[go: up one dir, main page]

WO2023062634A1 - Compositions comprenant des cannabinoïdes et leurs méthodes d'utilisation dans le traitement du cancer - Google Patents

Compositions comprenant des cannabinoïdes et leurs méthodes d'utilisation dans le traitement du cancer Download PDF

Info

Publication number
WO2023062634A1
WO2023062634A1 PCT/IL2022/051086 IL2022051086W WO2023062634A1 WO 2023062634 A1 WO2023062634 A1 WO 2023062634A1 IL 2022051086 W IL2022051086 W IL 2022051086W WO 2023062634 A1 WO2023062634 A1 WO 2023062634A1
Authority
WO
WIPO (PCT)
Prior art keywords
cbdv
cancer
cbga
cannabinoid
cannabinoids
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IL2022/051086
Other languages
English (en)
Inventor
Gabriel Adam YARIV
Eyal Ballan
Ilan HOCHMAN
Eyal BARAD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GRIN Ultra Ltd
Original Assignee
GRIN Ultra Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GRIN Ultra Ltd filed Critical GRIN Ultra Ltd
Publication of WO2023062634A1 publication Critical patent/WO2023062634A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention is in the field of cancer therapy.
  • the invention relates to cannabinoid compositions for treating cancer.
  • Cannabinoids bind to human cannabinoid receptors CB-1 and CB-2, thus causing a range of physiological effects in, for example, the nervous system, the immune system and in bone cells.
  • Cannabinoids up to date but despite the large attention and focus on the possible medicinal benefits of cannabis derived compounds, there is still lack of candidate cannabinoids which may be used to effectively treat cancer.
  • Cannabidivarin for example, is a non-psychoactive cannabinoid found in Cannabis.
  • CBDV has demonstrated anticonvulsant effects and GW Pharmaceuticals begun a phase 2 trial for adult epilepsy prompted by a demonstrated neurochemical pathway for previously observed anti-epileptic and anti-convulsive action.
  • WO2013/057487 discloses phytocannabinoids (THC and/or CBD) for use in the treatment of a breast cancer.
  • WO 2018/022668 discloses the use of a neuromodulating agent including phytocannabinoids for treating melanoma.
  • Cannabis plants contain many compounds that can influence the plant's effect on humans.
  • Several major cannabinoids in cannabis plant extracts represent up to 95% or more of the extract composition.
  • those cannabinoids may produce a synergistic effect or might interfere with each other and/or possibly interact with other drugs like chemotherapies.
  • the interaction of medicaments can be divided into three major categories; antagonist, wherein one molecule inhibits the effects of another molecule, additive, wherein the combined medicaments produce an effect that equals the sum of either drug taken alone, and synergy, wherein a combination of molecules has a greater effect than the additive effect.
  • Additive and synergistic antiproliferative effects may be favorable for the treatment and management of cancer as compared to administering either medicaments alone.
  • Nallathambi el al. (Cannabis and Cannabinoid Research 2018, 3, 120-135) disclose the identification of synergistic interaction between cannabis-derived compounds for cytotoxic activity in colorectal cancer cell lines and colon polyps that induces apoptosis-related cell death and distinct gene expression.
  • compositions comprising cannabinoids for use in the treatment of cancer.
  • the present invention provides pharmaceutical compositions (herein collectively referred to as “cannabinoid composition” or “cannabinoid compositions”) comprising two or more cannabinoids selected from cannabichromenic acid (CBCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), tetrahydrocannabivarin (THCV), cannabigerolic acid (CBGA) cannabichromene (CBC), cannabinol (CBN), cannabicyclol (CBL), cannabigerol (CBG), cannabinolic acid (CBNA), cannabidiol (CBD) and cannabitriol (CBT).
  • cannabinoid composition cannabinoid compositions
  • CBDA cannabichromenic acid
  • CBDV cannabidivarin
  • CBDVA cannabidivarinic acid
  • THCV can
  • compositions having at least two cannabinoids selected from the list of CBCA, CBDV, CBDVA, THCV, and CBGA are administered in an amount which exhibits a synergistic anti-cancer therapeutic effect.
  • the present invention provides pharmaceutical compositions comprising two cannabinoids selected from cannabichromene (CBC), cannabinol (CBN), cannabicyclol (CBL), cannabigerol (CBG), cannabinolic acid (CBNA), cannabidiol (CBD) and cannabitriol (CBT).
  • CBC cannabichromene
  • CBN cannabinol
  • CBL cannabicyclol
  • CBG cannabigerol
  • CBD cannabinolic acid
  • CBD cannabidiol
  • CBT cannabitriol
  • the herein cannabinoid compositions having at least two cannabinoids selected from the list of CBC, CBN, CBL, CBG, CBNA, CBD and CBT are administered in an amount which exhibits a synergistic anti-cancer therapeutic effect.
  • the present invention provides pharmaceutical compositions comprising two cannabinoids selected from CBC, CBN, CBL, CBG, CBNA, and CBT. In some embodiments, the present invention provides pharmaceutical compositions comprising at least two cannabinoids selected from CBCA, CBDV, CBDVA, THCV, CBGA CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the present invention provides pharmaceutical compositions comprising at least two cannabinoids selected from CBCA, CBDV, CBDVA, CBGA CBC, CBN, CBL, CBG, CBNA and CBT.
  • the present invention provides pharmaceutical compositions comprising at least two cannabinoids selected from CBCA, CBDV, CBDVA, THCV, CBGA CBC, CBN, CBL, CBG, CBNA and CBT.
  • the present invention provides pharmaceutical compositions comprising at least two cannabinoids selected from CBCA, CBDV, CBDVA, CBGA CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the present invention provides pharmaceutical compositions comprising at least two cannabinoids selected from CBCA, CBDV, CBDVA, THCV, CBGA CBC, CBN, CBL, CBG, CBNA, CBD and CBT, wherein the cannabinoid combination does not include CBD, and/or THCV.
  • the invention is based in part on the unexpected discovery that certain combinations of cannabinoids, specifically cannabinoid combinations selected from the list of: CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT produce a superior cell proliferation inhibition/anti-cancer effect in in-vitro and in-vivo cancer models. While certain cannabinoids present no effect on cancer cells proliferation, when the herein cannabinoids are combined with other cannabinoids (all from the herein cannabinoid list), they present an enhanced anti-cancerous effect.
  • the present invention pertains to neoadjuvant cancer therapy comprising cannabinoid(s) administration.
  • the present invention pertains to cannabinoid compositions that are used as neoadjuvant cannabinoid therapies.
  • the common cancer practice of most solid cancers includes performing an imaging of the suspected lesion and/or obtaining a sample from the suspected lesion and analyzing the staging of the lesion by histological means. Only after staging is determined, a treatment regimen is prescribed for the patient. This procedure typically includes a waiting period during which no treatment, whatsoever, is provided to the patient.
  • neoadjuvant therapy such as chemoradiation (nCRT)
  • IGH intratumoral genetic heterogeneity
  • Fabiana Bettoni, et. al.. The Effects of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer — The Impact in Intratumoral Heterogeneity; Front. Oncol., 27 September 2019 Sec. Radiation Oncology The present inventors have devised a novel treatment methodology in which treatment with the herein cannabinoid compositions is provided when a subject is suspected of being afflicted with cancer and/or prior to staging determination of the lesion.
  • Such treatment regimen allows the following attributes: early-stage intervention with cannabinoids which are typically associated with minimal reported adverse effects, allow lower tumor volume and tissue invasion and therefore more favorable staging, avoid losing time without any treatment until biopsy results are achieved, affords mental relief to the patient due to commencement of treatment, may overcome tumor drug resistance. Further, by avoiding the traditional neoadjuvant therapy (such as chemoradiation) and using cannabinoids, the herein invention can overcome post operative radio chemotherapy resistance, increasing cancer treatment success outcomes.
  • cannadjuvant therapy such as chemoradiation
  • the present invention provides a method of treatment comprising administering to a subject suspected of having cancer or having cancer that has not yet been classified, one or more cannabinoids, wherein the cannabinoids are administered to the subject as a neoadjuvant therapy.
  • the present invention provides a method of treating cancer comprising administering to a subject in need a cannabinoid composition comprising a combination of two cannabinoids selected from the group consisting of cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabichromenic acid (CBCA), cannabidivarinic acid (CBDV A), tetrahydrocannabivarin (THCV), cannabichromene (CBC), cannabinol (CBN), cannabicyclol (CBL), cannabigerol (CBG), cannabinolic acid (CBNA), cannabidiol (CBD) and cannabitriol (CBT), wherein the composition is administered to the subject as a neoadjuvant therapy.
  • CBD cannabigerolic acid
  • CBDA cannabidivarin
  • CBDV A cannabidivarinic acid
  • THCV cannabichromene
  • CBD can
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of two cannabinoids selected from the group consisting of cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabichromenic acid (CBCA), cannabidivarinic acid (CBDVA), tetrahydrocannabivarin (THCV), cannabichromene (CBC), cannabinol (CBN), cannabicyclol (CBL), cannabigerol (CBG), cannabinolic acid (CBNA), cannabidiol (CBD) and cannabitriol (CBT), wherein the composition is prescribed for administration to the subject as a neoadjuvant therapy.
  • CBD cannabigerolic acid
  • CBDA cannabidivarin
  • CBDVA cannabidivarinic acid
  • THCV tetrahydrocannabivarin
  • CBC cannabichromene
  • CBD can
  • the neoadjuvant therapy is administrated prior to: imaging, surgery, collection of a biopsy from a tumor, and/or administering an anticancer therapy other than cannabinoids.
  • the present invention provides a method of treating cancer comprising providing a cannabinoid composition and administering the cannabinoid composition to a subject having cancer, or suspected of having cancer, wherein the cannabinoid composition is administered to the subject prior to surgery /biopsy collection, imaging, and/or prior to a post staging treatment (i.e., an anticancer therapy other than cannabinoid(s)).
  • a post staging treatment i.e., an anticancer therapy other than cannabinoid(s)
  • the anti-cancer therapy is not a cannabinoid therapy. In one or more embodiments, the anti-cancer therapy is chemotherapy, and/or a biological therapy, and/or a radio therapy, and/or a hormone therapy.
  • the cancer is colorectal cancer and the treatment with the cannabinoids composition is administered as pre-staging or as a neoadjuvant cannabinoid treatment.
  • the cancer is melanoma cancer and the treatment with the cannabinoids composition is administered as pre-staging or as a neoadjuvant cannabinoid treatment.
  • the cancer is breast cancer and the treatment with the cannabinoids composition is administered as pre-staging or as a neoadjuvant cannabinoid treatment.
  • the cancer is lung cancer and the treatment with the cannabinoids composition is administered as pre-staging or as a neoadjuvant cannabinoid treatment.
  • the present inventors therefore designed and successfully practiced novel anticancer pharmaceutical compositions that can be used in methods of treating cancer.
  • the cannabinoid combinations of the present invention provide synergistic effects i.e., the cannabinoids combinations provide a greater therapeutic result in treating cancer than the additive effects achieved by each individual constituent when administered at a therapeutic dose.
  • a composition for treating cancer comprising at least two cannabinoids selected from the group consisting of cannabichromenic acid (CBCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA).
  • the invention provides a composition for treating cancer comprising at least two cannabinoids selected from the group consisting of cannabichromene (CBC), cannabinol (CBN), cannabicyclol (CBL), cannabigerol (CBG), cannabinolic acid (CBNA), cannabidiol (CBD) and cannabitriol (CBT).
  • cannabichromene CBC
  • cannabinol CBN
  • cannabicyclol CBL
  • CBG cannabigerol
  • CBDNA cannabinolic acid
  • CBD cannabidiol
  • CBT cannabitriol
  • the invention provides a composition for treating cancer comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the invention provides a composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT and a pharmaceutical acceptable carrier or excipient.
  • the invention provides a composition for treating cancer comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT, wherein the composition does not comprise CBD and THCV.
  • the composition comprises two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, and CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the composition comprises three cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the composition comprises four cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the composition comprises the five cannabinoids CBCA, CBDV, CBDVA, THCV, and CBGA.
  • the composition comprises at least two cannabinoids selected from the group consisting of CBGA and CBDV; CBGA and CBCA; CBGA and CBDVA; CBGA and THCV; CBDV and CBCA; CBDV and CBDVA; CBDV and THCV; CBCA and CBDVA; CBCA and THCV; and CBDVA and THCV.
  • the composition comprises a mixture of two cannabinoids selected from the group consisting of CBL and CBN, CBL, and CBT, CBD and CBT, CBDV, and CBGA, CBC and CBL, CBC and CBN, CBD and CBL, CBG and CBL, CBDV and CBG, CBDV and CBDV A, CBN and CBT, CBD and CBN, CBCA and CBDV, CBG and CBN, CBDV and CBL, CBC and THCV, CBL and THCV, CBC and CBDV, CBCA and CBGA, CBC and CBT, CBDV and CBN, CBD and CBDV, CBDV and CBT, CBCA and THCV, and CBCA and CBNA.
