Current Development of Chemical Penetration Enhancers for Transdermal Insulin Delivery

Abstract

The use of the transdermal delivery system has recently gained ample recognition due to the ability to deliver drug molecules across the skin membrane, serving as an alternative to conventional oral or injectable routes. Subcutaneous insulin injection is the mainstay treatment for diabetes mellitus which often leads to non-compliance among patients, especially in younger patients. Apart from its invasiveness, the long-term consequences of insulin injection cause the development of physical trauma, which includes lipohypertrophy at the site of administration, scarring, infection, and sometimes nerve damage. Hence, there is a quest for a better alternative to drug delivery that is non-invasive and easily adaptable. One of the potential solutions is the transdermal delivery method. However, the stratum corneum (the top layer of skin) is the greatest barrier in transporting large molecules like insulin. Therefore, various chemical enhancers have been proposed to promote stratum corneum permeability, or they are designed to increase the permeability of the full epidermis, such as the use of ionic liquid, peptides, chemical pre-treatment as well as packaging insulin with carriers or nanoparticles. In this review, the recent progress in the development of chemical enhancers for transdermal insulin delivery is discussed along with the possible mechanistic of action and the potential outlook on the proposed permeation approaches in comparison to other therapeutical drugs.

Keywords: chemical enhancers; deep eutectic solvents; diabetes; emulsions; insulin; ionic liquid; nanoparticles; peptides; transdermal.

Figure 1

Anatomy of the skin layers and the different pathways (intercellular, transcellular and intracellular) that could be utilized for transdermal drug delivery.

Figure 2

Examples of different types of chemical enhancers and the mechanism of action for the transdermal delivery of insulin. (A) Disruption in the lamellar structure of the stratum corneum (SC) was seen with the use of ILs in oil microemulsion (MEF), allowing the permeation of insulin into the skin. (B) Pre-treatment of iodine inhibits sulfhydryl compounds such as glutathione (GSH) and gamma-glutamylcysteine (γ-GC) which then aids the permeation of insulin. (C) Pre-treatment with trypsin allows the alteration in the protein structure of the SC from the alpha- to the beta- form allowing the permeation of insulin. (D) Gold nanorods (GNRs) based insulin (INS) complex in an oil phase (SO) with the addition of near-infrared light was administered. The complex was then able to absorb light energy to heat energy, breaking the SC layers and allowing the permeation of insulin to the skin. (E) A flexible vesicle with the addition of sodium cholate alters the lecithin alkyl chain and increases the fluidity of the lipid bilayer easing the vesicle into the skin.

Figure 3

Different types of chemical enhancers that have been used for the delivery of insulin and other pharmaceutical drugs.

Figure 4

Chemical structure of individual components of CAGE, (A) choline bicarbonate and (B) geranic acid.

Figure 5

Chemical structure of (A) Isopropyl myristate, (B) glutaraldehyde, and (C) polyvinyl alcohol.

Figure 6

Chemical structure of (A) ginsenoside and (B) lecithin.