Comparative studies on the influence of different fibrates on serum lipoproteins in endogenous hyperlipoproteinaemia

Summary Two trials have been performed in the same patients with hyperlipoproteinaemia Types IIb (12 cases), III (6 cases) and IV (11 cases). In the first study the lipid-lowering properties of bezafibrate, fenofibrate, gemfibrozil, etofibrate and etofylline clofibrate were compared and in a separate trial the influence of combined treatment with gemfibrozil plus colestipol and bezafibrate plus probucol on lipoproteins were investigated. The mean percentage lipid-lowering effect of each fibrate on serum and VLDL fraction was significant in the Types IIb, III and IV patients, but there were significant differences between the fibrates. In general, gemfibrozil and bezafibrate decreased plasma lipid levels more than etofibrate and etofylline clofibrate in Type IIb patients. In Type IV cases gemfibrozil and bezafibrate were significantly potent in reducing the triglyceride level than fenofibrate, etofibrate or etofylline clofibrate. All the fibrates produced an increase in HDL cholesterol, but there were significant differences between them were in the Type IV patients. The influence of fibrates on the LDL fraction was much more variable. In hyperlipoproteinaemia Type IIb, a decrease in both LDL cholesterol and LDL apolipoprotein B was observed. In Type III and IV patients, however, an increase in LDL concentration occurred. The addition of colestipol to gemfibrozil therapy led to a further decrease in total cholesterol, LDL cholesterol and LDL apolipoprotein B in Type IIb patients. In patients with hyperlipoproteinaemia Types III and IV colestipol prevented the increase in LDL concentration after treatment with gemfibrozil alone. The effect of probucol on LDL cholesterol was comparable to that of colestipol. Combined treatment with gemfibrozil and colestipol caused an increase in HDL cholesterol concentration in contrast to combined treatment with bezafibrate and probucol. It is concluded that combined therapy with fibrates plus bile acid sequestrant would be of practical value in patients with hyperlipoproteinaemia Types IIb, III and IV.     

星点设计—效应面法优化依托贝特缓释胶囊的制备

目的:制备依托贝特缓释胶囊,并采用星点设计—效应面法对依托贝特缓释胶囊的处方进行优化。方法:采用离心造粒法制备依托贝特母丸,PEG4000与依托贝特的丙酮溶液包增溶层,以丙烯酸树脂水分散体溶液(Eudragit RL30D)包缓释层。考察因素为增溶层与丸心质量比(X1)、增溶层中PEG4000用量(X2)、缓释层增重百分率(X3),考察指标为4,8和24 h的累积释放度,采用Design-Expert软件建立模型描述自变量及响应值之间的关系,根据模型绘制效应面图和等高线图,通过重叠等高线图确定优化处方并通过实验对拟合结果进行验证。结果:确定依托贝特的制备处方优化参数:增溶层与丸心质量比为0.7～1.2;PEG4000占增溶层比例为3.5%～12.8%;缓释层包衣增重8.0%～13.5%,与多元线性模型相比,二次多项式模型具较高的置信度;二次多项式模型方程表明考察因素和相对应的考察指标之间存在可信的定量关系;优化处方各考察指标的预测值和实际值非常接近。结论:星点设计—效应面法可用于依托贝特缓释胶囊的处方优化,所建模型具有良好的预测能力。     

依托贝特的合成

目的:合成依托贝特.方法:2-(4-氯苯氧基)-2-甲基丙酸与乙二醇酯化成其2-羟基乙酯后,与二氯亚砜作用生成2-(4-氯苯氧基)-2-甲基丙酸2-氯乙睹,再与3-吡啶甲酸钠作用合成目标物依托贝特.结果:目标物经红外光谱、核磁共振氢谱、质谱及元素分析确证其化学结构.结论:该法合成操作简便,依托贝特总收率达53%.