Michaelides Kyprianos, Al Tahan Mohamad Anas, Zhou Yundong, Trindade Gustavo F, Cant David J H, Pei Yiwen, Dulal Pawan, Al-Khattawi Ali
School of Pharmacy, Aston University, Birmingham B4 7ET, U.K.
Chemical and Biological Sciences Department, National Physical Laboratory, Hampton Road, Teddington TW11 0LW, U.K.
Mol Pharm. 2024 Dec 2;21(12):6245-6256. doi: 10.1021/acs.molpharmaceut.4c00686. Epub 2024 Oct 25.
Spray drying is one of the leading manufacturing methods for active pharmaceutical ingredients (APIs) owing to its rapid, single-step, and cost-effective nature. It also has the capacity to generate microspheres capable of controlled release of APIs including biomolecules and vaccines. However, one of the key challenges of spray-dried formulations especially with poly(lactic--glycolic acid) (PLGA)-based controlled-release injectables is burst release, where a significant fraction of the API is released prematurely within a short period of time following administration, leading to detrimental impact on the performance and quality of end products. This study uses a model API, bovine serum albumin (BSA) protein, to identify the sources of burst release that may affect the kinetics and performance of long-acting injectable microsphere formulations. Spray-dried microspheres with various formulations (i.e., variable BSA/PLGA ratios) were characterized in terms of their morphology, particle size, surface area, thermal properties, moisture content, as well as chemical compositions and their distributions to investigate the impact of spray drying on the burst release phenomenon. The results suggest that a relatively high initial release (85%) observed is mainly attributed to the protein distribution close to the particle surface. Morphology analysis provided evidence that the microspheres retained their spherical structure during the burst release phase. X-ray photoelectron spectroscopy, hard X-ray photoelectron spectroscopy, and argon cluster sputtering-assisted time-of-flight secondary ion mass spectrometry analysis suggest an enrichment of PLGA on particle surfaces with buried BSA protein. The statistically significant difference in particle size and surface area between three different formulations may be responsible for an initial variation in release but did not seem to alter the overall burst release profile. Considering the suggested source of burst release, the two-fluid spray-drying method, characterized by a single liquid feed delivering a preprepared emulsion, generated matrix-type microspheres with a surface layer of PLGA, as evidenced by surface analysis. The PLGA surface layer proved to be prone to degradation and pore formation, allowing for faster diffusion of BSA out of the microspheres, resulting in a burst release. Increasing the polymer concentration did not seem to halt this process.
喷雾干燥是活性药物成分（API）的主要制造方法之一，因其具有快速、单步且经济高效的特性。它还能够生成能够控制包括生物分子和疫苗在内的API释放的微球。然而，喷雾干燥制剂的关键挑战之一，尤其是基于聚（乳酸-乙醇酸）（PLGA）的控释注射剂，是突释现象，即在给药后的短时间内，很大一部分API会过早释放，从而对最终产品的性能和质量产生不利影响。本研究使用模型API牛血清白蛋白（BSA）蛋白，来确定可能影响长效注射微球制剂动力学和性能的突释来源。对具有各种配方（即不同BSA/PLGA比例）的喷雾干燥微球，在形态、粒径、表面积、热性能、水分含量以及化学成分及其分布方面进行了表征，以研究喷雾干燥对突释现象的影响。结果表明，观察到的相对较高的初始释放率（85%）主要归因于靠近颗粒表面的蛋白质分布。形态分析提供的证据表明，微球在突释阶段保持了其球形结构。X射线光电子能谱、硬X射线光电子能谱和氩簇溅射辅助飞行时间二次离子质谱分析表明，PLGA在含有埋藏的BSA蛋白的颗粒表面富集。三种不同配方之间粒径和表面积的统计学显著差异可能是释放初始差异的原因，但似乎并未改变整体突释曲线。考虑到所提出的突释来源，以单一液体进料输送预先制备的乳液为特征的双流喷雾干燥方法，生成了具有PLGA表面层的基质型微球，表面分析证明了这一点。事实证明，PLGA表面层易于降解和形成孔隙，使得BSA能够更快地从微球中扩散出来，从而导致突释。增加聚合物浓度似乎并不能阻止这一过程。
