Preparation And Study Of Glipizide Gastrointestinal Tract Bioadhesion Sustained-release Tablet

Objectives: Glipizide is second filial generation sulfonylurea oral hypoglycemic agent.Pharmacological action is direct excitationβ-cell of islet,to increase trypsin,to stop ATP sensibility K tunnel.Glipizide is utility medicine of treating non-insulin dependent diabetes.Glipizide for oral use can quickly and completlely absorb,after over dose 1～2h reaching spica concentration,average half-life time is 3～7h,needs taking orally 2～3vices every day.For this reason,we preparate bioadhesion sustained-release tablet.Gastrointestinal tract GBDDS is apply of modern bioadhesion technology in oral preparation.The aquestion for study uses glipizide as model medicine,carbopol 934 and stearyl alcohol as steleton materials.We prepared glipizide bioadhesion sustained-release tablet that can free medicine 16h.Self-made tablet can raise bioavailability of glipizide.We determined adhesive power of bioadhesion sustained-release tablet,study internal pharmacokinetics character and relative bioavailability of bioadhesion sustained-release tablet,provid experiment data for improvement of dosage form and clinical medication.Methods: On the basis of scientific materials and the pre-preparation investigation, we select stearyl alcohol and glipizide as material made SD,and checked formation of SD using DSC.On the basis of pre-preparation,we select carbopol 934 as bioadhesion materials,and carry out uni-factor investigation based on percentage of carbopol 934 and stearyl alcohol,at the same time,invest adhesiveness of tablet. After choosing suitable preparation technics, we use L9(34) orthogonal design to select the optimum formulation. According to accumulative release percentage at 4h,8h,16h to select optimal formula with the colligation evaluation.Accumulation release curve were investigated and evaluated by similarity factor.In vitro release test was performed in a dissolution apparatus using the second method according to CHP. The stirring rates in buffer phosphate was 50rpm. The temperature was maintained at (37±0.5)℃. At the predetermined intervals ( 4, 8, 12, 16h), 5ml samples were withdrawn from each vessel, filtered with a 0.8μm membrane, and then analyzed and determined for their drug contents at 275nm by ultraviolet spectrophotometer. The conventional glipizide controlled release tablets was studied by the same means. Bioadhesion sustained-release tablet based on optimize prescription 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 self-made bioadhesion sustained-release tablet under following circumstances: high humidities, high temperature, strong light . we also did accelerated test.Pharmacokinetics study in vivo: we selected the Beagle dogs as laboratory animal, which were divided into two groups in random. One group was given self-made bioadhesion sustained-release tablets and the other was given glipizide controlled release tablet. Plasma samples were obtained at different times. Crossover experiment was taken after two weeks. The plasma concentration glipizide was determined by HPLC with Ultraviolet detector.We dealed determined data with 3p97 pharmacokinetics procedure and calculated pharmacokinetics parameter.Results: We certified that glipizide SD was formed with DSC.Through the L₉(3⁴) orthogonal design, the optimum formulation was founded: A₃B₂C₂, that is: Carbopol 934:stearyl alcohol 1:3 Percentage of magnesium stearate 1% Content of Glipizide 5%The factors influence the tablet's release as following turn: A>B>C. Bioadhesion sustained-release tablets was prepared according to the optimum formulation. The release data were analyzed with three models: Higuchi equation, zero and first order kinetics, the regression equations: Q=38.575t^1/2-61.942, r=0.9996 Q=6.39t-7.3, r=0.9932 lnQ=0.1483t+2.355, r=0.9377 The results showed that self-made bioadhesion sustained-release tablets conformed to Higuchi equation better than the other two models. The releasing mechanism is bulk erosion mechanism.The tablet was sensitive to high humidity, high temperature and strong light. The recoveries of equivalent 80%, 100%, 120% of the optimum formula were (99.97±0.57)%,(100.2±0.29)%,(99.81±0.42)%(n=3)respectively. The contents of three batches of self-made tablet were (101.0±3.03)%,(100.0±2.26)%,(100.6±3.51)%(n=10), The content uniformity of the three batches optimum formula were within the stated range.The result of the pharmacokinetics in Beagle dogs shows that self-made tablet and the conventional tablet both conformed to one compartment model. Pharmacokinetics parameters of seif-made tablet and conventional tablet were respectively as following: Ka(h^-1):0.1873±0.01903,0.2588±0.02595 K(h^-1):0.08513±0.01023,0.1074±0.01837 T1/2Ka(h):3.733±0.3834,2.7025±0.2929 T1/2K(h):8.238±0.9804,6.602±1.040 Tmax(h):8.0085±0.8040,6.651±0.06450 Cmax(ng·ml^-1):792.83±54.80,710.5±31.60 AUC(ng·ml^-1)·h:14845.8±1286.3,9812.4±831.6 MRT(h):11.89±1.413,9.525±1.499The result of t-test showed significant difference between the parameters Ka(h^-1), T1/2(Ka), K(h^-1), T1/2K(h),Tmax, AUC and MRT of the two groups(P < 0.05).Self-made tablet have effective of lasting dwell time in vivo,increasing absorption and raising bioavailability.Conclusions: Through the release experiment in vitro and pharmacokinetics study in Beagle dogs, we know that the self-made bioadhesion sustained-release tablet showed obvious sustained-release properties in both vitro and vivo. The methods of assay and dissolution for glipizide bioadhesion sustained-release tablet were established, which provided a guideline with quality control. It will provide a potentially promising preparation for the clinical research and applications of glipizide.