  • the composition comprises CBDV and at least one additional cannabinoid selected from the group consisting of CBGA, CBCA, CBDVA, and THCV.
  • the composition comprises CBGA and at least one additional cannabinoid selected from the group consisting of CBDV, CBCA, CBDVA, and THCV.
  • the composition comprises CBCA and at least one additional cannabinoid selected from the group consisting of CBGA, CBDV, CBDVA, and THCV.
  • the composition comprises CBDVA and at least one additional cannabinoid selected from the group consisting of CBGA, CBCA, CBDV, and THCV.
  • the composition comprises THCV and at least one additional cannabinoid selected from the group consisting of CBGA, CBCA, CBDVA, and CBDV.
  • the composition comprises at least CBDV and CBGA.
  • the % w/w ratio of CBDV and CBGA in the composition is between 1 :99 and 99: 1.
  • the % w/w ratio of CBDV and CBGA in the composition is between 40:60 to 60:40.
  • the % w/w ratio of CBDV and CBGA in the composition is between 1 : 10 and 10: 1.
  • the % w/w ratio of CBDV and CBGA in the composition is 1 : 1.
  • the composition further comprises THC.
  • the concentration of THC is between 0.1 to 10 % w/w out of the total weight of THC, CBDV and CBGA. In some embodiments, the concentration of THC is 1 to 5 % w/w out of the total weight of THC, CBDV and CBGA. In some embodiments, the concentration of THC is 2.5 % w/w out of the total weight of THC, CBDV and CBGA. In some embodiments, the composition comprising CBDV/CBGA/THC at a % w/w ratio of 45:45: 10 to 49:49:2 out of the total weight of THC, CBDV and CBGA.
  • composition comprising CBDV/CBGA/THC at a % w/w ratio of 48.75: 48.75:2.5 out of the total weight of THC, CBDV and CBGA.
  • the composition is substantially free of THC (e.g., THC- d8).
  • the composition is essentially free of THC (e.g., THC-d8).
  • the composition is free of THC (e.g., THC-d8).
  • the composition further comprises CBD. In some embodiments, the composition is substantially free of CBD. In some embodiments, the composition is essentially free of CBD. In some embodiments, the composition is free of CBD.
  • the composition comprises an immediate release formulation and a sustained-release formulation.
  • the immediate release formulation comprises an edible oil and the sustained release formulation comprises at least one Lipid-based Drug Delivery System (LBDDS) agent.
  • LBDDS Lipid-based Drug Delivery System
  • the LBDDS is selected from the group consisting of a monoglyceride, a diglyceride, a carrageenan and any mixture thereof.
  • the carrageenan is selected from the group consisting of lambda-carrageenan, kappa- carrageenan, iota-carrageenan and any mixture thereof.
  • the sustained release formulation further comprises an edible oil.
  • the cannabinoid is selected from the group consisting of a synthetic cannabinoid, an isolated cannabinoid derived from a cannabis plant, a cannabis plant extract comprising at least 50% (w/w) of the herein cannabinoid.
  • the cannabinoids in the composition exhibit a synergistic anti-cancer effect.
  • the composition comprising cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA may further comprise a chemotherapeutic agent.
  • the chemotherapeutic agent is an antimetabolite drug, a DNA alkylating agent, a platinum compound, an enzyme inhibitor (such as a Topoisomerase inhibitor, or a Tyrosine kinase inhibitor), a vincalkaloid, a taxane, a receptor antagonist, and an antibiotic.
  • the antimetabolite drug is Capecitabine. In some embodiments, the taxane is Docetaxel. In some embodiments, the enzyme inhibitor is Epirubicin. In some embodiments, the antimetabolite drug is 5 -Fluorouracil. In some embodiments, the antimetabolite drug is Capecitabin. In some embodiments, the platinum compound is Oxaliplatin. In some embodiments, the enzyme inhibitor is a Topoisomerase inhibitor. In some embodiments, the Topoisomerase inhibitors is Irinotecan.
  • the composition is substantially free of a cannabinoid other than CBGA, CBDV, CBCA, CBDVA, CBC, CBN, CBL, CBG, CBNA, CBT, CBD and/or THCV.
  • the composition may exclude one or more of a cannabinoid selected from the group CBGA, CBDV, CBCA, CBDVA, CBC, CBN, CBL, CBG, CBNA, CBT, CBD and/or THCV.
  • the composition further comprises a carrier or excipient.
  • the present invention pertains to a method for treating cancer comprising administering to a subject in need a cannabinoid composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV CBGA, CBC, CBN, CBL, CBG, CBNA, CBD, and CBT.
  • a cannabinoid composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV CBGA, CBC, CBN, CBL, CBG, CBNA, CBD, and CBT.
  • the composition is administered to the subject in need on a daily basis.
  • the dosage of the composition is increased gradually until reaching a maximum dosage.
  • the dosage of the composition is increased over a period of 1 week to 6 months.
  • the dosage of the composition is increased over a period of up to 3 months.
  • the composition is administered on a daily basis at least until disappearance of a tumor associated with the cancer.
  • the composition is administered on a daily basis for a period of between 4 months to 2 years.
  • the composition is administered on a daily basis for a period of 1 year.
  • the treatment comprises inhibiting cancer cells' growth or proliferation, reducing or inhibiting the tumor volume, inducing cancer cells' death (via apoptosis and/or necrosis), or a combination thereof.
  • the cancer is a solid cancer. In some embodiments, the cancer is from an epithelial origin. In some embodiments, the solid cancer is selected from colorectal cancer, breast cancer and lung cancer. In some embodiments, the cancer is a skin cancer. In some embodiments, the skin cancer is melanoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer.
  • the method further comprises administering to the subject a chemotherapeutic agent.
  • the chemotherapeutic agent is administered concomitantly to, prior to or after administration of the cannabinoids composition.
  • the composition is prescribed for oral administration. In some embodiments, the composition is prescribed for systemic administration. In some embodiments, the composition is administered by injection. In some embodiments, the composition is administered for local administration.
  • the invention pertains to a composition
  • a composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT and a pharmaceutical acceptable carrier or excipient for use in the treatment of cancer.
  • the invention pertains to a composition
  • a composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT and a pharmaceutical acceptable carrier or excipient for the manufacture of a medicament for treating cancer.
  • the cannabinoid composition is for preparation of a medicament for treating cancer.
  • the invention provides a method for treating cancer comprising administering to a subject in need a therapeutic effective amount of the cannabinoid composition as defined herein.
  • the invention provides a method of inhibiting cancer cells' proliferation or inducing cancer cells' death, comprising contacting the cancer cells with an effective amount of the cannabinoid composition as defined herein.
  • the cancer cells are colorectal cells, lung cancer cells, skin cancer cells, or breast cancer cells.
  • the pharmaceutical composition of the present invention is particularly useful for treating or circumventing cancer.
  • the cancer is a solid tumor.
  • the cancer is selected from the group consisting of colorectal cancer, lung cancer, breast cancer, and melanoma cancer.
  • the cancer is a stomach cancer, an ovarian cancer, a pancreatic cancer, a head and neck cancer, a squamous cell carcinoma, a gastrointestinal cancer, a prostate cancer, a non-small cell lung cancer, a Non-Hodgkin's lymphoma, a multiple myeloma, leukemia (such as acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia), a brain cancer, neuroblastoma, and sarcomas.
  • the cancer is colorectal cancer.
  • the cancer is a colon cancer.
  • the cancer is a lung cancer. In one or more embodiments, the cancer is a breast cancer. In one or more embodiments, the cancer is skin cancer (e.g., melanoma). BRIEF DESCRIPTION OF THE DRAWINGS
  • FIGs. 1A-1B are bar graphs illustrating HT-29 colon cancer cells viability following exposure to each of CBDV and CBGA alone, or a combination thereof (FIG. 1 A), or to each of CBGA and THC-d8 alone, or a combination thereof (FIG. IB).
  • FIGs. 2A-2B are bar graphs illustrating A549 lung cancer cells viability following exposure to each of CBDV and CBGA alone, or a combination thereof (FIG. 2A), or to each of CBDVA and THC-d8 alone, or a combination thereof (FIG. 2B).
  • FIGs. 3A-3B are bar graphs illustrating MCF-7 breast cancer cells viability following exposure to each of CBDV and CBGA alone, or a combination thereof (FIG. 3 A), or to each of CBDVA and THC-d8 alone, or a combination thereof (FIG. 3B).
  • FIGs. 4A-4B are bar graphs illustrating the viability and the synergistic effect of CBGA (at XI concentration - 25.6pM; or X2 concentration - 51.2pM) and CBDV (at XI concentration - 23.4 pM; or X2 concentration - 46.8 pM) on HCT116 cells (FIG. 4A), or RKO cells (FIG. 4B).
  • FIGs. 5A-5B are bar graphs illustrating the viability and the synergistic effect of CBCA and THCV on cells of colon cancer biopsy (FIG. 5A) and the effect of CBG and CBDV on the viability of cells of colon cancer biopsy (FIG. 5B).
  • FIG. 6- is a bar graph illustrating the viability and the synergistic effect of CBGA (at XI concentration - 25.6pM; and X2 concentration - 51.2pM) and CBDV (at XI concentration - 23.5 pM; and X2 concentration - 47 pM) on cells of human colon cancer biopsy.
  • FIGs. 7A-7B are bar graphs illustrating the viability following treatment with CBDV plus CBGA, CBDV plus CBGA plus Capecitabine, or Capecitabine alone, on HCT116 cells (FIG. 7A); or RKO cells (FIG. 7B).
  • FIGs. 8A-8B are bar graphs illustrating the viability of HCT116 cells following treatment with CBDV plus CBGA, or CBDV plus CBGA plus Docetaxel, or Docetaxel alone (FIG. 8A); or CBDV plus CBGA, or CBDV plus CBGA plus Irinotecan, or Irinotecan alone (FIG. 8B).
  • FIGs. 9A-9B are a tumor growth line graph (FIG. 9A) and a Kaplan-Meier survival analysis (FIG. 9B) of colon cancer bearing mice treated with a combination of CBDV and CBGA v . vehicle as control.
  • FIG. 10A is a bar graph illustrating the viability and the synergistic effect of CBT (at XI concentration - 50 pM; or X2 concentration - 100 pM) and CBL (at XI concentration- 25.6 pM; or X2 concentration- 51.2 pM) on G-361 skin cancer cells.
  • FIG. 10B is a bar graph illustrating the viability and the synergistic effect of CBD (at XI concentration - 15 pM; or X2 concentration - 30 pM) and CBT (at XI concentration - 50 pM; or X2 concentration - 100 pM) on A-375 skin cancer cells.
  • FIG. 10C is a bar graph illustrating the viability and the synergistic effect of CBDV (at XI concentration - 23.5 pM; or X2 concentration - 47 pM) and CBGA (at XI concentration - 20 pM; or X2 concentration - 40 pM) on A-375 cells.
  • FIGs. 11 A - 11H are bar graphs illustrating the synergistic effect of combinations of cannabinoids at molar ratios of 1 :3 to 3 : 1 on A-375 cells.
  • FIGs. 12A - 12E are bar graphs illustrating the viability and the synergistic effect of CBDV and CBGA at molar ratios of 1 :3 to 3 : 1 on HCT-116 cells.
  • FIGs. 13 A - 13B are bar graphs illustrating the viability and the synergistic effect of CBCA and CBGA at molar ratios of 1 :3 to 3 : 1 on HCT-116 cells.
  • FIGs. 14A - 14B are bar graphs illustrating the viability and the synergistic effect of CBCA and CBDV at molar ratios of 1 :3 to 3: 1 on HCT-116 cells.
  • FIGs. 15 A - 15C are bar graphs illustrating the viability and the synergistic effect of combinations of three cannabinoids on A-375 cells. DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
  • the present invention pertains to novel cannabinoid compositions and to methods of using the same for treating cancer.
  • the inventors of the present invention have surprisingly found that a combination of two cannabinoids selected from cannabichromenic acid (CBCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), tetrahydrocannabivarin (THCV) cannabigerolic acid (CBGA), cannabichromene (CBC), cannabinol (CBN), cannabicyclol (CBL), cannabigerol (CBG), cannabinolic acid (CBNA), cannabidiol (CBD) and cannabitriol (CBT) exhibits an anti-proliferative effect on various cancer cells being profoundly higher than the effect exhibited by the individual cannabinoids.
  • CBCA cannabichromenic acid
  • CBDV cannabidivarin
  • CBDVA cannabidivarinic acid
  • the cannabinoid compositions of the invention may not include one or more of a cannabinoid from the list of the herein cannabinoids.
  • the herein cannabinoid composition may not include CBD and/or THCV, or CBG and/or CBDV, and/or CBCA and/or CBL, and/or CBT and/or CBGA, and/or CBDV and/or CBGA, and/or CBNA.
  • the inventors have further surprisingly found that the combined treatment of the herein cannabinoid combinations with chemotherapy agents may exhibits a synergistic anti-cancer therapeutic effect.
  • Cannabidivarin As used herein by Cannabidivarin (CBDV) it is meant to refer to the phytocannabinoid molecule 2-((l S,6S)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)- 5-propylbenzene-l,3-diol, having the CAS number 24274-48-4.
  • Cannabigerolic acid As used herein by Cannabigerolic acid (CBGA) it is meant to refer to the acidic form (COOH) of cannabigerolic acid (3-[(2E)-3,7-dimethylocta-2,6-dienyl]-2,4- dihydroxy-6-pentylbenzoic acid) or its corresponding salts, having the CAS number 25555-57-1.
