Development of glucocorticosteroids with enhanced ratio between topical and systemic effects.

A high potency at the application site and a low incidence of glucocorticoid side-effects form the desired profile of glucocorticosteroids for anti-inflammatory therapy. A new type of glucocorticosteroid 16,17-acetals with an improved topical/systemic activity ratio has been developed. Non-symmetric 16,17-acetal substitution increased the topical anti-inflammatory activity more than the systemic activity in rodents, whereas fluorine substitution in 9 alpha- or 6 alpha,9 alpha-positions increased the systemic more than the topical potency. The non-fluorinated, non-symmetric 16 alpha,17 alpha-acetal budesonide reached the highest ratio, which was five to ten times better than that of the earlier known 16,17-acetonides such as triamcinolone acetonide, or that of the 17 alpha-esters such as beclomethasone 17 alpha,21-dipropionate. Although budesonide and betamethasone 17 alpha,21-diproprionate have the same topical anti-inflammatory potency, the latter decreased plasma and urinary cortisol levels significantly more when ointment preparations were compared in volunteers. Budesonide is efficiently biotransformed in the liver to metabolites such as 6 beta-hydroxybudesonide and 16 alpha-hydroxyprednisolone, which are 50-100 times less potent than the parent steroid. In homogenates of rat or human adult livers budesonide is biotransformed two to five times more rapidly than desonide and triamcinolone acetonide.