Which drug characteristics make a good candidate for diffusion across the skin?

• A. Both aqueous and lipid solubility
• B. only aqueous solubility
• C. neither
• D. only lipid solubility

Answer: (A)

Diffusion through the skin relies on a drug being able to leave the formulation, partition into the skin’s lipid-rich outer layer (the stratum corneum), and then move through aqueous pathways to reach systemic circulation. A molecule needs sufficient lipid solubility to partition into the stratum corneum, but it also needs some aqueous solubility to dissolve and diffuse through the hydrophilic environments within the skin and to be carried in the aqueous receptor fluid. If a drug is only water-soluble, it won’t readily enter the lipid barrier, so permeation is poor. If it’s only lipid-soluble, it may partition into the skin but have trouble moving through the aqueous domains and reaching deeper layers. Therefore, having both aqueous and lipid solubility—an amphiphilic balance—makes a drug a better candidate for diffusion across the skin.