Method and compositions for disrupting the epithelial barrier function

#1. Field of the Invention

#This invention relates generally to a novel method for enhancing penetration of physiologically active substances for cutaneous or transdermal delivery through epithelium which comprises the stratum corneum/epidermis and keratinizing mucous membranes. More specifically, it relates to a method and composition for disrupting the epithelial barrier function in a host which employs at least one agent selected from the group consisting of inhibitors of ceramide synthesis, an inhibitor of glucosylceramide synthesis, an inhibitor of acylceramide synthesis, an inhibitor of sphingomyelin synthesis, an inhibitor of fatty acid synthesis, an inhibitor of cholesterol synthesis, inhibitors of phospholipid, glycosphingolipid, including glucosylceramide, acylceramide and sphingomyelin degradation, a degradation enzyme of free fatty acid, ceramide, acylceramide, or glucosylceramides and sphingomyelin, and both inhibitors and stimulators of metabolic enzymes of free fatty acids, ceramide, and cholesterol.

#2. Description of Related Art

#FIG. 1 schematically shows a biosynthetic and degradation pathway of ceramides, acylceramides and glucosylceramides.

#FIG. 2 schematically shows a biosynthetic pathway of free fatty acids.

#FIG. 3 schematically shows a biosynthetic and degradation pathway of cholesterol.

#This invention is based on the discovery that when the biosynthesis of one or more of the epithelial lipids, ceramides, acylceramide, glucosylceramides, sphingomyelin, cholesterol and free fatty acids is inhibited, or their distal utilization is increased, the lipid species is depleted perturbing the normal mole ratio, resulting in incompetent epithelial barrier function. Inhibition of enzymes involved in a biosynthetic pathway or inhibition of the degradation enzymes for the precursors of each of these key lipid constituents have also been specifically targeted according to the present invention. Further, it has been discovered that the inhibition of biosynthetic enzymes or stimulation of degradative enzymes aiming at two or more lipid constituents may be additive or synergistic in the opening of the epithelial barrier for percutaneous or transmucosal delivery of physiologically active substances.

#The composition of this invention principally employs an epithelial barrier-disrupting amount of at least one agent selected from the group consisting of inhibitors of ceramide synthesis, an inhibitor of sphingomyelin synthesis, an inhibitor of glucosylceramide synthesis, an inhibitor of acylceramide synthesis, an inhibitor of sphingomyelin synthesis, an inhibitor of fatty acid synthesis, an inhibitor of cholesterol synthesis, inhibitors of phospholipid, glycosphingolipid, including glucosylceramide, acylceramide and sphingomyelin degradation, a degradation enzyme of free fatty acid, ceramide, acylceramide, or glucosylceramides and sphingomyelin and both inhibitors and stimulators of metabolic enzymes of free fatty acids, ceramide, and cholesterol.

#As used herein, the term “an epithelial barrier-disrupting amount” means that the amount of enzyme inhibitor(s), stimulator(s) or degradation enzymes are of sufficient quantity to disrupt the barrier when these compounds are topically applied to the skin or mucous membrane of a host. The amount can vary according to the effectiveness of each enzyme inhibitor or stimulator, or degradation enzyme, as a percutaneous or transmucosal penetration enhancer, the host age, and response of the host. More importantly, the therapeutic amount should be determined based on the penetration efficiency of a given physiologically active substance when that substance is administered in conjunction with a particular combination of the enzyme inhibitors or stimulators, or degradation enzymes. The required quantity to be employed in this invention can be determined readily by those skilled in the art.