Marzaro, G.

Realdon, N.

Vettorato, E.

Zanin, Desire'

English

E. Vettorato

ZANIN, DESIRE'

G. Marzaro

N. Realdon

Archivio istituzionale della ricerca - Università di Padova

Original Citation:VESICULAR TRANSDERMAL DELIVERY SYSTEMS FOR CANNABINOIDSPublisher:Published version:DOI:Terms of use:Open Access(Article begins on next page)This article is made available under terms and conditions applicable to Open Access Guidelines, as described athttp://www.unipd.it/download/file/fid/55401 (Italian only)Availability:This version is available at: 11577/3296458 since: 2019-04-09T22:39:59ZUniversità degli Studi di PadovaPadua Research Archive - Institutional RepositoryVESICULAR TRANSDERMAL DELIVERY SYSTEMS FOR CANNABINOIDSE. Vettorato, D. Zanin, G. Marzaro, N. Realdon*.University of Padova, Department of Pharmaceutical and Pharmacological Sciences, Via Marzolo 5 – 35131, Padova, ITALY.*e-mail: nicola.realdon@unipd.itDuring the last years, Cannabis and cannabinoids have gained increasing interest despite their disputed clinical applications.1 The difficulty in guaranteeing a well-defined administered dose is one of the factors that leads to greater uncertainty in the study of these products. The development of new pharmaceutical forms, usinga model molecule mimicking the solubility behavior of THC, the psychoactive component, is currently being studied in this project. Desoxy-CBD (DH-CBD), synthesizedin the laboratory of Medicinal Chemistry, and CBD are the active ingredients selected for the development of transdermal vesicular systems, and subsequentlyincluded in hydrogels.CONCLUSIONSDesoxy-CBD (DH-CBD) resulted a promising molecule that improves the design of transdermal delivery systems as binary ethosomes. DH-CBD formulations showed lower dimensions and ahigher entrapment efficiency than the CBD formulations. The smaller dimensions of DH-CBD ethosomes can be an advantage for the transdermal drug delivery. Further studies on thediffusion and release properties will be made, and further analysis will show the potential transdermal delivery of the cannabinoids performed by these vesicular systems.REFERENCES1 Alexander, S., Therapeutic potential of cannabis-related drugs. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 64, 157-166.2 Touitou, E., Dayan, N., Bergelson, L., Godin, B., Eliaz, M. Ethosomes – novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. Journal of ControlledRelease, 2000, 65, 403-418.3 Wilkinson, S. M., Price, J. & Kassiou, M. Improved accessibility to the desoxy analogues of D9-tetrahydrocannabinol and cannabidiol. Tetrahedron Letters, 2013, 54, 52–54.4 Touitou, E. inventor and assignee. Compositions for applying active substances to or through the skin. United States patent US 5540934 A. 1996 Jul 30.DESOXY-CBD PRODUCTIONVESICLES CONTAINING DESOXY-CBDHYDROGELS CONTAINING VESICLESRELEASE STUDIES OF DESOXY-CBD Desoxy-CBD is a non-psychoactive synthetic cannabinoid not easily available on the market. In this work, DH-CBD was synthesized by condensation of p-mentha-2,8-dien-1-ol and m-pentylphenol. The first synthon was obtained from a non-expensive material, R-(+)-limonene, modifying the Wilkinson-Price-Kassiou pathway3,while the second was synthesized treating 3-methoxybenzylbromide with n-butyllithium and CuI. The condensation of the twosynthons was performed with BF3⋅ Et2O at -78°C and the product was purified with flash chromatography.Vesicles containing DH-CBD or CBD were prepared by simple mixing method with a mechanical stirrer4.The effect of variable concentrations of propylene glycol (PG) ranging from 20 to 50% in systems containing DH-CBDwere observed. Particle size was measured by DLS and optimal results were generally given by formulations with 40%PG, in which vesicle size was maintained at around 200 nm.Loaded dispersions were incorporated 1:1 in hydrogel with 0,75% Carbopol Ultrez 10. Gels were stored at +4°C. CBDand DH-CBD loaded gels composed by 1% drug, 5% PC, 20% ethanol, 50% PG, and water, were compared. Therheological behavior was observed with a rheometer, showing an optimal thixotropy in all the formulations. A relevantdifference in terms of critical resolved shear stress was registered between CBD and DH-CBD formulations.Release studies were performed using Perspex cells and cellulose nitrate synthetic membranes. The highest DH-CBD release profile was achieved with5% PC – 30% PG formulation, with 117,51 µg/cm2. The formulation composed by 4% PC – 30% PG showed a good overall profile in terms of particle size,stability in time, and entrapment efficiency. As compared to the equivalent DH-CBD formulation, hydrogels containing CBD showed a very high releaseprofile, reaching 242,28 µg/cm2, but higher variability over time. The release of this formulation was tested over 72 hours, resulting 508,36 µg/cm2, witha desirable continuous and linear release profile, suitable for a prolonged transdermal delivery.Soft vesicular systems composed of phosphatidyl-choline and ethanol have been developed in the last decades, starting from “Ethosomes” 2. Each ingredient affects size, 𝜁-potential, stability, and skin permeability. 0100200300400500600FormulationsParticle size (nm)Formulations of CBD and DH-CBD with PC 5% PG 50% CBD 1%DHCBD 1%Empty formulations0100200300400500PC 5% - PG 40% PC 4% - PG 40% PC 3% - PG 20% PC 2% - PG 25%Particle size (nm)FormulationsSize of DH-CBD vesicles and empty formulationsDH-CBD 1%Empty formulations0501001502002503003500 5 10 15 20 25 30 35Shear stress, 𝜏(Pa)Shear rate, D (s-1) DH-CBD hydrogels viscosityPC 5% - PG 40%PC 4% - PG 40%PC 3% - PG 20%PC 2% - PG 25%0204060801001201401600 5 10 15 20 25 30𝜂(Pa・s) Shear rate, D (s-1) CBD and CH-CBD hydrogel viscosityCBD 1%DH-CBD 1%4050607080901001101201302 4 6 8 10 12 14µg/cm2(mean)SQRT time (minutes)Release profiles of DH-CBD formulationsPC 2% - PG 25%PC 3% - PG 20%PC 4% - PG 40%PC 5% - PG 40%y = 8.8955x - 18.651R² = 0.976501002003004005006000 10 20 30 40 50 60 70µg/cm2(mean)SQRT time (minutes)72-hours release tests of DH-CBD 1% in PC 4% - PG 30% formulation0501001502002503000 2 4 6 8 10 12 14 16µg/cm2(mean)SQRT time (minutes)Release profile of CBD and DH-CBD formulationsCBD 1%DH-CBD 1%Different results can be obtained by tuning the ratio between the components. In this work, systems were composed by 2 –5% soybean phosphatidylcholine (PC), 20% ethanol, 10 – 50% propylene glycol (PG) and 1% drug, either DH-CBD or CBD.

VESICULAR TRANSDERMAL DELIVERY SYSTEMS FOR CANNABINOIDS

https://www.research.unipd.it/bitstream/11577/3296458/1/3rd%20European%20Conference_Poster%20Vettorato.pdf

VESICULAR TRANSDERMAL DELIVERY SYSTEMS FOR CANNABINOIDS

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