Small Molecule Pharmaceutical Sciences (SMPS), Genentech Inc., S. San Francisco, CA 94080, USA.
Small Molecule Pharmaceutical Sciences (SMPS), Genentech Inc., S. San Francisco, CA 94080, USA.
Eur J Pharm Biopharm. 2021 Aug;165:185-192. doi: 10.1016/j.ejpb.2021.05.008. Epub 2021 May 14.
Poly (lactic-co-glycolic acid) (PLGA), a biocompatible and biodegradable polymer, is one of the most commonly used vehicles for controlled-release (CR) implantable dosage forms. Drug molecules formulated in such CR vehicles are released slowly over an extended period of time - often months to years - posing challenges for batch release and quality control testing. Thus, reliable and reproducible accelerated testing methods are required to bridge this gap during early formulation development. This work describes the development of an accelerated in vitro release testing method to predict the real-time in vitro release of a synthetic peptide from a 6-month CR PLGA implant formulation. While accelerated methods have been previously reported for PLGA-based formulations, this work describes a unique case of an aggregation-prone peptide, which required careful attention to the impact of different conditions on both release kinetics and peptide stability. This method describes a suitable combination of release conditions that could help in understanding the release profiles of such peptides prone to aggregation. Parameters including pH, buffer species, temperature, and addition of organic co-solvents and surfactants were evaluated separately and in combination for their ability to achieve complete peptide release within 2 weeks while accurately recapitulating release rate, profile and peptide stability. The accelerated release method that gave the best agreement with real-time release was a mixed media of co-solvent (5% tetrahydrofuran), surfactant (5% TritonX-100) and elevated temperature (50 °C) in a neutral buffer (PBS pH 7.4). This optimized accelerated release method achieved complete release of the peptide load within 14-21 days compared to 3- to 6-months of real-time release and could discriminate critical differences in release behavior between different CR formulations to guide formulation and process development.
聚(乳酸-共-乙醇酸)(PLGA)是一种生物相容性和可生物降解的聚合物,是最常用于控制释放(CR)植入剂型的载体之一。在这种 CR 载体中配制的药物分子会在较长时间内缓慢释放 - 通常为数月至数年 - 这对批次放行和质量控制测试构成了挑战。因此,在早期制剂开发过程中,需要可靠且可重复的加速测试方法来弥补这一差距。本工作描述了一种加速体外释放测试方法的开发,以预测合成肽从 6 个月 CR PLGA 植入制剂的实时体外释放。虽然之前已经报道了用于 PLGA 制剂的加速方法,但本工作描述了一种独特的易于聚集的肽的情况,这需要仔细注意不同条件对释放动力学和肽稳定性的影响。该方法描述了一种合适的释放条件组合,可以帮助理解易聚集肽的释放特性。单独和组合评估了 pH、缓冲物种、温度以及添加有机溶剂共溶剂和表面活性剂等参数,以评估它们在 2 周内实现完全肽释放的能力,同时准确再现释放速率、曲线和肽稳定性。与实时释放最吻合的加速释放方法是中性缓冲液(PBS pH 7.4)中的混合溶剂(5%四氢呋喃)、表面活性剂(5%TritonX-100)和升高温度(50°C)。与 3 至 6 个月的实时释放相比,这种优化的加速释放方法在 14-21 天内实现了肽载量的完全释放,可以区分不同 CR 制剂之间释放行为的关键差异,从而指导制剂和工艺开发。
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