Active coating of immediate-release evogliptin tartrate to prepare fixed dose combination tablet with sustained-release metformin HCl.

This study was aimed to develop a fixed dose combination (FDC) tablet containing a low dose of evogliptin tartrate (6.87 mg) for immediate release combined with a high dose (1000 mg) of sustained-release (SR) metformin HCl appropriate for once daily dosing the treatment of type 2 diabetes. To prepare the FDC tablets, an active coating was used in this study, whereby evogliptin tartrate film was layered on a matrix core tablet containing metformin HCl. To overcome the problem caused by a low-dose drug in combination with a relatively large matrix tablet containing high-dose drug, it was also aimed to confirm the formulation and coating operation for satisfactory content uniformity, and to describe the chemical stability during storage of the amorphous active coating layer formulation in relation to molecular mobility. Furthermore, the in vitro release and in vivo pharmacokinetic profiles of metformin HCl and evogliptin tartrate in the FDC active coating tablet were compared to those of the commercially marketed reference drugs, Diabex XR® (Daewoong, Seoul, Korea) containing metformin HCl and Suganon® (Donga ST, Seoul, Korea) containing evogliptin tartrate. In conclusion, the newly developed FDC active coating tablet in this study was confirmed to be bioequivalent to the reference marketed products in beagle dogs, with satisfactory content uniformity and stability.

Changes in hepatic drug metabolizing enzymes and lipid peroxidation by methanol extract and major compound of Orostachys japonicus.

The effects of methanol extract and gallic acid (3,4,5-trihydroxybenzoic acid) of Orostachys japonicus A. Berger on hepatic drug metabolizing enzymes and lipid peroxidation were investigated in rats treated with bromobenzene. The methanol extract of Orostachys japonicus reduced the activities of phase I enzymes, aminopyrine N-demethylase and aniline hydroxylase, that had been increased by i.p. injection of bromobenzene. Gallic acid isolated from Orostachys japonicus also reduced the aniline hydroxylase activity, while it did not affect the aminopyrine N-demethylase activity. The methanol extract and gallic acid restored the activity of epoxide hydrolase which had been decreased by bromobenzene. Hepatic glutathione content was lowered, along with increase in hepatic lipid peroxide, by bromobenzene administration. The hepatic lipid peroxidation induced by bromobenzene was prevented with the methanol extract and gallic acid of Orostachys japonicus. However, the decrease in glutathione was not altered by gallic acid. The present results suggest that the methanol extract and gallic acid of Orostachys japonicus may protect liver from bromobenzene toxicity through, at least in part, inhibiting the cytochrome P450-dependent monooxygenase activities and enhancing the activity of epoxide hydrolase. Antioxidant effect also may contribute to the protection of Orostachys japonicus against the bromobenzene-induced hepatotoxicity.