WO2019227167A1

WO2019227167A1 - Compositions and treatments

Info

Publication number: WO2019227167A1
Application number: PCT/AU2019/050554
Authority: WO
Inventors: Amanda HUDSON; Emily Colvin; Helen Wheeler; Viive HOWELL; Jonathon ARNOLD; Iain McGregor
Original assignee: University of Sydney; Northern Sydney Local Health District
Current assignee: University of Sydney; Northern Sydney Local Health District
Priority date: 2018-06-01
Filing date: 2019-05-31
Publication date: 2019-12-05
Anticipated expiration: 2020-12-01

Abstract

The present invention relates to methods for treating mesothelioma comprising administering compositions comprising one or more cannabinoids selected from tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDV A), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA).

Description

Compositions and treatments

Field of the invention

The present invention relates to novel compositions and the use of said compositions in the treatment of mesothelioma.

Associated application

The present application claims priority from Australian provisional application AU 2018901971 , the contents and disclosure of which are hereby incorporated by reference in their entirety.

Background of the invention

Malignant mesothelioma (MM) is an aggressive malignancy that displays relatively low responses to existing therapies, resulting in short survival for those afflicted.

Since the early 1980s more than 10,000 Australians have succumbed to this cancer. Unfortunately, the majority of patients are diagnosed late, when systemic chemotherapy represents one of the only viable treatment options remaining. Moreover, the prognosis and survival rate for individuals diagnosed with mesothelioma is poor. In 2015 about 60,800 people had mesothelioma and 32,000 died from the disease. In New South Wales, Australia, only 4.5% of patients survive to 5 years after diagnosis. While rates of mesothelioma vary in different areas of the world, rates are higher in Australia, the United Kingdom, and lower in Japan.

More than 80% of mesothelioma cases are caused by exposure to asbestos fibres. The greater the exposure, the greater the risk. As of 2013 about 125 million people have been exposed to asbestos at work. High rates of disease occur in people who mine asbestos, produce products from asbestos, work with asbestos products, live with asbestos workers, or work in buildings containing asbestos. Asbestos exposure and the onset of cancer are generally separated by about 40 years. Washing the clothing of someone who worked with asbestos also increases the risk. Other risk factors include genetics and infection with the simian virus. The most effective and current standard of care chemotherapy was identified in 2003 and combines the use of pemetrexed with cisplatin. Typically, only 40% of patients respond to this chemotherapy, leading to a median survival time of only 12 months. There are currently no proven second line options for treating mesothelioma, leaving patients with a grim prognosis.

Current treatments for mesothelioma are grossly inadequate and there is a desperate need to develop new therapies. Moreover, any currently approved therapies also have significant side-effects including toxicity, fatigue and nausea. Therefore, there is also an urgent unmet need for more effective treatments, including treatments with reduced side-effects.

There is a need to identify new drugs and methods for use in the treatment of mesothelioma.

Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art.

Summary of the invention

The present invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of one or more cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual. In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of tetrahydrocannabinol (THC), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of tetrahydrocannabinolic acid (THCA), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of tetrahydrocannabivarin acid (THCV), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In a further embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabidiol (CBD), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In a further embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabidiolic acid (CBDA), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In a further embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabigerol (CBG), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual. In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabigerolic acid (CBGA), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabidivarin (CBDV), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabidivarinic acid (CBDVA), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabinol (CBN), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabichromene (CBC), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabichromenic acid (CBCA), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In one embodiment, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabichromevarinolic acid (CBCVA), or a pharmaceutically acceptable salt thereof, thereby treating mesothelioma in the individual.

In a further aspect, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBD, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

In a further aspect, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBDA, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

In a further aspect, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBG, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

Still further, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBGA, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

Still further, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBDV, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual. Further, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBDVA, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

Still further, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of THCA, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

In a further aspect, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of THC, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

In a further aspect, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of THCV, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

In a further aspect, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBN, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

In a further aspect, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBC, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

In a further aspect, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBCA, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

In a further aspect, the invention provides a method of treating mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of CBCVA, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), and cannabichromenic acid (CBCA), or pharmaceutically acceptable salts thereof, thereby treating mesothelioma in the individual.

In one embodiment of the invention, the method of treatment includes administration of at least one neutral cannabinoid (for example, one or more of THC, THCV, CBD, CBG, CBDV, CBN, and CBC). Preferably, the at least one neutral cannabinoid is CBD. The invention includes administration of at least one, two, three, four or more neutral cannabinoids.

In a further embodiment, the invention includes a method of treatment that comprises administration at least one acidic cannabinoid (for example, one or more of THCA, CBDA, CBGA, CBDVA, CBCA and CBCVA). The invention includes administration of at least one, two, three, four or more acidic cannabinoids.

In a preferred embodiment of the invention, the method of treatment includes administration of at least one neutral cannabinoid (for example, one or more of THC, THCV, CBD, CBG, CBDV, CBN, and CBC) and at least one acidic cannabinoid (for example, one or more of THCA, CBDA, CBGA, CBDVA, CBCA and CBCVA). Preferably, the at least one neutral cannabinoid is CBD. The invention may also include administration of at least one, two, three, or four neutral cannabinoids with at least one, two three or four acidic cannabinoids. For example, the invention includes administration of two neutral and one acidic cannabinoid, or two neutral and two acidic cannabinoids, or one neutral and two acidic cannabinoids etc.

In any embodiment, the invention may comprise administering therapeutically effective amounts of at least two cannabinoids wherein the two cannabinoids are selected from:

CBD and THC; CBD and THCA; CBD and THCV, CBD and THCV; CBD and CBDA; CBD and CBG; CBD and CBGA; CBD and CBDV; CBD and CBDVA; CBD and CBN; CBD and CBC; CBD and CBCA or CBD and CBCVA; or CBGA and THC; CBGA and THCA; CBGA and THCV; CBGA and CBD; CBGA and CBDA; CBGA and CBG; CBGA and CBDV; CBGA and CBDVA; CBGA and CBN; CBGA and CBC; CBGA and CBCA; CBGA and CBCVA or

CBDV and THC; CBDV and THCA; CBDV and THCV, CBDV and CBD; CBDV and CBDA; CBDV and CBGA; CBDV and CBDVA; CBDV and CBN; CBDV and CBC; CBDV and CBCA; CBDV and CBCVA or

CBDVA and THC; CBDVA and THCA; CBDVA and THCV; CBDVA and CBD; CBDVA and CBDA; CBDVA and CBG; CBDVA; and CBGA; CBDVA and CBDV; CBDVA and CBN; CBDVA and CBC; CBDVA and CBCA; CBDVA and CBCVA.

