Duan Xueyan, Liu Qingfei, Zhang Yu, Bi Kaishun, Chen Xi, Wang Yiming, Luo Guoan
Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, People's Republic of China.
Drug Dev Ind Pharm. 2009 Apr;35(4):499-507. doi: 10.1080/03639040802459437.
The objective of this study is to develop the monolithic osmotic pump tablet system (MOTS) containing isosorbide-5-mononitrate (5-ISMN), and to evaluate its in vitro and in vivo properties. The influences of tablet formulation variables, size and location of the delivery orifice, membrane variables, and pH value of the dissolution medium on 5-ISMN release from MOTS have been investigated. These results demonstrated that the tablet core played an important role in MOTS, and membrane variables could affect the 5-ISMN release rate. The optimal formulation of 5-ISMN MOTS was determined by uniform design. Furthermore, the dog pharmacokinetics and relative bioavailability of the test formulation (5-ISMN MOTS) have been compared with the reference formulation (Imdur: 60 mg/tablet, a sustained release, SR, tablet system) following an oral single dose of 60 mg given to each of six Beagle dogs. The mean drug fraction absorbed by the dog was calculated by the Wagner-Nelson technique. The results showed that drug concentration in plasma could be maintained more stable and longer after the administration of 5-ISMN MOTS compared with the matrix tablets of Imdur, and a level A "in vitro-in vivo correlation" was observed between the percentage released in vitro and percentage absorbed in vivo. It is concluded that 5-ISMN MOTS is more feasible for a long-acting preparation than 5-ISMN SR tablet system as once-a-day treatment, and it is very simple in preparation, and can release 5-ISMN at the rate of approximately zero order for the combination of hydroxypropylmethyl cellulose as retarder and NaCl as osmogent.
本研究的目的是开发含5-单硝酸异山梨酯（5-ISMN）的整体式渗透泵片系统（MOTS），并评估其体外和体内性质。研究了片剂处方变量、释药孔的大小和位置、包衣膜变量以及溶出介质的pH值对MOTS中5-ISMN释放的影响。这些结果表明，片芯在MOTS中起重要作用，包衣膜变量可影响5-ISMN的释放速率。通过均匀设计确定了5-ISMN MOTS的最佳处方。此外，将受试制剂（5-ISMN MOTS）与参比制剂（依姆多：60mg/片，一种缓释片剂系统）进行了犬体内药代动力学和相对生物利用度比较，对6只比格犬每只口服单剂量60mg。采用Wagner-Nelson法计算犬的平均药物吸收分数。结果表明，与依姆多的骨架片相比，给予5-ISMN MOTS后血浆中的药物浓度能维持更稳定和更长时间，并且观察到体外释放百分比与体内吸收百分比之间存在A级“体外-体内相关性”。结论是，5-ISMN MOTS作为每日一次治疗的长效制剂比5-ISMN缓释片剂系统更可行，其制备非常简单，并且由于羟丙基甲基纤维素作为阻滞剂和氯化钠作为渗透促进剂的组合，5-ISMN能以近似零级的速率释放。
