(T1130-07-40) Enhancement of Transdermal Permeation of Cannabinoids and Their Pharmacodynamic Evaluation in Rats

Purpose: The objective of the present study was to enhance the transdermal permeation of cannabinoids: cannabidiol (CBD), cannabigerol (CBG) and tetrahydrocannabivarin (THCV) using chemical permeation enhancer approach and to evaluate them for their anti-inflammatory effect in-vivo in a paw edema model in rats.

Methods: Solubility studies of cannabinoids were performed in all excipients used in the formulation. Transdermal gel formulations of cannabinoids were developed using FDA approved inactive ingredients: lactic acid (LA), polyethylene glycol-400 (PEG-400), N-methyl-2 pyrrolidone (NMP), and dimethyl sulfoxide (DMSO). Drug content assay in the formulations was performed using HPLC. The rheological properties of the gels were assessed. Formulations were then evaluated in Differential Scanning Calorimetry (DSC) to evaluate drug-excipient interaction. Further, all the formulations were characterized in in-vitro skin permeation studies (IVPT) using dermatomed human skin. Effect of different permeation enhancers including lactic acid, NMP and DMSO were evaluated on flux of cannabinoids. Finally, the anti-inflammatory effect of the gel formulations was assessed using carrageenan-induced paw edema model using Sprague Dawley (SD) rats. Animals were divided into 5 groups (4 rats each): group 1: control (no treatment); group 2: placebo gel (Gel K, without CBD/CBG/THCV); group 3: CBD gel (Gel A); group 4: CBG gel (Gel I); group 5: THCV gel (Gel J).

Results: Pre-formulations studies including solubility studies showed high solubility of cannabinoid in all excipients; rheology studies showed non-newtonian flow of all formulations. DSC thermogram of CBD API showed endothermic peak at its melting point 67.5 (°C), whereas CBD gel formulation thermogram didn’t show any peak at the melting point temperature of API. DSC thermogram of CBG API also showed endothermic peak at its melting point 56.5 (°C), whereas CBG gel formulation thermogram didn’t show any peak at the melting point temperature of API. DSC thermogram of THCV API showed endothermic peak at its melting point 247.5 (°C), however THCV gel formulation thermogram showed a shifted endothermic peak approximately 100°C less than the melting point In vitro skin permeation testing (IVPT) study showed flux of ~4.00 mg/cm2/hr for CBD, ~6.00 mg/cm2/hr for CBG and ~35.00 mg/cm2/hr for THCV for 72 hrs. Additionally, IVPT study showed cumulative drug permeation of ~200.10 mg/cm2, ~280.10 mg/cm2 and ~1500 mg/cm2 from CBD, CBG and THCV gel formulations respectively (Fig 1 and 2). Further, effect of excipients on cannabinoid permeation showed that, formulation containing lactic acid, NMP and DMSO showed significantly (p < 0.0001) enhanced flux of cannabinoids as compared to formulation without lactic, NMP and DMSO. Our in vivo anti-inflammatory study of cannabinoids formulations on SD rats showed significant (p < 0.0001) decrease in the paw edema inflammation in the group containing CBG followed by CBD and THCV at all time points as compared to no treatment group and placebo formulation (Fig 3).

Conclusion: In conclusion, flux of CBD, CBG and THCV was significantly enhanced using chemical permeation enhancers approach which helped in reducing rat paw edema.

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Acknowledgements: Authors are thankful to the Consortium for Medical Marijuana Clinical Outcomes Research,
Grant/Award number: SUB00002097, National Institute on Minority Health and Health
Disparities of National Institutes of Health, Grant/Award Number: U54 MD007582 and
NSFCREST Center for Complex Materials Design for Multidimensional Additive Processing
(CoManD), Grant/Award Number:1735968 for providing the funding for this research work.


Fig. 1. (A) IVPT study showing cumulative drug permeation from gel formulation at the end of 72 hrs (B) In-vitro skin deposition study showing CBD deposition from gel formulation at the end of 72 hrs (C) IVPT study showing cumulative drug permeation from gel formulation at 24, 48 and 72 hrs (D) IVPT study showing CBD flux from gel formulation at 24, 48 and 72 hrs


Fig. 2. (A) IVPT study showing cumulative drug permeation from CBG and THCV gel formulation at the end of 72 hrs (B) IVPT study showing cumulative drug permeation from CBG and THCV gel formulation at 24,48 and 72 hrs (C) IVPT study showing CBG and THCV flux from gel formulation at 24, 48 and 72 hrs (D) In vitro skin deposition study showing CBG and THCV deposition from gel formulation at the end of 72 hrs.


Fig. 3. Inflammatory rate of untreated and treated groups after induction of edema using sub-planter injection of carrageenan showing significant reduction in edema after application of CBD, CBG and THCV gel formulations.