Argireline's Mechanism, Efficacy and Safety

Argireline, developed as a topical mimetic of Botox, is a synthetic acetyl hexapeptide, patterned after the N-terminal end of the protein Synaptosomal-associated protein 25 (SNAP-25). Argireline competes with SNAP-25 for the binding with vesicle-associated membrane protein (VAMP). This destabilises the formation of a ternary Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptor (SNARE) complex resulting in the inhibition of neuronal exocytosis. As a result, Argireline inhibits the release of acetylcholine and reduces repetitive contraction of the intrinsic muscles of facial expression, thereby decreases hyperkinetic facial lines or expression wrinkles. However, unlike Botox, the acute toxicity is insignificant (≥2000 mgkg?1 for Argireline versus 20 ngkg?1 for Botox). In addition, Argireline has been found to be effective in reducing wrinkles, with efficacies up to 48% upon 4 weeks of twice daily treatment.[1]

Challenges in Argireline Transdermal Delivery and Formulation

While Argireline has good efficacy and safety profiles, the permeation of Argireline through skin is poor. With a high molecular weight of 889 Dalton and a low LogP value of ?6.3, Argireline remains mainly on the surface of the skin upon topical application. In an in vitro skin permeation study using human cadaver skin samples, it was found that the majority of Argireline remained on the surface of the skin and was washed away subsequently. Only 0.22% of the total amount permeated through the skin and retained within stratum corneum, the topmost layer skin; 0.01% of the peptide made it through to the epidermis. The poor skin permeation can lead to a significant wastage of peptide, resulting in unwanted high cost of production and an ineffective final dosage form.[2]

Alternative Enhancement Techniques and Structural Modification

To overcome the problem, several research groups have attempted to enhance transdermal delivery of Argireline by optimising the formulations. Hoppel et al. showed a clear superiority of water-rich water-in-oil-in-water (W/O/W) and oil-in-water (O/W) emulsions over oil-rich water-in-oil emulsion (W/O) emulsions, due to increased absorption of water-rich emulsions into the skin. However, there was no comparison to the pure Argireline solution and no comparison could be drawn to see the effect of emulsion. Kraeling et al. used a high concentration of Argireline (at 10% w/w in an O/W emulsion), yet, the results were disappointing when only 0.23% of the total amount of Argireline permeated through and stayed in the human epidermis. Also, this approach may result in costly products. Ruiz et al. attempted to incorporate Argireline into either a cream or gel dosage form and demonstrated that a cream based dosage form is superior to a gel dosage form in transdermal delivery of Argireline. While these methods were relatively simple to perform, the increase of Argireline delivery through skin was unsatisfactory.[3]

Other than modifying the formulation, several techniques have been put forth to overcome the stratum corneum for other peptide drugs, for e.g., chemical enhancers, iontophoresis, microneedles, sonophoresis, thermal ablation, radiofrequency ablation, jet injectors and electroporation. A number of commercial iontophoretic devices have been available for transdermal delivery, although their market penetration has been limited because of cost and technical issues. Other physical methods, such as electroporation or ablation, are generally inconvenient to users as they require special machineries and expertise to perform. In addition, microneedle is a physical enhancement method which creates micro-pores in the skin in a minimally invasive manner to deliver peptides. However, the idea of placing needles on the face may be of concern to users.

Another approach to enhance transdermal delivery of Argireline is structural modification of the amino acid side chains. Argireline exists in zwitterionic form and this charged state makes it very hydrophilic and poses a major obstacle for transdermal delivery, with the other being its high molecular weight. Chemical modification of the peptide structure to reduce the formation of zwitterions and/or to increase lipophilicity may result in increased permeability of Argireline into the skin. Wrinkles can have a negative effect on quality of life and Botox is one of the most effective and common treatments. Argireline, a mimetic of Botox, has been found to be safer than Botox and effective in reducing wrinkles, with efficacies up to 48% upon 4 weeks of twice daily treatment. However, the skin permeation of Argireline is poor, due to its large molecular weight and hydrophilicity. Argireline exists in zwitterionic form and this charged state hindered its skin permeation. Chemical modification of the peptide structure to reduce the formation of zwitterions may result in increased skin permeability

References

[1] Manriquez JJ, Majerson Gringberg D, Nicklas Diaz C. Wrinkles. BMJ Clin Evid. 2008;2008:1711.

[2] Blanes-Mira C, et al. A synthetic hexapeptide (Argireline) with antiwrinkle activity. International journal of cosmetic science.

[3] Kraeling, M. E., Zhou, W., Wang, P. & Ogunsola, O. A. In vitro skin penetration of acetyl hexapeptide-8 from a cosmetic formulation. Cutaneous and ocular toxicology, 10.3109/15569527.2014.894521 (2014).