Potential Benefit of Zygel:
Zygel is pharmaceutically manufactured in a cGMP (Current Good Manufacturing Practice) facility that will comply with rigorous efficacy and safety standards established by global regulatory agencies and is not extracted from the Cannabis plant. We believe that producing CBD this way ensures that we can provide consistent potency and efficiently scale manufacturing to meet the needs of the markets that we are targeting, without the cost and logistical requirements of growing and harvesting Cannabis .
Botanical cannabinoids may create significant challenges for drug manufacturers because of the natural resources and security measures required to grow and harvest Cannabis .
Challenge: CBD degradation to THC in the stomach
Addressing Limitations of Current Treatments
Zygel is a pharmaceutically-produced CBD formulated as a permeation-enhanced gel for transdermal delivery.
Zygel is an experimental treatment. This means that it is not approved by government regulatory bodies, including the United States Food and Drug Administration (FDA) and other agencies and must be tested to see if it is an effective and safe treatment.
An in vitro (performed in a lab in a test tube, culture dish, or elsewhere outside of a living organism) study, titled “Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid,” which was conducted by Zynerba and published in April 2016, demonstrated that CBD is degraded to THC in an acidic environment such as the stomach. THC is the principal psychoactive cannabinoid. As such, we believe that degradation of CBD into THC may lead to increased negative psychoactive effects.
Challenge: Oral administration
A number of trials in humans were conducted by Guy and colleagues to explore administration route efficiency of sprays, an aerosol, and a nebuliser containing CBD or CBD and THC (CBD dose 10 or 20 mg) (Guy and Flint, 2004; Guy and Robson, 2004a,b). Oromucosal spray, either buccal, sublingual, or oropharyngeal administration, resulted in mean Cmax between 2.5 and 3.3 ng/mL and mean Tmax between 1.64 and 4.2 h. Sublingual drops resulted in similar Cmax of 2.05 and 2.58 ng/mL and Tmax of 2.17 and 1.67 h, respectively. Other oromucosal single dose studies reported Cmax and Tmax values within similar ranges (Karschner et al., 2011; Atsmon et al., 2017b).
The mean half-life (t1/2) of CBD was reported as 1.1 and 2.4 h following nebuliser and aerosol administration (20 mg) (Guy and Flint, 2004), 1.09 and 1.97 h following single oral administration (10 and 20 mg) (Guy and Flint, 2004; Guy and Robson, 2004b), 2.95 and 3.21 h following 10 mg oral lipid capsules (Atsmon et al., 2017a,b), between 1.44 and 10.86 h after oromucosal spray administration (5–20 mg) (Guy and Robson, 2004b; Sellers et al., 2013; Stott et al., 2013a,b; Atsmon et al., 2017b), 24 h after i.v. infusion, 31 h after smoking (Ohlsson et al., 1986), and 2–5 days after chronic oral administration (Consroe et al., 1991).
(A) Mean or median Tmax (h) and range against CBD dose (mg) (B) mean or median area under the curve (AUC0-t) (h × ng/mL) and SD against CBD dose (mg) and (C) plasma mean or median concentration max (Cmax; ng/mL) against CBD dose (mg). It was not possible to present error bars for Cmax as SD and SEM were both reported in the data. IV, intravenous; SD, standard deviation; SEM, standard error of the mean.
In conclusion, this review demonstrates the lack of research in this area, particularly in routes of administration other than oral. An absence of studies has led to failure in addressing the bioavailability of CBD despite intravenous formulations being available. This is of critical importance due to the popularity of CBD products and will help interpret other PK values. Standardized and robust formulations of CBD and their PK data are required for both genders, with consideration of other factors such as adiposity, genetic factors that might influence absorption and metabolism, and the effects of disease states.
Kel: The first-order final elimination rate constant.