Bioequivalence Assessment of Oral Administration Vs. Oral Spray of a Cannabinoids (Tetrahydrocannabinol and Cannabidiol)
Condition: Pain
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Sativex buccal spray; CBD-THC-Piperine-PNL capsule
Intervention type(s): Drug; Drug
Intervention description(s): buccal spray; a capsule containing Cannabidiol and Tetrahydrocannabinol combination
Other intervention name(s): Sativex; Cannabidiol and dronabinol in ProNanoLiposphere formulation
Intervention MeSH terms: Dronabinol; Nabiximols; Cannabidiol; Piperine
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Biological Availability; Pharmacokinetics