Permeation enhancers in transdermal drug delivery: benefits and limitations

ABSTRACT

Introduction: Transdermal drug delivery has several clinical benefits over conventional routes of drug administration. To open the transdermal route for a wider range of drugs, including macromolecules, numerous physical and chemical techniques to overcome the natural low skin permeability have been developed.

Areas covered: This review focuses on permeation enhancers (penetration enhancers, percutaneous absorption promoters or accelerants), which are chemicals that increase drug flux through the skin barrier. First, skin components, drug permeation pathways, and drug properties are introduced. Next, we discuss properties of enhancers, their various classifications, structure-activity relationships, mechanisms of action, reversibility and toxicity, biodegradable enhancers, and synergistic enhancer combinations.

Expert opinion: Overcoming the remarkable skin barrier properties in an efficient, temporary and safe manner remains a challenge. High permeation-enhancing potency has long been perceived to be associated with toxicity and irritation potential of such compounds, which has limited their further development. In addition, the complexity of enhancer interactions with skin, formulation and drug, along with their vast chemical diversity hampered understanding of their mechanisms of action. The recent development in the field revealed highly potent yet safe enhancers or enhancer combinations, which suggest that enhancer-aided transdermal drug delivery has yet to reach its full potential.

KEYWORDS:

• Drug delivery
• penetration enhancers
• percutaneous absorption
• permeabilization
• skin barrier
• transdermal

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• Transdermal drug delivery, i.e. systemic drug absorption through the skin, has several clinical benefits over oral dosage forms or injections

• Broader application of transdermal patches requires techniques, such as the use of permeation enhancers, to overcome the skin´s remarkable barrier properties

• Although enhancers cannot permeabilize skin to the same extent as, for example, microneedles, some enhancer combinations show remarkable potency for the delivery of small molecule drugs and macromolecules

• Biodegradable enhancers and synergistic enhancer combinations enable drug delivery without noticeable irritation potential

• Enhancers are inexpensive, can be manufactured at scale and easily formulated into patches of various sizes, and they do not rely on energy source or any special skills

This box summarizes key points contained in the article.

Additional information

Funding

This paper was funded by the Czech Science Foundation (19-09135J) and the project EFSA-CDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841) co-funded by ERDF.