Several factors influence the rate and extent of dermal penetration through the skin, which can be broadly classified into physiological factors, formulation factors, and physicochemical properties of the drug.
Physiological Factors
A. Stratum Corneum Thickness:
The stratum corneum is the primary barrier to drug penetration.
Areas with thinner stratum corneum (e.g., the face, scalp) show higher permeability compared to thicker areas (e.g., palms, soles).
B. Skin Hydration:
Hydrated skin is more permeable.
Hydration can loosen the tight packing of the corneocytes, increasing the ability of a drug to diffuse through the stratum corneum.
C. Skin Age:
Younger skin tends to be more permeable due to thinner and less mature stratum corneum.
Elderly skin may also have compromised barrier function due to thinning of the epidermis, but this varies between individuals.
D. Skin Condition:
Diseases like psoriasis, eczema, or injuries (e.g., cuts, burns) can increase permeability by disrupting the barrier function of the stratum corneum.
E. Blood Flow:
Increased blood flow to the dermis (e.g., due to massage or vasodilation) can enhance systemic drug absorption by creating a greater concentration gradient for absorption from the skin into circulation.
F. Skin Temperature:
Higher skin temperatures can increase the rate of drug diffusion by enhancing molecular movement and blood circulation.
G. Regional Variation:
Skin permeability varies across different parts of the body.
For instance, the face and genitals have higher permeability than the forearms or back.
Physicochemical Properties of the Drug
A. Molecular Size/Weight:
Smaller molecules (generally below 500 Daltons) penetrate the skin more easily.
Larger molecules struggle to cross the stratum corneum.
B. Lipophilicity (Hydrophobicity):
Lipophilic drugs penetrate more easily through the lipid-rich intercellular matrix of the stratum corneum.
However, a balance between lipophilicity and hydrophilicity is needed for optimal absorption, as overly lipophilic drugs may stay within the skin's lipid layers and not reach deeper tissues or circulation.
C. Ionization:
Non-ionized (neutral) drugs generally penetrate the skin better than ionized (charged) molecules.
Ionization depends on the drug’s pKa and the pH of the environment.
D. Drug Concentration:
Higher drug concentrations in the formulation can increase the driving force for drug penetration (concentration gradient), promoting absorption.
Formulation Factors
A. Vehicle/Excipients:
The choice of vehicle (e.g., ointments, creams, gels) influences drug release and penetration.
Lipophilic vehicles like ointments enhance penetration of lipophilic drugs, whereas water-based formulations may be better suited for hydrophilic drugs.
B. Penetration Enhancers:
These are chemicals incorporated into formulations to temporarily disrupt the stratum corneum barrier, allowing better drug diffusion.
Examples include:
Surfactants (e.g., sodium lauryl sulfate)
Solvents (e.g., ethanol, propylene glycol)
Fatty acids (e.g., oleic acid)
C. Occlusion:
Occlusive formulations, like ointments, trap moisture on the skin, increasing hydration and enhancing drug penetration.
Wrapping the skin (e.g., with plastic wrap) after application can create an occlusive environment that improves absorption.
D. pH of the Formulation:
The pH of the formulation can affect drug ionization.
For example, a pH that favors the unionized form of a drug will enhance penetration.
E. Application Duration and Frequency:
The longer the drug is in contact with the skin, the more opportunity it has to penetrate.
Frequent reapplication can increase overall absorption.
F. Surface Area of Application:
Applying the drug to a larger surface area increases the total amount of drug absorbed, although the rate of penetration remains constant for a given area of skin.