In any embodiment of the invention, the method may include administering therapeutically effective amounts of at least three cannabinoids selected from the group consisting of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA).

For example, the method may include administering therapeutically effective amounts of:

- CBD, CBGA and THCA;

- CBD, CBGA and CBDV;

- CBD, CBGA and CBDVA;

- CBD, CBGA and CBG;

- CBD, THCA and CBDV;

- CBD, THCA and CBGA;

- CBD, THCA and CBDVA;

- CBD, THCA and CBG;

- CBD, CBDV and CBDVA;

- CBD, CBDV and CBG;

- CBD, CBDVA and CBG; - CBGA, THCA and CBDV;

- CBGA, THCA and CBDVA;

- CBGA, THCA and CBG;

- CBGA, CBDV and CBDVA;

- CBGA, CBDV and CBG;

- CBGA, CBDVA and CBG;

- THCA, CBDV and CBDVA;

- THCA, CBDV and CBG; or

- CBDV, CBDVA and CBG.

Still further, the method may include administering therapeutically effective amounts of at least four cannabinoids selected from the group consisting of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA).

Still further, the method may include administering therapeutically effective amounts of at least five cannabinoids selected from the group consisting of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA).

Still further, the method may include administering therapeutically effective amounts of at least six, seven, eight, nine, 10, 11 , 12 or 13 cannabinoids selected from the group consisting of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA). In any aspect of the invention, pharmaceutically acceptable salts of the recited cannabinoids may be used.

In a further aspect, the invention relates to a method of slowing the progression of, preventing or inhibiting metastasis of mesothelioma in an individual, the method comprising administering to the subject therapeutically effective amounts of one or more cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby slowing the progression of mesothelioma or preventing or inhibiting metastasis of mesothelioma in the individual.

In any embodiment of the invention, where two or more cannabinoids are administered, the cannabinoids may be administered sequentially or concomitantly. Where the cannabinoids are administered concomitantly, the cannabinoids may be administered as a single dosage form, or alternatively as individual dosage forms administered at the same time.

Where the cannabinoids are administered sequentially, the cannabinoids may be provided as different dosage forms.

In any method of the present invention, the one or more cannabinoids are administered orally. Alternatively, the one or more cannabinoids is administered intravenously, intranasally, intramuscularly, transdermally or subcutaneously.

In any method of the present invention, the one or more cannabinoids are administered as part of a first-line treatment for mesothelioma. Alternatively, the one or more cannabinoids are administered after first-line treatment (such as cisplatin and pemetrexed) have been administered. In any embodiment of the invention, the cannabinoids may be provided in the form of a cannabis extract. The cannabis extract may be enriched for specific cannabinoids, including a substantially purified form from a cannabis extract. For example, the extract may be enriched for one or more of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA). Preferably, the extract is enriched for CBD.

In alternative embodiments, the cannabinoids are synthetically produced.

The present invention also provides pharmaceutical compositions comprising at least one, two, three, four, five or six or more cannabinoids selected from the group consisting tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, wherein the composition comprises the cannabinoids and a pharmaceutically acceptable excipient.

Preferably, the present invention provides a pharmaceutical composition consisting, comprising or consisting essentially of a cannabinoid selected from tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), and a pharmaceutically acceptable excipient, for use in the treatment of mesothelioma.

The present invention also provides a pharmaceutical composition comprising tetrahydrocannabinolic acid (THCA), and a pharmaceutically acceptable excipient, for use in the treatment mesothelioma. The present invention also provides a pharmaceutical composition comprising cannabidiol (CBD), and a pharmaceutically acceptable excipient, for use in the treatment mesothelioma.

The present invention also provides a pharmaceutical composition comprising cannabidivarin (CBDV), and a pharmaceutically acceptable excipient, for use in the treatment mesothelioma.

The present invention also provides a pharmaceutical composition comprising cannabidivarinic acid (CBDVA), and a pharmaceutically acceptable excipient, for use in the treatment mesothelioma.

The present invention also provides a pharmaceutical composition comprising cannabigerol (CBG) and a pharmaceutically acceptable excipient, for use in the treatment mesothelioma.

The present invention also provides a pharmaceutical composition comprising cannabigerolic acid (CBGA) and a pharmaceutically acceptable excipient, for use in the treatment mesothelioma.

Still further, the invention provides for the use of one or more cannabinoids selected from the group consisting of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), in the manufacture of a medicament for the treatment of mesothelioma.

Preferably, the medicament comprises at least CBD. Alternatively, the medicament comprises at least tetrahydrocannabinolic acid (THCA), cannabidivarin (CBDV), at least tetrahydrocannabinol (THC), at least tetrahydrocannabivarin (THCV), at least cannabidiolic acid (CBDA), at least cannabigerol (CBG), at least cannabigerolic acid (CBGA), at least cannabidivarin (CBDV), at least cannabidivarinic acid (CBDVA), at least cannabinol (CBN), at least cannabichromene (CBC), at least cannabichromenic acid (CBCA) or at least cannabichromevarinolic acid (CBCVA). In any method or use of the invention, the number of malignant mesothelioma cells in the individual is reduced.

Still further, in any method or use of the invention, the migration of malignant mesothelioma cells in the individual is inhibited, prevented, or reduced. Further, in any method of use of the invention, the cannabinoid is useful for killing malignant mesothelioma cells, but does not have a significant impact on the number of non-malignant mesothelial cells in the individual.

The present invention also provides for a kit comprising one or more pharmaceutical compositions or medicaments as herein described, for use or when used in the treatment of mesothelioma. Preferably, the kit comprises written instructions for use of the kit components.

As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.

