The sorption and rate of permeation of scopolamine base in human skin have been measured as a function of drug concentration in aqueous solution contacting the stratum corneum surface of the skin. The sorption isotherm is nonlinear, and the apparent penetrant diffusivity computed from steady state permeation data is greater than that estimated from unsteady state (time lag) measurements. By assuming that sorption occurs by both ordinary dissolution and binding of penetrant to immobile sites in the membrane, the experimental sorption isotherm can be predicted, and the disparity between steady state and time lag diffusivities can be reconciled.
The effect of the presence of dimethyl sulfoxide (in admixture with water) on the sorption and permeation rate of scopolamine base in human skin in vitro has been measured as a function of drug concentration in aqueous solution. The equilibrium sorption of scopolamine by skin from solution appears to be unaffected by the presence of even high concentrations of dimethyl sulfoxide in the solution phase. In the absence of a transdermal gradient of DMSO (or water), the permeability of skin to scopolamine in the presence of DMSO i.; about twofold higher than in its absence, suggesting that the diffusivity of scopolamine in the stratum corneum is somewhat elevated by the solvating action of DMSO.When, however, a gradient of DMSO concentration is impressed across the skin (irrespective of whether that gradient is of the same or opposite sign to that of the drug), the permeability of the skin to scopolamine is increased by one to two orders of magnitude. Microscopic examination of the skin subjected to such treatment reveals marked swelling, distortion, and intercellular delamination of the stratum corneum, which is only partially reversible following complete extraction with water. These effects are believed due to development of very high osmotic stresses produced within the stratum corneum, as both water and DMSO are transported into the tissue. SCOPEThis paper is the third in a series devoted to the measurement and interpretation of the transport of relatively small, biologically active molecules though intact human skin, who3e objective has been to explain the often puzzling barrier properties of skin on rational, physicochemical principles of solution thermodynamics and molecular diffusion kinetics.For many years, certain super solvents such as dimethyl sulfoxide (DMSO) have been recognized as exceedingly skin-permeable substances and have been shown to greatly elevate the permeability of skin to many compounds to which intact human skin is normally an effective barrier.These observations have evoked numerous hypotheses about the role of substances such as DMSO on skin permeation, some of which call upon active transport mechanisms, or coupled-flow, piggyback diffusion processes, which have few, if any, counterparts in passive membrane transport systems.In the studies herein reported, we have found that the effects of DMSO on skin permeability in vitro are entirely consistent with accepted theories of solution diffusion models of membrane transport, when changes in penetrant activity with changes in solvent composition are properly allowed for, and when changes in tissue microstructure accompanying osmotic shock are duly considered. CONCLUSIONS A N D SIGNIFICANCEThe principal barrier to the transport of drugs and other relatively small molecules through intact human skin is localized with the stratum corneum, which is comprised of dead, keratinized, partially desiccated epidermal cells. Drug permeation through the stratum corneum occurs principally by a passive diffusion process independent of metabolic assistance...
The dual sorption theory has been extended to the transport of drug molecules through human skin in vitro. By assuming that sorption of drug molecules occurs by both dissolution and binding of drug to immobile sites in the skin, the experimental sorption isotherm can be predicted, and the disparity between steady state and time lag diffusivities can be reconciled. Furthermore, the dual sorption model has been used to develop techniques for controlling these sorption transport processes in order to rapidly achieve predictable transdermal drug delivery in vivo.
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