  • Cannabichromenic acid it is meant to refer to a precursor of cannabichromen (CBC) biosynthesis, a non-psychoactive cannabinoid of Cannabis, having the formal name: 5-hydroxy-2-methyl-2-(4-methyl-3-penten-l-yl)-7- pentyl-2H-l-benzopyran-6-carboxylic acid and having the CAS number 185505-15-1.
  • CBDVA Cannabidivarinic acid
  • Tetrahydrocannabivarin As used herein by Tetrahydrocannabivarin (THCV) it is meant to refer to 6aR,7,8,10aR-tetrahydro-6,6,9-trimethyl-3-propyl-6H-dibenzo [b, d] pyran-l-ol, having the CAS number 31262-37-0.
  • cannabichromene As used herein by cannabichromene (CBC) it is meant to refer to 2-methyl-2-(4- methyl-3-penten-l-yl)-7-pentyl-2H-l-benzopyran-5-ol, having the CAS number 20675- 51-8.
  • cannabinol As used herein by cannabinol (CBN) it is meant to refer to 6,6,9-trimethyl-3- pentyl-6H-dibenzo[b,d]pyran-l-ol, having the CAS number 521-35-7.
  • cannabicyclol As used herein by cannabicyclol (CBL) it is meant to refer to (laS,lalR,3aR,8bR)-l,l,3a-trimethyl-6-pentyl-la,lal,2,3,3a,8b-hexahydro-lH-4 oxabenzo[f]cyclobuta[cd]inden-8-ol, having the CAS number 21366-63-2.
  • CBD cannabigerol
  • CBDNA cannabinolic acid
  • cannabitriol As used herein by cannabitriol (CBT) it is meant to refer to 6,6,9-trimethyl-3- pentyl-8,10-dihydro-7H-benzo[c]chromene-l,9,10-triol, having the CAS Number 11003-36-4.
  • CBD cannabidiol
  • the scope of the invention also includes all different geometrical isomers (including cis, trans) of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD, and CBT.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the composition comprises at least three cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the composition comprises at least four cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the composition comprises CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the composition comprises two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition comprises three cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition comprises four cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition comprises CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the composition consists essentially of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition consists essentially of three cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition consists essentially of four cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition consists essentially of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition consists essentially of CBCA,
  • the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition consists of three cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition consists of four cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition consists of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT. In some embodiments, the composition consists of CBCA, CBDV, CBDVA, THCV,
  • the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding CBCA and CBDV. In some embodiments, the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding CBCA and CBDVA. In some embodiments, the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding CBCA and THCV.
  • the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding CBCA and CBGA. In some embodiments, the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding CBDV and CBDVA. In some embodiments, the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding CBDV and THCV.
  • the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding CBDV and CBGA. In some embodiments, the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding CBDVA and THCV. In some embodiments, the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding CBDVA and CBGA. In some embodiments, the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA excluding THCV and CBGA.
  • the herein cannabinoid compositions further comprise THC.
  • the composition comprises THC and a mixture of two or more cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA.
  • the composition comprises CBCA and CBDV. In some embodiments, the composition comprises CBCA and CBDVA. In some embodiments, the composition comprises, CBCA and THCV. In some embodiments, the composition comprises CBCA and CBGA. In some embodiments, the composition comprises CBDV and CBDVA. In some embodiments, the composition comprises CBDV and THCV. In some embodiments, the composition comprises CBDV and CBGA. In some embodiments, the composition comprises CBDVA and THCV. In some embodiments, the composition comprises CBDVA and CBGA. In some embodiments, the composition comprises THCV and CBGA. In some embodiments, the composition comprises CBL and CBN. In some embodiments, the composition comprises CBL and CBT.
  • the composition comprises CBC and CBL. In some embodiments, the composition comprises CBC and CBN. In some embodiments, the composition comprises CBG and CBL. In some embodiments, the composition comprises CBDV and CBG. In some embodiments, the composition comprises CBN and CBT. In some embodiments, the composition comprises CBG and CBN. In some embodiments, the composition comprises CBDV and CBL. In some embodiments, the composition comprises CBC and CBDV. In some embodiments, the composition comprises CBC and CBT. In some embodiments, the composition comprises CBDV and CBN. In some embodiments, the composition comprises CBCA and CBNA. In some embodiments, the composition comprises CBD and CBT. In some embodiments, the composition comprises CBD and CBL.
  • the composition comprises CBD and CBN. In some embodiments, the composition comprises CBC and THCV. In some embodiments, the composition comprises CBL and THCV. In some embodiments, the composition comprises CBD and CBDV. In some embodiments, the composition comprises CBDV and CBT. In some embodiments, the composition comprises CBGA and CBN. In some embodiments, the composition comprises CBC and CBG. In some embodiments, the composition comprises CBG and CBGA. In some embodiments, the composition comprises CBCA and CBN. In some embodiments, the composition comprises CBDV and CBNA. In some embodiments, the composition comprises CBN and CBNA. In some embodiments, the composition comprises CBCA and CBG. In some embodiments, the composition comprises CBG and CBNA.
  • the composition comprises CBCA and CBDV and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBCA and CBDVA and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises, CBCA and THCV and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBCA and CBGA and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBDV and CBDVA and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBDV and THCV and is for use in the treatment of colorectal cancer.
  • the composition comprises CBDV and CBGA and is for use in the treatment of colorectal cancer.
  • the composition comprises CBDVA and THCV and is for use in the treatment of colorectal cancer.
  • the composition comprises CBDVA and CBGA and is for use in the treatment of colorectal cancer.
  • the composition comprises THCV and CBGA and is for use in the treatment of colorectal cancer.
  • the composition comprises CBL and CBN and is for use in the treatment of colorectal cancer.
  • the composition comprises CBL and CBT and is for use in the treatment of colorectal cancer.
  • the composition comprises CBC and CBL and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBC and CBN and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBG and CBL and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBDV and CBG and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBN and CBT and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBG and CBN and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBDV and CBL and is for use in the treatment of colorectal cancer.
  • the composition comprises CBC and CBDV and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBC and CBT and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBDV and CBN and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBCA and CBNA and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBD and CBT and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBD and CBL and is for use in the treatment of colorectal cancer. In some embodiments, the composition comprises CBD and CBN and is for use in the treatment of colorectal cancer.
  • the composition comprises CBC and THCV and is for use in the treatment of colorectal cancer.
  • the composition comprises CBL and THCV and is for use in the treatment of colorectal cancer.
  • the composition comprises CBD and CBDV and is for use in the treatment of colorectal cancer.
  • the composition comprises CBDV and CBT and is for use in the treatment of colorectal cancer.
  • the composition comprises CBGA and CBN and is for use in the treatment of colorectal cancer.
  • the composition comprises CBC and CBG and is for use in the treatment of colorectal cancer.
  • the composition comprises CBG and CBGA and is for use in the treatment of colorectal cancer.
  • the composition comprises CBCA and CBN and is for use in the treatment of colorectal cancer.
  • the composition comprises CBDV and CBNA and is for use in the treatment of colorectal cancer.
  • the composition comprises CBN and CBNA and is for use in the treatment of colorectal cancer.
  • the composition comprises CBCA and CBG and is for use in the treatment of colorectal cancer.
  • the composition comprises CBG and CBNA and is for use in the treatment of colorectal cancer.
  • the composition comprises CBCA and CBDV and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBCA and CBDVA and is for use in the treatment of breast cancer. In some embodiments, the composition comprises, CBCA and THCV and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBCA and CBGA and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBDV and CBDVA and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBDV and THCV and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBDV and CBGA and is for use in the treatment of breast cancer.
  • the composition comprises CBDVA and THCV and is for use in the treatment of breast cancer.
  • the composition comprises CBDVA and CBGA and is for use in the treatment of breast cancer.
  • the composition comprises THCV and CBGA and is for use in the treatment of breast cancer.
  • the composition comprises CBL and CBN and is for use in the treatment of breast cancer.
  • the composition comprises CBL and CBT and is for use in the treatment of breast cancer.
  • the composition comprises CBC and CBL and is for use in the treatment of breast cancer.
  • the composition comprises CBC and CBN and is for use in the treatment of breast cancer.
  • the composition comprises CBG and CBL and is for use in the treatment of breast cancer.
  • the composition comprises CBDV and CBG and is for use in the treatment of breast cancer.
  • the composition comprises CBN and CBT and is for use in the treatment of breast cancer.
  • the composition comprises CBG and CBN and is for use in the treatment of breast cancer.
  • the composition comprises CBDV and CBL and is for use in the treatment of breast cancer.
  • the composition comprises CBC and CBDV and is for use in the treatment of breast cancer.
  • the composition comprises CBC and CBT and is for use in the treatment of breast cancer.
  • the composition comprises CBDV and CBN and is for use in the treatment of breast cancer.
  • the composition comprises CBCA and CBNA and is for use in the treatment of breast cancer.
  • the composition comprises CBD and CBT and is for use in the treatment of breast cancer.
  • the composition comprises CBD and CBL and is for use in the treatment of breast cancer.
  • the composition comprises CBD and CBN and is for use in the treatment of breast cancer.
  • the composition comprises CBC and THCV and is for use in the treatment of breast cancer.
  • the composition comprises CBL and THCV and is for use in the treatment of breast cancer.
  • the composition comprises CBD and CBDV and is for use in the treatment of breast cancer.
  • the composition comprises CBDV and CBT and is for use in the treatment of breast cancer.
  • the composition comprises CBGA and CBN and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBC and CBG and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBG and CBGA and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBCA and CBN and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBDV and CBNA and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBN and CBNA and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBCA and CBG and is for use in the treatment of breast cancer. In some embodiments, the composition comprises CBG and CBNA and is for use in the treatment of breast cancer.
  • the composition comprises CBCA and CBDV and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBCA and CBDVA and is for use in the treatment of lung cancer. In some embodiments, the composition comprises, CBCA and THCV and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBCA and CBGA and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBDV and CBDVA and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBDV and THCV and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBDV and CBGA and is for use in the treatment of lung cancer.
  • the composition comprises CBDVA and THCV and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBDVA and CBGA and is for use in the treatment of lung cancer. In some embodiments, the composition comprises THCV and CBGA and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBL and CBN and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBL and CBT and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBC and CBL and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBC and CBN and is for use in the treatment of lung cancer.
  • the composition comprises CBG and CBL and is for use in the treatment of lung cancer.
  • the composition comprises CBDV and CBG and is for use in the treatment of lung cancer.
  • the composition comprises CBN and CBT and is for use in the treatment of lung cancer.
  • the composition comprises CBG and CBN and is for use in the treatment of lung cancer.
