组织工程脚手架和药物淘汰支架的情况下缓慢地应用。