Abstract

PRECLINICAL PHARMACOKINETIC EVALUATION OF CAPTOPRIL FLOATING TABLETS FORMUALTED USING CROSS LINKED STARCH UREA - A NEW MODIFIED STARCH

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

ABSTRACT

The objective of the present study is optimization of Captopril floating tablet formulation by 23 factorial design and to evaluate the optimized Captopril floating tablets for in vitro drug release, preclinical pharmacokinetics and also for in vitro – in vivo correlation (IVIVC). Captopril is an orally active anti-hypertensive drug, majorly absorbed from stomach and upper small intestine. Formulation of sustained release floating tablets of Captopril is needed because of its short biological half-life and instability at alkaline pH of intestines. Captopril floating tablets were formulated as per 23 factorial design and were evaluated. Captopril 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 h with a floating lag time in the range 10-35 seconds. Higher levels (20%) of sodium bicarbonate gave shorter floating lag time. Captopril 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. Captopril 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 captopril 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 = 3.19 – 5.68(X1) + 0.56 (X2) + 2.27 (X1 X2) - 0.38 (X3) + 0.37(X1 X3) – 0.08 (X2 X3) + 0.25(X1 X2 X3). Based on the polynomial equation developed, the optimized captopril floating tablet formulation with a floating lag time of 20 seconds could be formulated employing sodium bicarbonate (140mg/tablet), beeswax (28mg/tablet) and starch acetate (60mg/tablet). The optimized formulation (Fopt) exhibited a floating time of more than 12 h with a lag time of 20-22 seconds fulfilling the target floating lag time set indicating validity of the optimization technique employed. These tablets also gave sustained release of captopril over 12. The optimized Captopril tablets formulated at two strengths 100 mg/tablet and 60 mg/tablet gave slow, gradual and complete release of Captopril in 12h. Captopril was absorbed rapidly from IR tablets and slowly over longer period of time from floating tablets. Based on (AUC)oα, the relative bioavailability ( BA) of Captopril from FTs was 108.21% when compared to Captopril IR tablets (100%). A good level A correlation (r = 0.9651) was observed between percent drug released (in vitro) and (AUC)oα (in vivo).

Keywords: Cross Linked starch Urea, Floating tablets, Captopril, Optimization, Preclinical, Pharmacokinetics.