  • the composition comprises CBDV and CBL and is for use in the treatment of lung cancer.
  • the composition comprises CBC and CBDV and is for use in the treatment of lung cancer.
  • the composition comprises CBC and CBT and is for use in the treatment of lung cancer.
  • the composition comprises CBDV and CBN and is for use in the treatment of lung cancer.
  • the composition comprises CBC A and CBNA and is for use in the treatment of lung cancer.
  • the composition comprises CBD and CBT and is for use in the treatment of lung cancer.
  • the composition comprises CBD and CBL and is for use in the treatment of lung cancer.
  • the composition comprises CBD and CBN and is for use in the treatment of lung cancer.
  • the composition comprises CBC and THCV and is for use in the treatment of lung cancer.
  • the composition comprises CBL and THCV and is for use in the treatment of lung cancer.
  • the composition comprises CBD and CBDV and is for use in the treatment of lung cancer.
  • the composition comprises CBDV and CBT and is for use in the treatment of lung cancer.
  • the composition comprises CBGA and CBN and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBC and CBG and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBG and CBGA and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBCA and CBN and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBDV and CBNA and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBN and CBNA and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBCA and CBG and is for use in the treatment of lung cancer. In some embodiments, the composition comprises CBG and CBNA and is for use in the treatment of lung cancer.
  • the composition comprises CBCA and CBDV and is for use in the treatment of skin cancer (e.g., melanoma). In some embodiments, the composition comprises CBCA and CBDVA and is for use in the treatment of skin cancer (e.g., melanoma). In some embodiments, the composition comprises, CBCA and THCV and is for use in the treatment of skin cancer (e.g., melanoma). In some embodiments, the composition comprises CBCA and CBGA and is for use in the treatment of skin cancer (e.g., melanoma). In some embodiments, the composition comprises CBDV and CBDVA and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBDV and THCV and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBDV and CBGA and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBDVA and THCV and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBDVA and CBGA and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises THCV and CBGA and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBL and CBN and is for use in the treatment of skin cancer (e.g., melanoma). In some embodiments, the composition comprises CBL and CBT and is for use in the treatment of skin cancer (e.g., melanoma). In some embodiments, the composition comprises CBC and CBL and is for use in the treatment of skin cancer (e.g., melanoma). In some embodiments, the composition comprises CBC and CBN and is for use in the treatment of skin cancer (e.g., melanoma). In some embodiments, the composition comprises CBG and CBL and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBDV and CBG and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBN and CBT and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBG and CBN and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBDV and CBL and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBC and CBDV and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBC and CBT and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBDV and CBN and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBCA and CBNA and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBD and CBT and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBD and CBL and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBD and CBN and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBC and THCV and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBL and THCV and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBD and CBDV and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBDV and CBT and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBGA and CBN and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBC and CBG and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBG and CBGA and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBCA and CBN and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBDV and CBNA and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBN and CBNA and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBCA and CBG and is for use in the treatment of skin cancer (e.g., melanoma).
  • the composition comprises CBG and CBNA and is for use in the treatment of skin cancer (e.g., melanoma).
  • compositions comprising, consisting essentially of, or consisting of at least one cannabinoid selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the invention pertains to methods of treating cancer comprising administering a pharmaceutical composition comprising, consisting essentially of, or consisting of at least one cannabinoid selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • a pharmaceutical composition comprising, consisting essentially of, or consisting of at least one cannabinoid selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the herein composition is substantially free, or essentially free, or entirely free of any other cannabinoid except for the one, two, or more of the cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the herein composition is substantially free or essentially free, or entirely free of any other cannabinoid except for THC and the one, two, or more of cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the composition is substantially free, or essentially free, or entirely free of any cannabinoids other than the one or two or more cannabinoids selected from the group listed above.
  • the composition further comprises THC.
  • THC One of the possible benefits of adding THC to the composition is to increase appetite and/or induce weight gain and/or muscle mass.
  • the composition further comprises CBD.
  • the composition comprises THC but excludes CBD.
  • the composition comprises CBD but excludes THC.
  • the composition consists essentially of THC, CBDV and CBGA.
  • the composition comprises THC, CBDV and CBGA, and is substantially free of any other cannabinoid.
  • the composition is free of any other cannabinoid except for the herein CBCA, CBDV, CBDVA, THCV, and CBGA cannabinoids.
  • CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT can be obtained from a synthetic source or a natural plant source or from a cannabis plant extract.
  • a synthetic source means that the compound is synthesized by a chemical manmade process involving reacting a precursor or precursors in a chemical reaction to obtain a product in a single step or a multi-step synthesis.
  • a natural plant source refers to cannabinoids purified or isolated from a plant, typically extracted out from a mixture of compounds such as a mixture obtained by extraction of a plant source.
  • the plant source may be a part of a plant, several parts of a plant or the whole plant.
  • the plant can be Cannabis.
  • the cannabis plant can be, for example, from the strains Cannabis sativa or Cannabis indica.
  • a natural source can be a botanical drug substance such as an extract comprising a substantive amount of the target cannabinoid, for example, above about 90% w/w of the at least one cannabinoid selected from CBDV, CBGA, CBCA, CBDVA, THCV, CBC, CBN, CBL, CBG, CBNA, CBD or CBT (referred to herein also as "the designated cannabinoid ⁇ .
  • the weight to weight ratio between the two cannabinoids may be between 1:99 to 99:1.
  • the weight ratio is between 1:90 to 90:1, between 1:80 to 80:1, between 1:70 to 70:1, between 1:60 to 60:1, between 1:50 to 50:1, between 1:40 to 40:1, between 1:30, to 30:1, between 1:20 to 20:1, between 1:10 to 10:1, between 10:90 to 90:10, between 1:8 to 8:1, between 1:7 to 7:1, between 1:6 to 6:1, between 1:5 to 5:1, between 1:4 to 4:1, between 1:3 to 3:1, between 1:2 to 2:1, or between 1:1.5 to 1.5:1.
  • the weight ratio is between 20:80 to 80:20, in some embodiments between 30:70 to 70:30 and in some embodiments between 40:60 to 60:40, respectively.
  • the weight-to-weight ratio between the two cannabinoid ingredients is 1:1 to 1:10, or 1:1 to 1:9, or 1:1 to 1:8, or 1:1 to 1:7, or 1:1 to 1:6, or 1:1 to 1:5, or 1:1 to 1:4, or 1:1 to 1:3, or 1:1 to 1:2, or any value in between.
  • the weight-to-weight ratio between the two cannabinoid ingredients is 1 : 1.
  • the weight-to-weight ratio between CBDV and CBGA is 1 : 1.5 to 1.5 : 1 , or any value in between.
  • the molar ratio between the two cannabinoids that are selected from CBCA, CBDV, CBDVA, THCV CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT (e g. CBDV and CBGA) may be between 1:99 to 99:1.
  • the molar ratio is between 1:90 to 90:1, between 1:80 to 80:1, between 1:70 to 70:1, between 1:60 to 60:1, between 1:50 to 50:1, between 1:40 to 40:1, between 1:30, to 30:1, between 1:20 to 20:1, between 1:10 to 10:1, between 10:90 to 90:10, between 1:8 to 8:1, between 1:7 to 7:1, between 1:6 to 6:1, between 1:5 to 5:1, between 1:4 to 4:1, between 1:3 to 3:1, between 1:2 to 2:1, or between 1:1.5 to 1.5:1, or any value inbetween.
  • the molar ratio is between 20:80 to 80:20, in some embodiments between 30:70 to 70:30 and in some embodiments between 40:60 to 60:40, respectively.
  • the molar ratio between the two cannabinoid ingredients is 1:1 to 1:10, or 1:1 to 1:9, or 1:1 to 1:8, or 1:1 to 1:7, or 1:1 to 1:6, or 1:1 to 1:5, or 1:1 to 1:4, or 1:1 to 1:3, or 1:1 to 1:2, or any value in between.
  • molar ratio between the two cannabinoid ingredients is 1:1.
  • molar ratio between the two cannabinoid ingredients is 3:1 to 1:3.
  • the molar ratio between CBGA and CBDV is between 1:10 to 10:1, or between 1:5 to 5:1, or between 1:4 to 4:1, or between 1:3 to 3:1, or between 1:3.5 to 8.5:1, or between 1:1.5 to 1.5:1, or is 1:1. In some embodiments, the molar ratio between CBCA and CBDV is between 1 : 10 to 10: 1, or between 1:5 to 5:1, or between 1:4 to 4:1, or between 1:3 to 3:1, or between 1:1.5 to 1.5:1, or is 1:3.
  • the molar ratio between CBCA and CBGA is between 1:10 to 10:1, or between 1:5 to 5:1, or between 1:4 to 4:1, or between 1:3 to 3:1, or between 1:3.5 to 8.5:1, or between 1:1.5 to 1.5:1, or is 1:1. In some embodiments, the molar ratio between CBGA and CBDV is 1 : 1.25, or any value in between.
  • each cannabinoid is independently present in the composition at a concentration of up to about 1000 pM. For example, up to about 500 pM, up to about 400 pM, up to about 300 pM, up to about 200 pM, or up to about 100 pM.
  • the cannabinoid may be present in the composition at a concentration of between about 2 pM and about 100 pM, between about 5 pM and about 100 pM, between about 5 pM and about 90 pM, between 5 pM and 80 pM, between 5 pM and 70 pM, between about 5 pM and about 60 pM, or between 10 pM and about 55 pM, or any value in between.
  • each cannabinoid is independently present in the composition at a concentration of between about 5mM and about 1000 mM, between about 5mM and about 500 mM. between about 5mM and about 100 mM. For example, between about 5mM and about 50 mM, between 5mM and 40 mM, between 5mM and about 30mM, between about 5mM and about 20mM, or between 10 mM and about 20mM, or any value in between, or any value in between.
  • the CBDV is present in the composition at a concentration of between about 5mM and about 1000 mM, between about 5mM and about 500 mM. Between about 5mM and about 100 mM. For example, between about 5mM and about 50 mM, between 5mM and 40 mM, between 5mM and about 30mM, between about 5mM and about 20mM, or between 10 mM and about 20mM, or any value in between. In an exemplary embodiment, the CBDV is present in the composition at a concentration of 17.46 mM.
  • the CBGA is present in the composition at a concentration of between about 5mM and about 1000 mM, between about 5mM and about 500 mM, between about 5mM and about 100 mM. For example, between about 5mM and about 50 mM, between 5mM and 40 mM, between 5mM and about 30mM, between about 5mM and about 20mM, or between 10 mM and about 20mM. In an exemplary embodiment, the CBGA is present in the composition at a concentration of 13.87 mM.
  • the weight to volume of each cannabinoid in the composition is between 1% w/v to 80% w/v.
  • the weight to volume of each cannabinoid is 10% w/v.
  • the herein cannabinoid compositions may comprise THC in a relatively small amount as compared to the amount of the one or at least two other cannabinoids in the composition.
  • the concentration of THC is between 0.1 to 10 % w/w, 1 to 5 % w/w, or 2.5 % w/w out of the total weight of THC and the one, or two or more other cannabinoids (e.g., CBDV and CBGA).
  • the composition comprises CBDV/CBGA/THC at a weight-to-weight ratio of 45:45: 10 (the ratio is the weight ratio out of the total weight of CBDV, CBGA and THC).
  • the composition comprises CBDV/CBGA/THC at a weight-to-weight ratio of 48.75:48.75:2.5. In some embodiments, it comprises a weight-to-weight ratio of 45:45: 10 to 49:49:2 % w/w out of the total weight of THC, CBDV and CBGA.
  • the composition may contain 100 mg CBDV, 100 mg CBGA and 2.5 mg THC.
  • the total amount of cannabinoids selected from CBCA, CBDV, CBDVA, THCV CBGA, CBC, CBN, CBL, CBG, CBNA, and CBT in a dosage unit form can be up to about 2000 mg, For example, between about 10 mg and about 2000 mg.
  • the total amount can be about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1500 mg, or 2000 mg.
  • the total amount of cannabinoids can be between about 10 mg and 1500 mg, between about 10 mg and 1000 mg, between about 10 mg and about 800 mg, between about 10 mg and 500 mg, between about 100 mg and 800 mg, or between about 100 mg and 500 mg, or any value in between.
