Preparation And Study Of Dipfluzine Intragastric Floating And Residence Sustained-release Tablet

Objectives: Dipfluzine (Dip), a novel piperazines calcium antagonist, can selectively dilate vertebral artery, basilar artery and coronary artery. Its effects is more potential than Cinnarizine's. Pharmacological researches show that: it can abate hydrocephalus, increase cerebral blood stream, improve brain ischemia, and attenuate the infarct size after occlusion. It may be potentially effective to treat ischemic brain injury. According to Dip's pre-preparation research, it is well soluble in acid medium and poorly soluble under neutral and alkaline circumstances. In order to increase Dip's in vivo absorption, steady the drug concentration in blood, reduce its adverse effects, and enhance its bioavailability, the intragastric floating sustained-release tablet was prepared with HPMC hydrophilic matrix. It will provide a potential sustained-release dosege form for Dip's clinical research and application.Methods: On the basis of scientific materials and the pre-preparation investigation, we select HPMC as the hydrophilic matrix, add PEG-6000 as the porogeneous compound, stearic acid and stearylalcohol as the retarder, and MgCO3 as the gas-generating agent in the formulation. Considering the release properties and floating ability of the tablet , We carried through monofactorial investigations. After choosing suitable preparation technics, we use L9(34) orthogonal design to select the optimum formulation in terms of the floating capabilities and in vitro accumulative release percentage.Cylindrical basket was used in the experiment of in vitro dissolution test . The dissolution test is carried out in simulated gastric fluid 0.1mol·L-1HCL with rotation rate 100r·min-1 at temperature 37±0.5℃. Samples were withdrawn periodically at 0.5,1,2,3,4,5,6,7,8,10,12h from the dissolution medium, replenished with the same volume of fresh medium each time, and then analyzed and determined for their drug contents at 249nm by ultraviolet spectrophotometer. The conventional Dip tablet was studied by the same means. Three batches of Dip-HBS were prepared and studied through release experiment to investigate the stability of formulation and technics。The release data were analyzed with three models: Higuchi equation, zero order kinetics, and first order kinetics. We studied the stability of Dip-HBS under following circumstances: high humidities, high temperature, strong light and natural store condition. To elucidate the mechanism of drug release we used Peppas equation to analyze the release data. Its floating properties was investigated in 37±0.5℃ 0.1mol·L-1HCL under two conditions: under 50r·min-1 paddle agitation, and with cylindrical basket method(100r·min-1).In vivo study: The intragastric residence experimemt was carried in rabbits. The release properties in vivo were investigated as following: 12 rabbits were divided into two groups.One was given Dip-HBS, and the other group was given the conventional tablet. Plasma samples were obtained at different time after the administration. Choose Cinnarizine as the internal standard. The plasma concentration of Dip was determined by High performance Liquid Chromatograph with Ultraviolet detector.Results: Through the L9(34) orthogonal design, the optimum formulation was founded: A2B2C1D1, that is:HPMC(A) 45mgstearic acid-PEG6000(B)-Dip(20:10:5)SD 35mgstearyl alcohol(C) 10mgMgCO3 (D) 10mgThe factors influence the tablet's release and floating properties as following turn: C>A>B>D. Three batches HBS tablets were prepared according to the optimum formulation. The release data were analyzed with three models: Higuchi equation, zero and first order kinetics, the regression equations:Ft=7.401t+15.33, r=0.9865Ft=31.54t1/2-13.09, r=0.9955㏒(F∝-Ft)=-0.1033t+2.087, r=-0.9766The results showed that Dip-HBS conformed to Higuchi equation better than the other two models. The drug release mechanism was non-Fick's diffusion, that was concurrence of the...