Brief description of the drawings

Figure 1 : A and B Cell viability of rat (A) and human (B) mesothelioma cell lines, or of non-cancerous rat mesothelial cells was assessed using MTT assays in the presence of cannabinoid as indicated. The cannabinoids tested were THC, THCA, THCV, CBD, CBDA, CBG, CBGA, CBDV, CBDVA, CBN, CBC, CBCA, and CBCVA. The drug dose causing 50% growth inhibition (IC50 drug dose) was calculated. CBD is the most potent of the cannabinoids tested against mesothelioma cells. The IC50 values demonstrate THC, THCV, CBD, CBG, CBDV, CBDVA and CBN have increased toxicity for mesothelioma cells compared to non-cancerous mesothelial cells. (p<0.05; IC50 values are at least 1.8-fold higher for the non-cancerous 4/4 RM4 mesothelial cells relative to the II-45 rat mesothelioma cells).

Bars show the mean and the error bars show the standard error from at least three independent experiments. Black bars represent non-cancerous mesothelial cells.

C. IC50 values for current first-line therapies cisplatin and pemetrexed for mesothelioma and non-cancerous mesothelial cells. Similar concentrations of drug are required for toxicity in both cell types, indicating the non-selectivity of cisplatin and pemetrexed.

Figure 2: THCA, CBD, CBDV, CBDVA and CBGA significantly inhibit migration of rat and human mesothelioma cells. Cell migration data are shown for II-45 rat mesothelioma cells, for H2452 human mesothelioma cells and for MSTO human mesothelioma cells. Cell migration was assessed using transwell migration assays in the presence or absence (control) of sub-cytotoxic concentrations of cannabinoid as indicated. The number of migrated mesothelioma cells per 10 fields of view (FOV) was counted, graphed and analysed. P-values were calculated using a one-way Anova test with a value of less than 0.05 indicating significance. *p<0.05, ** p<0.01 , *** p<0.001 relative to non-treated mesothelioma cells (control).

Figure 3: Animals with mesothelioma treated with chemotherapy or CBD had significantly prolonged survival in comparison to vehicle only treated control animals. Rats were pleurally engrafted with mesothelioma cells and then treated with chemotherapy or CBD for 3 weeks (dotted line indicates end of treatment). Asterisks denote p-values relative to control animals and were calculated using Log-rank (Mantel- Cox) test with a value of less than 0.05 indicating significance.

Detailed description of the embodiments

It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the embodiments, it will be understood that the intention is not to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.

One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

All of the patents and publications referred to herein are incorporated by reference in their entirety.

Unless specifically noted otherwise herein, the definitions of the terms used are standard definitions used in the art of pharmaceutical sciences. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.

As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

Also, the use of "or" means "and/or" unless stated otherwise. Similarly, "comprise," "comprises," "comprising," "include," "includes," and "including" are interchangeable and not intended to be limiting. For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

Mesothelioma

Current treatments for mesothelioma are grossly inadequate and there is a desperate need to develop new therapies. Failure of standard of care chemotherapy is inevitable and therefore there is an urgent unmet need for more effective treatments.

Mesothelioma is not curable. The majority of people are diagnosed too late when systemic chemotherapy represents one of the only viable treatment options. Mesothelioma is also inherently chemo-resistant with limited patients responding to this treatment. Even allowing for responses, the median survival is only 12 months. Further, there is no proven second line therapy after the inevitable failure of first line chemotherapy. This makes treating mesothelioma extremely difficult and highlights the urgent need for new therapies.

Cannabinoids represent promising new therapies for cancer treatment and patient management due to their plethora of effects. Cannabis extracts have already been approved in some countries for the treatment of chemotherapy-induced nausea and vomiting and pain relief. Some extracts have also displayed a number of anti- cancer properties. Decreased cancer cell growth and metastatic potential have been reported following cannabis extract treatment of laboratory models of glioblastoma, breast, lung, prostate and colon cancer. Flowever, given the aggressive nature of mesothelioma, and the high amount of local spread, it is not apparent that a cannabis extract would be useful in treating this condition.

Cannabis is a complex mixture which contains over 100 cannabinoid compounds. Flowever, the specific active constituent/s associated with the anti-cancer effect of Cannabis remains to be elucidated. The present inventors have determined that certain cannabinoids, and combinations of cannabinoids, are particularly effective anti-mesothelioma compounds. Using cell culture techniques, the inventors have shown that a number of cannabinoids have cytotoxic and anti-migratory effects in human and rat mesothelioma cell lines. In addition, using a mesothelioma rat model, the inventors have shown that certain cannabinoids significantly prolong survival in comparison to untreated animals.

The present invention has a further advantage over existing therapies because the cannabinoids identified by the inventors as being useful for treating mesothelioma, not only kill cancer cells but also slow the spread of the cancer. Moreover, unlike currently approved therapies, which have significant side-effects including toxicity, fatigue and nausea, the cannabinoids tested have been shown by the inventors not to have any overt toxicity or side effects in an animal model. More specifically, the present inventors surprisingly found that CBD was marginally more effective than the standard first-line treatment, pemetrexed and cisplatin, in prolonging lifespan in a rat model of mesothelioma but has significant advantages in terms of off-target effects and non- specific toxicity. Moreover, CBD as a first-line therapy would have significant advantages over standard first-line chemotherapeutic regimens as human trials have shown CBD to be a very safe drug with limited toxicity.

A further advantage of the present invention over existing treatments for mesothelioma is the selectivity of cannabinoids for mesothelioma cells over non- cancerous cells. More specifically, the inventors have found that many of the tested cannabinoids inhibited cell growth at concentrations lower (and in some cases, much lower) in cancer cell lines as compared with healthy mesothelial cells. This selectivity is not observed for existing treatments such as cisplatin/pemetrexed which generally have equivalent IC50 values (i.e. , the concentration of the drug required for 50% inhibition of growth) indicating that the treatment is non-selective for cancerous and non-cancerous cells.

In addition, the inventors have found that an array of neutral and acidic cannabinoid compounds may complement each other to reduce the proliferation and migration of mesothelioma cancer cells, without the need for concomitant standard therapy. This finding was also unexpected and therefore mixtures of specific cannabinoids herein described may therefore provide a possible second-line treatment for mesothelioma.

Mesothelioma is a form of cancer that develops from the mesothelium, a thin layer of tissue that covers many of the internal organs. The most commonly affected area is the lining of the lungs and chest wall (pleural mesothelioma). Less commonly, the lining of the abdomen (peritoneal mesothelioma) and rarely the sac surrounding the heart (pericardial mesothelioma) or the sac surrounding the testis may be affected.

