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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.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

An angle analysis and linear analysis are popularly used in clinical orthodontics. Downs analysis and Northwestern analysis are two methods of angle analysis, and the mean values reported by Iizuka in 1963 are still used. However in Japan each generation's constitution (height, weight) tends to increase year by year. For example, the mean height and weight of adult males (23 years old) have increased by 5.0cm and 7.6kg as compared with nearly 20 years ago. Therefore the mean of 20 years ago may not be appropriate. Analytical values at normal occlusion Japanese adults by Kayukawa, Iizuka, Ishikawa, Yamauchi, Miura, Iwazawa and, most recently by Asai in 1973. We obtained these values and determined the validity of currently used values.