Studies On Tegaserod Maleate Sustained-Release Tablets

Tegaserod maleate(TM), a potent selective partial agonist of 5-HT4 receptor, has been mainly in clinical therapeutic use for irritable bowel syndrome and gastroesophageal reflux disease. The partition coefficient , ionization constant , melting point , contact angle and molar enthalpy of solution of TM from preformulation studies were respectively, 23.65, 9.76, 185.3℃, 63.52° and 39.35KJ/mol . Solubility of TM in increasing pH buffer solution showed typical V curve. TM decomposed to 5-methoxyl indole -3-carbaldehyde in 0.1mol/L hydrochloride, while the color of solution turning red. Based on this observation, we established the qualitative and quantitative analysis method for TM in 0.1mol/L hydrochloride .We further investigated the UV absorption, drug release kinetics and stability of TM here.We studied the properties of Eudragit L/S 100(1:4, w/w) free film, such as tensile strength, solubility parameter and permeability etc, and optimized the coating operation conditions, formulation of core tablet, constituent of coating solution and conditions of dissolution media. The optimal sustained-release coretablet containing 8.3mg TM was prepared with lactose, carboxymethyl starch sodium (CMS-Na) and poloxamer as constituents, which was coated with Eudragit L100-Eudragit S100 combination (1:4, w/w) dissolved in alcohol at the level 5.0%(w/w, total solid applied). Then the plasticizer diethyl phthalate (DEP) and additives polyethylene glycol 400(PEG400) were added directly to the polymer solution. It is essential to prepare TM coated sustained- release tablets in order to improve the stability of TM in gastric juice, thus to minimize side effects of TM conventional tablets due to fast absorption following administration. The result from the drug release mechanism was consistent with Hixson-Crowell model.The stability test showed that the sustained-release tablets were stable when exposed to strong light, high temperature and humidity.The plasma concentration of TM sustained-release tablets in dogs was determined by HPLC-MS. The new formula exhibited sustained-release efficiency, with longer Tmax (8.00h), T1/2(9.42h), Tlag (1.997h), and lower Cmax (16.39ng/ml) and Ka (0.1439h-1), than conventional tablets. The relative bioavailability was 116.8%. Clear correlation existed between absorption percentage in vivo and release rate in vitro.