N-substituted (aminomethyl)benzoate 21-esters of corticosteroids as water-soluble, solution-stable and biolabile prodrugs.

Various N-substituted 3- or 4-(aminomethyl)benzoate 21-esters of hydrocortisone, prednisolone and methylprednisolone were synthesized and evaluated as water-soluble prodrug forms, with the aim of developing improved preparations for parenteral or ophthalmic administration. All esters were readily hydrolyzed enzymatically by human plasma. The half lives of hydrolysis in 80% plasma ranged from 8 min to 342 min, the rate being dependent on the structure of the amino group and its position relative to the ester moiety, as well as on the structure of the steroid. The esters showed maximal stability in aqueous solution at pH 3-4. From temperature-accelerated studies of the 3-[(4-methylpiperazin-1-yl)methyl)]benzoate ester of hydrocortisone, the shelf life of an aqueous solution (pH 4.0) of this ester was predicted to be 6 years at 25 degrees C. This estimated shelf life is not reduced by precipitation of the slightly soluble parent drug since the ester was shown to be capable of solubilizing hydrocortisone, possibly by self-micelization.