In any embodiment of the invention, the mesothelioma requiring treatment is pleural mesothelioma. Pleural mesothelioma is a form of cancer that starts in the membrane that covers the lungs. Although it develops in the chest and involves the lining of the lungs, it is not a lung cancer and it is treated differently to lung cancer.

The main symptoms of pleural mesothelioma include: shortness of breath - which usually worsens with activity or when lying down, chest pain or pain in the shoulder and upper arm, loss of appetite, weight loss, persistent cough or a change in a person’s usual cough, heavy sweating, particularly at night.

Signs and symptoms of mesothelioma may include shortness of breath due to fluid around the lung, a swollen abdomen, chest wall pain, cough, feeling tired, and weight loss. These symptoms typically come on slowly.

In still further embodiments of the invention, the mesothelioma for treatment according to the present invention is peritoneal mesothelioma, which develops in the lining of the abdomen.

The main symptoms of peritoneal mesothelioma include: swollen or painful abdomen, loss of appetite, nausea, fever, bowel or urinary problems.

Less commonly, mesothelioma begins in the membrane around the heart or the reproductive organs. Growths form which gradually grow and spread to surrounding areas. Rarely, a person may develop mesothelioma in more than one place.

As used herein, treating an individual for mesothelioma includes reference to any indication of success in the treatment or amelioration of mesothelioma, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of signs or symptoms of mesothelioma; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving an individual’s physical or mental well-being. Treating mesothelioma, in the context of the present invention, may also include reducing the number of mesothelioma cells in the individual.

As used herein,“minimising the progression of mesothelioma” means treating the individual so as to delay the progression of the disease, including preventing or delaying metastasis of a mesothelioma tumour. Minimising the progression of mesothelioma may include, in the context of the present invention, inhibiting, preventing or reducing migration of mesothelioma cells in the individual. Minimising the progression of mesothelioma also includes preventing or delaying the recurrence of mesothelioma, following a treatment for mesothelioma. The recurrence that is being prevented includes a recurrence for example, in the tumour bed, following surgical excision. Alternatively, recurrence includes metastasis of the mesothelioma in another part of the body. The terms “preventing recurrence” and “preventing relapse” as used herein, are interchangeable.

The "individual" requiring treatment according to the present invention includes a mammal. The mammal may be a human, or may be a domestic, zoo, or companion animal. While it is particularly contemplated that the methods of the invention are suitable for medical treatment of humans, they are also applicable to veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, cattle and sheep, or zoo animals such as felids, canids, bovids, and ungulates. A subject or individual may be afflicted with cancer or other disorder, or may not be afflicted with cancer or other disorder (i.e., free of detectable disease).

The skilled person will be familiar with methods for identifying individuals requiring treatment according to the present invention. More specifically, the skilled person will be familiar with methods for diagnosing mesothelioma, including methods for monitoring the progress of the disease, and methods for monitoring the success of any treatment of the disease. A history of exposure to asbestos may increase clinical suspicion for mesothelioma. Diagnosis of mesothelioma is usually suspected following imaging but is typically confirmed with biopsy. The skilled person will be familiar with methods for clinically and histologically differentiating mesothelioma from other pleural and pulmonary malignancies, including reactive pleural disease, primary lung carcinoma, pleural metastases of other cancers, and other primary pleural cancers. Primary pericardial mesothelioma is often diagnosed after it has metastasized to lymph nodes or the lungs.

Imaging tests to diagnose mesothelioma may include: x-rays to identify evidence of mesothelioma in the lungs, including thickening of the pleura or fluid in the space between the lungs and the chest wall; CT scans of lymph nodes. X-rays are also used to identify fluid in the abdomen, which can be evidence of peritoneal mesothelioma.

The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma. A CT (or CAT) scan or an MRI may also be performed. If a large amount of fluid is present, abnormal cells may be detected by cytopathology if this fluid is aspirated with a syringe.

For pleural fluid, this is done by thoracentesis or tube thoracostomy (chest tube); for ascites, with paracentesis or ascitic drain; and for pericardial effusion with pericardiocentesis.

While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g. tuberculosis, heart failure). However, with primary pericardial mesothelioma, pericardial fluid may not contain malignant cells and a tissue biopsy is more useful in diagnosis. Using conventional cytology diagnosis of malignant mesothelioma is difficult, but immunohistochemistry has greatly enhanced the accuracy of cytology.

Generally, a biopsy is needed to confirm a diagnosis of malignant mesothelioma. Lung biopsies can be obtained in two ways: via VATS (Video-assisted thoracoscopic surgery); or via CT-guided core biopsy.

The skilled person will also be familiar with immunohistochemical methods for differentiating malignant mesothelioma from neoplastic mimics, such as breast or lung cancer that has metastasized to the pleura. Further, the skilled person will be familiar with methods for determining the success of any treatment of the invention, or the utility of any of the compositions described herein. For example, the skilled person will be familiar with methods for monitoring the progress of mesothelioma, including methods for determining whether the rate of progression of the disease is slowed, or whether there is an improvement in any of the signs or symptoms of the disease as described herein.

Cannabinoids

The cannabinoids used in any aspect of the invention may be isolated, purified, substantially purified or synthetic.

Cannabis is a genus of flowering plants comprising three species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Cannabis plants have long been used for hemp fiber, for seed and seed oils, for medicinal purposes, and as a recreational drug.

Cannabis extract is composed of at least 480 known chemical compounds, which include cannabinoids, terpenoids, flavonoids, nitrogenous compounds, amino acids, proteins, glycoproteins, enzymes, sugars and related compounds, hydrocarbons, simple alcohols, aldehydes, ketones, simple acids, fatty acids, simple esters, lactones, steroids, terpenes, non-cannabinoid phenols, vitamins, pigments, and elements. These compounds are secreted on the glandular trichomes. Cannabinoids are unique to the cannabis plant and there have been 100 cannabinoids that have been isolated as purified (single) molecules.

A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid receptors in cells that alter neurotransmitter release in the brain, although they may also act on a variety of other receptors. Ligands for these receptor proteins include the endocannabinoids (produced naturally in the body by animals), the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured artificially). The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is another major constituent of the plant. As used herein, the term "cannabinoid" may refer to any substance that acts upon a cannabinoid receptor. For example the term cannabinoid includes cannabinoid ligands such as agonists, partial agonists, inverse agonists, or antagonists, as demonstrated by binding studies and functional assays. In some instances, cannabinoids can bind to other receptors in the brain. In many examples, a cannabinoid can be identified because its chemical name will include the text string "*cannabi* in the name.