  • the amount of THC in the composition can be between 0.1 mg to 30 mg per dosage unit form. In some embodiments, the amount of THC in the composition can be 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 15 mg.
  • the amount of CBD in the composition can be between 0.05 mg to 5 mg per dosage unit form. In some embodiments, the amount of CBS in the composition can be 0.1, 0.15, 0.20, 0.25, 0.50, 1.0 or 1.5 mg, or any value in between.
  • both THC and CBD are present in the composition and the total amount of THC and CBD in the composition is between 1 to 10 mg. In some embodiments, THC and CBD are present in the composition in a relative ratio of THC/CBD 95:5 wt% out of the total weight of THC and CBD.
  • the composition exhibits a synergistic effect of the two or more cannabinoids selected from the list provided above. In some embodiments, the composition exhibits a synergistic effect of CBDV and CBGA.
  • the herein composition may be prescribed for administration or provided along with the treatment of a chemotherapeutic agent.
  • the herein cannabinoid compositions comprising cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA may additionally include a chemotherapeutic agent.
  • the composition can be administered before, concomitantly to or after the administration of a chemotherapeutic agent.
  • chemotherapeutic agents are drug treatments that uses chemicals to eradicate fast-growing cells.
  • the chemotherapeutic agent is not a cannabinoid.
  • APIs administered concomitantly may illustrate an additive reaction or a synergistic reaction that will increase the toxicity of the chemotherapeutic drug.
  • FIGs. 7A-7B, and 8A the combined anti-cancer effect of Capecitabine with CBDV and CBGA is synergistic (FIGs. 7A-7B).
  • additional chemotherapy agents such as Docetaxel
  • the herein cannabinoid composition comprises one or more cannabinoid selected from CBCA, CBDV, CBDVA, THCV and CBGA, and one or more chemotherapeutic agents.
  • the herein cannabinoid compositions as described supra may be formulated as an oral composition.
  • Oral compositions generally include incorporating the mixture of cannabinoid(s) with an edible carrier or an inert diluent.
  • the composition is prescribed for systemic administration by an injection (e.g., intravenous, intraperitoneal, intramuscular). In other embodiments, the composition is prescribed for local administration.
  • intravenous administration z.v.
  • sublingual administration a direct pulmonary dosing
  • intraperitoneal administration intranasal administration for a direct pulmonary dosing a rectal administration
  • intramuscular administration subcutaneous administration
  • transdermal administration and/or intraocular administration.
  • the composition can be formulated as granules, powder, capsules, tablet, film, emulsion, lozenge, tincture, sachets, a chewing gum, a hard or soft gelatin capsule or a suspension.
  • the oral composition is enclosed in a soft gelatin capsule.
  • the composition is compressed into tablets.
  • the oral composition is formulated as a mouth wash by using one or more diluents in which the cannabinoid or a mixture thereof is dissolved, suspended or emulsified in the fluid carrier.
  • Exemplary diluents are water and alcohols, for example, ethanol, benzyl alcohol and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • the mouth wash is applied orally to the buccal cavity and it may then be swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • Capsules may contain surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and com starch.
  • Tablet forms may include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenges can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active formulation in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active formulation, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active formulation in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active formulation, such carriers as are known in the art.
  • the composition can be formulated in a slow-release form, an immediate release form or a combination thereof.
  • the immediate release formulation may comprise an edible oil and the sustained release formulation may comprise at least one Lipid-based Drug Delivery System (LBDDS) agent.
  • LBDDS agent is selected from the group consisting of a monoglyceride, a diglyceride, a carrageenan and any mixture thereof.
  • the carrageenan is selected from the group consisting of lambda- carrageenan, kappa-carrageenan, iota-carrageenan and any mixture of the carrageenan.
  • the composition comprises carrageenan in a relative amount of about 0.005 V/V out of the total volume of the composition.
  • the sustained release formulation further comprises an edible oil such as coconut oil, wheat sprout oil, olive oil, sprouted wheat oil, sesame oil, peanut oil, grape seed oil, palm oil, papaya seed oil or any combination thereof.
  • an edible oil such as coconut oil, wheat sprout oil, olive oil, sprouted wheat oil, sesame oil, peanut oil, grape seed oil, palm oil, papaya seed oil or any combination thereof.
  • the composition may further comprise cannabis extract in a relative amount range of about 0.01 V/V to about 0.02 V/V out of the total volume of the composition and the cannabinoid(s) comprises between 10 to 200 of mg of each one of CBDV and CBGA, CBCA, CBDVA, and THCV.
  • the composition comprises mono- and diglyceride in a relative amount of about 0.075 V/V. In some embodiments, the composition comprises coconut oil in a relative amount of about 0.92 V/V.
  • the composition further comprises at least one excipient selected from the group consisting of a diluent, a binder, a lubricant, a disintegrant, a flavoring agent, a coloring agent, a stabilizer, a surfactant, a glidant, a plasticizer, a preservative, an essential oil and a sweetener.
  • the therapeutic effect of the composition has direct immediate effect and/or a duration of up to 24 hours or from 4 to 24 hours.
  • the composition comprising cannabinoid(s) (e.g., cannabis extract, isolated cannabinoid, synthetic cannabinoid) in a relative amount of about 0.01 V/V, Carrageenan in a relative amount of about 0.005 V/V, Mono and Diglyceride in a relative amount of about 0.075 V/V and coconut oil in a relative amount of about 0.92 V/V out of the total volume of the composition.
  • cannabinoid(s) e.g., cannabis extract, isolated cannabinoid, synthetic cannabinoid
  • cannabinoid(s) e.g., cannabis extract, isolated cannabinoid, synthetic cannabinoid
  • Carrageenan in a relative amount of about 0.005 V/V
  • Mono and Diglyceride in a relative amount of about 0.075 V/V
  • coconut oil in a relative amount of about 0.92 V/V out of the total volume of the composition.
  • both the immediate release portion and the slow-release portion of the composition comprises a homogenous mixture of all the cannabinoids and optionally chemotherapeutic agents of the composition.
  • the immediate release portion of the composition comprises THC
  • the slow-release portion comprises the two other cannabinoids of the composition.
  • the composition may contain THC in the immediate release formulation and a mixture of CBDV and CBGA in the slow-release formulation.
  • Such an immediate release slow-release composition can achieve two purposes - a palliative effect by the THC ingredient and a slow-release anti-cancer effect by the two other cannabinoids.
  • the THC which is released from the immediate release component can be present in a lower concentration than the two cannabinoid mixture in the slow- release component of the composition.
  • the invention provides a method for treating a subject suffering from cancer comprising administering to the subject in need a therapeutically effective amount of the cannabinoid composition of this invention.
  • the invention provides a method for inhibiting cancer cells' growth or cancer cells' proliferation, or reducing or inhibiting cancer cells' viability, or inducing cancer cells apoptosis and/or necrosis, the method comprising contacting cancer cells with an effective amount of the cannabinoid composition of this invention.
  • the invention provides a method for treating a subject suffering from cancer comprising administering to the subject in need a therapeutically effective amount of the cannabinoids selected from selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA and a chemotherapeutic agent composition of this invention.
  • the invention provides a method for inhibiting cancer cells' growth or cancer cells' proliferation, or inducing cancer cells apoptosis and/or necrosis, the method comprising contacting cancer cells with an effective amount of the herein cannabinoid composition and chemotherapeutic agent.
  • the invention provides a pharmaceutical composition comprising a therapeutic effective amount of the cannabinoid composition of this invention for use in the treatment of cancer.
  • treating or “treatment” of cancer in a patient refers to administration of the herein cannabinoid composition for preventing one or more of the cancer symptoms, inhibiting cancer progression, stabilizing its progression, reducing the volume of the tumor, or ameliorating or delaying the appearance of one or more of its symptoms.
  • subject refers to a human or a non-human mammal.
  • administration refers to providing or giving a subject a therapeutic agent by any effective route.
  • an effective amount refers to a quantity sufficient to, when administered to the subject, affect a beneficial or desired result, including clinical results such as inhibiting cellular growth/proliferation, such as tumor or cancer cells' growth (or both), tumor volume, or a combination thereof.
  • the method for treating cancer includes administrating to the subject in need a dosage of a therapeutically effective amount of the composition.
  • the herein cannabinoid composition is provided as a neoadjuvant therapy, i.e., it is provided in order to stop the spread of cancer, and/or prior to determining the stage of the cancer (pre-staging), and/or prior to providing a therapy which is not based on cannabinoid(s) and that is commonly administered post staging.
  • the herein method of treatment affords a broader repertoire of treatments to patients and is aimed at overcoming the known effect of tumor resistance associated with neoadjuvant chemoradiation.
  • the herein method of neoadjuvant cannabinoid treatment is provided to a subject suspected of having cancer. In one embodiment, the herein method of neoadjuvant cannabinoid treatment is provided to a subject diagnosed as having cancer, wherein the cancer staging/classification has not yet been performed or completed. In one embodiment, the herein method of neoadjuvant cannabinoid treatment is provided to a subject prior to treatment with an anticancer agent other than cannabinoid(s). In one embodiment, the herein method of neoadjuvant cannabinoid treatment is provided to a subject prior to treatment with an anticancer therapy (such as chemotherapy, radiotherapy, biological therapy, or a combination thereof).
  • an anticancer therapy such as chemotherapy, radiotherapy, biological therapy, or a combination thereof.
  • the herein method includes the following steps: identifying a subject that is afflicted with cancer or is suspected of having cancer; treating the subject with one or more cannabinoids; identifying the caner stage; and treating the cancer with an anti-cancer therapy.
  • the anti-cancer therapy is not a cannabinoid therapy. In one or more embodiments, the anti-cancer therapy is chemotherapy. In one or more embodiments, the anti-cancer therapy is a biological therapy. In one or more embodiments, the anti-cancer therapy is a radio therapy. In one or more embodiments, the anti-cancer therapy is a hormone therapy. In one or more embodiments, the anticancer therapy is a chemoradiation.
  • Various cannabinoids are herein contemplated to be administered as neoadjuvant therapeutic regimen.
  • Exemplary cannabinoids include, for example, THC, CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • the one or more cannabinoids is selected from CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT.
  • neoadjuvant therapy is interchangeable with the term “neoadjuvant cannabinoid therapy” and refers to a treatment given before the primary treatment as a first step to shrink a tumor before the main treatment and/or before staging.
  • neoadjuvant treatment that is given before surgery may allow breast conserving surgery.
  • determining the stage of the cancer it is meant to refer to determining the cancer type, stage, origin, and/or providing prognosis using a specimen of the cancer using surgery or biopsy. Determining the stage of the cancer is also referred to as “staging” or “classification”.
  • the dose for administration is a daily administration dose.
  • the therapeutically effective amount dosage to be administered and the particular mode of administration will vary depending upon such factors as the age, weight of the particular subject, the therapeutic or diagnostic use contemplated, and the form of the formulation.
  • the administration of a therapeutically effective amount of the composition is preceded by a build-up period in which less than the target therapeutically effective amount is administered daily to the patient and is gradually increase until reaching the therapeutic effective amount of the composition to the patient. This allows the patient to gradually accustom to the composition, which may among other benefits, allow better compliance of the subject to the treatment.
  • the buildup period may last for several days to several weeks. In some embodiments, the buildup period can last 5, 10 or 15 days.
  • the buildup period can take 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks.
  • the treatment may start with administering a single daily dosage to the subject in need during the first week of treatment, then increasing the regimen to two daily dosages in the second week, three daily dosages during the third week and reaching the target four daily dosages in the fourth week.
