Felder Ch B, Blanco-Príeto M J, Heizmann J, Merkle H P, Gander B
Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
J Microencapsul. 2003 Sep-Oct;20(5):553-67. doi: 10.1080/0265204031000148059.
Peptide and protein microencapsulation into poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) microspheres continues to represent a technological challenge in terms of product sterility and up-scaling. The primary objective of this study was to examine the feasibility of a novel method for peptide and protein entrapment into PLA and PLGA microspheres, particularly suitable for up-scaling and aseptic processing. The method involves ultrasonic atomization of an organic polymer solution combined with subsequent organic solvent extraction by a hardening agent. The study evaluated the critical atomization conditions, the required molecular cohesion parameters of polymer solvents and hardening agent for particle preparation as well as the quality of entrapment and release as a function of polymer and peptide/protein type. Suitable polymer solvents and hardening agents were restricted to defined domains of fractional cohesion parameters: f(p) = 0.2-0.35 and f(h) = 0.2-0.4 for the polymer solvents, and f(p) = 0-0.1 and f(h) = 0-0.25 for the hardening agents. Microsphere size (0.1-100 micro m) was largely controlled by the viscosity of the atomized solution. Microencapsulation of the freely water-soluble bovine serum albumin and tetrapeptide thymocartin yielded modest efficiencies of 12-35%, whereas the slightly water-soluble octapeptide vapreotide pamoate was entrapped with 63-93% efficiency. Drug release was mainly governed by the polymer type, lasting over 100 days for BSA entrapped in PLA microspheres and; 20 days for vapreotide pamoate in PLGA 50 : 50 and for thymocartin in PLA. Very importantly, the novel method was readily accommodated within a laminar air-flow cabinet. Under aseptic conditions, sterile microspheres could be prepared. In conclusion, the novel method described may have potential in industrial environments.
将肽和蛋白质微囊化到聚乳酸（PLA）和聚乳酸-乙醇酸共聚物（PLGA）微球中，在产品无菌性和放大生产方面仍然是一项技术挑战。本研究的主要目的是检验一种将肽和蛋白质包封到PLA和PLGA微球中的新方法的可行性，该方法特别适用于放大生产和无菌处理。该方法包括对有机聚合物溶液进行超声雾化，随后用硬化剂进行有机溶剂萃取。本研究评估了关键的雾化条件、制备颗粒所需的聚合物溶剂和硬化剂的分子内聚参数，以及包封率和释放质量与聚合物及肽/蛋白质类型的关系。合适的聚合物溶剂和硬化剂限于分数内聚参数的特定范围：聚合物溶剂的f(p)=0.2-0.35和f(h)=0.2-0.4，硬化剂的f(p)=0-0.1和f(h)=0-0.25。微球尺寸（0.1-100μm）在很大程度上由雾化溶液的粘度控制。自由水溶性的牛血清白蛋白和四肽胸腺卡特因的微囊化效率适中，为12-35%，而微溶性的八肽醋酸伐普肽棕榈酸盐的包封效率为63-93%。药物释放主要由聚合物类型决定，包封在PLA微球中的牛血清白蛋白释放持续超过100天；PLGA 50:50中的醋酸伐普肽棕榈酸盐和PLA中的胸腺卡特因释放持续20天。非常重要的是，该新方法很容易在层流通风橱中进行。在无菌条件下，可以制备无菌微球。总之，所描述的新方法在工业环境中可能具有潜力。
