FORMULATION OF SITE-SPECIFIC MUCOADHESIVE LIQUID SUPPOSITORIES AS A METHOD TO DECREASE HEPATOTOXICITY IN RABBITS

Mucoadhesive liquid suppositories containing diclofenac sodium (DS) as a NSAID were prepared using poloxamers as a liquid suppository base. Various formulations composed of different ratios of P407 and P188 (10/20, 15/15, 21/9, 24/6 and 27/3% w/w of P 407/P188) were prepared. The physicochemical characters; the gelation temperature, gel strength and mucoadhesive properties of the prepared suppositories were evaluated and compared with conventional suppositories. The dissolution and pharmacokinetic parameters of DS from such suppositories were also estimated. It was also important to study the histopathological changes in rabbit rectum and liver after administration of liquid and conventional suppositories. The gelation temperatures were 49.5, 45.5, 32.5, 22.5 and 20.5°C for 10/20, 15/15, 21/9, 24/6 and 27/3% w/w of P407/P188, respectively. P407/P188 mixture in the concentration of 21/9%, w/w was selected as the system of choice since it exhibited adequate physicochemical properties. The addition of DS increased the gelation temperature (from 18 to 32.5°C) for 21/9 poloxamer mixture and reduced the gel strength (from 4.03 sec to 3.4 sec) and the mucoadhesive force (from 3.5 to 1.72 x 102 dyne/cm2). It was found that the dissolution of DS-loaded poloxamer-based suppositories was significantly higher than that from the conventional suppositories (51.3 versus 26.7%, respectively). Furthermore, the pharmacokinetic study showed that DS-loaded poloxamer-based suppositories gave significantly higher initial plasma concentrations, AUC (70.313 µg. hr/ml) and Cmax (29.417 µg/ml) of DS than did conventional suppositories (55.023 µg.hr/ml and 22 µg/ml), respectively. Histopathological study of rectal tissues indicated no pathological damage after 6h of rectal administration. The histopathological study of liver tissues revealed that no hepatocellular damage occurred after 30 days of administration of DSloaded poloxamer-based suppository; however hepatotoxicity could not be totally avoided by rectal administration of conventional suppositories. DS-loaded poloxamer-based suppository was an effective rectal dosage form with alleviated adverse effects.