基于介质研磨法的蛇床子素纳米结晶的制备、表征及体外水溶性评价  

Preparation,Characterization and in Vitro Solubility Evaluation of Osthole Nanocrystallization Based on Wet Medium Grinding

作　　者：王梦颜 杨曼 巨倩茹 聂嘉璇 高丹 刘喜纲[1] 常金花[1] WANG Mengyan;YANG Man;JU Qianru;NIE Jiaxuan;GAO Dan;LIU Xigang;CHANG Jinhua(Hebei Province Key Laboratory of Research and Development for Chinese Medicine,Chengde Medical College,Chengde 067000,China;Pharmacy of Traditional Chinese Medicine,Cangzhou People′s Hospital,Cangzhou 061000,China)

机构地区：[1]承德医学院,河北省中药研究与开发实验室,河北承德067000 [2]沧州市人民医院中药房,河北沧州061000

出　　处：《中国药学杂志》2024年第22期2169-2178,共10页Chinese Pharmaceutical Journal

基　　金：河北省自然科学基金项目资助(H2022406073);河北省中央引导地方科技发展资金项目资助(246Z2504G);河北省高等学校科学技术研究项目资助(ZD2022121);承德医学院中药学学科建设项目资助。

摘　　要：目的以蛇床子素(osthole,OST)为模型药物,研究纳米结晶技术提高OST水溶性的适用性。方法采用介质研磨法制备蛇床子素纳米混悬液(OST-NSs),以平均粒径和多分散系数(PDI)为指标,优化处方和工艺参数;对蛇床子素纳米结晶(OST-NCs)的晶体形态、晶型及其与稳定剂相互作用进行表征;并考察其表面润湿性、平衡溶解度及其在多种介质中的体外溶出度,f2值评价溶出曲线相似性。结果OST-NCs处方和工艺参数为:OST(30 mg·mL^(-1)):聚乙烯吡咯烷酮-乙酸乙烯酯聚合物(PVP-VA64)-脱氧胆酸钠=25∶5∶1;研磨珠(0.4~0.6 mm)与OST混悬液的体积比2∶1,450 r·min^(-1)研磨70 min;90 mg·mL^(-1)甘露醇为冻干保护剂,制备OST-NCs。OST-NSs的稳定性随着温度增加而降低;OST-NCs复溶后,粒径为(354.2±9.857)nm,PDI为(0.259±0.023),Zeta电位为(-22.2±0.896)mV;OST-NCs基本保持晶体结构,呈棒状,OST和稳定剂之间无相互作用,表面润湿性优于OST及其物理混合物;OST-NCs在纯水中平衡溶解度是OST的2.31倍;在6种溶出介质中,OST-NCs的溶出速度和累积溶出度均显著优于OST及其物理混合物,而且与OST的溶出曲线相比,物理混合物的f2值均大于50,而OST-NCs的f2值均小于50。结论介质研磨法制备OST-NCs,重现性好;在制备OST-NSs时,应降低研磨温度,减少研磨时间;OST-NCs的溶出行为与OST显著不同,粒径减小是OST-NCs提高OST水溶性的主要原因;提示基于介质研磨法的纳米结晶策略能够有效改善OST的水溶性和疏水性,在OST新药开发方面具有较好的应用前景。OBJECTIVE To prepare osthole(OST)nanocrystallization and evaluate its characterization.METHODS OST-NSs were prepared by a media grinding method,and the average particle size and polydispersity index(PDI)were used as indicators to optimize the formulation and process parameters.The crystal morphology,crystal form,and interaction between OST-NCs and stabilizers were characterized.Their surface wettability,equilibrium solubility,and in vitro dissolution in various media were investigated,and the f2 value was used to evaluate the similarity of the dissolution curves.RESULTS The formulation and process parameters for preparing OST-NCs were as follows:OST(3%):PVP-VA64,sodium deoxycholate 25∶5∶1,the volume ratio of grinding beads(0.4-0.6 mm)to OST suspension was 2∶1,and it was ground at 450 r·min^(-1) for 70 min,and 9%mannitol was used as a lyophilized protective agent to prepare OST-NCs.The stability of OST-NCs decreases with increasing temperature.After reconstitution,the particle size of OST-NCs was(354.2±9.857)nm,the PDI was(0.259±0.023),and the Zeta potential was(-22.2±0.896)mV.OST-NCs basically maintain the rod-shaped crystal structure.There is no interaction between OST and the stabilizer.The surface wettability of OST-NCs is better than that of OST and its physical mixture.The equilibrium solubility of OST-NCs in pure water is 231%that of OST.Among the six dissolution media,the dissolution rate and cumulative dissolution of OST-NCs were significantly better than those of OST and its physical mixture.Additionally,the f_(2) values for the physical mixtures were greater than 50,whereas those for OST-NCs were less than 50,as compared with the dissolution curves of OST.CONCLUSION The results show that the reproducibility of OST-NCs is good during their preparation.The grinding temperature should be reduced,and the grinding time should be optimized.The dissolution behavior of OST-NCs is significantly different from that of OST.The reduction of particle size is the main reason for the improved water solubilit

关 键 词：蛇床子素 纳米混悬液 纳米结晶 介质研磨法 质量评价 

分 类 号：R944[医药卫生—药剂学]