Design, in vitro stability, and ocular hypotensive activity of t-butalone chemical delivery systems

The objective of this work was to synthesize two bioreversible diacyl deriv atives of t-butalone (chemical delivery systems), determine their chemical and in vitro stability, and investigate their potential use as topical anti glaucoma agents. The stability of these compounds was determined in isotoni c phosphate buffers (pH range 5-8) and in selected biological media, includ ing human whole blood, rabbit and rat blood, and the anterior segment tissu es of rabbit. The ocular hypotensive activity of these compounds in unrestr ained, normotensive albino rabbits was determined with a pneumatonometer. T he two compounds were stable at lower pH. The stability decreased as the pH increased, suggesting their lability to base-catalyzed hydrolysis. These c ompounds exhibited significant differences in the hydrolytic rates in the w hole blood among species examined (rat > rabbit > human). The observed rate s of disappearance in different ocular tissues were indicative of relative enzyme activity in these media (iris-ciliary body > cornea > aqueous humor) . The two compounds exhibited a significant ocular hypotensive activity (P < 0.01) at 2% dose level. The peak activity was found between 2 and 4 h, an d the activity was maintained for 4.5 to 7 h. The dipivalyl derivative of t -butalone exhibited more pronounced decrease in intraocular pressure than t hat of diisovaleryl derivative. The present study suggests the possible use of diacyl derivatives of t-butalone as ocular hypotensive agents. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.