Transdermal drug delivery is one of the oldest methods of administering medications to humans. These methods can be traced back to the Ancient Egyptians, who used oils, fats, perfumes, and other ingredients to make cosmetic and dermatological products. Yet technological advancements such as 3D bioprinted skin with immune components, advanced microneedles, and smart, connected systems for advanced precision medicine are renewing the relevance of transdermal drug development.
Drugs administered via the skin rather than through injection or oral ingestion have always offered many benefits. It avoids the first-pass effect in the liver and degradation in the gastrointestinal tract, allows for lower doses, maintains a constant, effective blood drug concentration, and, above all, is an easy and convenient route of administration for patients.
These benefits of transdermal drug delivery, coupled with significant scientific advancements, mean developers are continuing to leverage this method and are researching ways to make it even more effective. To make the most of it, the following four tips should be at the forefront of that pursuit.
1. Prioritize Permeability
Transdermal drugs must penetrate the skin’s outermost layer, the stratum corneum, in order to be effective. This primary barrier is composed of dead cells surrounded by a lipid matrix and is highly lipophilic and resistant to diffusion. Only very small lipophilic molecules (e.g., nicotine) can naturally cross this barrier.
As a result, increasing the drugs ability to cross the outer dermal layer, is a key battle for developers. One approach is to increase the permeability of the skin prior to drug delivery, which allows researchers to raise the flux, the rate at which a drug passes across the skin. This enables therapeutically meaningful doses to reach local tissues or systemic circulation, and expands the range of drugs suitable for transdermal delivery.
Researchers regularly use chemical and physical permeation enhancers to improve drug permeability. Chemical methods are relatively affordable, easy to produce, offer design flexibility, and allow patients to self-administer drugs. However, enhancing permeability with this method can pose additional challenges, including increased toxicity.
2. Address Toxicological Risks
When aiming to increase permeability, developers must avoid certain pitfalls. For example, harsh penetration enhancers can damage the skin, while chronic use can disrupt the skin barrier and increase the risk of further damage. Toxicological risks are numerous.
Irritation and barrier disruption
Risk: Higher concentrations of solvents can cause skin erythema, edema, and desquamation, and chronic exposure can lead to hyperkeratosis, dermatitis, or eczema. Ionic liquids may disrupt keratinocyte membranes at high doses.
Solution: Developers should define and respect No-Observed Effect Levels (NOELs) using dose-response irritation data, demonstrate reversibility of barrier effects, deploy repeated-dose toxicity studies, and structure toxicity optimization for ionic liquids.
Sensitization and allergic reactions
Risk: Ionic liquids can trigger T-cell-mediated hypersensitivity, and solvents can promote contact dermatitis.
Solution: Researchers can either exclude or strictly limit skin sensitizers and use conservative exposure margins.
Phototoxicity
Risk: Some solvents are photo-reactive, causing oxidative stress under UV exposure.
Solution: Developers should set toxicological thresholds that consider worst-case UV exposure and apply risk-based exclusion to the development strategy.
Systemic toxicity
Risk: Solvents can increase the penetration of drugs as well as toxins. High concentrations and doses of solvents and ionic liquids can result in specific organ toxicity as a result.
Solution: Researchers should apply strict toxicology thresholds, evaluate co-transport risk, and conduct target-organ risk assessments.
Evaluating the toxicological liabilities of permeability enhancers should be a top priority for developers, and researchers should ensure they assess all of the above using in silico, in vitro, ex vivo, and in vivo models. Early screening can help avoid costly late-stage failures.
3. Improve In Vivo Translation
In vivo translation is crucial to transdermal drug development because it relies on dynamic, living skin physiology that cannot be fully captured in vitro. Developers risk misjudging dose, efficacy, safety, and regulatory acceptability without effective translation.
In vitro models pose several limitations to developers, including:
- Lack of physiological complexity
- Simplified tissue architecture
- Limited cell-to-cell interaction
- No systemic and immune response mechanisms
- Failure to accurately predict long-term or chronic effects
To improve translation, developers need to focus on integrating in vivo and in vitro data and on designing experiments with translation in mind. Predictive PK/PD models, using the most useful biomarkers and surrogate endpoints, and emphasizing collaboration and data sharing, are also essential.
Ex vivo models, such as reconstructed skin, can serve as a bridge between in vitro and in vivo testing. Models such as EpiDerm and SkinEthic demonstrate high reliability, correlate with human data, and are validated by regulators.
4. Navigate Regulatory Hurdles
Regulators focus primarily on local skin toxicity, systemic exposure and toxicokinetics, enhancer and excipient safety, and long-term and cumulative effects when evaluating the safety of transdermal systems.
Because global regulation is only partially harmonized through ICH guidelines and OECD test methods, sponsors must design transdermal programs to a globally conservative standard, using globally accepted scientific principles while anticipating region-specific guidelines. Developers should also treat transdermal systems as combination products. For example, patches must comply with both device and drug regulations in some territories.
A Final Word
As scientific innovations advance, the number of applications for transdermal drug delivery will increase dramatically, providing new treatment options for patients worldwide. For developers seeking to make the most of this boom, focusing on permeability, in vivo translation, regulatory quirks, and toxicological risks can ensure they’re ahead of the competition, as can working closely with a lab partner that can navigate a rapidly evolving market.
