Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis.

BACKGROUND: Current arthritis treatments often have side-effects attributable to active compounds as well as route of administration. Cannabidiol (CBD) attenuates inflammation and pain without side-effects, but CBD is hydrophobic and has poor oral bioavailability. Topical drug application avoids gastrointestinal administration, first pass metabolism, providing more constant plasma levels. METHODS: This study examined efficacy of transdermal CBD for reduction in inflammation and pain, assessing any adverse effects in a rat complete Freund's adjuvant-induced monoarthritic knee joint model. CBD gels (0.6, 3.1, 6.2 or 62.3 mg/day) were applied for 4 consecutive days after arthritis induction. Joint circumference and immune cell invasion in histological sections were measured to indicate level of inflammation. Paw withdrawal latency (PWL) in response to noxious heat stimulation determined nociceptive sensitization, and exploratory behaviour ascertained animal's activity level. RESULTS: Measurement of plasma CBD concentration provided by transdermal absorption revealed linearity with 0.6-6.2 mg/day doses. Transdermal CBD gel significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner. PWL recovered to near baseline level. Immunohistochemical analysis of spinal cord (CGRP, OX42) and dorsal root ganglia (TNFα) revealed dose-dependent reductions of pro-inflammatory biomarkers. Results showed 6.2 and 62 mg/day were effective doses. Exploratory behaviour was not altered by CBD indicating limited effect on higher brain function. CONCLUSIONS: These data indicate that topical CBD application has therapeutic potential for relief of arthritis pain-related behaviours and inflammation without evident side-effects.

Annette Bunge: developing the principles in percutaneous absorption using chemical engineering principles.

Annette Bunge and her research group have had the central theme of mathematically modeling the dermal absorption process. Most of the research focus has been on estimating dermal absorption for the purpose of risk assessment, for exposure scenarios in the environment and in the occupational setting. Her work is the basis for the United States Environmental Protection Agency's estimations for dermal absorption from contaminated water. It is also the basis of the dermal absorption estimates used in determining if chemicals should be assigned a 'skin notation' for potential systemic toxicity following occupational skin exposure. The work is truly translational in that it started with mathematical theory, is validated with preclinical and human experiments, and then is used in guidelines to protect human health. Her valued research has also extended into the topical drug bioavailability and bioequivalence assessment field.

Chemical uptake into human stratum corneum in vivo from volatile and non-volatile solvents.

PURPOSE: Simple, safe and quick in vivo methods for estimating chemical uptake into the stratum corneum (SC) from volatile and non-volatile solvents are invaluable to health risk assessors. This study compares the human in vivo SC uptake of a model compound (4-cyanophenol) from water and acetone using quantitative attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. METHODS: Small areas on the ventral forearms of human volunteers were treated with 4-cyanophenol (CP) dissolved either in water or acetone. After the skin was cleansed of remaining surface CP, SC samples were taken by a standard tape-stripping method. CP concentration profiles across the SC were quantitated by direct measurement of the permeant on the individual tape-strips using ATR-FTIR. RESULTS: Increasing the duration of exposure to CP aqueous solutions resulted in increasing CP uptake into the SC; the kinetics of uptake correlated well with predictive diffusion equations. Increasing the 'dose' of CP in acetone also resulted in increasing uptake into the SC, but uptake eventually plateaued at a maximum level. The amount of CP taken up into the SC from acetone was 2 to 8-fold greater than that from water following similar short-time exposures. CONCLUSIONS: These safe, simple experimental methods provide practical and predictive assessments of chemical uptake into human SC in vivo.

Characterization of the permeability barrier of human skin in vivo.

