Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, United States.
Office of Research and Standards, Office of Generic Drugs, Center for DrugEvaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MA 20993, United States.
Int J Pharm. 2022 Aug 25;624:121842. doi: 10.1016/j.ijpharm.2022.121842. Epub 2022 May 21.
Sandostatin long-acting release (SLAR) depot for 1-month controlled release of octreotide is a somatostatin analogue product that has been used extensively in the pharmacological treatment of acromegaly. The complexities in the SLAR coacervation manufacturing processes and the use of a unique glucose-starpoly(lactic-co-glycolic acid) (PLGA-glu) may have contributed to the lack of US FDA-approved generic products referencing SLAR in the USA. To address this challenge, we encapsulated octreotide acetate by the commonly used solvent evaporation method in microspheres of a similar composition to SLAR, including the use of a comparable PLGA-glu. Based on our previous study that identified key formulation variables to prepare octreotide acetate/PLGA-glu microspheres, including lowering initial peptide pH and introducing an annealing step post loading, here we added NaCl to the external water phase to further improve the formulation. The resulting microspheres exhibited highly similar release and stability performance in vitro to SLAR, including an exceptionally low initial burst. The very low initial burst was also confirmed by pharmacokinetics in rats. Full erosion behavior analysis (polymer MW, water uptake and mass loss) revealed a slightly faster degradation of SLAR than the solvent evaporation formulations. Analysis of kinetics of dry Tg of the formulations reflected (a) the elevated residual solvent in SLAR and was not duplicated in the solvent evaporation formulations, and (b) the slightly higher Tg of peptide loaded formulations relative to than blank microspheres, consistent with the interaction of the acetate salt of octreotide with linear PLGA chains in the PLGA-glu. These data indicate that it is possible to prepare peptide loaded microspheres by the solvent evaporation method with extraordinarily similar performance to microspheres, such as those in SLAR, that are prepared by the low-burst release coacervation method.
奥曲肽长效释放（SLAR）混悬剂是一种用于治疗肢端肥大症的生长抑素类似物产品，它具有 1 个月的控释作用。SLAR 凝聚包封制造工艺的复杂性以及使用独特的葡萄糖-star 聚（乳酸-共-乙醇酸）（PLGA-glu）可能是导致美国食品和药物管理局（FDA）未批准美国参照 SLAR 的通用产品的原因。为了解决这一挑战，我们采用常用的溶剂蒸发法将奥曲肽醋酸盐包封在微球中，其组成与 SLAR 相似，包括使用类似的 PLGA-glu。基于我们之前的研究，确定了制备奥曲肽醋酸盐/PLGA-glu 微球的关键配方变量，包括降低初始肽 pH 值和在加载后引入退火步骤，在此基础上，我们在外部水相中添加 NaCl 以进一步改善配方。所得微球在体外表现出与 SLAR 高度相似的释放和稳定性性能，包括极低的初始突释。在大鼠的药代动力学研究中也证实了初始突释非常低。完全侵蚀行为分析（聚合物 MW、吸水率和质量损失）表明，SLAR 的降解速度略快于溶剂蒸发制剂。对制剂干燥 Tg 动力学的分析反映了（a）SLAR 中残留溶剂较高，而在溶剂蒸发制剂中没有重复出现，（b）与空白微球相比，负载肽的制剂的 Tg 略高，这与奥曲肽醋酸盐与 PLGA-glu 中的线性 PLGA 链相互作用一致。这些数据表明，通过溶剂蒸发法制备肽负载微球是可行的，其性能与通过低突释凝聚包封法制备的微球非常相似，例如 SLAR 中的微球。
