Development, evaluation and pharmacokinetics of time-dependent ketorolac tromethamine tablets

Abstract

Objective: The present study was intended to develop a time-dependent colon-targeted compression-coated tablets of ketorolac tromethamine (KTM) using hydroxypropyl methylcellulose (HPMC) that release the drug slowly but completely in the colonic region by retarding the drug releases in stomach and small intestine.

Methods: KTM core tablets were prepared by direct compression method and were compression coated with HPMC. The formulation is optimized based on the in vitro drug release studies and further evaluated by X-ray imaging technique in healthy humans to ensure the colonic delivery. To prove these results, in vivo pharmacokinetic studies in human volunteers were designed to study the in vitro–in vivo correlation.

Results and discussions: From the in vitro dissolution study, optimized formulation F3 showed negligible drug release (6.75 ± 0.49%) in the initial lag period followed by slow release (97.47 ± 0.93%) for 24 h which clearly indicates that the drug is delivered to the colon. The X-ray imaging studies showed that the tablets reached the colon without disintegrating in upper gastrointestinal system. From the pharmacokinetic evaluation, the immediate-release tablets producing peak plasma concentration (C_max) was 4482.74 ng/ml at 2 h T_max and colon-targeted tablets showed C_max = 3562.67 ng/ml at 10 h T_max. The area under the curve for the immediate-release and compression-coated tablets was 10595.14 and 18796.70 ng h/ml and the mean resident time was 3.82 and 10.75 h, respectively.

Conclusion: Thus, the compression-coated tablets based on time-dependent approach were preferred for colon-targeted delivery of ketorolac.

Keywords::

• colon targeting
• compression coat
• in vivo X-ray imaging studies
• lag period
• mean resident time
• time dependent

Acknowledgement

The authors would like to thank Dr. Vijaya Kumar Bontha, Principal and Management, Jangaon Institute of Pharmaceutical Sciences for providing facilities. The authors acknowledge Bright Labs, Hyderabad, India and Matrix Laboratories, Hyderabad, India for gift sample of ketorolac tromethamine and HPMC K4M.