]. Soc. Cosmet. Chem., 22, 615-634 (Septcmber 17, 1971) Biophysical Factors Penetration in Skin BERNARD IDSON, Ph.D.* Presented, in part, before the New York Chapter, April 7, 1971, Clifton, N.J. Synopsis--The factors that affect rates and extent of PENETRATION of agents into the SKIN are dependent primarily on the physical-chemical properties of the penetrant and secondarily on pH, concentration, particle size, and vehicles. PHYSIOLOGICAL VARI- ABLES exerting penetrant influence are the intact or injured condition of the skin, the skin age, area of skin involved, and blood flow to that area. PHYSICO-CHEMICAL FACTORS involve the hydration and temperature of the skin and the concentration, solubility, and molecular characteristics of the penetrant. VEHICLES, under specialized conditions, can materially affect skin penetration. INTRODUCTION The skin is under constant assault by a huge variety of noxious chemicals as well as from substances applied to the skin as cosmetics or medicinals. The degree of penetration is dependent primarily on physio- logic factors of the skin and physical-chemical factors due to the penetrant and somewhat secondarily on the vehicle or formulation. Generally, localized action is desired for cosmetics and medicinals. A maximum of agent should be concentrated at a particular epidermal site. Subsequent systemic absorption should be kept to a minimum to both prolong the contact of the drug with the skin tissues and reduce undesirable systemic side-effects. This review attempts to draw together the more significant work on these biophysical and formulation factors in the hope of im- proved correlative understanding. •* Hoffman-La Roche Inc., Nutley, N.J. 07110. 615

616 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS PHYSIOLOGICAL FACTORS IN SKIN PENETRATION Skin Condition The intact skin presents a formidable barrier to skin penetration. In diseases characterized by a defective horny layer, percutaneous absorption is increased (1-6). Removal of the skin barrier by cellophane tape stripping will enhance the absorption of almost any substance (7-10). Chemical agents such as acids, alkalies, or mustard gas injure barrier cells and increase water loss. Solvents, other than water, appear to cause varied alteration in the resistance of the skin barrier (11-15). Tregear (16) has reviewed the permeability of the skin to aqueous solutes, organic liquids, and solutes in organic liquids and solids. Treatment with ether does not alter the penetration rate of salicylates or surfactants (14), while the polar solvents, acetone, alcohol, and hexane increase the penetration of water into the skin (17). Excised stratum corneum is virtually "opened" by delipidiza- tion of the stratum concern by holding it in a mixture of a polar and a nonpolar solvent, such as chloroform-methanol. Removal of the lipid fraction of the stratum comeurn can be considered to make "holes" or "artificial shunts" in the membrane (18). Skin Age Relationship of age to skin permeability has rarely been investigated. Fetal and infant skin appears more permeable than adult skin (19). Percutaneous absorption of topical steroids occurs more readily in children than adults (20). The significant derreal atrophy and gross epidermal changes in the elderly denote absorption influence (21). Regional Skin Sites There are relatively few references in the literature to the variations in absorption from one skin site to another, and much of it is con- flicting (22-36). In different "normal" individuals, there are wide variations in the absorption rate of a given substance through the same skin site, and penetration rates for the most permeable regions (pos- terior auricular skin) in some subjects are comparable to rates for the least permeable regions (plantar skin) in others (26). Variations in pene- tration rates have been demonstrated for full thickness cadaver skin, isolated from different sites. These permeations may be in direct propor- tion to the thickness of the area, for the penetration across skin, the flux, is inversely proportional to the thickness.