Jones AJ, Putney S, Johnson OL, Cleland JL
Alkermes, Cambridge, MA 02139, USA
Adv Drug Deliv Rev. 1997 Oct 13;28(1):71-84. doi: 10.1016/s0169-409x(97)00051-3.
The development of a sustained release formulation of recombinant human growth hormone (rhGH) has focused on a depot preparation using the biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), for microsphere production. These formulations have been designed to assure the maintenance of protein integrity both during the microencapsulation process and upon subsequent release in vitro and in vivo. In addition, animal models were developed to assess both the in vivo release kinetics and the potency of the released protein. These studies emphasized the importance of obtaining a correlation between the in vivo and in vitro release at an early stage of development. Juvenile rhesus monkey studies revealed that continuous rhGH administration resulted in a greater total insulin-like growth factor-I (IGF-I) response than daily rhGH administration, indicating that a continuous rhGH dose may provide comparable efficacy to daily dosing at a lower total dose of rhGH. The use of a conventional water-in-oil-in-water process yielded a triphasic release of biologically active and non-immunogenic rhGH, while the novel cryogenic process achieved a continuous release of rhGH that is biologically active and non-immunogenic. The rhGH PLGA formulation produced by the novel cryogenic process was manufactured under aseptic GMP conditions and was shown to be safe in growth hormone-deficient adults. This protein and these studies should serve as a model for the future development of PLGA formulations for therapeutic proteins.
重组人生长激素（rhGH）缓释制剂的研发主要集中在利用可生物降解聚合物聚乳酸-乙醇酸共聚物（PLGA）制备微球的长效制剂。这些制剂的设计目的是确保在微囊化过程中以及随后的体外和体内释放过程中蛋白质的完整性得以维持。此外，还建立了动物模型来评估体内释放动力学和释放蛋白的效力。这些研究强调了在研发早期建立体内和体外释放相关性的重要性。幼年恒河猴研究表明，持续给予rhGH比每日给予rhGH产生的总胰岛素样生长因子-I（IGF-I）反应更大，这表明持续rhGH剂量在较低的rhGH总剂量下可能提供与每日给药相当的疗效。使用传统的水包油包水工艺可实现具有生物活性和非免疫原性的rhGH的三相释放，而新型低温工艺可实现具有生物活性和非免疫原性的rhGH的持续释放。通过新型低温工艺生产的rhGH PLGA制剂是在无菌GMP条件下制造的，并已证明对生长激素缺乏的成年人是安全的。这种蛋白质和这些研究应为未来治疗性蛋白质PLGA制剂的开发提供一个范例。
