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作 者:邹茜茜 郜珍叶 张伟捷 吴飞[1] 金拓[1] ZOU Xixi;GAO Zhenye;ZHANG Weijie;WU Fei;JIN Tuo(School of Pharmacy,Shanghai Jiao Tong University,Shanghai 200240)
出 处:《中国医药工业杂志》2022年第10期1439-1445,共7页Chinese Journal of Pharmaceuticals
基 金:国家自然科学基金项目(81872802)。
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(10~14h)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,22d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1h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。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 F8 was 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 dl 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.
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