State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Nanjing Kang Bixin Pharmaceutical Technology Co., Ltd, Nanjing 210046, PR China.
Int J Pharm. 2014 May 15;466(1-2):276-85. doi: 10.1016/j.ijpharm.2014.03.002. Epub 2014 Mar 5.
The marketed compound tablet of metformin hydrochloride (MH) and repaglinide (RG) exhibits perfect multidrug therapeutic effect of type 2 diabetes. However, due to the short half life of the drugs, the tablet has to be administered 2 to 3 times a day, causing inconvenience to patient and fluctuations of plasma concentration. Here, a sandwiched osmotic pump tablet was developed to deliver the two drugs simultaneously at zero-order rate, in which MH and RG were loaded in different layers separated by a push layer. The osmotic pump tablet was prepared by a combination of three tableting procedure and film coating method. The factors including type and amount of propellant, osmotic active agents, amount of porogenic agent, coating weight, orifice diameter were optimized. The pharmacokinetic study was performed in beagle dogs, and the drug concentration in plasma samples was assayed by HPLC-MS/MS method. Simultaneous, controlled release of MH and RG in the first 12 and 8h was achieved from the optimized formulation. A significantly decreased Cmax, prolonged Tmax and satisfactory bioavailability of the osmotic pump tablet were obtained, and a good in vivo-in vitro correlation of the two drugs was also established. In summary, the sandwiched osmotic pump tablet released the MH and RG simultaneously at zero-order rate, and exhibited significant sustained release effect in vivo and good in vivo-in vitro correlation. The designed controlled release system for MH and RG proposed a promising replacement for the marked compound product in the therapy of type 2 diabetes.
盐酸二甲双胍（MH）和瑞格列奈（RG）的市售复方片剂具有完美的 2 型糖尿病多药物治疗效果。然而，由于药物半衰期短，该片剂必须每天服用 2 至 3 次，给患者带来不便，并导致血浆浓度波动。在这里，开发了一种夹心渗透泵片剂，以零级速率同时递送两种药物，其中 MH 和 RG 装载在由推动层分隔的不同层中。渗透泵片剂通过三种压片程序和包衣方法的组合制备。优化了推进剂的类型和用量、渗透活性物质、致孔剂的用量、包衣重量、孔径等因素。在比格犬中进行了药代动力学研究，并通过 HPLC-MS/MS 法测定血浆样品中的药物浓度。从优化的制剂中，MH 和 RG 在最初 12 和 8 小时内实现了同时、控制释放。从渗透泵片剂中获得了 MH 和 RG 的 Cmax 显著降低、Tmax 延长和令人满意的生物利用度，并且还建立了两种药物的良好体内-体外相关性。总之，夹心渗透泵片剂以零级速率同时释放 MH 和 RG，并在体内表现出显著的持续释放效果和良好的体内-体外相关性。为 MH 和 RG 设计的控释系统为 2 型糖尿病的治疗提供了一种有前途的标记复方产品替代品。
