Transport of thyrotropin releasing hormone in rabbit buccal mucosa in vitro.

The transport of thyrotropin releasing hormone (TRH) in rabbit buccal mucosa in vitro has been investigated with respect to (a) rate and type of metabolism of TRH on mucosal and serosal sides of buccal mucosa, (b) mechanism of TRH transport including charge effect on its permeability, and (c) pathway and rate-limiting regions of TRH movement. In addition, the integrity of excised buccal mucosa has been evaluated for purposes of in vitro solute diffusion experiments using tissue ATP level data, transmission electron microscopy, and TRH transport kinetic data. The results indicate that excised rabbit buccal mucosa can be used for TRH diffusion studies for approximately 6 hr. In addition, TRH apparently traverses buccal mucosa by simple diffusion with a steady-state permeability of about 10(-7) cm/sec, and this permeability is independent of pH. Moreover, the primary pathway appears to be via the intercellular space in the rate-limiting barrier, i.e., the upper 50 microns of the epithelium. Finally, TRH is degraded predominantly by deamidase activity, which is followed by, to a lesser degree, carboxypeptidase metabolism.

Strategies in the design of solution-stable, water-soluble prodrugs I: a physical-organic approach to pro-moiety selection for 21-esters of corticosteroids.

The ideal water-soluble prodrug should exhibit sufficient aqueous solution stability to allow long-term storage of its solutions (i.e., 2 years at room temperature) and yet should be converted rapidly in vivo to the active parent drug--two severe and seemingly conflicting demands which limit the utility of many common solubilizing pro-moieties. For example, succinate esters, which are commonly utilized as water-soluble prodrugs, are unstable in solution and may undergo slow and incomplete bioconversion in vivo. In this study, the solution stability problems associated with 21-esters of corticosteroids are reviewed. It is concluded that the most important reaction limiting shelf life is ester hydrolysis. From a consideration of the influence of molecular structure on ester reactivity, a strategy for the design of solution-stable, water-soluble prodrugs of corticosteroids has been developed. Two key requirements for dilute solution stability are high solubility at the pH of optimum stability and appropriate design of the pH-rate profile. Several 21-esters of methylprednisolone have been synthesized, and the rates of their aqueous solution hydrolysis have been determined to test the strategy. Compounds exhibiting estimated shelf lives in dilute solution of greater than 2 years at 25 degrees C have been identified.

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.