【作者】 石凯； 蒋艳博； 崔福德；

【Author】 SHI Kai 1, JIANG Yan-bo 1 , CUI Fu-de 1 (1. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China)

【机构】 沈阳药科大学药学院；

【摘要】 目的研究结晶度对球形化自组装干扰素体内外释放行为的影响。方法采用静态结晶技术制备球形化干扰素,以结晶度为指标表征不同自组装物的分子有序度;对其体外溶出特性进行考察,并比较家兔皮下注射给药的体内药动学行为。结果调节自组装过程中的蛋白质过饱和度,可获得无定形及结晶化的球形干扰素。无定形聚集体回收率可达到96.5%,平均粒径～0.6μm;两种结晶化干扰素外观呈单分散球形颗粒,回收率均大于80%,平均粒径10～20μm,结晶度分别为23.2%和30.8%。随着结晶度的提高,自组装物的体外溶出速率显著降低。家兔皮下吸收无定形和结晶化球形干扰素后,血药达峰时间(Tmax)分别由(6.00±1.40)h推迟至(13.20±2.68)h和(22.40±3.57)h,消除半衰期(t1/2)由(4.75±0.82)h延长至(10.68±1.97)h和(29.17±4.93)h。结论结晶化球形自组装干扰素能够显著改善其体内外释药性能,可作为一种新型蛋白质类药物缓释传递系统。更多还原

【Abstract】 OBJECTIVE To investigate effect of crystallinity on in vitro and in vivo release behaviors of spherical self-assembly of rhIFN. METHODS Recombinant human interferon-alpha (rhIFN) can form spherical self-assembly by static crystallization method. The crystallinity was determined by X-ray to characterize molecular ordered degree of various spherical self-assembly. The drug dissolution in vitro and the pharmacokinetics in vivo were compared. RESULTS The spherical self-assembly of rhIFN in amorphous and crystalline forms were obtained through adjusting protein supersaturation during self-assembly process. The amorphous precipitates were characterized as recovery of 96.5% and mean diameter size of ～0.6μm. Two kinds of crystallized rhIFN were characterized as mono-dispersed spheres, with yield of >80%, mean diameter size of 10~20μm. Their crystallinity was 23.2% and 30.8%, respectively. The dissolving rates of spherical self-assemblies were decreased significantly as increased in crystallinity. After s.c. administration of spherical self-assembly of rhIFN in amorphous and crystalline forms, the peak time (T max ) were retarded from (6.00±1.40)h to (13.20±2.68)h and (22.40±3.57)h, the corresponding half life (t 1/2 ) were prolonged from (4.75±0.82)h to (10.68±1.97)h and (29.17±4.93)h. CONCLUSION The spherical self-assemblies of rhIFN in crystalline form can improve their release performance either in vitro or in vivo, which provide a new candidate for sustained delivery of therapeutic proteins.更多还原