  • the single daily dosage may, for example, comprise 100 mg of CBDV, 100 mg of CBGA and optionally also 5 mg of THC, to be taken once a day during the first week, twice a day (for example every 12 hours) during the second week, three times a daily (for example every 8 hours) during the third week and every 6 hours during the fourth week onwards.
  • the dosage units can be taken separately as exemplified above or together, either as several dosages taken together at the same occasion daily or by administering a single dosage having an increased amount of active ingredients (i.e., a capsule having 100 mg of CBDV, 100 mg of CBGA and optionally 5 mg of THC during the first week, a capsule having 200 mg of CBDV, 200 mg of CBGA and optionally 10 mg of THC during the second week, and so forth).
  • active ingredients i.e., a capsule having 100 mg of CBDV, 100 mg of CBGA and optionally 5 mg of THC during the first week, a capsule having 200 mg of CBDV, 200 mg of CBGA and optionally 10 mg of THC during the second week, and so forth).
  • the herein cannabinoid composition is administered concomitant to, after, or before the administration of a chemotherapeutic agent.
  • treatment includes cannabinoid(s) administration wherein the cannabinoids are provided as separate unit dosage forms.
  • the treatment period (starting from the first day of the buildup period) can last for as long as the condition of the subject in need requires, i.e., until the offset of symptoms of the disease such as the disappearance of the tumor as may be indicated by imaging techniques, or blood levels of markers or combination thereof.
  • the duration of the treatment is about four months. In some embodiments, the treatment duration is 6, 8, 10, 12 or 18 months.
  • the invention provides the use of the composition according to the invention in the manufacture of a medicament for treating cancer.
  • the invention provides the use of the composition of the invention for the treatment of cancer.
  • the cancer amendable for treatment by the present invention include solid tumor and optionally a hematological tumor.
  • the cancers for treatment may include, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • cancers include squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), skin cancer (e.g., melanoma), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer, as well as B-cell lymphoma (including low grade/follicular nonHodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade
  • the cancer is selected from the group consisting of colon, kidney, adrenocortical and hepatocellular cancers; breast cancer, Acute Myelogenous Leukemia (AML), Chronic lymphocytic leukemia (CLL), pro- lymphocytic leukemia, esophageal carcinoma, non-small-cell lung cancers, soft-tissue sarcomas and osteosarcomas.
  • AML Acute Myelogenous Leukemia
  • CLL Chronic lymphocytic leukemia
  • pro- lymphocytic leukemia esophageal carcinoma
  • non-small-cell lung cancers non-small-cell lung cancers
  • soft-tissue sarcomas soft-tissue sarcomas and osteosarcomas.
  • the cancer is colorectal cancer.
  • colon cancer it is meant to refer to both colon cancer and rectal cancer.
  • the cancer is adenocarcinoma. It is to be noted that more than 90% of colorectal carcinomas are adenocarcinomas, originating from epithelial cells of the colorectal mucosa.
  • the cancer is melanoma.
  • melanoma it is meant to refer to a malignant tumor of melanocytes.
  • the cancer is not a mesothelioma. In an alternative embodiment, the cancer is a mesothelioma.
  • the herein pharmaceutical composition may be administered orally, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, intravenously, intraperitoneally, topically, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.
  • Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • phytocannabinoids are cannabinoids that originate from nature and can be found in the cannabis plant.
  • the phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
  • Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.
  • synthetic compound refers to a chemical man-made compound/molecule functionally and structurally similar to its corresponding natural compound. Synthetic compounds are not derived from plants. Synthetic compounds bind to same receptors to which the natural corresponding plant compounds attach. These synthetic analogs often, but not necessarily, have greater binding affinity and greater potency to the respective receptor.
  • the synthetic compound herein refers to a cannabinoid selected from CBCA, CBDV, CBDVA, THCV, CBGA, CBC, CBN, CBL, CBG, CBNA, CBD and CBT and CBGA (hereinafter "the designated cannabinoid”), and optionally THC.
  • isolated cannabinoid As used herein, the terms “isolated cannabinoid” , “purified cannabinoid' and “Highly purified cannabinoid” are interchangeable and refer to a compound (herein “the designated cannabinoid") which is extracted from the cannabis plant and purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.
  • cannabinoid a compound which is extracted from the cannabis plant and purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.
  • isolated can be taken to mean that no substantial or essential amounts of components with which the designated cannabinoid is usually associated in nature or in in vitro conditions other than the designated compound and optionally its carrier or solvent is detectable by high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the isolated compound is substantially free of any compounds other than the designated cannabinoid.
  • the isolated cannabinoid is essentially free of any compounds other than the designated compound.
  • the isolated cannabinoid is free of compounds other than the designated cannabinoid.
  • substantially free refers to a compound provided in a highly purified/isolated form such that it comprises less than about 0.5%, or less than about 0.4%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1%, or any percentage in between of compounds other than the designated cannabinoid.
  • the term “essentially free” refers to a compound provided in a highly purified/isolated form such that it comprises less than about 0.05%, or less than about 0.04%, or less than about 0.03%, or less than about 0.02%, or less than about 0.01%, or less than about 0.005%, or any percentage in between, or having only trace amounts of compounds other than the designated cannabinoid.
  • extract refers hereinafter to any fraction or concentrate derived from a plant which contains at least one of the herein designated cannabinoids.
  • a natural phytocannabinoid may be extracted and/or fractioned from its respective cannabis plant using any one of the many known methods, such as nonhydrocarbons extraction methods (e.g., carbon dioxide extraction) and hydrocarbons extraction methods (e.g., butane, propane or alcohol extractions). It further refers to extracts treated by separation or purification or fractionation processes.
  • the extract or fraction may be enriched with the designated cannabinoid, namely, the designated cannabinoid with which the extract is enriched is present in an amount that is higher than that of the other compounds.
  • the designated cannabinoid is present in the extract in an amount greater than 40% (w/w) of the total extract.
  • the designated cannabinoid is present in an amount greater than 50% (w/w), greater than 60% (w/w), greater than 75%, greater than 80%, greater than 85%, or greater than 90% of the extract.
  • a fraction or extract typically includes other compounds or ingredients of the extracted or fractioned plant.
  • the fraction or extract includes at least about 0.5% of the plant derived compounds other than the designated cannabinoid.
  • fractions that contain certain amounts of additional compounds, other than the designated cannabinoid allow for an enhanced efficacy due to the entourage effect of the combination of compounds.
  • composition especially composition comprising a cannabis plant derived molecule includes one or more of terpene and/or terpenoid.
  • a composition comprising a cannabis plant derived molecule does not include any terpenes and/or terpenoids.
  • the terpene/terpenoid may be provided within a cannabis extract or fraction.
  • Terpenes or “terpenoids” as used herein refers to a class of hydrocarbon molecules, which often provide a unique smell. Terpenes are derived from units of isoprene, which has the molecular formula CsHs. The basic molecular formula of terpenes are multiples of the isoprene unit, i.e. (CsHs)n where n is the number of linked isoprene units. Terpenoids are terpene compounds that have been further metabolized in the plant, typically through an oxidative process, and therefore usually contain at least one oxygen atom.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • the term “synergistic” refers to e.g., an observed effect which is higher in the presence of the cannabinoids together than the sum of the individual effects of each cannabinoid when administered separately.
  • the observed combined effect of the cannabinoids is significantly higher than the sum of the individual effects.
  • the term significant means that the statistical p value observed is less than 0.05, i.e., p ⁇ 0.05. It is contemplated that the therapeutic effects achieved as a result of the combination of two or more cannabinoids selected from CBCA, CBDV, CBDVA, THCV and CBGA are significantly better than the expected additive therapeutic effects. Thus, the doses of each of the agents can be reduced.
  • M designates mortality; wherein MAB- is a calculation of mortality, e.g., of cells exposed to a combination of cannabinoid A and cannabinoid B; MA is the mortality of cells exposed to cannabinoid A only; MB is the mortality of cells exposed to cannabinoid B only. MAB designates the observed mortality of cells exposed to the combination of cannabinoid A and cannabinoid B.
  • the synergistic effect can be calculated according to the cells survival experimental results according to the Bliss equation as follows:
  • S designates mortality; wherein SAB (Cal)- is a calculation of survival, e.g., of cells exposed to a combination of cannabinoid A and cannabinoid B; SA is the survival of cells exposed to cannabinoid A only; SB is the survival of cells exposed to cannabinoid B only. SAB (Exp) designates the observed survival of cells exposed to the combination of cannabinoid A and cannabinoid B.
  • the amounts in the examples should be read with the prefix “about”.
  • Cannabinoids - the cannabinoids used in the experiments were either synthetic cannabinoids obtained from Restek Corporation USA, or plant derived purified cannabinoids. Cannabinoid solutions were prepared by dissolving the cannabinoid in dimthylsulphoxide (DMSO) at the desired concentration.
  • Cell lines - cell lines used in the experiments were obtained from ATCC®. Human colon cancer cell lines that were used in the experiments were: HCT-116, RKO, HT-29, HT-8, LS-174T, SK-CO1. Mouse colon cancer cell line: CT-26.
  • Lung cancer cell lines used in the experiments were: A549, DMS-79, NCI-H69, NCI-H211, and SHP77.
  • Cell viability was performed by CellTiter-Glo (CTG) Luminescent Cell Viability Assay. IC50 of each cannabinoid on the cancer cell lines was determined by standard methods and the use of the software GraphPad Prism.
  • Synergistic calculation - synergism was calculated according to the Bliss equation defined supra.
  • Example 1 - certain cannabinoid combinations exhibit colon, breast, and lung cancers cells viability inhibition effect.
  • colon cancer cell lines i.e., HT-29, HCT-8, HCT-116, LS-174T, CT-26, RKO, and SK-CO1
  • lung cancer cell lines i.e., A549, DMS-79, NCI-H69, NCI-H211, and SHP77
  • breast cancer cell lines i.e., AU565, BT-549, MCF-7, and SW-527 were incubated at 37°C with various cannabinoids for 48 hours.
  • the numbers/colors represent the relative synergy intensity (rank) of all cannabinoid pairs tested, based on the synergy calculation according to Bliss.
  • the low numbers/bright background represent strong synergy ranking.
  • the high numbers/dark background represent weak synergy/no synergy ranking.
  • the numbers/colors represent the relative synergy intensity (rank) of all cannabinoid pairs tested, based on the synergy calculation according to Bliss.
  • the low numbers/bright background represent strong synergy ranking.
  • the high numbers/dark background represent weak synergy/no synergy ranking.
  • the numbers/colors represent the relative synergy intensity (rank) of all cannabinoid pairs tested, based on the synergy calculation according to Bliss.
  • the low numbers/bright background represent strong synergy ranking.
  • the high numbers/dark background represent weak synergy/no synergy ranking.
  • Example 2 the combination of CBDV and CBGA possesses a strong synergistic anti-proliferative effect on HT-29 colon cancer cells.
  • the colon cancer cell line HT-29 was exposed to each of CBDV (at a concentration of 23.5 pM) and CBGA (at a concentration of 25.6 pM) alone, and a combination thereof and to each of CBGA (at a concentration of 25.6 pM) and THC-d8 (at a concentration of 17.5 pM) alone, and a combination thereof at 37°C for 48 hours.
  • the viability of the tested cells was examined.
  • Tables 4 and 5 illustrate the obtained results (shown also graphically at FIGs. 1 A and IB). As can be seen in table 4 and in FIG. 1 A, each of CBDV and CBGA alone illustrated a slight growth inhibition effect.
  • the combination of the two cannabinoids presents a substantial and strong synergistic anti-cancer effect.
  • the combination of CBGA with THC-d8 illustrated no anti-cancer synergistic effect, suggesting that CBGA possesses synergistic anti-cancer effect when combined with certain cannabinoids only.
  • Table 4- the combination of CBDV and CBGA possesses a strong synergistic growth inhibition effect on HT-29 colon cancer cells.