In any embodiment of the invention, the cannabinoid used in any method or composition of the invention, may be derived from a purified extract of cannabis (i.e. , an extract from a plant of the genus Cannabis including Cannabis sativa, Cannabis indica, or Canabis ruderalis).

Cannabinoids and other plant molecules may be extracted using various solvents and technologies including, but not limited to ethanol, butane, methane, carbon dioxide, ice, water, steam. Cannabinoids and other plant molecules may be extracted from plants bred to express desired cannabinoid and/or terpene and/or flavonoid profiles for purity.

Methods for obtaining purified or substantially purified solutions of cannabinoids, for example in the form of a cannabis extract, are known in the art, for example, in WO/2004/026857 and WO/2016/121351 , the entire contents of which are incorporated herein in their entirety. WO/2004/026857 document describes general methods for obtaining cannabinoid and cannabinoid acids from plant material.

In a preferred embodiment an "extract containing a cannabinoid" may be a solvent extract of a plant material. Preferred extraction solvents for use in the preparation of this extract include non-polar solvents, also alcohols such as ethanol or methanol and liquid carbon dioxide.

Non-polar solvents are particularly preferred for preparing an initial extract from the starting plant material. Any non-polar solvent capable of solubilising cannabinoids or cannabinoid acids may be used. Preferred non-polar solvents include liquid non-polar solvents comprising lower C5-C12, preferably C5 to C8, straight chain or branched chain alkanes. The most preferred non-polar solvent for the preparation of free cannabinoids is hexane.

Preferably the extract is prepared by dissolving plant material in an extraction solvent, removing insoluble material from the resultant solution (preferably by filtration), and removing the extraction solvent from the solution (preferably by rotary evaporation) to form an extract containing a cannabinoid or cannabinoid acid.

In a preferred embodiment of the invention, the cannabis extract comprises at least 60% of the preferred cannabinoid (for example, where the method of treatment requires administration of CBD, preferably the cannabis extract used comprises at least 60% CBD, or alternatively, at least 60%, THCA, CBGA, CBDV, CBDVA, or CBG), and preferably is in the form of a highly purified botanical extract of cannabis, having greater than 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, of the total extract.

A "substantially pure" preparation of cannabinoid is defined herein as a preparation having a chromatographic purity (of the relevant cannabinoid) of greater than 95%, more preferably greater than 96% , more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99% and most preferably greater than 99.5%, as determined by area normalisation of an HPLC profile.

Within the context of this disclosure, where a compound comprises stereogenic centers, the term "purified" includes enantiomerically pure compositions and also mixtures of enantiomers or isomers.

In certain embodiments the cannabinoid extract has been treated to substantially remove the psychoactive cannabinoids tetrahydrocannabinol (THC). Preferably, the extract comprises less than 5%, less than 4%, less than 3%, less than 2% or more preferably, less than 1 % w/w THC.

US 6,403,126 discloses a process in which THC is removed from a cannabis extract using chromatography (the entire contents of this document are herein incorporated in their entirety).

In any embodiment of the present invention, the cannabinoid, including CBD, CBGA, THCA, CBDV, CBDVA or CBG is synthetically produced. Methods for the biosynthetic production of cannabinoids, such as for example in yeast, are described in Zirpel et al., (2017) Journal of Biotechnology, 259: 204-212, International Patent Application, WO2016010827, Baek et al. (1996) Arch. Pharm. Res. 19: 228-230; Appendino et al., (2008) J. Nat. Prod. 71 : 1427-1430, the entire contents of which are hereby incorporated in their entirety.

In any embodiment of the present invention, the cannabinoid may be a pharmaceutical grade cannabinoid, obtained commercially, for example, from THCPharm (Germany) or from Echo Pharmaceuticals (Netherlands). CBG can also be obtained from Cayman Chm (product 15293), Restek (product 32921 ), Sigma Aldrich or Cerilliant.

The cannabinoids which may be used in accordance with the methods or compositions of the present invention include: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA).

The following table provides exemplary structures of the above mentioned cannabinoids:

Cannabidiol (CBD) Cannabidiolic acid (CBDA)

Cannabigerol (CBG) Cannabigerolic acid (CBGA)

Tetrahydrocannabinol (THC) Tetrahydrocannabinolic acid (THCA)

Cannabivarin (CBDV) Cannabivarinic acid (CBDVA)

Cannabinol (CBN) Cannabichromevarinic acid (CBCVA)

Tetrahydrocannabivarin (THCV)

Cannabichromene (CBC) Cannabichromenic acid (CBCA) Pharmaceutical compositions and formulations

The present invention also provides pharmaceutical compositions and formulations comprising one or more cannabinoids as herein described, including a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient.

By the term“excipient” herein is meant a pharmaceutically acceptable material that is employed together with the cannabinoid for the proper and successful administration of the cannabinoid to a patient. Suitable excipients are well known in the art, and are described, for example, in the Physicians’ Desk Reference, the Merck Index, and Remington's Pharmaceutical Sciences.

The formulation of the cannabinoids for use in accordance with the present invention, may be adapted for administration by a variety of routes. For example, the formulation may be adapted for parenteral administration, such as intravenous, intraarterial, intramuscular, intrathecal, subcutaneous or intraperitoneal injection. Alternatively, the formulation may be adapted for intranasal, gastrointestinal, or other commonly used routes for administration of a pharmaceutical. Preferably, the formulation is adapted for oral administration.

The term“administered” means administration of a therapeutically effective dose of one or more cannabinoids, as herein described, to an individual.

By‘therapeutically effective amount’ is meant a dose that produces the effects for which it is administered. A therapeutically effective amount of the one or more cannabinoids, as herein described, is an amount effective to alleviate, i.e. , noticeably reduce, one or more of the signs or symptoms of mesothelioma. Further the term may refer to an amount of the one or more cannabinoids that is capable of minimising the progression of, treating, preventing recurrence of or ameliorating cancer or the spread (metastasis) thereof. A therapeutically effective amount may be determined empirically and in a routine manner in relation to treating cancer, and will result in increased life expectancy.

