STRATEGIES IN THE DESIGN OF SOLUTION-STABLE, WATER-SOLUBLE PRODRUGS .2. PROPERTIES OF MICELLAR PRODRUGS OF METHYL-PREDNISOLONE

In a previous study, a physical-organic approach to the design of solution-stable, water-soluble prodrugs of the corticosteroid methylprednisolone was outlined, and several 21-esters were synthesized to test the approach. Compounds exhibiting dilute solution stabilities approaching 2 yr at 25.degree. C were reported. A complicating factor in more concentrated aqueous solutions of water-soluble prodrugs is the limited extent to which hydrolysis can occur before the solution becomes saturated with respect to the relatively insoluble parent drug. In this study the advantages of micellar prodrugs as water-soluble delivery systems for parenteral administration of relatively insoluble parent drugs are explored. Micellar prodrugs, besides being highly water soluble, have additional advantages in that their micelles solubilize poorly soluble degradation products which may otherwise precipitate and may act as a self-stabilizing influence due to protection of the hydrolytically labile prodrug linkage within the micelle interior. Two 21-esters of methylprednisolone previously identified as having promising dilute solution stability self-associated in aqueous solution at higher concentrations, as determined by solubility, kinetic and light-scattering measurements. One consequence of self-association is that free methylprednisolone, the product of prodrug hydrolysis, is solubilized in concentrated prodrug formulations. Acid- and base-catalyzed hydrolysis rate constants are altered in the micelles, resulting in further prolongation of shelf life in concentrated solutions. Due to the added benefits of self-micellization, the water-soluble 21-esters investigated exhibit shelf lives exceeding 2 yr at 30.degree. C, the upper limit of the controlled room temperature range.