二盐酸沙丙蝶呤速释片的制备及体内外评价  

Preparation and in vitro/in vivo Evaluation of Sapropterin Dihydrochloride Immediate Release Tablets

作　　者：冯中 贾俊伟 张贵民 燕继永 侯培磊 FENG Zhong;JIA Junwei;ZHANG Guimin;YAN Jiyong;HOU Peilei(National Chiral Pharmaceuticals Engineering and Technology Research Center,Lunan Pharmaceutical Group Co.,Ltd.,Linyi 273400)

机构地区：[1]鲁南制药集团股份有限公司国家手性制药工程技术研究中心

出　　处：《中国医药工业杂志》2019年第8期883-889,共7页Chinese Journal of Pharmaceuticals

基　　金：国家手性制药工程技术研究中心(2016GGH4528)

摘　　要：在对原研制剂Kuvan处方分析的基础上,以片剂崩解时间和溶出度为评价指标,采用Box-Behnken法优化筛选出二盐酸沙丙蝶呤速释片中主要辅料甘露醇、维生素C和交联聚维酮的最佳配比;并通过单因素试验法确定压片前干颗粒粒径。最终得到的优化处方中甘露醇用量45.70%,维生素C用量9.06%,交联聚维酮用量4%;采用干法制粒得到粒径主要分布在150μm的干颗粒后压片制备了3批自制速释片。试验表明,3批制品的平均崩解时间为(35.7±5.0)s,10 min溶出率为(96.0±1.5)%。进一步考察了该自制速释片与Kuvan在Beagle犬体内的药动学特征。建立了LC-MS法测定血浆中二盐酸沙丙蝶呤的浓度。体内试验表明,自制片和Kuvan的cmax为(96.20±13.10)和(102.28±7.42)ng/ml,tmax为(2.21±1.60)和(2.17±0.41)h;自制片AUC0→t、AUC0→∞、cmax的90%置信区间均在原研制剂相应参数的80%~125%范围内。自制片的口服相对生物利用度为(92.0±8.5)%。On the basis of the research and analysis of the reference listed drug(Kuvan),the amounts of main excipient(mannitol),stabilizer(vitamin C)and disintegrant(crospovidone)in the self-made sapropterin dihydrochloride immediate release tablets were optimized by Box-Behnken design with disintegration time and dissolution at 10 min as the indexes.Moreover,particle size distribution of the granules prepared by dry granulation was screened with single factor experiment.According to the experimental results,the optimal formulation of final tablets was as follows:mannitol was 45.70%,vitamin C was 9.06%,crospovidone was 4%,and particle size of the granules before compression was about 150μm.The disintegration time and dissolution at 10 min of three batches of the final tablets were(35.7±5.0)s,(96.0±1.5)%.Furthermore,the pharmacokinetic behaviors of the final tablets and Kuvan in Beagle dogs were investigated.The drug concentration in plasma was determined by LC-MS method.The results showed that cmax values of the self-made tablets and Kuvan were(96.20±13.10)and(102.28±7.42)ng/ml,tmax values were(2.21±1.60)and(2.17±0.41)h,respectively.The 90%confidence interval(CI)for AUC0→t,AUC0→∞and cmax of the self-made tablets were within the range from 80%to 125%of the corresponding parameters of the reference preparation.The oral relative bioavailability of the self-made tablets was(92.0±8.5)%.

关 键 词：二盐酸沙丙蝶呤 速释片 处方优化 体外溶出 药动学 

分 类 号：R944.4[医药卫生—药剂学]