Recent Advances in the Transdermal Delivery of Protein Therapeutics with a Combinatorial System of Chemical Adjuvants and Physical Penetration Enhancements

Since the development of protein‐based therapeutics, research has been underway to deliver protein therapeutics into the systemic circulation and target sites have been actively conducted. Most protein‐based therapeutics require parenteral administration, due to their intrinsic vulnerability and susceptibility to enzyme‐mediated degradation. Among the routes of administration, the transdermal delivery system has been regarded as a promising technique to deliver protein therapeutics, offering the advantages of painless administration, ease of termination, and avoidance of first‐pass metabolism. However, unlike small molecular drugs, protein therapeutics have limited skin penetration, due to their macromolecular and hydrophilic properties. Both cheimcal adjuvants (CAs)‐treatment methods and physical penetration enhancer methods (PPEs) have been utilized to increase skin permeability for protein therapeutics. The CAs, which include chemical penetration enhancers and nanocarriers, permit the protein therapeutics to transport easily into the skin, by modifying the stratum corneum (SC) or fabricating their stable formulation. The PPEs, including iontophoresis, electroporation, and ultrasound, can improve the skin permeability of the therapeutic agent through disrupting the SC. In this review, the techniques of both chemical and physical enhancement methods are introduced and an overview of the latest approaches to the transdermal delivery of protein therapeutics is provided. Transdermal delivery of protein therapeutics is a promising technology for the next generation of drug administration. Instead of invasive delivery technology, such as microneedles, this Review covers the recent advances in non‐invasive technologies, including chemical adjuvants and physical penetration enhancers, for transdermal delivery of protein therapeutics. The limitation of current technologies and future perspectives on clinical implications are also discussed.