Development of glucocorticosteroids with enhanced ratio between topical and systemic effects

Abstract

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 9α- or 6α,9α-positions increased the systemic more than the topical potency. The non-fluorinated, non-symmetric 16α,17α-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 17α-esters such as beclomethasone 17α,21-dipropionate. Although budesonide and betamethasone 17α,21-dipropionate 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 6β-hydroxybudesonide and 16α-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.