Strategies in the design of solution-stable, water-soluble prodrugs II: properties of micellar prodrugs of methylprednisolone.
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 years at 25 degrees C were reported. A complicating factor in more concentrated aqueous solutions of water-soluble prodrugs, however, 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 have now been shown to self-associate 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. In addition, 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 years at 30 degrees C, the upper limit of the controlled room temperature range.
D002626:Chemistry, Pharmaceutical; D002853:Chromatography, Liquid; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008027:Light; D008775:Methylprednisolone / Q000031:analogs & derivatives*; D008823:Micelles; D009391:Nephelometry and Turbidimetry; D012542:Scattering, Radiation; D012995:Solubility
D008823:Micelles; D008775:Methylprednisolone