Transdermal absorption is the process by which substances applied to the skin move through its layers to reach the bloodstream, resulting in a systemic effect. This method is an important alternative to traditional oral or injectable routes. By bypassing the digestive system, transdermal delivery offers a non-invasive way to administer therapeutic agents directly into the circulation. The effectiveness of this system relies on a substance’s ability to navigate the complex structure of the skin.
The Skin’s Barrier Structure
The primary challenge for any substance entering the body through the skin is the outermost layer, the stratum corneum. This layer, only 10 to 30 micrometers thick, functions as the body’s main physical and chemical interface with the external environment. It consists of specialized, dead cells called corneocytes that are tightly packed and surrounded by a continuous lipid matrix.
The stratum corneum structure is often described using the “brick and mortar” model. The corneocytes represent the bricks; these are protein-rich cells composed largely of keratin. These dead cells are relatively hydrophilic, meaning they tend to repel fats and attract water.
The mortar is the intercellular lipid matrix, a complex mixture of ceramides, cholesterol, and free fatty acids. This lipid-rich matrix is overwhelmingly hydrophobic. It acts as the skin’s main permeability barrier, dictating which compounds can penetrate.
The layers beneath the stratum corneum—the viable epidermis and the dermis—present less resistance. Once a substance crosses the lipid barrier, it diffuses through these deeper, more aqueous layers. Systemic transdermal delivery aims to reach the dermis, which contains a dense network of capillaries that distribute the substance throughout the bloodstream.
Pathways of Absorption
A substance seeking to cross the stratum corneum can utilize one of three physical routes. The transepidermal route is the most significant, accounting for the vast majority of absorption. This route is divided into two mechanisms: intercellular and transcellular.
The intercellular pathway involves the substance moving through the continuous lipid matrix, the “mortar” between the cells. Because this matrix is lipid-rich, this route is preferred by lipophilic substances. The path requires the molecule to navigate a complex structure of lipid bilayers.
The transcellular pathway requires the substance to pass directly through the corneocytes, penetrating both the cell wall and the inner protein structure. This route necessitates the substance to partition in and out of both the hydrophobic lipid membranes and the hydrophilic keratin interior. Molecules that are slightly more polar sometimes utilize this route.
The third option is the transappendageal or shunt pathway, which circumvents the main stratum corneum. This involves movement through the skin’s accessory structures, primarily the hair follicles and sweat glands. While these routes offer an easy passage, they represent a very small surface area, typically less than one percent of the total skin surface. For larger or highly polar compounds, this shunt route may be the only way to achieve measurable absorption.
Factors Influencing Permeability
Transdermal absorption depends highly on a substance’s physicochemical properties. Molecular size is a limiting factor, as the skin barrier restricts the passage of larger compounds. For effective diffusion through the stratum corneum, molecular weight must be less than 600 Daltons.
A substance’s lipophilicity must be balanced for optimal skin penetration. The molecule must be hydrophobic enough to dissolve into and pass through the lipid “mortar.” If the compound is too lipophilic, however, it may get trapped within the barrier layer and be unable to partition into the deeper, aqueous layers of the dermis.
Absorption is also governed by Fick’s Law of Diffusion, which emphasizes the concentration gradient. The rate of movement is proportional to the difference in concentration between the formulation on the skin and the concentration in the blood. Applying a higher concentration creates a stronger driving force, pushing molecules across the barrier more quickly.
The condition of the skin also impacts permeability. Increased skin hydration causes the stratum corneum to swell, loosening the lipid structure and increasing absorption. Conversely, damaged or compromised skin shows significantly higher permeability. Compounds with a high number of hydrogen bond donors or acceptors tend to have lower skin permeability, as these characteristics hinder crossing the hydrophobic lipid barrier.
Medical and Commercial Applications
Transdermal delivery offers advantages over traditional dosing methods. A primary benefit is the avoidance of first-pass metabolism, where a drug is broken down by the liver after absorption from the digestive tract. By entering the bloodstream directly through the skin, the drug remains chemically intact and more effective.
This route allows for the continuous, controlled delivery of medication over an extended period. Patches and gels maintain stable, therapeutic drug levels in the blood, avoiding the sharp peaks and troughs common with oral dosing. This steady administration reduces the frequency of dosing and minimizes potential side effects.
Transdermal products are commonly formulated as patches, which contain the medication in a reservoir or within the adhesive layer, or as creams and gels. Well-established transdermal applications include:
- Hormone replacement therapy.
- Nicotine for smoking cessation.
- Pain relief medications such as fentanyl and buprenorphine.
- Scopolamine patches for motion sickness.
- Nitroglycerin for angina.
To overcome the skin’s resistance, many commercial formulations incorporate chemical penetration enhancers. These compounds, such as certain alcohols or fatty acids, temporarily interact with the intercellular lipids to increase their fluidity. This modification loosens the barrier structure and facilitates the passage of the therapeutic agent. Advanced methods like microneedles or iontophoresis are also being developed to physically or electrically disrupt the stratum corneum, enabling the delivery of larger drugs.