Attenuated-total-reflectance Fourier-transform-infrared spectroscopy has been used to rapidly and noninvasively quantify in vivo the uptake of a chemical into the outermost, and least permeable, layer of human skin (the stratum corneum). The objective of the experiment was to develop a general model to predict the rate and extent of chemical absorption for diverse exposure scenarios from simple, and safe, short-duration studies. Measurement of the concentration profile of the chemical in the stratum corneum, and analysis of the data using the unsteady-state diffusion equation, enabled estimation of the permeability coefficient and calculation of the time required to achieve maximal transdermal flux. Validation of the spectroscopic technique employed was established, and quantitation of chemical uptake into the stratum corneum was confirmed independently using trace amounts of radiolabeled chemical in conjunction with liquid scintillation counting and accelerator mass spectrometry. The results presented have pharmacological and toxicological implications, as the technology lends itself both to the prediction of transdermal drug delivery, and the feasibility of this route of administration, and to the assessment of risk after dermal contact with toxic chemicals.

Permeation of buprenorphine and its 3-alkyl-ester prodrugs through human skin.

PURPOSE: Homologous 3-alkyl-ester prodrugs (C2 to C4) of buprenorphine with decreased crystallinity have been synthesized and evaluated for transdermal delivery commensurate with opioid dependence treatment. METHODS: To assess the influence of derivatization on delivery, the permeation of the prodrugs through human skin was determined in vitro. Prodrug metabolism was measured in human blood and skin supernatant in vitro along with chemical hydrolysis controls. The prodrugs octanol/water partition coefficients were measured. RESULTS: Without exception, the prodrugs were completely hydrolyzed on passing through the skin and appeared as buprenorphine in the receptor compartment. However, using saturation conditions, in no instance did the buprenorphine flux through skin from a prodrug solution exceed the flux of buprenorphine base itself in vitro. Moreover, the flux of the acetyl ester, the least hydrophobic of the prodrugs, was not significantly elevated upon stripping the skin. Whether in blood or the skin supernatant, the prodrugs hydrolyzed in an apparent first-order fashion and rate constants and half-lives were calculated. CONCLUSIONS: We conclude from the results that the prodrugs' very high octanol/water partition coefficients (hydrophobicity) placed them in viable tissue layer controlled diffusion. Consequently, one does not derive the potential flux-increasing benefit of reducing crystallinity that was expected.

Transdermal prodrug concepts: permeation of buprenorphine and its alkyl esters through hairless mouse skin and influence of vehicles.

In vitro skin permeation of buprenorphine (BUP) and three of its alkyl ester prodrugs was evaluated using hairless mouse skin. The three esters selected were the acetyl ester (Ac-BUP), butyl ester (Bu-BUP), and isobutyl ester (Isb-BUP). These drugs were applied on the skin as saturated slurries in three vehicles commonly used to formulate agents for transdermal purposes: propylene glycol, polyethylene glycol 400 (PEG 400), and light mineral oil. Unique solubilities were found for each drug on each vehicle. Fluxes through hairless mouse skin were evaluated for each combination of drug and vehicle using Franz diffusion cells. From PEG 400 formulations, the skin fluxes of BUP, Ac-BUP, Bu-BUP, and Isb-BUP were 0.47 +/- 0.08, 1.64 +/- 0.31, 0.33 +/- 0.05, 0.75 +/- 0.20 micrograms/cm2/h, respectively. Thus, among the three potential prodrugs chosen, only Ac-BUP showed significantly higher skin flux than BUP. There were no inter-vehicle differences in the fluxes from saturated slurries between the vehicles. Moreover, all the esters were detected substantially in the form of regenerated parent drug (BUP) in the receptor compartment. Indeed, only Ac-BUP exited the skin in a measurably intact form, but the fraction escaping metabolism in transit was small (approximately 2%). However, based on drug dispositions in the skin, the regeneration of buprenorphine seems to depend on the alkyl chain length of the ester moiety. The molar percentages of regenerated parent drug in whole drug collected from the skin following the permeation experiments were: Ac-BUP, 9.2%; Bu-BUP, 40.7%; Isb-BUP, 9.6%, respectively. Thus, only Ac-BUP appears promising as a prodrug of buprenorphine, because it is not overly hydrophilic for skin permeation and is also highly metabolized to the parent compound while in the skin.