Preclinical safety pharmacological studies on the amorphous formulation of celecoxib.

Safety pharmacological studies need to be performed according to ICH S7A Guidelines for finished formulations that substantially alter the pharmacokinetics and/or pharmacodynamics of the active substance in comparison to formulations previously tested (i. e. through active excipients such as penetration enhancers, liposomes, and other changes such as polymorphous system). In the present study, amorphous formulation of celecoxib (CAS 169590-42-5), a new patented formulation with altered pharmacokinetic profile was investigated in comparison with the standard crystalline celecoxib (CEL) for its undesirable pharmacodynamic effects using certain safety pharmacological studies. The effects of the new formulation on vital functions using safety pharmacology core battery like central nervous system (CNS) (functional observation battery, locomotor activity, and motor coordination) and cardiovascular system (CVS) (blood pressure, heart rate and QT interval) were investigated in laboratory rodents. In addition, supplementary safety pharmacology study on gastrointestinal system (GIT) (gastric injury potential, gastric secretion) was also carried out. Oral administration of a single dose of the amorphous celecoxib formulation (CF) varying of 50, 150 and 500 mg/kg was studied in comparison with vehicle treated control and crystalline celecoxib in animals. The maximum tolerated dose (MTD) was identified by administration of insufferable doses of amorphous formulation, extended up to 2000 mg/kg during the experiments on physiological parameters. There were no CNS and GIT safety concerns raised with respect to use of CF except the arrythmogenic risk associated with QT interval prolongation upon the high dose of CF.