Development of anti-influenza drugs: II. Improvement of oral and intranasal absorption and the anti-influenza activity of stachyflin derivatives

The in-vivo anti-influenza-virus activity of Stachyflin derivatives (III an d its phosphate ester, III-Phos), a new class of haemagglutinin fusion inhi bitor, and the improvement of their absorption after oral or intranasal adm inistration were studied in mice, rats, and ferrets. The absorption of III in PEG 4000 and III-Phos aqueous solution increased a bout three and four fold in AUC after oral administration to uninfected mic e compared with that of 0.5% HPMC (hydroxypropyl-methylcellulose) suspensio n. Using a mouse influenza virus infection model, significant anti-influenz a-virus activity was observed in infected mice treated orally with these co mpounds dissolved in PEG 4000 or distilled water, respectively, but not in mice treated with 0.5% HPMC, The in-vivo anti-influenza-virus activity in f errets, a good model for influenza virus infection in man, was also studied . Although the concentration of III in plasma was above the IC50 against th e influenza virus strain used for 6h after the oral administration of III i n PEG 400 to uninfected ferrets, no in-vivo antiinfluenza-virus activity wa s observed at the same dosage given 4 times daily for 3 days. The intranasa l administration of III-Phos, which was expected to have a more notable in- vivo anti-influenza-virus activity, was examined. III-Phos, whose intranasa l absorption had been improved by the modification of III with phosphate es ter in rats, inhibited viral replication in the nasal cavity and suppressed influenza-virus-induced fever when administered intranasally to infected f errets. This study demonstrates that intranasally administered compounds with anti- influenza-virus activity must permeate the nasal membranes to produce their anti-influenza-virus effect.