Abstract :
The objective of the present study is optimization of valsartan floating tablet formulation by 23 factorial design and to evaluate the optimized
valsartan floating tablets for in vitro drug release, preclinical pharmacokinetics and also for in vitro – in vivo correlation (IVIVC). Valsartan is
an orally active anti-hypertensive drug, majorly absorbed from stomach and upper small intestine. Formulation of sustained release floating
tablets of valsartan is needed because of its poor oral bioavailability and short biological half-life. Valsartan floating tablets were formulated as
per 23 factorial design and were evaluated.
Valsartan 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. Formulations Fa, Fab,
Fac and Fabc exhibited excellent floating over >12 h with a floating lag time in the range 12-40 seconds. Higher levels (20 %) of sodium
bicarbonate gave shorter floating lag time. Valsartan 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. Valsartan release from the floating
tablets was by non-fickian 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 valsartan 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 = 8.996 - 8.596 (X1) + 2.396 (X2) – 2.431 (X1 X2) + 0.561 (X3) - 0.521 (X1 X3) + 0.396 (X2 X3) - 0.271 (X1 X2 X3). Based on
the polynomial equation developed, the optimized valsartan 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 (10mg/tablet). The optimized formulation
(Fopt) exhibited a floating time of 12-14 h with a lag time of 21 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 12 h with a lag
time of 21 and 12seconds respectively) and good sustained release of valsartan over 12– 14h. The optimized valsartan tablets formulated at two
strengths 80 mg/tablet and 40 mg/tablet gave slow, gradual and complete release of valsartan in 12h. Valsartan was absorbed rapidly from IR
tablets and slowly over longer period of time from floating tablets. Based on (AUC)o
α , the relative bioavailability ( BA) of Valsartan from FTs
was 166.0 % when compared to Valsartan IR tablets (100%). A good level A correlation (r = 0.961) was observed between percent drug released
(in vitro) and (AUC)o
α (in vivo).
Keyword :
Cross Linked starch Urea, Floating tablets, Valsartan, Optimization, Preclinical, Pharmacokinetics.