Bioequivalence Assessment of Cannabidiol (CBD) Administrated in Oral Formulations

Cannabidiol (CBD) is considered the non-psychoactive component of the cannabis plant with a myriad of pharmacological attributes. There is preliminary data that CBD can be a useful treatment for different therapeutic conditions such as epilepsy, anxiety, pain etc. CBD has been investigated for its analgesic effect in patients with neuropathic and chronic pain, especially resistant to other treatments. Further supportive evidence for CBD's efficacy in treatment of pain, is established pre-clinically and requires additional research in a clinical setting. The use of CBD in epilepsy has been assimilated in treatment guidelines in many countries including Israel. However, the potential medical use of whole-plant cannabis extracts, particularly in children with a developing brain, is limited by the psychoactive properties and the adverse effects associated with long-term THC use.

Although a therapeutic rational for the use of CBD has been demonstrated, an optimal oral dosage form to deliver this compound is not available yet. Oral administration is challenging because of CBD's poor solubility and extensive first pass metabolism, leading to an oral bioavailability of approximately 6%.

In this project, investigators utilize a bio-pharmaceutical method to enhance the bioavailability of CBD using an advanced self-emulsifying drug delivery system termed Long Chain Nano Lipospheres (LNL). The LNL formulation is composed of long chain triglycerides, surfactants and co-solvent. This constellation is termed the pre-concentrate, which dissolves CBD in its lipid core and administered in a soft gelatin capsule. When reaching the aqueous phase of the GI tract, this pre-concentrate spontaneously forms a drug encapsulated O/W nano emulsion. Previously, investigators have shown in a pre-clinical investigation that incorporation of CBD into the LNL is a promising strategy to increase the compound's bioavailability.

The primary goal of this study is to evaluate the bioequivalence of the developed CBD-LNL product to CBD in a sesame oil vehicle and CBD in powder form. Sesame oil is the commonly used vehicle for cannabinoids oral uptake for lack of other options. However, this option often leads to significant inter and intra subject variability in cannabinoids' plasma concentrations.

The study will be performed on 12 healthy male volunteers. It will be randomized, open label three way cross-over study intended to evaluate the pharmacokinetics of CBD. Each volunteer will receive CBD-LNL capsule, CBD in sesame oil vehicle capsule and CBD without any vehicle in powder form. All study groups will receive the same dose of CBD-90 mg. Blood samples will be drawn from forearm 30 minutes before (pre-dose) and every 30 minutes interval for the first 4 hours, then samples will be taken at 5,6,7,8,12 and 24 hours after the intake of the study drug. Blood concentration profiles of CBD and its main metabolites 7-hydroxy-CBD and CBD-glucoronide-11 will be determined in order to calculate the pharmacokinetic parameters of CBD.

The secondary study objectives is to examine pharmacodynamic (PD) variables of the developed CBD-LNL product to CBD in a sesame oil vehicle and CBD in powder form.

In order to assess the pharmacodynamic variables all study participants will be requested to undergo an experimental pain test: cold pressor test.

Cold pressor test model: During each pain cycle, the non-dominant hand is immersed in ice cold water up to the elbow over 2 minutes. Using the dominant hand, the computerized VAS device is manipulated by the subject to record the on-line VAS pain score at intervals of approximately 10 seconds. The area under the curve of the VAS pain score against time curve is determined electronically. If the hand has to be removed due to intolerable pain, this is taken as a VAS of 100 at that time point.

The test will be conducted upon arrival and at 0.5h, 1h, 2h, 3h, 4h , 6h, 8h after arrival at the clinic and completed at study cycles 1,2,3.

Study participants will also be requested to fill out a computerized test called "Alertness". The subject will be asked to press a button whenever an X appears on the screen. Which will be completed on all study cycles 1,2,3. This assessment will be performed at the following times, upon arrival at clinic, 0.5 h, 1h , 2h, 3h, 4h, 6h and 8h after arrival at clinic.

Furthermore, an additional control group- follow-up visit, will be added to this trial, in order to assess study participants pharmacodynamic (PD) variables, when subjects are not under any stress.

Control group will consist of all study subjects who will be asked to come for an additional follow -up visit during which their pharmacodynamic (PD) variables will be assessed.

During this follow up visit study participants will be requested to undergo an experimental pain model test-cold pressor test (CPT) upon arrival and at 0.5h, 1h, 2h, 3h, 4h , 6h, 8h after arrival at the clinic, as completed at study cycles 1,2,3.

Study participants will be requested to fill out a computerized test called "Alertness". The subject will be asked to press a button whenever an X appears on the screen as completed on previous study cycles 1,2,3. This assessment will be performed at the following times, upon arrival at clinic, 0.5 h, 1h , 2h, 3h, 4h, 6h and 8h after arrival at clinic.

Vital signs monitoring will also be measured for all study participants at this follow-up visit upon arrival at clinic and at 30 min, 1 h, 2 h, 3h, 4h, 6h, 8h following arrival. These measurements will be compared to participants hemodynamic measurements assessed from cycle 1,2, and 3.