The Study Of Trimebutine Maleate Floating Tablet

Floating tablets are desighed according to the principle of hydrodynamically balancedSystem. Unlike the conventional sustained release dosage forms, this kind of special sustainedrelease dosage's advantages are that the tablets will float on the surface of gastric content whentaken orally and its gastric retention is rarely influenced. The tablets have along residence time inthe stomach. Trimebutine maleate has been used as a spasmolytic drug for gastrointestinalmuscle. Its biological half-life is about 2.7 hours, therefore it is normally administed in shorterintervals, and that may result in bigger fluctuation in plasma concentration and bigger sideeffects. The purpose of this research is to prepare trimebutine maleate floating tablet on the basisof orginal works in laboratory. The pharmacokinetics of the tablets was investigated, and thecorrelation between in vivo and in vitro and in vitro of the tablet was evaluated.1. studies on floating tablet's floating characteristicsHPMC in K4M,K15M,K20M three models were prepared by using gel matrix materials,lactose,starch,cetyl alcohol and sodium bicarbonate as additives. The floatage and integritywere evaluated in four aspects, including water uptake kineties, swelling kineties and erodingkineties. The tablets directly pressed with HPMC K20M disintegrated rapidly and did not havethe characteristics of sustained-release. Tablets directly pressed with HPMC K4M and K15M cancontinuous floating. Lactose,starch and cetyl alcohol had similar impacts on the tablets. Sodiumbicarbonate can accelerate the disintegration, and help drug release. Based on the Higuchiequation, the influence of different excipients on floating and properties was assessed.2. Preparation of trimebutine maleate floating tabletOn basis of pre-experiments, a four-factor(HPMC K15M, NaHCO3, magnesium stearate andcetyl alcohol) at three-level orthogonal design was employed for formulation development andoptimization, and the floating capability and release of the drug were used as the evaluationindex. The result showed that in the influences of these materials, NaHCO₃ has biggest influenceon floating and release, and then HPMC K15m, magnesium stearate, cetyl alcohol.Followed Chinese Pharmacopoeia, the stability of the preparation were investigated, whichincluded influence factors and acceleration test. Under the strong light, high temperature, highhumidity condition, appearance of tablets, release and content determination were detected forthe stability studies. The results showed that the tablet was sensitive to moisture and should bekept in dry environment.3. Studies on trimebutine maleate floating tablet's pharmacokinetics in dogs A RP-HPLC method was developed to determine the trimebutine maleate content in dogplasma, respectively. The linearity, specificity, and recovery of this method met with the ChineseParmacopoeia (2005 edition). This method was used to study the pharmacokinetics oftrimebutine maleate in dogs. Test formulation and reference formulation were given orally todogs, and the experimental data of drugs was analyzed by WinNonlin and non-compartmentmodel theory. The C_max(ng·mL^-1),T_max(h),t_1/2(h),k_a(h^-1),AUC_0-t(ng·h·mL^-1),AUC_0-∞(ng·h·mL^-1)of test preparations of trimebutine maleate were 167.85±57.82,3.67±0.58,2.57±0.41,0.27±0.08,468.23±154.6,545.69±178.35. The C_max(ng·mL^-1),T_max(h),t_1/2(h),k_a(h^-1),AUC_0-t(ng·h·mL^-1),AUC_0-∞(ng·h·mL^-1)of reference preparationsof trimebutine maleate were 475.41±186.80,0.75±0.25,2.43±0.18,0.29±0.03,650.64±173.2,740.48±185.62, respectively. The relative bioavailability of trimebutine maleate floatingtablet was 90.05±26.99 %, compared with trimebutine maleate tablet. Trimebutine maleatefloating tablets were characterized with sustained-releasing. The oral absorption of trimebutinemaleate floating tablet was good correlated with the release rate in vitro(r=0.951).