Effects of Amorphous and Polymorphs of PF1022A, a New Antinematode Drug, on Angiostrongylus costaricensis in Mice

Abstract

To enhance the bioavailability of PF1022A (cyclo(D-lactyl-L-N-methylleucyl-D-3-phenyllactyl-L-N-methyileucyl-D-lactyl-L-N-methylleucyl-D-3-phenyllactyl-L-N-methylleucyl)), a newly developed antinematode drug, we examined whether the new drug has polymorphism or not. First, four forms of PF1022A, designated as form α, form I, form II and form III of PF1022A, were prepared. By examining physicochemical properties of these forms by various methods including X-ray powder diffractometry and differential scanning calorimetry, it became apparent that PF1022A had one amorphous (form α) and three crystalline polymorphic forms, form I, form II and form III. Secondly, a dissolution study was carried out, and form α and form III were found to have higher solubility than form I and form II. Thirdly, anti-larval effects of the 4 forms of PF1022A on tissue-dwelling nematode, Angiostrongylus costaricensis, in mice were compared when given orally for 5 successive days at 10 or 40 mg/kg/day. Significant effects were observed in almost all parameters in host mice and worms in the groups treated with form α or form III, each at 40 mg/kg, but form I and form II had little effect. The present results suggest that PF1022A has polymorphism and that the form α and form III were more effective against tissue-dwelling nematodes than the form I and form II when given orally.