At the same time that Wang et al. conducted their experiment on the skin of aged mice as noted above, they performed a multicenter clinical trial in 60 human subjects who received a randomized treatment of Argireline or placebo in a ratio of 3:1 to assess its safety and efficacy. For 4 weeks, the test product or placebo was applied to periorbital wrinkles twice daily. The researchers found the total antiwrinkle efficacy in the Argireline group to be 48.9% based on the subjective evaluation, compared with 0% in the placebo group. The objective evaluation indicated that all parameters of roughness were diminished in the Argireline group (P < .01), with no reduction observed in the placebo group (P < .05).4 There was a little more to appreciate from this study compared with the one reported by Blanes et al., insofar as subjective evaluations and objective evaluations with silica replicas were done. However, this study was not blinded, so the 48.9% wrinkle reduction in the Argireline group vs. 0% in the control group seems suspicious. Additionally, there was a greater focus on static rather than dynamic wrinkles.
In 2017, Raikou et al. conducted a prospective, randomized controlled study to assess the effects of acetyl hexapeptide-3 (Argireline) and tripeptide-10 citrulline in 24 healthy female volunteers (aged 30-60 years) and determine if there was any synergistic action between the peptides. Subjects were randomized to receive a combination of the peptides, tripeptide-10 citrulline only, acetyl hexapeptide-3 only, or neither peptide for 60 days. The researchers found a significant reduction in transepidermal water loss (TEWL) in the Argireline group, compared with the placebo group.5 The result of this study makes me question if the decrease in depth of the wrinkles measured in the former studies is really just a measure of increased skin hydration from the Argireline, rather than a neurotoxic effect of Argireline.
Formulation and penetration: Can Argireline get through your skin?
One of the fundamental questions regarding Argireline is whether it can penetrate through the stratum corneum and find its target – the facial muscles – where it is intended to function. Argireline is a charged, hydrophilic, and large–molecular weight peptide, and each of these factors impairs penetration through the stratum corneum. Therefore, studies assessing penetration are particularly important.
In 2015, Kraeling et al. conducted an in vitro evaluation of the skin penetration of acetyl hexapeptide-8 in hairless guinea pig and human cadaver skin. An oil-in-water (O/W) emulsion containing 10% acetyl hexapeptide-8 was applied (2 mg/cm2) and penetration was quantified in skin layers via hydrophilic interaction liquid chromatography with tandem mass spectrometry. Most of the acetyl hexapeptide-8 was found to have been washed from human cadaver, as well as guinea pig, skin. Less than 1% of the peptide penetrated the guinea pig or human skin. Of this small amount that penetrated the skin, most stayed in the stratum corneum of guinea pigs (0.54%) and human cadavers (0.22%). The levels of acetyl hexapeptide-8 declined further with each layer of tape stripping removal. Epidermal levels of the peptide in tested skin were similar at 0.01%, and none of the peptide was found in the dermis.6 These results indicate negligible penetration by this highly touted peptide ingredient.
Some studies have shown that altering the formulation of acetyl hexapeptide-8 can enhance penetration. Hoppel et al. demonstrated that formulations of the peptide, especially in a water-oil-water (W/O/W emulsion [as compared with O/W and W/O emulsions] can increase penetration into the stratum corneum in porcine skin.7 Notably, this is still very superficial relative to the dermis and muscles. Irrespective of formulation, studies have shown that Argireline barely penetrates the stratum corneum, let alone the dermis. Therefore, I would give pause to attributing any clinical impact or benefit of Argireline to its neurotoxinlike effects measured in vitro.
Conclusion
Despite the growing popularity of this ingredient in cosmeceuticals and the praise it gets in media for acting as a topical neurotoxin, there are no rigorous clinical trials or data demonstrating its efficacy in suppressing dynamic facial wrinkles like BoNT does. Most importantly, without penetration into the stratum corneum and deeper layers of the skin, it seems unlikely that Argireline’s clinical benefit derives from a neurotoxiclike mechanism of action. It seems more likely that the Argireline-containing product enhances hydration or imparts some other quality to the skin surface. While there is certainly great appeal for a neurotoxinlike product without injections, I do not believe this ingredient will replace injections of BoNT in the foreseeable future, or at least until scientists can figure out how to enable these products to penetrate into the deeper layers of the skin.
Dr. Goldman is a dermatologist in private practice in Miami and specializes in cosmetic and general dermatology. She practices at Baumann Cosmetic & Research Institute and is also opening a general dermatology practice. Dr. Goldman has no relevant disclosures. Write to her at dermnews@mdedge.com or message her on Instagram @DrChloeGoldman.
References
1. Reddy BY et al. Exp Dermatol. 2012 Aug;21(8):569-75.
2. Blanes-Mira C et al. Int J Cosmet Sci. 2002 Oct;24(5):303-10.
3. Wang Y et al. J Cosmet Laser Ther. 2013 Aug;15(4):237-41.
4. Wang Y et al. J Cosmet Laser Ther. 2013;14(2):147-53.
5. Raikou V et al. J Cosmet Dermatol. 2017 Jun;16(2):271-8.
6. Kraeling ME et al. Cutan Ocul Toxicol. 2015 Mar;34(1):46-52.
7. Hoppel M et al. Eur J Pharm Sci. 2015 Feb 20;68:27-35.