Journal of Bioequivalence & Bioavailability

IVIVC from theory to application- Development of once daily extended release formulation of Trimetazidine di HCl using IVIVC

3^rd World Congress Bioavailability & Bioequivalence

March 26-28, 2012 Marriott Hotel & Convention Centre, Hyderabad, India

Varinder Kumar, Lalit K. Khurana, Shavej Ahmad and Romi Singh

Posters: J Bioequiv Availab

Abstract:

I n-vitro in-vivo correlation (IVIVC) models are developed to explore the relationships between in vitro dissolution/release and in vivo absorption profiles. This model relationship facilitates the rational development and evaluation of immediate/ extended-release dosage forms as a tool for formulation and defining the critical variable depending on pharmacokinetic profile of the drug. IVIVC modeling involves three stages: (a) Assume IVIVC Development, (b) In- vitro and vivo profiling and (c) model application to develop retrospective IVIVC. The purpose of this paper is to utilize IVIVC tools in the development of oral controlled formulation of Trimetazidine Di HCl (TDH). TDH is anti anginal drug. It increases cell tolerance to ischemia by maintaining cellular homeostasis. It is freely soluble in water and has a short half life (6hr); making it ideal candidate for controlled release dosage form. Commercially two dosage forms are available; 20mg immediate release tablet as twice or thrice a day and sustained release tablet 35mg as twice a day. This provides an opportunity of developing once daily (OD) extended release formulation thereby reducing dose frequency. The development of OD formulation was initiated from development of ?Assumed IVIVC?. Assumed IVIVC was developed by obtaining in-vivo data from literature of single dose IR formulation and twice dosing sustained release formulation and generating in-vitro data in lab for same. In-vivo absorption was calculated using Wagner-Nelson method and same was used as target to develop OD formulation. In- vitro dissolution profile as a surrogate to in-vivo absorption was studied by evaluating the pH and RPM dependency of OD formulation. In-vivo study of the selected formulation was carried out on healthy human volunteers as a single dose fasting study and retrospective IVIVC was developed using software WinNonlin and IVIVC toolkit ver 5.3. A linear model with a time-scaling factor clarified the relationship between in vitro and in vivo data. The predictability of the final model was consistent based on internal validation. Average percent prediction errors for pharmacokinetic parameters were ? 10% and individual values for all formulations were ? 15%. Therefore, a Level A IVIVC was developed and validated providing robust predictions of in vivo profiles based on in vitro dissolution profiles