Abstract

FORMULATION DEVELOPMENT OF LOSARTAN FLOATING TABLETS EMPLOYING A NEW MODIFIED STARCH OPTIMIZATION BY 23 FACTORIAL DESIGN

Swathi G.* , K. P. R. Chowdary and A. Muralidhar Rao

ABSTRACT

The objective of the present study is optimization of losartan floating tablet formulation by 23 factorial design. Floating tablets of losartan (100 mg) were formulated employing Cross linked starch-urea, a new modified starch (50 %) as matrix forming polymer, sodium bicarbonate as gas generating agent and beeswax and starch acetate as floating enhancers. Losartan potassium is an orally active non‐peptide angiotensin ‐II receptor antagonist used in treatment of hypertension due to mainly blockade of AT1 receptors13. The main limitation of low therapeutic effectiveness is due to narrow therapeutic index, poor bioavailability (25‐35%), and short biological half life (1.5‐2h). It is majorly absorbed from stomach and upper small intestine. To increase its oral bioavailability, therapeutic efficacy, reduce frequency of administration and for better patient compliance twice daily sustained release floating tablets of losartan potassium are aimed. Losartan floating tablets were formulated as per 23 factorial design. The three factors involved in the 23 factorial design are sodium bicarbonate (Factor A), beeswax (Factor B) and starch acetate (Factor C). The two levels of sodium bicarbonate (Factor A) are 10 % and 20 %, the two levels of beeswax (Factor B) are 2 % and 5 % and the two levels of starch acetate (Factor C) are 5% and 10%. Eight losartan floating tablet formulations were prepared employing selected combinations of the levels of the three factors as per 23 factorial design. All the floating tablets prepared were evaluated for drug content, hardness, friability, disintegration time, floating lag time, floating time and drug release characteristics. Losartan floating tablets prepared as per 23 factorial design were non-disintegrating in water and aqueous acidic (pH 1.2) and alkaline (pH 7.4) fluids and were of good quality with regard to drug content, hardness, friability and suitable for controlled release. The individual effects of sodium bicarbonate (Factor A) and starch acetate (Factor C) and their combined effect (AC) on the floating lag time were significant (P < 0.05).Whereas the individual effect of bees wax (Factor B) and all other combined effects of the three factors involved were not significant in influencing floating lag time of the tablets. Formulations Fab, Fac and Fabc exhibited excellent floating over 12-14 h with a floating lag time in the range 15-35 seconds. Higher levels (20 %) of sodium bicarbonate gave shorter floating lag time. Losartan release from the floating tablets prepared except formulation Fa was slow and spread over 12 h and dependent on the composition of the tablets. Drug release from formulation Fa was very rapid. Losartan release from the floating tablets was by nonfickian diffusion mechanism in all the cases except Fa. In the case of formulation Fa that gave rapid release of drug fickian diffusion was the drug release mechanism. Optimization of losartan floating tablet formulation was done taking floating lag time as the parameter for optimization. For optimization, floating lag time was taken as response (Y) and level of sodium bicarbonate as (X1), level of bees wax as (X2) and level of starch acetate as (X3). The polynomial equation describing the relationship between the response, Y and the variables, X1 , X 2 and X3 based on the observed data was found to be Y = 11.59 - 11.18 (X1) + 4.36 (X2) – 4.37 (X1 X2) -1.08 (X3) + 0.895(X1 X3) – 0.735 (X2 X3) + 0.79(X1 X2 X3). Based on the polynomial equation developed, the optimized losartan floating tablet formulation with a floating lag time of 20 seconds could be formulated employing sodium bicarbonate (160mg/tablet), beeswax (28mg/tablet) and starch acetate (60mg/tablet). The optimized formulation (Fopt) exhibited a floating time of 12-14 h with a lag time of 19-20 seconds fulfilling the target floating lag time set indicating validity of the optimization technique employed. Formulations Fopt and Fab prepared exhibited excellent floating characteristics (floating over 13-14h with a lag time of 19 and 15seconds respectively) and good sustained release of losartan over 12 – 14h. Formulations Fopt and Fab are considered as the best floating tablet formulations of losartan suitable for b.i.d administration.

Keywords: Floating tablets, Losartan, Optimization, Factorial design, Sustained release.