硝酸异山梨酯片的制备和体内外评价  

Preparation of isosorbide dinitrate tablets and in vitro and in vivo evaluation

作　　者：王楠 李正照 贾俊伟 冯中 WANG Nan;LI Zheng-zhao;JIA Jun-wei;FENG Zhong(School of Pharmacy,Shandong University of traditional Chinese medicine,Jinan 250355,China;School of Pharmacy,Ocean University of China,Qingdao 266100,China;Lunan Pharmaceutical Group Co.,Ltd.,Shandong Pharmaceutical International Engineering Laboratory,Linyi 273400,China)

机构地区：[1]山东中医药大学药学院,济南250355 [2]中国海洋大学药学院,青岛266100 [3]鲁南制药集团股份有限公司/山东省药物国际化工程实验室,临沂273400

出　　处：《中国新药杂志》2025年第8期863-870,共8页Chinese Journal of New Drugs

基　　金：泰山产业领军人才项目(TSCX202306086)。

摘　　要：目的:制备硝酸异山梨酯自研片并测定其体外溶出曲线,进行处方优化及体内外评价,并考察药动学特征。方法:以溶出度为考察指标,采用Box-Behnken法优化筛选硝酸异山梨酯片中主要辅料硬脂酸镁、微晶纤维素PH102和聚维酮K30的最佳占比;采用干法制粒工艺,考察整粒筛网孔径、压辊油压和螺旋进料转速等因素对体外溶出的影响;采用平行人工渗透膜法预测自研片与原研制剂是否生物等效;通过对Beagle犬进行口服给药,研究药物在其体内的药动学特征。结果:优化处方为羧甲淀粉钠9.23%、硬脂酸镁1.02%、交联聚维酮4.74%,10 min内累积释放率为91.13%。优化工艺为整粒筛网孔径大小为1.0 mm,压辊油压为130 bar,螺旋进料转速为50 r·min-1。自研片和原研制剂的渗透速率分别为0.0206和0.0195μg·mL-1·min-1,膜渗透性分别为2.23×10-4和2.09×10-4 cm·s-1,自研片的置信区间为99.58%~109.29%。两者的药动学参数均无统计学差异(P>0.05),自制制剂中2-硝酸异山梨酯的相对生物利用度为106.16%,5-硝酸异山梨酯的相对生物利用度为102.62%,硝酸异山梨酯的相对生物利用度为110.58%,与参比制剂生物等效。结论:本文研究的硝酸异山梨酯片处方工艺可行,稳定性和生物等效性较好,与参比制剂相似。Objective:To prepare isosorbide dinitrate tablets and determine its dissolution curve in vitro,optimize the formulation,conduct evaluate in vitro and in vivo,and investigate its pharmacokinetics in rats.Methods:The dissolution of isosorbide dinitrate tablets was determined by Box-Behnken method to optimize the proportions of the main excipients,magnesium distearate cellulose PH102 and polyvidone K30 in isosorbide dinitrate tablets,and the dry granulation process was used.The effects of the proportion of raw materials,the pore size of the whole sieve,the pressure of the press roller,and the rotating speed of the screw feed on the dissolution in vitro were investigated.Results:The optimized formulation was as follows:carboxymethyl starch sodium 9.23%,magnesium distearate 1.02%,and cross-linked povidone 4.74%,and the cumulative release rate within 10 min was 91.13%.The optimized process was as follows:the proportion of raw material was isosorbide dinitrate lactose 4∶6,the size of the whole sieve mesh was 1.0 mm,the oil pressure of the roller was 130 bar,and the rotational speed of the screw feed was 50 r·min-1.The permeation rates of the self-developed tablets and the original preparation were 0.0206 and 0.0195μg·mL-1·min-1,respectively.The membrane permeation rates were 2.23×10-4 and 2.09×10-4 cm·s-1,respectively.The confidence interval of the self-developed tablets was 99.58%~109.29%.The pharmacokinetic parameters of the two preparations had no statistical difference(P>0.05),the relative bioavailability of homemade preparations 2-ISDN was 106.16%,that of 5-ISDN was 102.62%,while that of ISDN was 110.58%,all equivalent to the reference preparation.Conclusion:The preparation process of isosorbide dinitrate tablets established in this paper is feasible and stable,and the products are bioequivalent to the reference preparation.

关 键 词：硝酸异山梨酯片 Box-Behnken法 平行人工膜渗透法 处方工艺 体外溶出 

分 类 号：R943[医药卫生—药剂学]