The primary physiological process by which lipophilic therapeutic compounds, including most steroid hormones, passively traverse the skin’s outermost layer, the stratum corneum. This diffusion involves the drug partitioning into and migrating through the continuous, highly organized intercellular lipid matrix, which is composed of ceramides, cholesterol, and fatty acids. It represents the rate-limiting step for the transdermal absorption of the majority of systemically acting agents.
Origin
This concept is a cornerstone of transdermal pharmacology, fundamentally derived from the widely accepted “brick-and-mortar” model of the stratum corneum structure. The intercellular lipid matrix, representing the ‘mortar,’ was identified as the main continuous pathway for non-polar molecules due to its inherently lipophilic nature. Research focused on modulating this diffusion pathway has been the driving force behind the development of modern transdermal delivery systems.
Mechanism
The drug molecule must first dissolve in the lipid lamellae, then diffuse through the tortuous, highly structured lipid environment down its concentration gradient, thereby bypassing the protein-rich corneocytes. The rate of diffusion is directly proportional to the drug’s lipid solubility and inversely related to its molecular size and the path length. Temporary alteration of the fluidity or structure of this lipid matrix, often achieved through chemical enhancers, is the primary strategy to increase the drug’s penetration rate.
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