In vitro and in vivo evaluation of tegaserod maleate pH-dependent tablets.
The purpose of this study was to prepare tegaserod maleate (TM) pH-dependent tablets and evaluate their advantages as a sustained release delivery system. TM, insoluble in water and unstable in gastric milieu, was formulated into pH-dependent tablets coated with combinations of two methacrylic acid copolymers - Eudragit L100 and Eudragit S100. The influence of core tablet compositions, polymer combination ratios and coating levels on the in vitro release rate of TM from coated tablets was investigated. The optimum formulation was evaluated for in vitro release rate and in vivo bioavailability study on beagle dogs. In addition, physico-chemical properties of the drug, including solubility at different pH and temperatures, and dissociation constant were determined. The results showed that no drug was released in 0.1 mol/L hydrochloric acid within 2h, and about 90% of the drug was released in the pH 6.8 phosphate buffer within 12h in a sustained manner. The pharmacokinetic investigation showed that TM pH-dependent tablets exhibited a sustained plasma concentration, a lag time of approximately 2.3h and a relative bioavailability of 159% compared to plain tablets. A close correlation existed between the in vitro release rate of the pH-dependent system and its in vivo absorption percentage. The results of the present study have demonstrated that the pH-dependent tablet system is a promising vehicle for preventing rapid hydrolysis in gastric milieu and improving oral bioavailability of TM for the treatment of irritable bowel syndrome.
Department of Physical Chemistry, Shenyang Pharmaceutical University, Shenyang, China. zhangshq@hotmail.com <zhangshq@hotmail.com>
Shuang-Qing
SQ
Zhang
Sridhar
S
Thumma
Guo-Hua
GH
Chen
Wei-Bin
WB
Deng
Michael A
MA
Repka
San-Ming
SM
Li
D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry; D008689:Methacrylates / Q000737:chemistry; D008956:Models, Chemical; D011108:Polymers / Q000737:chemistry; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage* / Q000737:chemistry; D012995:Solubility; D013270:Stomach / Q000187:drug effects*; D013607:Tablets; D014867:Water / Q000737:chemistry
D003692:Delayed-Action Preparations; D007211:Indoles; D008689:Methacrylates; D011108:Polymers; D017366:Serotonin Receptor Agonists; D013607:Tablets; D014867:Water; C008384:methacrylic acid; C105050:tegaserod