Protective effects of dried mature Citrus unshiu peel (Chenpi) and hesperidin on aspirin-induced oxidative damage.

Here we investigated the inhibitory effects in rats of mature Citrus unshiu peel (Chenpi) and its component hesperidin on aspirin-induced oxidative damage. The content of hesperidin in Chenpi extract was approximately 11.4%. Wistar rats were orally administered Chenpi extract or hesperidin (20 mg/kg body weight) and then were orally administered aspirin (200 mg/kg body weight) to induce oxidative damage to the stomach, liver, and kidneys. Such damage was evaluated using the formamidopyrimidine DNA glycosylase-modified comet assay. We also measured the amount of the oxidative marker 8-oxo-7,8-dihydroguanine (8-oxodG) in the stomach. Aspirin-induced damage to the gastric mucosa was evaluated using a bleeding score. Chenpi extract and hesperidin significantly inhibited aspirin-induced oxidative DNA damage. The bleeding score of the aspirin-induced gastric mucosa was significantly reduced by treatment with Chenpi extract and hesperidin. To investigate the effects of Chenpi extract and hesperidin on the analgesic effect of aspirin on ddY mice, we employed the acetic acid-induced writhing response test. Chenpi extract and hesperidin did not significantly affect the analgesic effect of aspirin. These results suggest that Chenpi extract and hesperidin significantly inhibit aspirin-induced gastric mucosal damage.

UniORV, a New Multi-Unit Dosage Form, Improved Biopharmaceutical Properties of Tacrolimus in Rats and Humans.

PURPOSE: The aim of the present study was to develop a new multi-unit dosage formulation, Universal ORbicular Vehicle (UniORV), to improve the biopharmaceutical properties of tacrolimus (TAC). METHODS: TAC-loaded UniORV (UO/TAC) was produced by the dripping and gelling of a solution comprising TAC, gelatin, starch syrup, and triethyl citrate at 0.5 w/w% drug loading. Its microstructure was elucidated by polarized light microscopy and the Raman mapping technique. The pharmacokinetic profiles of TAC after the oral administration of UO/TAC were evaluated in rats and healthy humans. RESULTS: The dissolution behavior of UO/TAC was similar to that of commercial capsules, and the formation of nanoparticles was detected by TEM in dissolved media. In a stability study on UO/TAC, only 2.6 and 4.7% decreases in TAC concentrations were observed at 40± 2°C/75 ± 5% relative humidity for 4 months and at 50± 2°C for 2 months, respectively. A pharmacokinetic study on rats revealed a 30-fold higher AUC than that with crystalline TAC. A randomized double-blind crossover study on 8 healthy males showed that UniORV achieved a 1.4-fold increase in AUC and 34% decrease in inter-individual variation from the reference formulation. CONCLUSION: The new dosage form UniORV is a promising approach to improve the dissolution, amorphous stability, and biopharmaceutical properties of TAC, which is a poorly water-soluble drug.

Cyclosporine a-loaded UniORV®: Pharmacokinetic and safety characterization.

This study aimed to improve pharmacokinetic behavior and reduce safety concern of cyclosporine A (CsA) by UniORV® approach, a new platform for solid dispersion formulation. CsA-loaded UniORV® (UO/CsA) was prepared, and its physicochemical properties were evaluated in terms of droplet size distribution and dissolution. The pharmacokinetic behavior and nephrotoxic potential of orally-dosed CsA samples (10 mg-CsA/kg) were assessed in rats. After re-dispersion of UO/CsA in water, fine droplets were observed, and the mean diameter of droplets was calculated to be 45 nm. The UniORV® approach markedly improved the dissolution behavior compared with amorphous CsA in water. After oral administration of amorphous CsA, Neoral®, and UO/CsA in rats, UO/CsA exhibited a 32% lower maximum concentration and 5.1 h longer mean residence time than those of Neoral®. The oral absorption of CsA formulations was higher compared with amorphous CsA; in particular, the oral bioavailability of UO/CsA was 71-fold higher than that of amorphous CsA. Neoral® elicited nephrotoxicity with plasma creatinine level of 1.29 mg/dL; however, Neoral®-induced nephrotoxicity was attenuated in UO/CsA, as evidenced by a 15% lower plasma creatinine level of UO/CsA than that of Neoral®. From these findings, UO/CsA might be a promising dosage form with improved biopharmaceutical properties of CsA.