  • Table 5- the combination of CBGA and THC-d8 does not possess a synergistic growth inhibition effect on HT-29 colon cancer cells.
  • Example 3 the combination of CBDV and CBGA possesses a strong synergistic anti-proliferative effect on A549 lung cancer cells.
  • the lung cancer cell line A549 was exposed to each of CBDV (at a concentration of 23.5 pM) and CBGA (at a concentration of25.6 pM) alone, and a combination thereof at 37°C for 48 hours.
  • the viability of the tested cells was examined.
  • Table 6 illustrates the obtained results (shown also graphically in FIGs. 2A-2B).
  • each of CBDV and CBGA alone illustrated a slight growth inhibition effect.
  • the combination of the two cannabinoids presents a substantial and strong synergistic anti-cancer effect.
  • Table 7- CBDVA and THC-d8 do not possess a synergistic growth inhibition effect on A549 lung cancer cells.
  • Example 4 the combination of CBDV and CBGA possesses a strong synergistic anti-proliferative effect on MCF-7 breast cancer cells.
  • the breast cancer cell line MCF-7 was exposed to each of CBDV (at a concentration of 23.5 pM) and CBGA (at a concentration of 20 pM) alone, and to a combination thereof at 37°C for 48 hours. The viability of the tested cells was examined.
  • Table 8 illustrates the obtained results (shown also graphically in FIGs. 3A-3B).
  • each of CBDV and CBGA alone illustrated a slight growth inhibition effect.
  • the combination of the two cannabinoids presents a substantial and strong synergistic anti-cancer effect.
  • Example 5 the combination of CBDV and CBGA possesses a synergistic anti-proliferative effect on RKO and HCT116 colon cancer cells.
  • the colon cancer cell lines RKO, and HCT116 were exposed to various cannabinoid combinations, at 37°C for 48h. The viability of the tested cells was examined. Further, synergism was evaluated using the Bliss equation. Table 10 below illustrates the obtained results.
  • CBDV and CBGA presented a particularly strong synergistic interaction and were therefore further tested.
  • the colon cancer cell lines RKO, and HCT116 were exposed to CBDV and CBGA combinations, at 37°C for 48h. The viability of the tested cells was examined.
  • CBDV and CBGA were tested at concentrations of 46.9 pM and 51.2 pM, respectively (shown as X2 in FIGs. 4A-4B).
  • the effect of contacting each cannabinoid on the cells at half the concentration (i.e., 23.4 pM and 25.6 pM for CBDV and CBGA, respectively) was further tested (shown as XI in FIGs. 4A-4B).
  • Mixtures of CBDV and CBGA each at a XI concentration were further prepared (“low concentration solutions”). The effect of the low concentration solution on the viability of the cancer cells was tested.
  • the expected calculated (SAB) (Cal) viability value of the CBDV and CBGA binary composition according to the Bliss independence drug interaction model is 98.5 and 94.3 for HCT 116 and RKO, respectively.
  • Table 12 - CBDV and CBGA possess a strong synergistic growth inhibition effect on RKO cancer cells.
  • Example 6 -synergy ratio between CBDV and CBGA.
  • the numbers/colors represent the relative synergy intensity (rank) of all cannabinoid pairs tested, based on the synergy calculation according to Bliss.
  • the low numbers/bright background represent strong synergy ranking.
  • the high numbers/dark background represent weak synergy/no synergy ranking.
  • Table 18 illustrates (shown also graphically at FIG. 5 A) the synergistic antitumor effect of a combination of the cannabinoids THCV (at a concentration of 24 pM) and CBCA (at a concentration of 14.5 pM) on colon cancer biopsies.
  • the combination of THCV and CBCA yielded a synergistic cell viability inhibitory effect.
  • table 19 shows also graphically in FIG. 5B
  • Table 18- THCV and CBCA possess a strong synergistic growth inhibition effect on colon cancer biopsy.
  • FIG. 6 illustrates graphically the combination of CBGA and CBDV on colon cancer biopsies taken from a patient.
  • the concentration of each component was: CBGA (X2- 51.2 pM), CBGA (XI- 25.6 pM), CBDV (X2- 47 pM), CBGA (XI- 23.5 pM).
  • CBGA(Xl) and CBDV(Xl) yielded a synergistic cell viability inhibitory effect.
  • the effect of the combination of the cannabinoids on the cell viability was more profound than each of the cannabinoids alone at the higher (X2 concentration).
  • Example 8 synergistic anti-tumor effect of a combination of the cannabinoids CBDV and CBGA and chemotherapy on colon cancer cells
  • FIGs. 7A-7B illustrate the human colon cell lines (HCT116 and RKO) that were incubated with CBGA at a concentration of 35pM, CBDV at a concentration of 25 pM, Capecitabine at a concentration of 250pM, and a combination thereof.
  • capecitabine alone had no toxicity effect on the cells.
  • the combination of CBGA and CBDV had a substantial anti-cancer effect on the cells.
  • the combination of the three agents together, i.e., CBGA, CBDV and Capecitabine had a significant anti -cancer effect which was higher than the effect of the combined treatment of CBGA and CBDV, resulting in a growth inhibition of above about 80% of the cells. Taken together, these results demonstrate a synergistic anti-proliferative effect of CBDV and CBGA and the chemotherapy tested.
  • docetaxel (at a concentration of 80 pM) also presented synergistic interaction with the combination of CBDV (at a concentration of 10 pM) and CBGA (at a concentration of 10 pM).
  • Example 9- the combination of CBGA and CBDV substantially inhibits growth of colon cancer tumors in mice
  • mice (Athymic nude mice, about 6-8 weeks of age), 7 mice per group, were inoculated subcutaneously with HT-29 human colorectal adenocarcinoma cells. After reaching a tumor volume of 100 mm 3 , the mice were intraperitoneally injected daily (for
  • HT-29 By a single subcutaneous (SC) injection of l * I O 6 cells/animal mixed with Matrigel (1 : 1 v/v) at a dose volume of 200 pl/ Animal on day 0.
  • SC subcutaneous
  • Randomization Randomization of mice to test groups was carried out when tumors reach a mean volume of 100 mm 3 (tumor size range of 70-120 mm 3 ) and up to 2 weeks from injection of tumor cells.
  • Monitoring of tumor size was performed by measurement of tumor size up to 3* weekly.
  • Treatment once daily repeated IP injections for 4 successive weeks at a volume of 200pl.
  • Study Duration Up to 6 weeks (1-2 weeks for tumor development & 4-week treatment period). Study may be extended in due course of the study according to the results obtained.
  • mice were euthanized the tumor was be excised, weighed, and photographed next to a ruler.
  • the experiment formulation contains:
  • mice treated with CBDV and CBGA combination illustrated prolonged survival as compared to control mice.
  • Example 10 Example 10 -clinical studies for determining the effect of CBDV, CBGA and THC on colon cancer patients.
  • AE Number of Participants With Adverse Event
  • CTCAE Common Terminology Criteria for Adverse Events
  • Fatal adverse events are classified as grade 5.
  • Serious adverse events include any event that is fatal, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or other significant medical hazard.
  • Treatment-related AEs are those that the investigator will consider a reasonable possibility that might be caused by study drug.
  • PFS Progression-Free Survival
  • PFS Progression-free Survival
  • Exclusion Criteria patients with other primary malignant tumors within 1 year. intentional, severe liver and kidney disease patients with serious obstacle and function. pregnancy or lactating women, mental disorders to cooperate to complete the study. is in other subjects or attended other drugs test interval ⁇ 3 months, do not meet the inclusion criteria.
  • melanoma cell lines i.e., G-361, A-375, and SK-MEL1 were incubated at 37°C with various cannabinoids for 48 hours.
  • various combinations of the cannabinoids CBC, CBN, CBL, CBDV, CBGA, CBG, CBCA, CBDVA, CBNA, CBT, CBD and THCV at concentrations range of 10-100 pM, illustrated a synergistic proliferation/viability inhibition effect on the cancer cells.
  • the numbers/colors represent the relative synergy intensity (rank) of all cannabinoid pairs tested, based on the synergy calculation according to Bliss.
  • the low numbers/bright background represent strong synergy ranking.
  • the high numbers/dark background represent weaker synergy ranking.
  • Example 12 the combination of CBL and CBT possesses a strong synergistic anti-proliferative effect on G-361 skin cancer cells.
  • the skin cancer cell line G-361 was exposed to each of CBL and CBT alone, and to a combination thereof at 37°C for 48 hours. The viability of the tested cells was examined. CBL and CBT were tested at concentrations of 51.2 pM and 100 pM, respectively (shown as X2 in FIG. 10A). The effect of contacting each cannabinoid on the cells at half the concentration (i.e., 25.6 pM and 50 pM for CBL and CBT, respectively) was further tested (shown as XI in FIG. 10 A).
  • the cell viability results upon exposure of G-361 human skin cancer cell lines to (i) CBL, CBT at concentration X2, (ii) CBL, CBT at XI and (iii) to the binary mixture CBL and CBT each at the XI concentration are presented in FIG. 10A.
  • FIG. 10A there was a substantial decrease in G-361 cells' viability after exposure to the cannabinoids mixture (CBL+ CBT) relative to the effect on the cells when exposed to a single cannabinoid at X2.
  • the results show that the cannabinoids mixture exhibits better anti-proliferation effect than the calculated additive effect or the double concentration of a single cannabinoid on the cells.
  • Example 13 the combination of CBD and CBT possesses a strong synergistic anti-proliferative effect on human A-375 skin cancer cells.
  • the skin cancer cell line A-375 was exposed to each of CBD and CBT alone, and to a combination thereof at 37°C for 48 hours. The viability of the tested cells was examined. CBD and CBT were tested at concentrations of 30 pM and 100 pM, respectively (shown as X2 in FIG. 10B). The effect of contacting each cannabinoid on the cells at half the concentration (i.e., 15 pM and 50 pM for CBD and CBT respectively) was further tested (shown as XI in FIG. 10B).
  • Example 14 the combination of CBDV and CBGA possesses a strong synergistic anti-proliferative effect on human A-375 skin cancer cells.
  • the skin cancer cell line A-375 was exposed to each of CBDV and CBGA alone, and to a combination thereof at 37°C for 48 hours. The viability of the tested cells was examined. CBDV and CBGA were tested at concentrations of 47 pM and 40 pM, respectively (shown as X2 in FIG. 10C). The effect of contacting each cannabinoid on the cells at half the concentration (i.e., 23.5 pM and 20 pM for CBDV and CBGA respectively) was further tested (shown as XI in FIG. 10C).
  • FIG. IOC there was a substantial decrease in A-375 cells' viability after exposure to the cannabinoids mixture relative to the effect on the cells when exposed to a single cannabinoid at X2.
  • Example 15 Example 15 -synergy ratio between the cannabinoid combinations CBL and CBN, CBDV and CBGA, CBL and CBC, CBC and CBN, CBL and CBG, CBDV and CBG, CBCA and CBGA, and CBDV and CBCA.
  • Human skin cell lines A-375 were incubated with 1 :3, 1 : 1 and 3 : 1 molar ratios between CBL and CBN, CBDV and CBGA, CBL and CBC, CBC and CBN, CBL and CBG, CBDV and CBG, CBCA and CBGA and CBDV and CBCA. Cells' viability and corresponding synergy according to Bliss were determined. As can be seen in FIGs. 11 A - 11H, all ratios tested showed synergistic interaction between the cannabinoids.
  • Example 16 -synergy ratio between the cannabinoid combinations CBDV and CBGA, CBCA and CBGA, and CBDV and CBCA.
  • Human colorectal HCT-116 cells were incubated with 1 :3, 1 : 1 and 3: 1 molar ratios between CBDV and CBGA, CBCA and CBGA and CBDV and CBCA. Cells' viability and corresponding synergy according to Bliss were determined.
  • FIG. 12A As can be seen in FIG. 12A concerning CBDV and CBGA all ratios tested showed synergistic interaction between the cannabinoids on the cells. The strongest synergistic interaction was demonstrated at a molar ratio of 1 : 1, nevertheless molar ratios of 1 :3 and 3: 1 also presented a substantial synergistic interaction.
  • FIGs. 12C-12E illustrate the effect of CBDV and CBGA when provided alone or in combination with each other at various concentrations and ratios between the cannabinoids.
  • FIG. 13 A illustrates the viability of the cells in the various ratios tested.
  • FIG. 14A illustrates the viability of the cells in the various ratios tested.
  • Example 17 illustrates the viability of the cells in the various ratios tested.
  • Example 17 the combination of three cannabinoids possesses a strong synergistic anti-proliferative effect on human A-375 skin cancer cells.
  • Table 22- a combination of CBDV, CBGA and THCV possesses a strong synergistic growth inhibition effect on skin cancer cells.
  • Table 23- a combination of CBDV, CBGA and CBDVA possesses a strong synergistic growth inhibition effect on skin cancer cells.
  • Table 24- a combination of CBDV, CBGA and CBCA possesses a strong synergistic growth inhibition effect on skin cancer cells.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur des combinaisons de deux cannabinoïdes choisis parmi l'acide cannabichroménique (CBCA), la cannabidivarine (CBDV), l'acide cannabidivarinique (CBDVA), la tétrahydrocannabivarine (THCV), l'acide cannabigérolique (CBGA), le cannabichromène (CBC), le cannabinol (CBN), le cannabicyclol (CBL), le cannabigérol (CBG), l'acide cannabinolique (CBNA), le cannabidiol (CBD) et le cannabitriol (CBT), et des méthodes de traitement du cancer comprenant ceux-ci.
PCT/IL2022/051086 2021-10-13 2022-10-12 Compositions comprenant des cannabinoïdes et leurs méthodes d'utilisation dans le traitement du cancer Ceased WO2023062634A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202163255194P 2021-10-13 2021-10-13
US202163255206P 2021-10-13 2021-10-13
US63/255,194 2021-10-13
US63/255,206 2021-10-13

