【摘要】 凝血因子Ⅷ(F8)作为治疗血友病常用药物之一，存在半衰期短(10～14 h)的缺点，其注射剂需每周多次给药。为获得F8的长效缓释制剂，该研究通过热开环聚合法得到具反向热敏性质的三嵌段聚合物PLGA-PEG-PLGA作为温敏水凝胶基质，制备了一种新型长效缓释的温度敏感型水凝胶载F8制剂，在4℃及以下呈溶液，37℃附近呈凝胶，并考察了其体外活性及体内外释放行为。结果显示，体外释放试验中，d1突释了约17.4%的载药量，总共实现了3周左右的释放，22 d时F8的累积释放率达到92%；制剂成胶前后F8活性达到97%以上，且释放过程中释放液中的F8活性仍能维持在60%以上，提示温敏水凝胶中的F8能维持稳定。体内释放曲线表明，大鼠在给药后1 h达到血药浓度峰值，为(113.21±14.50)ng/ml，整个缓释周期内，血药浓度可维持在最低治疗浓度(10ng/ml)以上长达15d。该研究成功开发了一种F8长效缓释制剂，具有临床应用潜力。更多还原

【Abstract】 Coagulation factor Ⅷ(F8), one of the most common drug for treating hemophilia, has the disadvantage of a short half-life(10-14 h), and its injection needs to be administered several times a week. In order to obtain a long-acting sustained-release preparation of F8, a triblock polymer PLGA-PEG-PLGA with reverse thermosensitive properties synthesized by thermal ring-opening polymerization was used as a thermosensitive hydrogel matrix to prepare a novel long-acting sustained-release preparation loaded with F8. This thermosensitive hydrogels of F8was an aqueous solution below 4 ℃ and turns into gel at around 37 ℃. In vitro activity and in vitro and in vivo release behaviors of F8-loaded hydrogel formulation were investigated. The results of in vitro release test showed that 17.4% of the drug loading, namely initial burst release, was observed on d1 and the drug release from the gels could maintain for 3 weeks. The cumulative amount of F8 at 22 d reached 92%. The results showed that the bioactivities of F8 in the solution before and after gelation was more than 97%, and the bioactivities of F8 in release media were all above 60% during the release process, indicating the stability of F8 in the thermosensitive hydrogels. The results of in vivo test showed that F8 quickly reached the peak plasma concentration[(113.21±14.50)ng/ml] within one hour after injection administration to the rats. During the whole release period, the plasma concentration could maintain above the lowest therapeutic concentration(10 ng/ml) for up to 15 days. In this study, we successfully developed a long-acting sustained-release formulation of F8, which had potential for clinical application.更多还原