头孢托仑匹酯超饱和自乳化颗粒剂的制备及质量评价

Preparation of cefditoren pivoxil supersaturated self-emulsifying drug delivery systems granules

目的制备添加了沉淀抑制剂的头孢托仑匹酯超饱和自乳化释药系统(CEFP-S-SEDDSs)及其颗粒剂,并评价其质量。方法通过溶解度实验和伪三元相图确定头孢托仑匹酯自乳化释药系统(CEFP-SEDDSs)的处方组成及比例,并以羟丙基甲基纤维素(HPMC-E5)作为沉淀抑制剂,制备得到CEFP-S-SEDDSs;采用硅酸铝镁作为载体固化CEFP-SSEDDSs,并与其他辅料混合制备成CEFP-S-SEDDSs颗粒剂;评价CEFP-S-SEDDSs颗粒剂的理化性质——热力学稳定性、自乳化效果、稀释稳定性、微观形态;比较CEFP-S-SEDDSs颗粒剂和市售头孢托仑匹酯颗粒剂的体外溶出度。结果CEFPSEDDSs的处方组成:单亚油酸甘油酯(Maisine CC)为油相,15-羟基硬脂酸聚乙二醇酯(Solutol HS15)为乳化剂,二乙二醇单乙基醚(Transcutol HP)为助乳化剂,配比为6∶2∶2。CEFP-S-SEDDSs及其颗粒剂经pH 1.2盐酸溶液稀释后均形成的微乳呈球状,分散性良好,其形成的微乳粒径分别为(104.6±3.7)、(139.5±3.8)nm,分散性指数(PDI)分别为(0.174±0.009)和(0.208±0.012),Zeta电位分别为(−13.6±0.6)mV和(−13.4±0.3)mV。CEFP-S-SEDDSs颗粒剂在pH 1.2盐酸介质溶液中溶出速度与市售头孢托仑匹酯颗粒剂相当;但当介质溶液pH值升高至6.8后,市售CEFP颗粒剂中的药物浓度急剧下降,大量药物以沉淀形式析出,CEFP-S-SEDDSs颗粒剂仅有少部分以沉淀形式析出。结论CEFP-SSEDDSs颗粒剂能够有效抑制因pH值变化而导致CEFP析出沉淀,有望促进药物充分吸收,提高药物生物利用度.

Objective To prepare cefditoren pivoxil supersaturated self-emulsifying drug delivery systems(CEFP-S-SEDDSs)and its granules,and to evaluate their properties.Methods The composition and proportion of CEFP-SEDDSs were determined by solubility test and pseudo-ternary phase diagram,and HPMC-E5 was used as a precipitation inhibitor to prepare CEFP-S-SEDDSs.The CEFP-S-SEDDSs granules were prepared by using aluminum magnesium silicate as a carrier and mixing with other excipients.The physicochemical properties(thermodynamic stability,self-emulsification effect,dilution stability,microstructure)of CEFP-SSEDDSs granules were evaluated.The in vitro dissolution of ceftoren pivoxil granules and CEFP-S-SEDDSs granules were compared.Results The formulation of CEFP-SEDDSs was composed of Maisine CC as the oil phase,Solutol HS15 as the emulsifiers,and Transcutol HP as the co-emulsifiers,with the ratio of 6:2:2.The microemulsions formed by CEFP-S-SEDDSs and its granules diluted with pH 1.2 hydrochloric acid solution were spherical and well dispersed.The particle size of the microemulsions formed by CEFP-S-SEDDSs and its granules were(104.6±3.7)nm and(139.5±3.8)nm,the PDI were(0.174±0.009)and(0.208±0.012),the Zeta potential were(−13.6±0.6)mV and(−13.4±0.3)mV,respectively.The dissolution rate of CEFP-SSEDDSs granules in pH1.2 hydrochloric acid medium solution was equivalent to that of cefditoren pivoxil granules,however,when the pH value of the medium solution increases to 6.8,the drug concentration in commercially available CEFP granules sharply decreases,and a large number of drugs precipitate in the form of precipitation,and only a small portion of CEFP-S-SEDDSs granules precipitate in the form of precipitation.Conclusion CEFP-S-SEDDSs granules can effectively inhibit the precipitation of CEFP caused by pH changes,which is expected to promote full drug absorption and improve drug bioavailability.