Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Massachusetts 20993, United States.
Mol Pharm. 2020 Nov 2;17(11):4141-4151. doi: 10.1021/acs.molpharmaceut.0c00619. Epub 2020 Oct 19.
Sandostatin LAR (SLAR) is an injectable long-acting release (LAR) microsphere formulation for octreotide based on a biodegradeable glucose star copolymer of d,l-lactic and glycolic acids (PLGA-glu), which is primarily used for the treatment of patients with acromegaly. There currently is no generic SLAR approved in the United States despite expiration of patent coverage. To understand better this important formulation, SLAR was assessed for its composition and physical-chemical properties. Octreotide release kinetics was monitored under physiological conditions over 56 days together with several bioerosion parameters [mass loss, water uptake, pH of release media, polymer molecular weight (Mw), and confocal microscopy after BODIPY uptake]. A significant increase in the amount of released peptide occurred after day 14. After 1 day of incubation in PBST, octreotide was not extractable completely from SLAR during 2 h of the extraction process, but complete extraction was accomplished after 24 h, which suggested that strong and noncovalent PLGA-octreotide interactions occurred beginning in the initial release phase. Leuprolide is considered as a cationic peptide competitor for octreotide-PLGA interactions and its presence in the release medium resulted in more continuous octreotide release from SLAR, which was linearly correlated with the mass loss from the polymer (, an indication of erosion-controlled release). These data strongly suggest that octreotide forms a salt with acid end groups of linear PLGA chains that are either present as impurities in, and/or produced by the degradation of, the PLGA-Glu. This salt is expected to catalyze octreotide acylation and extend peptide release beyond that driven by erosion control. The characterization studies of physicochemical properties of SLAR described here could be useful for the development and regulatory evaluation of generic octreotide microspheres as well as new polymer formulations, in which the polymer strongly interacts with encapsulated peptides.
生长抑素类似物长效微球（SLAR）是一种基于可生物降解的葡萄糖星嵌段共聚物（d,l-乳酸和乙醇酸的共聚物，PLGA-glu）的奥曲肽注射用长效释放（LAR）微球制剂，主要用于治疗肢端肥大症患者。尽管专利保护已经过期，但目前美国尚未批准任何通用的 SLAR。为了更好地了解这种重要的制剂，对 SLAR 的组成和物理化学性质进行了评估。在生理条件下监测了奥曲肽的释放动力学，共监测了 56 天，并监测了几个生物侵蚀参数[质量损失、吸水率、释放介质的 pH 值、聚合物分子量（Mw）和 BODIPY 摄取后的共焦显微镜]。在第 14 天之后，释放的肽的量显著增加。在 PBST 中孵育 1 天后，在提取过程的前 2 小时内，奥曲肽不能从 SLAR 中完全提取，但在 24 小时后完全提取，这表明在初始释放阶段就开始发生强的和非共价的 PLGA-奥曲肽相互作用。亮丙瑞林被认为是奥曲肽-PLGA 相互作用的阳离子肽竞争物，其存在于释放介质中导致从 SLAR 中更连续地释放奥曲肽，这与聚合物的质量损失线性相关（，表明是侵蚀控制释放）。这些数据强烈表明，奥曲肽与线性 PLGA 链的酸端基形成盐，这些酸端基要么以杂质的形式存在于 PLGA-Glu 中，要么由 PLGA-Glu 的降解产生。这种盐预计会催化奥曲肽的酰化作用，并使肽的释放延长超过侵蚀控制所驱动的释放。这里描述的 SLAR 的物理化学性质的特征研究对于开发和监管评估通用奥曲肽微球以及与封装肽强烈相互作用的新聚合物制剂可能是有用的。
