Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.
Evaluation and Research, Office of Research and Standards, Office of Generic Drugs, Center for Drug, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MA, 20993, USA.
Drug Deliv Transl Res. 2022 Mar;12(3):695-707. doi: 10.1007/s13346-021-01013-5. Epub 2021 Jul 3.
Sandostatin long-acting release® (SLAR) is a long-acting injectable somatostatin analogue formulation composed of octreotide encapsulated in glucose-initiated poly(lactic-co-glycolic acid) (PLGA) microspheres. Despite the end of patent protection, SLAR remains resistant to generic competition likely due to complexity of production process, the uniqueness of the glucose star polymer, and the instability of octreotide in the formulation. Here, we describe development of glucose-PLGA-based composition-equivalent to SLAR formulations prepared by double emulsion-solvent evaporation method and the effect of variations in encapsulation variables on release kinetics and other formulation characteristics. The following encapsulation variables were adjusted at constant theoretical loading of 7.0% peptide: PLGA concentration, pH of inner water phase, and stirring rate. After final drying, the microspheres were examined with and without annealing at 50 °C under vacuum for 3 days. The loading and encapsulation efficiency (EE) of octreotide acetate, manufacturing yield, and in vitro drug release kinetics in PBStc (10 mM phosphate-buffered saline (PBS) with 1% triethyl citrate and 0.02% sodium azide at pH 7.4) were determined by UPLC. The in vitro release and acylation kinetics of octreotide for the solvent evaporation formulations prepared were similar to SLAR although the initial burst was slightly higher. Key formulation steps identified to maximize microsphere yield and minimize residual solvent and initial burst release included (a) addition of acetic acid to the peptide before preparation and (b) annealing the microspheres under vacuum after drying. Controlled release octreotide formulations prepared and investigated in this study could provide a better understanding of the effect of production variables on release performance and supply information useful for making progress in manufacturing of SLAR generic equivalents.
善龙（注射用醋酸奥曲肽微球）是一种长效的注射用生长抑素类似物，由包裹在葡萄糖起始的聚乳酸-羟基乙酸共聚物（PLGA）微球中的奥曲肽组成。尽管专利保护已经结束，但善龙仍然难以被仿制药替代，这可能是由于其生产工艺的复杂性、葡萄糖起始星型聚合物的独特性以及配方中奥曲肽的不稳定性所致。在这里，我们描述了基于葡萄糖的 PLGA 组成物的开发——相当于通过复乳-溶剂蒸发法制备的善龙制剂，以及在恒定理论载药量为 7.0%肽的情况下，改变包封变量对释放动力学和其他制剂特性的影响。以下包封变量在调整时保持 PLGA 浓度、内水相 pH 和搅拌速度不变：奥曲肽醋酸盐的载药量和包封效率（EE）、制剂产率以及在 PBStc（10 mM 磷酸盐缓冲盐水（PBS）中含有 1%柠檬酸三乙酯和 0.02%叠氮化钠，pH 值为 7.4）中的体外药物释放动力学。通过 UPLC 测定了奥曲肽醋酸盐的载药量和包封效率（EE）、制剂产率以及在 PBStc（10 mM 磷酸盐缓冲盐水（PBS）中含有 1%柠檬酸三乙酯和 0.02%叠氮化钠，pH 值为 7.4）中的体外药物释放动力学。通过 UPLC 测定了奥曲肽醋酸盐的载药量和包封效率（EE）、制剂产率以及在 PBStc（10 mM 磷酸盐缓冲盐水（PBS）中含有 1%柠檬酸三乙酯和 0.02%叠氮化钠，pH 值为 7.4）中的体外药物释放动力学。通过 UPLC 测定了奥曲肽醋酸盐的载药量和包封效率（EE）、制剂产率以及在 PBStc（10 mM 磷酸盐缓冲盐水（PBS）中含有 1%柠檬酸三乙酯和 0.02%叠氮化钠，pH 值为 7.4）中的体外药物释放动力学。通过 UPLC 测定了
溶剂蒸发制剂的体外释放和奥曲肽的酰化动力学与善龙相似，尽管初始突释略高。为了最大限度地提高微球产率并最小化残留溶剂和初始突释释放，确定了关键的制剂步骤，包括（a）在制备前向肽中添加醋酸，以及（b）在干燥后将微球在真空下退火。本研究中制备和研究的控释奥曲肽制剂可以更好地了解生产变量对释放性能的影响，并提供有助于善龙仿制药生产的有用信息。
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