The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art and described above, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art. The dosage of any compositions of the present disclosure will vary depending on the symptoms, age, and body weight of the patient, the nature and severity of the mesothelioma to be treated or prevented, the route of administration, and the form of the subject composition. Any of the subject formulations can be administered in a single dose or in divided doses.

As used herein, “administering a therapeutically effective amount of the cannabinoid” includes administering a composition that comprises or consists essentially of the relevant cannabinoid along with pharmaceutically acceptable excipients. It also includes administering a composition from which the one or more cannabinoids is provided either systemically or locally once taken by the individual or subject receiving treatment. For example, in one embodiment, administering“one or more cannabinoids according to the invention” may include administering a prodrug to an individual, wherein the prodrug is metabolised by the individual to release the active cannabinoid (e.g., CBD, CBGA, THCA, CBDV, CBDVA or CBG) into the circulation of the individual. The skilled person will appreciate that central to the present invention, is the provision of the one or more cannabinoids in vivo to the individual, and that this can be accomplished by a number of methods, known to those of skill in the art.

In certain embodiments, the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg.

For administration to mammals, and particularly humans, it is expected that the daily dosage of the active agent will be from 1 pg/kg to 10 mg/kg body weight, typically around 10 pg /kg to 1 mg/kg body weight. The physician in any event will determine the actual dosage which will be most suitable for an individual which will be dependent on factors including the age, weight, sex and response of the individual. The above dosages are exemplary of the average case. There can, of course, be instances where higher or lower dosages are merited, and such are within the scope of this invention. In an embodiment of the present invention, the therapeutically effective amount of the one or more cannabinoids may be administered to a subject once a day, twice a day, or three times a day to treat or minimise the progression of mesothelioma.

The precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, and the like.

The pharmaceutical compositions of the invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment or transdermal patch; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. They may, for example, be administered in a form suitable for immediate release or extended release, for example, by the use of devices such as subcutaneous implants, encapsulated spheroids or osmotic pumps.

A pharmaceutical composition adapted for parenteral administration may be an aqueous and non-aqueous sterile injection solution which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation substantially isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents. Excipients which can be used for injectable solutions include water, alcohols, polyols, glycerine and vegetable oils, for example. The composition can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carried, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets. A pharmaceutical composition adapted for oral administration, can be presented as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions)

Suitable excipients for tablets or hard gelatine capsules include lactose, maize starch or derivatives thereof, stearic acid or salts thereof. Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid, or liquid polyols etc.

For the preparation of solutions and syrups, excipients which can be used include for example water, polyols and sugars. For the preparation of suspensions, oils (e.g. vegetable oils) can be used to provide oil-in-water or water in oil suspensions.

A pharmaceutical composition adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. A suitable composition wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, may comprise an aqueous or oil solution of the active ingredient.

Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists that can be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.

A pharmaceutical composition adapted for transdermal administration may be presented as a discrete patch intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient can be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research. 3(6):318 (1986).

A pharmaceutical composition adapted for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil. For infections of the eye or other external tissues, for example mouth and skin, the composition may be applied as a topical ointment or cream. When formulated in an ointment, the active ingredient can be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water cream base or a water-in-oil base. A pharmaceutical composition adapted for topical administration to the eye may comprise eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. A pharmaceutical composition adapted for topical administration in the mouth may comprise lozenges, pastilles or mouth washes.

The pharmaceutical composition may contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colourants, odourants, salts (substances of the present invention can themselves be provided in the form of a pharmaceutically acceptable salt), buffers, coating agents or antioxidants.

The compositions of the invention may also contain one or more other prophylactically or therapeutically active agents in addition to the recited cannabinoids.

The pharmaceutical compositions of the invention may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavours, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.

The pharmaceutical compositions of the invention, and preparations or formulations thereof may be prepared by admixing together the components of the composition (for example, where two or more cannabinoids are combined). The admixing may be performed sequentially or simultaneously.

The pharmaceutical compositions of the invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the one or more cannabinoids into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the cannabinoids into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. The cannabinoids are provided in a dosage unit form in an amount sufficient to produce the desired effect upon the process or condition of diseases after single or repeated administration.

The pharmaceutical compositions of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the one or more cannabinoids in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the one or more cannabinoids are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the one or more cannabinoids are mixed with water or an oil medium, for example hemp oil, peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the one or more cannabinoids in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the one or more cannabinoids in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the one or more cannabinids in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxy ethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. They may also contain a demulcent, a preservative and flavouring and colouring agents.

The pharmaceutical compositions of invention may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The pharmaceutical compositions of the first and second aspects may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

In a particular embodiment, the pharmaceutical compositions of the invention are formulated as suppositories for rectal administration of the drug. These formulations can be prepared by mixing the one or more cannabinoids with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Rectal administration may be used to eliminate entero-hepatic first pass effect in the gastro-intestinal tract related to oral administration of enzymes.

The pharmaceutical compositions of the invention, may also be formulated in liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The liposome formulation may contain stabilisers, preservatives, excipients and the like. The preferred lipids are the phospholipids and phosphatidyl cholines, both natural and synthetic. Methods to form liposomes are known in the art.

The pharmaceutical compositions of the invention may be included in a container, pack, or dispenser together with instructions for administration. The one or more cannabinoids of the pharmaceutical composition may be provided as separated components in the container, pack, or dispenser, to be taken separately or together at the same or different time in a use or method of the invention described herein.

For oral administration, the pharmaceutical compositions may be provided in the form of tablets containing the one or more cannabinoids particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 750.0, 1000, 1500, 2000, 2500, 3000, 3500, and 4000 milligrams of the cannabinoids for the symptomatic adjustment of the dosage to the patient to be treated.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

The composition of the invention can be provided in unit dosage form, will generally be provided in a sealed container and may be provided as part of a kit. Such a kit would normally (although not necessarily) include instructions for use. It can include a plurality of said unit dosage forms.

Accordingly, in yet another aspect, the present invention provides a kit of parts comprising a composition of the invention.

In yet another aspect, the present invention provides a kit of parts comprising a composition of the invention and one or more additional therapeutic agents for separate, subsequent or simultaneous administration to a subject.

