权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigation of peptide-polymer interactions in PLGA microspheres

PLGA 微球中肽-聚合物相互作用的研究

基本信息

批准号：
9346576
负责人：
STEVEN P. SCHWENDEMAN
金额：
$ 25万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-05 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9346576
关键词：
Investigation peptide polymer interactions PLGA

项目摘要

There is a scientific gap in our current understanding of how formulation and raw material variables used to manufacture poly(lactic-co-glycolic acid) (PLGA) microspheres encapsulating peptides lead to differing levels of peptide-polymer interactions and peptide acylation during encapsulation, storage, and release in vitro and in vivo. Batch-to-batch variation and unpredictable acylation levels could lead to differences in pharmacokinetics (PK) and loss of bioequivalence of generic long-acting release (LAR) formulations seeking to mimic LAR products. Such differences in bioequivalence may lead to differences in safety and efficacy. A key factor leading to the loss of parent drug is the poorly defined interaction between the peptide and the polymer, which has been shown to be a precursor to the acylation reaction. For example, salt formation between the cationic and acylation-labile octreotide, found in the Sandostatin LAR (SLAR) microsphere product, with the ionized carboxylic acid end-groups of PLGA has been shown to be necessary for acylation to occur. We hypothesize the key underlying time-dependent factors responsible for differences in peptide-polymer interactions and acylation for microspheres of similar compositions include: (a) microclimate pH in the microspheres affecting ionization of polymer carboxylic acids necessary to bind to a cationic peptide; (b) the extent to which the polymer allows penetration of the peptide into the polymer phase, and (c) the architecture of the polymer (star vs. linear) and end-capping that affect the strength and type of intermolecular forces responsible for peptide- polymer interactions. The following tasks will be developed to test our hypothesis and close the aforementioned scientific gap: 1. Develop techniques for assessing peptide-polymer interactions and peptide acylation impurities with the reference product, SLAR; 2. Reverse engineer the composition of SLAR; 3. Create Q1/Q2 formulations for the SLAR as a function of microencapsulation conditions, and determine product attributes relative to SLAR. 4. Create microsphere formulations with virtually the same composition of SLAR but with different PLGA architecture and molecular weight, and determine product attributes; 5. Compare peptide-polymer interactions, acylation, erosion behavior and release kinetics in all formulations to identify key formulation and polymer architecture controlling differences in peptide acylation and release kinetics in vitro; and 6. Verify in vitro differences observed in Task 1 and 5 by assessing key formulations for PK after intramuscular injection and direct measurements after recovery from a novel in vivo cage model. We will apply a wide range of novel experimental approaches developed by our group over the last 20 years to interrogate the peptide-polymer interactions necessary to initiate octreotide acylation in PLGAs. We will further combine this approach with a large number of rigorous and new in vitro assays to test formulations with relevance to future regulatory guidance to generics and verify their relevance to the not yet predictable in vivo environment.

我们目前对配方和原材料变量如何用于生产聚（乳酸-共-乙醇酸）（PLGA）微球封装肽导致不同的水平肽-聚合物相互作用和肽酰化过程中的封装，储存，并在体外和体内释放 vivo.批次间差异和不可预测的酰化水平可能导致药代动力学差异 (PK)和寻求模拟LAR的仿制长效释放（LAR）制剂的生物等效性丧失产品.这种生物等效性的差异可能导致安全性和有效性的差异。一个关键因素导致母体药物损失的是肽和聚合物之间不明确的相互作用，已被证明是酰化反应的前体。例如，在阳离子聚合物之间的盐的形成是可能的。和在Sandostatin LAR（SLAR）微球产品中发现的酰化不稳定的奥曲肽， PLGA的羧酸端基已被证明是发生酰化所必需的。我们假设负责肽-聚合物相互作用差异的关键潜在时间依赖性因素，用于类似组成的微球的酰化包括：（a）微球中的微气候pH，（B）与阳离子肽结合所必需的聚合物羧酸的电离程度; 聚合物允许肽渗透到聚合物相中，和（c）聚合物的结构（星星 vs.线性）和封端，其影响负责肽- 聚合物相互作用将开发以下任务来测试我们的假设并关闭上述科学差距：1。开发用于评估肽-聚合物相互作用和肽酰化杂质与参比产品SLAR; 2.逆向工程SLAR的组成; 3.创建作为微胶囊化条件的函数的SLAR的Q1/Q2制剂，并确定产品相对于SLAR的属性。4.创建具有几乎相同组成的SLAR的微球制剂但具有不同的PLGA结构和分子量，并确定产品属性; 5.比较肽-聚合物相互作用，酰化，侵蚀行为和释放动力学，以确定关键的控制肽酰化和体外释放动力学差异的制剂和聚合物结构; 和6.通过评估关键制剂的PK，验证任务1和任务5中观察到的体外差异，肌内注射和从新的体内笼模型恢复后直接测量。我们将应用在过去的20年里，我们的团队开发了一系列新颖的实验方法，在PLGA中引发奥曲肽酰化所必需的肽-聚合物相互作用。我们将进一步联合收割机这种方法具有大量严格的和新的体外测定，以测试与以下相关的制剂：未来的监管指南仿制药，并验证其相关性，目前还无法预测的体内环境。