574 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Release lrom Suspensions The presence of undissolved drug as suspended particles in a topical vehicle does not indicate per se that release of drug from the vehicle is rate-limiting. It is true, however, that these systems are among the most likely to release the drug sufficiently slowly so as to control the absorp- tion process. When the solubility of the drug in the vehicle is very small (Cv Co), then the following simple expression applies: ICoC,h •t = X, 2t ? (2) It can be seen that as the amount of drug in suspension (Co) decreases and becomes equal to the vehicle solubility (Cv), i.e., C,•: C0, eq 2 ap- proximates eq 1. It can also be seen that at a given concentration, re- lease is ordinarily faster from the vehicle in which the drug is com- pletely solubilized. Equations 1 and 2 have some interesting practical implications. Re- lease can be controlled by altering the diffusion coefficient, the total drug concentration, and the drug solubility in the vehicle. As Higuchi (16) stresses, the relationship between release and concentration is not a direct one. Consequently, doubling the concentration of a drug in a formulation of the ointment-suspension type does not increase the re- ]ease by twofold. Instead, only about a 40% increase in release is pre- dicted by eq 2. This has been found to be quite true in in vitro release experiments conducted in our laboratories with steroid ointment sus- pensions. Corticoid-lrehicle-Shin and Penetration Flux In skin penetration, further consideration is required of those param- eters which describe the diffusional process of drug transport across a membrane. The flux is proportional to the product of force and con. centration (18). The following simplified equation can be utilized for defining pene- tration: dQ CvD(PC) 2t - h (3) In eq 3, those parameters which are alterable and may be modified by vehicle ccomposition to facilitate skin penetration are D, PC, and Cv

CORTICOID, VEHICLE, AND SKIN INTERACTION 575 (h denoting effective thickness of the skin barrier). The diffusion co- efficient, D, of the drug in the barrier can be minimally modified by the influence of the vehicle components on the nature of the barrier. The partition coefficient, PC, of the drug between the skin and the vehicle can be optimized by decreasing its solubility in the vehicle. The con- centration of diffnsible drug in the vehicle, C,,, for a given labeled strength can be optimized by insuring that all of the drug is in solution. Partition Coe•icient Numerous investigators have found that a special relationship exists between the permeability of skin to penerrants and their partition co- efficients determined in some arbitrarily selected two-phase system. Katz and Shaikh (19) found a correlation between the vasoconstrictor p.otency of a ser .es of topical corticosteroids with partition coefficient and aqueous solubility. Realistically, the only partition coefficient measurement [or a pene- rrant that can be surely related to its rate of diffusion through the skin is a PC value determined [or the equilibrium distribution of the pene- rrant between the stratum corneum and the vehicle. Measurements of this type have recently been made by Scheuplein (20) and are of immense value in relating the physical and chemical properties of a compound to its pentration rate. It is useful to view the partition coefficient of a drug between the skin and the vehicle as an index of mutual affinity between the drug and vehicle. A large PC value thus indicates the vehicle has poor affinity for the drug. A low PC value would indicate a high degree of mutual interaction and reflects the tendency of the drug to remain in the vehicle. Solubility and Partition Coelficient In order to investigate the possible effect of vehicle composition on drug penetration, we studied s,ome very simple pro_p_y_!..•n_•glycol-water mixtures gelled with Carbopol ©* resin as model vehicles for corticoste- roids. In many respects, these sinrole vehicles were ideal because the solu- bility of the corticosteroids could be varied considerably by varying the concentration of propylene glycol in the gel formulation. For instance, the solubility of fluocinolone acetonide varied from approximately 0.06 mg/ml in pure water to 16.8 mg/ml in pure propylene glycol, a 2800-fold difference. * Carboxy vinyl copolymer, B. F. Goodrich Co., Cleveland, Ohio.