Examples

Example 1 : cytotoxicity studies

Materials and Methods:

Cell lines

The syngeneic rat mesothelioma II45 cell line (Craighead et al. 1987) was a kind gift from Associate/Professor Emanuela Felley-Bosco (Zurich University). The chemotherapy-resistant II45 rat (GemR and ComboRx) mesothelioma cell lines have been described previously (Hudson et al., 2014). The normal mesothelial 4/4 RM.4 cell line from female Fischer 344 rats as well as the human mesothelioma cell lines (H2452 and MSTO) were purchased from the ATCC. Cells were cultured and maintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS) and grown in standard conditions (37°C humidified incubator with 5% CO2).

Cannabinoids were sourced from THC Pharm (Germany) or were made in-house using chemical synthesis.

Cytotoxicity assays

Assays were performed in triplicate in a final volume of 200 pi. 2 x 10³ (for rat mesothelioma), 1 x 10⁴ (for rat non-cancerous mesothelial) or 5 x 10⁴ (for human mesothelioma) cells in 100 mI were plated into 96-well microtitre plates and left to adhere for approximately 4 hrs. Serial drug dilutions (100 mI) were then added and plates were incubated for 72 hrs in standard cell culture conditions. The MTT(3-(4,5- dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay was performed as previously described (Mosmann, 1983) to determine cell viability and to establish the drug dose causing 50% growth inhibition (IC50 drug dose). GraphPad Prism non-linear (curve fit) regression algorithms were used to calculate the IC50 drug dose.

Method

Cell viability of rat and human mesothelioma cell lines was assessed using MTT assays in the presence of various cannabinoids. The drug dose causing 50% growth inhibition (IC50 drug dose) was calculated and the results are shown in Figure 1 (A and B).

Results and brief discussion:

The results (shown in Figure 1 ) demonstrate that the tested cannabinoids are cytotoxic to mesothelioma cells at micromolar ranges, with CBD being the most potent.

In addition, the results show that some cannabinoids have a significantly reduced IC50 for killing of mesothelioma cells as compared to normal mesothelial cells. For example, CBN, CBCA, CBDVA and CBGA all have significantly higher IC50 values for killing of non-cancerous cells, indicating an advantage in terms of reducing cytotoxic effects on non-cancerous cells compared to other cannabinoids.

Example 2: migration studies

In addition to cytotoxicity studies, a number of cannabinoids were tested for their ability to reduce migration of mesothelioma cells.

Materials and Methods:

Migration assays were performed using Boyden 6.5 mm transwell chambers with 8 pm pore inserts in duplicate (Chen, 2005). Standard media containing FBS, with and without cannabinoids, was used as the chemotactic agent. 500 pi of this was added to the bottom chamber and cells (1.25 x 10⁴ for II-45 rat mesothelioma and FI2452 human mesothelioma or 5 x 10⁴ cells for MSTO human mesothelioma cells) in 350 pL of serum free media (control) were seeded into the upper chamber. After incubating for 6 hrs (for rat mesothelioma cells) or 24 hrs (for human mesothelioma cells), in 350 pL of serum free media (control) were seeded into the upper chamber. After incubating for 24 hrs, the transwells were fixed in ethanol and unmigrated cells removed from the top of the membranes using cotton swabs. Membranes were then mounted onto slides using Prolong gold antifade mountant with DAP I and images taken at 200x magnification using a florescent microscope. The number of cells in 10 randomly chosen fields of view (FOV) was calculated using ImageJ.

Cell migration was assessed using transwell migration assays in the presence or absence (control) of sub-cytotoxic concentrations of the given cannabinoids. The number of migrated mesothelioma cells per 10 fields of view (FOV) was counted, graphed and analysed.

P-values were calculated using a one-way ANOVA test with a value of less than 0.05 indicating significance.

Results and brief discussion:

The results (shown in Figure 2) demonstrate that TFICA, CBD, CBDV, CBDVA and CBGA significantly reduce migration of both rat and human mesothelioma cells.

Example 3: In vivo studies

Background:

A pre-clinical rat mesothelioma model was used as a platform for testing novel therapeutic agents. This model has been thoroughly characterised and displays many features corresponding with the human disease (Fludson et al. , 2014, Scientific Reports, 4:6152). In addition, as it is an immune-competent orthotopic model, it has the advantage of representing the dynamics of the complete tumour by allowing essential interactions between tumour cell receptors, the stromal ligands and a functioning immune system creating a more realistic environment for tumour development (Abolhassani, M. et al. 2011 Investigational New Drugs, v30:(4)).

Materials and Methods:

All procedures involving animals were carried out in accordance with the recommendations in the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. The protocol for this study was approved by the Royal North Shore Hospital Animal Care and Ethics Committee (protocol numbers RESP/17/30). Female Fischer 344 rats weighing 150-200 g were maintained at the Kearns Facility under standard conditions (12 hrs. light/dark cycles and free access to food and water).

Tumour induction and analysis

A total of 100 pL of serum free media containing 1 x 10⁴ II-45 cells was injected into the pleural cavity of female Fischer rats approximately 0.5 cm proximal to the 2nd nipple (day zero). Rats were euthanized at ethically approved endpoints (weight loss of >20% or difficulty in breathing) and blood, tissue and tumour samples collected.

Drug treatment

Rats were pleurally engrafted with mesothelioma cells and then treated with cannabinoids as indicated for 3 weeks.

Drug treatment began 3 days after engraftment of 11-45 cells. CBD was given at a dose of 20 mg/kg intraperitoneally (IP) for 5 days on, 2 days off, for 3 weeks (n=6). Chemotherapy was given as 2 doses, 14 days apart, on day 3 and 17, by IP injection at 1 mg/kg cisplatin + 6.7 mg/kg pemetrexed (n=8). Control animals received vehicle only (Hemp oil) using the same schedule as CBD.

P-values were calculated using Log-rank (Mantel-Cox) test with a value of less than 0.05 indicating significance relative to non-treated animals (control).

Results and brief discussion:

The results (shown in Figure 3) show that animals treated with CBD have significantly prolonged survival compared to controls. Animals receiving chemotherapy and CBD had similar survival rates.

Claims

1. A method of treating, preventing or delaying the progression of, mesothelioma in an individual, comprising administering to the individual a therapeutically effective amount of one or more cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating preventing or delaying the progression of mesothelioma in the individual.

