Lee H J, Riley G, Johnson O, Cleland J L, Kim N, Charnis M, Bailey L, Duenas E, Shahzamani A, Marian M, Jones A J, Putney S D
Alkermes, Inc., Cambridge, Massachusetts 02139, USA.
J Pharmacol Exp Ther. 1997 Jun;281(3):1431-9.
Long-acting formulations of recombinant human growth hormone (rhGH) were prepared by stabilizing and encapsulating the protein into three different injectable, biodegradable microsphere formulations composed of polymers of lactic and glycolic acid. The formulations were compared in juvenile rhesus monkeys by measuring the serum levels of rhGH and two proteins induced by hGH, insulin-like growth factor-I and IGF binding protein-3 (IGFBP-3) after single s.c. administration. All three formulations, which differed principally in the composition of the polymer, provided sustained elevated levels of all three proteins for several weeks, and the rate of release of rhGH differed among the formulations consistent with the molecular weight of the polymer used. All three formulations induced a higher level of insulin-like growth factor-I and insulin-like growth factor binding protein than was induced by daily injections of the same amount of rhGH in solution. After three monthly injections of one of the formulations, both the rhGH and IGF-I levels remained elevated for nearly 90 days. Immunogenicity of the rhGH released from this formulation, as assessed by the incidence of seroconversion to hGH and the titer of anti-hGH antibody in both the rhesus monkeys and transgenic mice expressing rhGH, was no greater than that of the unencapsulated protein. In addition, the microsphere injection sites appeared normal by macroscopic evaluation between 1 to 2 mo after microsphere administration and by microscopic evaluation between 2 to 3 mo. These results show that serum levels of a therapeutic protein can be sustained for an extended period when encapsulated into different formulations of injectable, biodegradable microspheres.
重组人生长激素（rhGH）的长效制剂是通过将该蛋白质稳定并封装到由乳酸和乙醇酸聚合物组成的三种不同的可注射、可生物降解微球制剂中制备而成。通过单次皮下给药后测量rhGH以及两种由hGH诱导产生的蛋白质——胰岛素样生长因子-I（IGF-I）和IGF结合蛋白-3（IGFBP-3）的血清水平，在幼年恒河猴中对这些制剂进行了比较。所有三种制剂主要在聚合物组成上有所不同，均能在数周内使所有三种蛋白质的水平持续升高，并且rhGH的释放速率在不同制剂之间存在差异，这与所使用聚合物的分子量一致。与每日注射相同量的溶液形式的rhGH相比，所有三种制剂诱导产生的胰岛素样生长因子-I和胰岛素样生长因子结合蛋白水平更高。在对其中一种制剂进行三次每月一次的注射后，rhGH和IGF-I水平在近90天内均保持升高。通过恒河猴和表达rhGH的转基因小鼠中血清转化为hGH的发生率以及抗hGH抗体的滴度评估，该制剂释放的rhGH的免疫原性不高于未封装的蛋白质。此外，在微球给药后1至2个月通过宏观评估以及2至3个月通过微观评估，微球注射部位外观正常。这些结果表明，当封装到不同的可注射、可生物降解微球制剂中时，治疗性蛋白质的血清水平可以长期维持。
