硝苯地平-海藻酸钠骨架缓释片的制备及处方工艺优化

Preparation of Nifedipine-Sodium Alginate Sustained-Release Matrix Tables and Optimization of Their Formulation

目的:研制硝苯地平-海藻酸钠骨架缓释片并优化处方工艺。方法:以海藻酸钠为缓释骨架材料,乳糖为填充剂,硬脂酸镁为润滑剂,乙醇为黏合剂,湿法制粒并制备硝苯地平骨架缓释片。在处方单因素考察的基础上,选择对缓释片释放行为影响较大的3个处方因素——海藻酸钠用量、磷酸氢钙用量和海藻酸钠黏度,以累积释放度为指标,利用正交实验设计L9(34)对缓释片处方进行优化。考察制备的硝苯地平骨架缓释片的释放机制。将自制缓释片的体外释放行为和大鼠体内药动学与市售缓释片进行比较。结果:在3个处方因素中,磷酸氢钙用量对硝苯地平-海藻酸钠骨架缓释片的体外释放度影响最大,最佳处方组成为45%海藻酸钠、20%磷酸氢钙和黏度为105m Pa·s的海藻酸钠。处方优化的硝苯地平骨架缓释片体外释放行为符合一级动力学方程,属于Baker-Lonsdale球形扩散机制。与市售产品相比,自制缓释片的缓释效果更好;其经口给予大鼠后,硝苯地平的tmax明显延长,药物作用时间延长及生物利用度提高。结论:自制的硝苯地平-海藻酸钠骨架缓释片具有明显的缓释效果,并优于市售产品。

Objective： To prepare nifedipine- sodium alginate sustained-release matrix tablets and to optimize their formulation. The nil^dipine sustained-release matrix tablets were prepared with sodium alginate as the matrix, lactose as the filler, magnesium stearate as the lubricant and ethanol as the adhesive by a wet granulation compression method. On the basis of single-thctor investigation and taking cumulative release percentage degree as index, the formulation of the tablets was optimized by L9（3a） orthogonal test design for 3 factors amount of sodium alginate, amount of calcium perphosphate and viscosity of sodium alginate significantly affecting the release behavior of the tablets. And the releasing mechanism of the tablets was investigated. The comparison between the homemade and the commercially available nifedipine sustained- release tablets in in vitro release behavior and in vivo pharmacokinetics in rats was made. Among the 3 factors, the amount of calcium perphosphate showed the biggest impact on the in vitro release percentage degree of the homemade tablets. The most desirable formulation included 45% sodium alginate, 20% calcium perphosphate and a viscosity of 105 mPa ~ s for sodium alginate. The in vitro release of the homemade tablets with the optimized formulation followed first order kinetics and belonged to the Baker-Lonsdale spherical diffusion mechanism. Compared with the commercially available product, the sustained-release effect of the homemade tablets was better and the in vivo t,,,,x of nifedipine was prolonged significantly after the homemade tablets were orally administrated in rats, suggesting that the acting time was longer and the bioavailability was improved for the drug. the homemade nifedipinesodium alginate sustained-release matrix tablets can significantly prolong drug-release time and are superior to the commercially available product.