Bioequivalence Assessment of Oral Administration Vs. Oral Spray of a Cannabinoids (Tetrahydrocannabinol and Cannabidiol)
|ClinicalTrials.gov Identifier: NCT01893424|
Recruitment Status : Completed
First Posted : July 9, 2013
Last Update Posted : March 24, 2016
This project is intended to evaluate self-emulsifying drug delivery system termed Piperine-Pro-Nano-Lipospheres (P-PNL) for enhancing the oral bioavailability of tetrahydrocannabinol (THC) and cannabidiol (CBD).The oral bioavailability of these cannabinoids is hampered by extensive first pass metabolism, resulting in relative bioavailability of 6%.
The main goal of this study is to evaluate the bioequivalence of THC-CBD P-PNL product for oral administration to Sativex® buccal spray, as measured by AUC 0-24h, Tmax and Cmax.
|Condition or disease||Intervention/treatment||Phase|
|Pain||Drug: Sativex buccal spray Drug: CBD-THC-Piperine-PNL capsule||Phase 1|
Multiple sclerosis (MS) is a disabling, lifelong disease of the central nervous system. The currently available treatments with analgesic drugs for the management of MS associated pain are limited in their efficacy, and frequently uncontrolled.
The most successful treatment for this MS pain was found to be the use of the combination of Δ 9 -Tetrahydrocannabinol (THC) and Cannabidiol (CBD) in 1:1 ratio. The rationale for the combination of the two cannabinoids was aroused by the reports in the scientific literature that CBD could not only potentiate the therapeutic effects of THC but also diminish the undesirable effects of THC such as anxiety, panic, sedation, dysphonia and tachycardia. Additionally, co-administration of THC and CBD was reported to be safe with no tolerance, abuse or withdrawal effects.
Although therapeutic rationale for the THC and CBD combination was established, an optimal oral dosage form to deliver this cannabinoids combination is not available yet. The reason for that is the marked "first pass" metabolic effect of the cannabinoids in the gastrointestinal tract leading to very limited oral bioavailability of 6%.
In this project we shall utilize our biopharmaceutical experience using an advanced self-emulsifying drug delivery system termed Piperine-Pro-Nano-Lipospheres (P-PNL) for enhancing the oral bioavailability of THC and CBD. P-PNL is an isotropic mixture of a natural alkaloid (piperine) and the active compounds (THC and CBD) in a combination of lipids, surfactants and co-solvent termed the pre-concentrate, which is administered in a soft gelatin capsule. We have shown in pre-clinical investigation that incorporation of THC and CBD into P-PNL is a promising strategy to enhance their oral bioavailability.
Thus, the primary goal of this study: is to evaluate the bioequivalence of the developed THC-CBD P-PNL product for oral administration to Sativex®. This is a currently available product of THC and CBD combination. Sativex® is a solution that has to be administered by spray onto the oromucosal surface to bypass the "first pass" metabolism of the cannabinoids associated with intestinal absorption. SATIVEX® is approved in various countries (i.e. Canada, UK, Spain, New Zealand and Israel-distributed by Neopharm) for a MS pain treatment and in Canada also for cancer pain treatment.
The study will be performed on 12 healthy male volunteers. It will be an open label, cross-over single-arm two sequences study intended to evaluate the pharmacokinetics of THC and CBD. Each volunteer will receive THC:CBD capsule and Sativex® . Both study groups THC-CBD-Piperine-PNL vs. Sativex® will receive identical doses of THC and CBD; 21.6 mg and 20 mg respectively. blood samples will be withdrawn through indwelling cannula from the forearm 30 minutes before (pre-dose) and every 30 minutes interval for the first 4 hours then blood samples will be taken at, 5, 6, 7, 8, 12 and 24 hours after the intake of the study drug. Blood concentration profiles of THC, CBD and their main metabolites:
11-hydroxy-THC, 11-nor-9-carboxy-THC and CBD-glucoronide will be determined in order to calculate the pharmacokinetic parameters of THC and CBD.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||12 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Bioequivalence Assessment of Oral Administration Vs. Oral Spray of a Cannabinoid Combination (Δ9 -Tetrahydrocannabinol (THC) and Cannabidiol (CBD) In 1:1 Ratio)|
|Study Start Date :||August 2013|
|Primary Completion Date :||January 2014|
|Study Completion Date :||January 2015|
Active Comparator: Sativex buccal spray
volunteers will receive a single dose of 8 actuations of Sativex® which will be administrated within 1-2 min by the study physician. The dose of THC and CBD to be administered is the following: THC 21.6 mg and CBD 20 mg. Sativex® actuations will be directed sublingually and at the buccal mucosa.
Drug: Sativex buccal spray
Other Name: Sativex
Experimental: CBD-THC-Piperine-PNL capsule
12 volunteers will receive a single oral dose of THC:CBD P-PNL capsule with 200 mL of water. The dose of THC and CBD to be administered is the same as in the Sativex arm: THC 21.6 mg and CBD 20 mg.
Drug: CBD-THC-Piperine-PNL capsule
a capsule containing Cannabidiol and Tetrahydrocannabinol combination
Other Name: Cannabidiol and dronabinol in ProNanoLiposphere formulation
- Pharmacokinetic parameters of THC and CBD [ Time Frame: 1 year ]
- exposure to the metabolites of the study drugs [ Time Frame: 1 year ]
Assessment of the metabolic profile of major THC's and CBD's metabolites:
11-hydroxy-THC, 11-nor-9-carboxy-THC and CBD-glucoronide in healthy volunteers. Plasma metabolites concentrations will be determined using HPLC-MS/MS validated assay. The unit of measure will be provided as ng/ml.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01893424
|Hadassah medical organization|
|Principal Investigator:||Elyad Davidson, MD||Director of the pain relief unit in Hadassah Hebrew University Medical Center|