Publications (1)

Publication Number Publication Date
WO2023062634A1 true WO2023062634A1 (fr) 2023-04-20

Family

ID=85987607

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2022/051086 Ceased WO2023062634A1 (fr) 2021-10-13 2022-10-12 Compositions comprenant des cannabinoïdes et leurs méthodes d'utilisation dans le traitement du cancer

Country Status (1)

Country Link
WO (1) WO2023062634A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11975036B2 (en) 2021-10-26 2024-05-07 Ecofibre USA Inc. Methods of treating ovarian cancer with hemp extract
US11986505B2 (en) 2021-10-26 2024-05-21 Ecofibre USA Inc. Methods of treating endometriosis and other noncancer gynecological disorders with hemp extract
US12011451B2 (en) 2022-10-26 2024-06-18 Ecofibre USA Inc. Stabilized compositions comprising cannabidiol
US12097211B2 (en) 2022-10-26 2024-09-24 Ecofibre USA Inc. Methods of treating estrogen sensitive diseases with cannabis extract
US12102657B2 (en) 2021-10-26 2024-10-01 Ecofibre USA Inc. Systems and methods for producing hemp extracts and compositions

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110117216A1 (en) * 2008-06-04 2011-05-19 Guillermo Velasco Diez Anti-tumoural effects of cannabinoid combinations
US20140221469A1 (en) * 2011-09-12 2014-08-07 Otsuka Pharmaceutical Co., Ltd. Phytocannabinoids for use in the treatment of cancer
US20170143642A1 (en) * 2014-06-27 2017-05-25 Gw Pharma Limited Active pharmaceutical ingredient (api) comprising cannabinoids for use in the treatment of cancer
WO2019227167A1 (fr) * 2018-06-01 2019-12-05 The University Of Sydney Compositions et traitements
WO2020223510A1 (fr) * 2019-04-30 2020-11-05 Greenway Herbal Products, Llc Compositions de cannabinoïdes et procédés d'utilisation
WO2021209990A1 (fr) * 2020-04-13 2021-10-21 Cannabics Pharmaceuticals Inc. Composition et méthode pour le traitement du cancer faisant intervenir des cannabinoïdes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110117216A1 (en) * 2008-06-04 2011-05-19 Guillermo Velasco Diez Anti-tumoural effects of cannabinoid combinations
US8632825B2 (en) * 2008-06-04 2014-01-21 Gw Pharma Limited Anti-tumoural effects of cannabinoid combinations
US20140221469A1 (en) * 2011-09-12 2014-08-07 Otsuka Pharmaceutical Co., Ltd. Phytocannabinoids for use in the treatment of cancer
US20170143642A1 (en) * 2014-06-27 2017-05-25 Gw Pharma Limited Active pharmaceutical ingredient (api) comprising cannabinoids for use in the treatment of cancer
WO2019227167A1 (fr) * 2018-06-01 2019-12-05 The University Of Sydney Compositions et traitements
WO2020223510A1 (fr) * 2019-04-30 2020-11-05 Greenway Herbal Products, Llc Compositions de cannabinoïdes et procédés d'utilisation
WO2021209990A1 (fr) * 2020-04-13 2021-10-21 Cannabics Pharmaceuticals Inc. Composition et méthode pour le traitement du cancer faisant intervenir des cannabinoïdes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RUSSO ET AL.: "A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol", MEDICAL HYPOTHESIS, vol. 66, no. 2, 4 October 2005 (2005-10-04), pages 234 - 246, XP005198767, DOI: 10.1016/j.mehy.2005.08.026 *
SARFARAZ SAMI, ADHAMI VAQAR M., SYED DEEBA N., AFAQ FARRUKH, MUKHTAR HASAN: "Cannabinoids for Cancer Treatment: Progress and Promise", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 68, no. 2, 15 January 2008 (2008-01-15), US, pages 339 - 342, XP093059623, ISSN: 0008-5472, DOI: 10.1158/0008-5472.CAN-07-2785 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11975036B2 (en) 2021-10-26 2024-05-07 Ecofibre USA Inc. Methods of treating ovarian cancer with hemp extract
US11986505B2 (en) 2021-10-26 2024-05-21 Ecofibre USA Inc. Methods of treating endometriosis and other noncancer gynecological disorders with hemp extract
US12102657B2 (en) 2021-10-26 2024-10-01 Ecofibre USA Inc. Systems and methods for producing hemp extracts and compositions
US12251411B2 (en) 2021-10-26 2025-03-18 Ecofibre USA Inc. Methods of treating endometrial cancer using hemp extract
US12409199B2 (en) 2021-10-26 2025-09-09 Ecofibre USA Inc. Methods of treating endometriosis and other noncancer gynecological disorders with hemp extract
US12440528B2 (en) 2021-10-26 2025-10-14 Ecofibre USA Inc. Methods of treating ovarian cancer with hemp extract
US12011451B2 (en) 2022-10-26 2024-06-18 Ecofibre USA Inc. Stabilized compositions comprising cannabidiol
US12097211B2 (en) 2022-10-26 2024-09-24 Ecofibre USA Inc. Methods of treating estrogen sensitive diseases with cannabis extract
US12318399B2 (en) 2022-10-26 2025-06-03 Ecofibre USA Inc. Stabilized compositions comprising cannabidiol

Similar Documents

Publication Publication Date Title
WO2023062634A1 (fr) Compositions comprenant des cannabinoïdes et leurs méthodes d'utilisation dans le traitement du cancer
JP7516472B2 (ja) 癌を治療するための方法
JP7564119B2 (ja) ナルトレキソン及びカンナビノイドを含む癌の治療
Kang et al. Inhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhancing oxidative stress coincident with activation of both the intrinsic and extrinsic apoptotic pathways
JP5785569B2 (ja) がんの治療におけるフィトカンナビノイド
EP2768493B1 (fr) Phytocannabinoïdes destinés à être utilisés dans le traitement du cancer du sein
Nahler Cannabidiol and other phytocannabinoids as cancer therapeutics
JP2004538245A (ja) 抗増殖薬
CA2988869A1 (fr) Nouvelles polytherapies a base de cannabinoides pour le myelome multiple (mm)
JP2012236857A (ja) 抗ｅｇｆｒ療法に二次的な皮疹の予防および処置のためのビタミンｋ
WO2021028646A1 (fr) Régimes d'administration de cannabinoïdes combinés à des agents chimiothérapeutiques contre le cancer
US20230190844A1 (en) Composition and method for treating cancer with cannabinoids
AU2014318623B2 (en) Wilforlide A for overcoming chemotherapy resistance
JP2015214579A (ja) 癌細胞アポトーシス
KR102826773B1 (ko) 암 치료
Li et al. Overcome multidrug resistance in colorectal cancer by natural compounds
JP6367801B2 (ja) 化学療法耐性を克服するための、トリプテリジウム・ウィルフォルディ由来の抽出物の使用
Ross Cannabis and Cancer
Šmejkal Treating Epilepsy with Natural Products: Nonsense or Possibility?
Toyofuku et al. An open-label pilot study on the use of milnacipran for glossodynia patients
HK1225677B (en) Use of wilforlide a for overcoming chemotherapy resistance

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22880540

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 19.08.2024)

122 Ep: pct application non-entry in european phase

Ref document number: 22880540

Country of ref document: EP

Kind code of ref document: A1