Katre N V, Asherman J, Schaefer H, Hora M
DepoTech Corporation, 10450 Science Center Drive, San Diego, California 92121 and Chiron Corporation, 4560 Horton Street, Emeryville, California 94608, USA.
J Pharm Sci. 1998 Nov;87(11):1341-6. doi: 10.1021/js980080t.
Insulin-like Growth Factor I (IGF-I), a 7.65 kD protein which has a variety of metabolic functions, is being evaluated for its therapeutic benefit in several disease states. To sustain therapeutic blood levels in a number of these instances, IGF-I needs to be administered repeatedly. The objective of these studies was the development of a sustained-release depot delivery system for this protein which would replace repeated administration. Using a multivesicular liposome drug delivery system (DepoFoam), sustained delivery kinetics have been observed for IGF-I. IGF-I was successfully encapsulated in this system with good efficiency. The integrity of the encapsulated protein was maintained, as characterized by physiochemical (HPLC, SDS-PAGE), and by biological methods (mitogenic activity). The DepoIGF-I particles were also characterized by their morphology (particles were smooth, multivesicular, and there was no debris), particle size (ranged from 18 to 20 microm), and in vitro and in vivo release kinetics of IGF-I. The DepoIGF-I particles released the protein drug in a sustained manner both in vitro and in vivo without a rapid initial release, and the released protein maintained its structural integrity and biological activity. The in vitro studies in human plasma at 37 degreesC showed that the DepoIGF-I particles released IGF-I slowly over several days; 70-80% of the protein was released in 6-7 days. In a pharmacokinetic in vivo study, after subcutaneous injections in rats, IGF-I levels were sustained for 5-7 days with DepoIGF-I formulation, whereas IGF-I in the free form was cleared in 1 day. DepoFoam technology provides a pharmaceutically useful system of sustained delivery for proteins, which can be extended to other therapeutic macromolecules.
胰岛素样生长因子I（IGF-I）是一种具有多种代谢功能的7.65千道尔顿蛋白质，目前正在多种疾病状态下评估其治疗益处。在许多情况下，为维持治疗性血药浓度，需要反复给予IGF-I。这些研究的目的是开发一种用于该蛋白质的缓释贮库给药系统，以替代反复给药。使用多囊脂质体药物递送系统（DepoFoam），已观察到IGF-I的持续释放动力学。IGF-I成功高效地封装在该系统中。通过物理化学方法（高效液相色谱法、十二烷基硫酸钠-聚丙烯酰胺凝胶电泳）和生物学方法（促有丝分裂活性）表征，证实封装蛋白质的完整性得以维持。DepoIGF-I颗粒还通过其形态（颗粒光滑、多囊，无碎片）、粒径（范围为18至20微米）以及IGF-I的体外和体内释放动力学进行表征。DepoIGF-I颗粒在体外和体内均以持续方式释放蛋白质药物，无快速初始释放，且释放的蛋白质保持其结构完整性和生物学活性。在37℃人血浆中的体外研究表明，DepoIGF-I颗粒在数天内缓慢释放IGF-I；6至7天内释放70 - 80%的蛋白质。在大鼠体内的药代动力学研究中，皮下注射DepoIGF-I制剂后，IGF-I水平可持续5至7天，而游离形式的IGF-I在1天内清除。DepoFoam技术为蛋白质提供了一种药学上有用的持续递送系统，该系统可扩展至其他治疗性大分子。
