单硝酸异山梨酯择时释放渗透泵控释片的研制.Ⅰ.星点设计-效应面法优化处方

Preparation of a Timed-and Controlled-release Osmotic Pump Tablets of Isosorbide Mononitrate.Ⅰ. Formulation Optimization by Central Composite Design-response Surface Methodology

基于渗透泵原理,通过在单层渗透泵片芯外包隔离衣和控释衣,研制具有4 h时滞、零级释药特性并能完全释药的单硝酸异山梨酯择时释放渗透泵控释片。以控释衣增重量、控释衣中致孔剂含量、隔离衣增重比例和片芯中渗透压促进剂含量为考察因素,4和16 h的累积释放率和累积释放率-时间方程的线性系数为优化指标,应用星点设计-效应面法优化处方。结果显示,时滞的长短主要由控释衣和隔离衣的水化共同决定。所得优化处方在不同pH值介质中均存在4 h时滞(4 h累积释放率<10%),16 h累积释放率>90%,释药动力主要是渗透压。

The timed- and controlled-release isosorbide mononitrate osmotic pump tablets were preparea on me basis of the principle of osmotic pump. To achieve the goals such as 4 h lag time, zero-order in vitro release kinetics and complete release, hypromellose-based isolation layer and cellulose acetate-based semi-permeable layer were deposited on the cores. And the formulation was optimized by the central composite design-response surface methodology with 4 h and 16 h cumulative release and correlation coefficient of drug release profile as dependent factors and semi-permeable coat weight gain, pore-former amount, isolation layer weight gain and osmotic agent amount as independent factors. The results showed that the lag time was mainly decided by the hydration time of semi-permeable and isolation layer. The optimal formulations had a 4 h lag time （4 h cumulative release below 10%） and 16 h cumulative release above 90%0 in media with different pH values. Moreover, it showed that the osmotic pressure-controlled delivery was greatly responsible for the release of the developed tablets.