Putney S D, Burke P A
Alkermes, Inc., Cambridge, MA 02139, USA.
Nat Biotechnol. 1998 Feb;16(2):153-7. doi: 10.1038/nbt0298-153.
Although numerous protein therapeutics have been approved or are in advanced clinical testing, the development of more sophisticated delivery systems for this rapidly expanding class of therapeutic agents has not kept pace. The short in vivo half-lives, the physical and chemical instability, and the low oral bioavailability of proteins currently necessitate their administration by frequent injections of protein solutions. This problem can be overcome by use of injectable depot formulations in which the protein is encapsulated in, and released slowly from, microspheres made of biodegradable polymers. Although the first report of sustained release of a microencapsulated protein was more than 20 years ago, the instability of proteins in these dosage forms has prevented their clinical use. Advances in protein stabilization, however, have allowed development of sustained-release forms of several therapeutic proteins, and clinical testing of a monthly formulation human growth hormone is currently in progress. The obvious advantage of this method of delivery is that the protein is administered less frequently, sometimes at lower overall doses, than when formulated as a solution. More importantly, it can justify commercial development of proteins that, for a variety of reasons, could not be marketed as solution formulations.
尽管众多蛋白质疗法已获批准或正处于晚期临床试验阶段，但针对这类迅速扩展的治疗药物开发更先进的递送系统却未能跟上步伐。蛋白质目前在体内的半衰期短、物理和化学性质不稳定以及口服生物利用度低，这使得它们目前需要通过频繁注射蛋白质溶液来给药。使用可注射长效制剂可以克服这个问题，在这种制剂中，蛋白质被包裹在由可生物降解聚合物制成的微球中，并从微球中缓慢释放。尽管微囊化蛋白质缓释的首次报道距今已有20多年，但这些剂型中蛋白质的不稳定性阻碍了它们的临床应用。然而，蛋白质稳定化方面的进展使得几种治疗性蛋白质的缓释剂型得以开发，一种每月给药一次的人生长激素制剂目前正在进行临床试验。这种给药方法的明显优势在于，与制成溶液剂型相比，蛋白质的给药频率更低，有时总剂量也更低。更重要的是，对于因各种原因无法作为溶液剂型上市的蛋白质，这种方法可以推动其商业化开发。
