Pharmacokinetic evaluation of differential drug release formulations of rabeprazole in dogs

Abstract

Objectives: To develop novel dual release prototype capsule formulations of rabeprazole and evaluation of pharmacokinetic properties relative to the reference product (Aciphex^®) in Beagle dogs.

Methods: The dual release prototype formulations of rabeprazole were developed by preparing optimized mini-tablets core which was subsequently coated with barrier/enteric coating using standard excipients. Both novel prototype formulations were subjected for in vitro release and assay by HPLC-UV to assess long term stability. Single dose pharmacokinetic study used a single sequence three treatments crossover design. In Periods 1 and 2, four dogs received oral 20 mg dose of two prototype formulations. In Period 3, all dogs received a 20 mg oral dose of Aciphex^® reference product. There was a 1-week washout time between two successive periods. A quantitative analysis of rabeprazole/sulfide metabolite in plasma samples was performed using a validated LC-MS/MS assay and PK parameters were estimated by non-compartmental analysis.

Results: The stability of the prototype formulations was confirmed over a period of 24 months with an acceptable assay and dissolution data. One of the novel prototype formulations showed 70% oral bioavailability relative to the reference product. Despite a 30% reduced bioavailability, this showed 1 h delay in peak concentration, longer plasma residence time of rabeprazole (up to 12 h) and longer apparent elimination half-life.

Conclusions: The use of a canine model has enabled the selection of a novel dual-release prototype formulation of rabeprazole for further clinical development.

Keywords:

• Dual release formulation
• relative bioavailability
• proton pump inhibitor
• pharmacokinetics
• bioanalysis
• dissolution
• assay
• Rabeprazole
• Rabeprazole sulfide

Ethics approval

Applicable procedures and institutional guidance were used for handling and usage of animals for this study. The study protocol (ZRC/DMPK/NP/014/12-2K14) was approved by Independent Institutional Animal Ethic Committee (IAEC) of Zydus Research Center and Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA), Government of India. ZRC communication no. 580.

Disclosure statement

The authors involved in this research work have declared no conflict of interest.