Development of anti-influenza virus drugs I: improvement of oral absorption and in vivo anti-influenza activity of Stachyflin and its derivatives.

Abstract

Stachyflin and its derivatives which are active against the influenza virus in vitro, were studied to improve their reduced in vivo activity after oral administration by chemical modification and some vehicles. The solubility was examined for different vehicles. The improvement of gastrointestinal absorption was evaluated by the plasma concentration after oral administration to mice or the in situ loop method with rats. The in vivo anti-influenza activity was examined using mice infected with the influenza virus and evaluated based on the virus titer in the lung by TCID50. PEG 400 showed the highest solubility of Stachyflin and its derivative among the vehicles studied. While no viral inhibition was found in the lung after oral administration of 0.5% HPMC suspension of Stachyflin, in vivo anti-influenza virus activity was found with the PEG 400 solution. The absorption of Stachyflin by PEG 400 showed about a fifty-fold increase in AUC compared with that of 0.5% HPMC suspension. Improving the oral absorption of Stachyflin led to an increase in the in vivo anti-influenza virus activity. When the Stachyflin derivative in PEG 4000 was administered orally, there was more enhancement of the oral absorption than with PEG 400. When the aqueous solution of the phosphate ester prodrugs of Stachyflin and its derivative was administered orally, the absorption of the parent compound was improved and in vivo anti-influenza virus activity was found. When Stachyflin and its derivatives were administered orally to mice with a solution in PEG and an aqueous solution of their phosphate ester, their oral absorption was improved and in vivo anti-influenza virus activity was observed.