Studies on the Formulation of Topical Corticosteroids

Abstract

The stabilities of betamethasone-17-valerate and hydrocortisone-17-butyrate have been investigated. It has been shown that the 17-esters undergo acyl migration to the 21-isomers. These 21-isomers hydrolyse to the free alcohols which further degrade to other products. In order to elucidate the complex decomposition pathway, two normal phase and reversed phase HPLC systems were developed for assaying these two corticosteroids in the presence of their major decomposition products. The development and applications of these systems were discussed. The kinetics of decomposition were subjected to non-linear regression analysis. The rate constants for the various decomposition pathways were quantified. Attempts were made to formulate a stable 0.1% w/w hydrocortisone-17-butyrate gel with various polymers. Carbopol gel was the most cosmetically acceptable base. Stability studies of the corticosteroid in semi-aqueous Carbopol gels revealed that the decomposition pathway parallel those in aqueous propylene glycol. Steroid gels with a shelf-life of about one year were formulated. The percutaneous absorption of hydrocortisone and its 17- and 21-butyrates and 21-acetate were studied using three in vitro models which enabled simultaneous monitoring of more than one steroid. The studies included release from Carbopol gel into isopropyl myristate; penetration through mouse skin and 3-phase partitioning. Vehicle effects were related to the solubility of the corticosteroids in aqueous propylene glycol and to their partition coefficients between isopropyl myristate and aqueous propylene glycol. The cutaneous biotransformation of betamethasone-17-valerate and hydrocortisone-17-butyrate were compared with their 21-isomers using esterases from hog liver and mouse skin homogenates. The results showed that the 21-esters were very sensitive to the esterases. Based on the quantitative data on the decomposition of these corticosteroids, it was clearly shown that the steroid-17-esters were resistant to the esterases. The resistance of beclomethasone-17, 21-dipropionate and its 17-monopropionate to these enzymes further suggested that for steroids to be susceptible to enzymic degradation, the 17-hydroxyl group must remain free.