Title:Deformable Vesicles with Edge Activators for the Transdermal Delivery of
Non-Psychoactive Cannabinoids
Volume: 30
Issue: 12
Author(s): Elisa Vettorato*, Marisa Fiordelisi, Silvia Ferro, Desirè Zanin, Erica Franceschinis, Giovanni Marzaro and Nicola Realdon
Affiliation:
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo, 5, Padova 35131, Italy
Keywords:
Desoxy-cannabidiol, cannabidiol, skin, phospholipids, vesicles, propylene glycol, oleic acid, limonene.
Abstract:
Background: Transdermal delivery of highly lipophilic molecules is challenging due to the strong
barrier function of the skin. Vesicles with penetration enhancers are safe and efficient systems that could improve
the transdermal delivery of non-psychoactive cannabinoids such as cannabidiol and desoxy-cannabidiol.
In the last decades, research interest in desoxy-cannabidiol as a potent drug with anti-nociceptive properties
has risen. Still, its scarce market availability poses a limit for both research and clinical applications. Therefore,
it is necessary to improve the synthesis to produce sufficient amounts of desoxy-cannabidiol. Moreover,
also the formulation aspects for this drug are challenging and require to be addressed to meet an efficient delivery
to the patients.
Objective: This work aimed to develop innovative phospholipid-based vesicles with propylene glycol (PG),
oleic acid (OA), or limonene as edge activators, for the transdermal delivery of highly lipophilic drugs such as
non-psychoactive cannabinoids. In particular, desoxy-cannabidiol was selected thanks to its anti-nociceptive
activity, and its synthesis was improved enhancing the stereoselectivity of its synthon's production.
Methods: Desoxy-cannabidiol was synthesized by Lewis acid-mediated condensation of p-mentha-2,8-dien-
1-ol and m-pentylphenol, improving the stereoselectivity of the first synthon's production. Transethosomes
containing 20-50% w/w PG, 0.4-0.8% w/w OA, or 0.1-1% w/w limonene were optimized and loaded with
cannabidiol or desoxy-cannabidiol (0.07-0.8% w/w, 0.6-7.0 mg/mL). Ex-vivo studies were performed to assess
both the skin permeation and accumulation of the cannabinoids, as well as the penetration depth of fluorescein-
loaded systems used as models.
Results: An enantioselective bromination was added to the pathway, thus raising the production yield of pmentha-
2,8-dien-1-ol to 81% against 35%, and the overall yield of desoxy-cannabidiol synthesis from 12% to
48%. Optimized transethosomes containing 0.6 mg/mL cannabinoids were prepared with 1:10 PG:lipid weight
ratio, 0.54 OA:lipid molar ratio, and 0.3 limonene:lipid molar ratio, showing good nanometric size (208 ± 20.8
nm - 321 ± 26.3 nm) and entrapment efficiency (> 80%). Ex-vivo tests showed both improved skin permeation
rates of cannabinoids (up to 21.32 ± 4.27 μg/cm2 cannabidiol), and skin penetration (depth of fluorescein up to
240 μm, with PG).
Conclusion: Desoxy-cannabidiol was successfully produced at high yields, and formulated into transethosomes
optimized for transdermal delivery. Loaded vesicles showed improved skin penetration of desoxy-cannabidiol,
cannabidiol and a lipophilic probe. These results suggest the potential of these carriers for the transdermal
delivery of highly lipophilic drugs.