2. A method of treating, preventing or delaying the progression of, mesothelioma in an individual in need thereof, comprising administering to the individual, a therapeutically effective amount of cannabidiol (CBD), or a pharmaceutically acceptable salt thereof, thereby treating, preventing or delaying the progression of mesothelioma in the individual.

3. The method of claim 1 , wherein the one or more cannabinoids is cannabidiolic acid (CBDA).

4. The method of claim 1 , wherein the one or more cannabinoids is cannabigerol (CBG).

5. The method of claim 1 , wherein one or more the cannabinoids is cannabigerolic acid (CBGA).

6. The method of claim 1 , wherein the one or more cannabinoids is cannabidivarin (CBDV).

7. The method of claim 1 , wherein the one or more cannabinoids is cannabidivarinic acid (CBDVA).

8. The method of claim 1 , wherein the one or more cannabinoids is cannabinol (CBN).

9. The method of claim 1 , wherein the one or more cannabinoids is cannabinol (CBN).

10. The method of claim 1 , wherein the one or more cannabinoids is cannabichromene (CBC).

11. The method of claim 1 , wherein the one or more cannabinoids is cannabichromenic acid (CBCA).

12. The method of claim 1 , wherein the one or more cannabinoids is cannabichromevarinolic acid (CBCVA).

13. The method of claim 2, wherein the method further includes administering to the individual, one or more additional cannabinoids selected from the group consisting of: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, thereby treating, preventing or delaying the progression of mesothelioma in the individual.

14. A method of treating, preventing or delaying the progression of mesothelioma in an individual, comprising administering to the individual a therapeutically effective amount of two or more cannabinoids wherein at least one of the cannabinoids is a neutral cannabinoid and at least one of the cannabinoids is an acidic cannabinoid, thereby treating, preventing or delaying the progression of mesothelioma in the individual.

15. The method according to claim 14, wherein the at least one neutral cannabinoid is selected from: tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabidivarin (CBDV), cannabinol (CBN), cannabichromene (CBC), and wherein the at least one acidic cannabinoid is selected from: tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA).

16. The method according to claim 15, wherein the at least one neutral cannabinoid is cannabidiol (CBD) and the at least one acidic cannabinoid is cannabidiolic acid (CBDA),

17. The method according to claim 15, wherein the at least one neutral cannabinoid is cannabidiol (CBD) and the at least one acidic cannabinoid is cannabigerolic acid (CBGA).

18. The method according to claim 15, wherein the at least one neutral cannabinoid is cannabidiol (CBD) and the at least one acidic cannabinoid is cannabidivarinic acid (CBDVA).

19. The method according to claim 15, wherein the at least one neutral cannabinoid is cannabidiol (CBD) and the at least one acidic cannabinoid is tetrahydrocannabinolic acid (THCA).

20. The method according to claim 15, wherein the at least one neutral cannabinoid is cannabidiol (CBD) and the at least one acidic cannabinoid is cannabichromenic acid (CBCA),

21. The method according to claim 15, wherein the at least one neutral cannabinoid is cannabidiol (CBD) and the at least one acidic cannabinoid is cannabichromevarinolic acid (CBCVA).

22. The method according to any one of claims 15 to 21 wherein the treatment further comprises administration of a further cannabinoid.

23. The method according to any one of claims 1 to 22, wherein the one or more cannabinoids is administered orally.

24. The method according to any one of claims 1 to 22, wherein the at least one cannabinoid is administered intravenously, intramuscularly, intranasally, transdermally or subcutaneously.

25. The method of any one of the preceding claims, wherein the at least one cannabinoid is provided in the form of a cannabis extract.

26. The method of claim 25 wherein the cannabis extract is enriched for at least one of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA).

27. The method of claim 26, wherein the extract is enriched for CBD.

28. The method of any one of claims 1 to 24, wherein the cannabinoid is provided in a substantially purified form, obtained from a cannabis extract.

29. The method of any of any one of claims 1 to 24, wherein the cannabinoid is synthetically produced.

30. The method of any one of the preceding claims, wherein two or more cannabinoids are administered sequentially or concomitantly.

31. The method of claim 30, wherein the cannabinoids are administered concomitantly as a single dosage form.

32. The method according to any one of the preceding claims wherein individual has received or is receiving chemotherapy, radiotherapy or immunotherapy for the treatment of mesothelioma.

33. The method according to claim 32 wherein the chemotherapy treatment comprises pemetrexed and/or cisplatin.

34. A pharmaceutical composition comprising: one or more cannabinoids selected from the group consisting of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient, for treating or for preventing or delaying the progression of mesothelioma.

35. The pharmaceutical composition of claim 34, wherein the composition comprises at least CBD.

36. The pharmaceutical composition of claim 34 or 35, wherein the composition is adapted for administration via the oral, intravenous, intradermal, intranasal, intramuscular or subcutaneous route.

37. The pharmaceutical composition of any one of claims 34 to 36, wherein the cannabinoid is provided in the form of a cannabis extract, optionally, a cannabis extract enriched for one or more cannabinoids.

38. The pharmaceutical composition of claim 37, wherein the extract is enriched for CBD or comprises substantially purified CBD.

39. The pharmaceutical composition of any one of claims 34 to 36, wherein the cannabinoid is synthetically produced, preferably wherein the cannabinoid is CBD.

40. Use of one or more cannabinoids selected from the group consisting of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), in the manufacture of a medicament for the treatment of, prevention or delay of progression of mesothelioma.

41. The use of claim 40, wherein the medicament is adapted for administration via the oral, intravenous, intradermal, intranasal, intramuscular or subcutaneous route.

42. The use of claim 40 or 41 , wherein the at least one cannabinoid is provided in the medicament in the form of a cannabis extract, optionally, a cannabis extract enriched for one or more cannabinoids.

43. The use of claim 42, wherein the medicament comprises a cannabis extract that is enriched for CBD or comprises substantially purified CBD.

44. The use of claim 40 or 41 wherein the medicament comprises a synthetically produced cannabinoid, wherein preferably the cannabinoid is CBD.

45. One or more of tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol

(THC), tetrahydrocannabivarin (THCV) cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), and cannabichromevarinolic acid (CBCVA), for use in the treatment of or for use in delaying the progression of mesothelioma.