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 10[2] dyne/cm[2]]. 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 micro g. hr/ml] and C[max] [29.417 micro g/ml] of DS than did conventional suppositories [55.023 micro g. hr/ml and 22 micro g/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 hepato-cellular damage occurred after 30 days of administration of DS-loaded 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

Effect of penetration enhancers on the permeability of ketoconazole gels through rabbit skin

The influence of several penetration enhancers on the percutaneous penetration of ketoconazole [KC] from hydroxypropylmethyl cellulose [HPMC], sodium carboxymethyl cellulose [NaCMC] and carbopol 934 gel formulations was investigated. Skin permeation studies were performed using Franz-type diffusion cells and full-thickness abdominal rabbit skin. Various types of compounds such as oleic acid [OA], menthol [M] and isopropyl myristate [IPM] in various concentrations were employed as penetration enhancers. The steady-state flux, permeability coefficients, and enhancement ratios ER of [offlux] KC for each formulation were calculated. The results showed that the skin permeability of KC from gels tested was significantly increased [P< 0.05] by 10% w/w OA, 5% w/w M and 5% w/w IPM. ER [flux] of KC gels containing 10% OA were 19.5, 16.4 and 11.9 for NaCMC, HPMC and carbopol gel respectively. ER [flux] of 5% w/w M were 13.5, 13.3 and 10.9 for HPMC, NaCMC and carbopol gel respectively. About 11 fold increase in the ER [flux] at 5% w/w IPM for all gels. Kinetic analysis of the data indicated that the permeation of [KC] from different gel formulations obeyed Higuchi-diffusion model. In conclusion, OA, M and IPM could be considered as penetration enhancers for KC topical formulations

Phonophoresis of theophylline through cellophane membrane and rabbit skin

The influence of ultrasound waves upon the permeation of theophylline through cellophane membrane and rabbit skin was studied in vitro. Sonication was carried out with continuous mode at intensities [0.5, 1, 1.5, and 2 W/cm 2 at constant frequency 800 KHz for one sr. Different gel formulations with [hydroxypropylmethyl cellulose, sodium carboxymethylcellulose and carbopol 934P] in different concentrations [1-4% w/w] were utilized. Phonophoresis of theophylline through rabbit skin were significantly less than that obtained with the cellophane membrane. Ultrasound application has showed a significant increase in the amount of theophylline permeation with increasing intensity. For all the tested gelling agents, the amount of drug released was decreased by increasing polymer concentrations. The Flux values were 5.99, 3.69 and 2.4 [micro g/min cm 2] for 2% HPMC, 4% Na CMC and 2% carbopol 934P gels respectively. It was found that drug release from HPMC gels obeys Zero-Order model while its release from Na CMC and carbopol 934P were fitted with First-Order and Higuchi-diffusion model respectively