结晶度对球形化自组装干扰素体内外释放行为的影响

Effect of Crystallinity on in Vitro and in Vivo Release Behaviors of Spherical Self-Assembly of rhIFN

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达到96．5％，平均粒径约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。家兔皮下注射无定形和结晶化球形干扰素后，血药达峰时间（tmax）由（6．00±1．40）h推迟至（13．20±2．68）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）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。

OBJECTIVE To investigate effect of crystallinity on in vitro and in vivo release behaviors of spherical self-assem- bly of Recombinant human interferon-alpha （rhlFN）. METHODS rhIFN can form spherical self-assembly by static crystalliza- tion method. The crystallinity was determined by X-ray to characterize molecular ordered degree of various spherical crystals. The drug dissolution in vitro and the pharmacokinetics in vivo of various rhIFN forms were further investigated. 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 0.6 μm. 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 de- creased significantly with increased crystallinity. After s. c. administration of spherical self-assembly of rhIFN in amorphous and crystalline forms, the peak time （tmax） were retarded from （6.00＋1.40） h to （13.20_＋2.68） and （22.40±3.57） h, the corresponding half life （tL/2） were prolonged from （4.75 ±0.82） h to （ 10.68±1.97） 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.