[0001] This specification includes two figures.

Field of the invention

[0002] The present invention relates to the use of compositions comprising cannabinoids for the treatment or alleviation of pain in patients in need thereof. The present invention also relates to the use of compositions comprising cannabinoids for the treatment or alleviation of anxiety in patients in need thereof. The compositions may comprise mixtures of cannabinoids and appropriate terpenes.

[0003] In particular, the invention relates to the use of controlled amounts of D-9 Tetra Hydra Cannabinol (D9 THC) cannabinoids in compositions for the indications discussed herein.

Background of the invention

[0004] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

[0005] Cannabinoids

[0006] Cannabis sativa L. (cannabis) produces more than 60 terpeno-phenols that are not found in any other plant. Many of these compounds are thought to be of medical importance. A ⁹ -tetrahydrocannabinol (D ⁹ -THO) (Gaoni & Mechoulam, 1964) is an important member of this group and has been the subject of research for many years. D ⁹ -THO is known as the major psychoactive component obtainable from cannabis products, and as such, is often less favoured as a compound of interest by medical researchers. Other components of cannabis are not known to be psychoactive, and have been extensively researched for their medical properties. Examples include Cannabidiol (CBD), which has been found to possess anti inflammatory, antischizophrenic and antiepileptic properties (Pertwee, 2005). Another compound, Cannabichromene (CBC), has been found to be effective as an anti-inflammatory (Morales et al, 2017). Maor et al. (2005) indicated that a homolog of cannabigerol (CBG-DMH) has hypotensive and vasorelaxant properties. [0007] The acid forms of cannabinoids are precursors of the neutral cannabinoids. These, such as THC acid and CBD acid, have been found by investigators to be antibiotic and have previously shown utility in veterinary medicine.

[0008] Terpenes found in cannabis are thought to affect the functionality and bioavailability of the cannabinoids in cannabis products.

[0009] Endocannabinoids are cannabinoids naturally occurring in the human body. These compounds include the well-known anandamide and 2-arachidonoyl glycerol, and have been found to be involved in the regulation of the immune, cardiovascular, reproductive, respiratory, skeletal and central nervous systems of the human body. The appear to target the CB1/CB2 receptors amongst others (Howlett et ai, 2002), and it is thought that the plant cannabinoids may be able to bind and influence the same receptors.

[0010] The two most widely studied cannabinoids are CBD and THC.

[0011] CBD administered alone has been found to have antipsychotic effects as efficacious as standard anti-psychotic drugs but with fewer side effects. It also has shown impressive efficacy in treating intractable childhood epilepsy that cannot be treated with conventional anti-convulsants.

[0012] Since THC is known to be the principal psychoactive constituent of cannabis and is one of only three cannabinoids scheduled by the UN Convention on Psychotropic Substances listed under Schedule II, less interest has been placed onto this substance in relation to its medical uses. However, Dronabinol, a synthetic form of THC for use as an appetite stimulant in AIDS patients and as an antiemetic during chemotherapy, has been approved by the US FDA and is available on prescription in the United States, Canada, Germany, and New Zealand.

[0013] In June 2018 in the United States, the Food and Drug Administration approved the CBD-containing drug Epidiolex for the treatment of two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. However, the side effects of long-term use of the drug were said to include somnolence, decreased appetite, diarrhea, fatigue, malaise, weakness, sleeping problems, and others.

[0014] In the UK, an oral-mucosal CBD spray formulation combined with A9-THC (Sativex), was approved in 2010 for treatment of severe medicament-resistant spasticity due to multiple sclerosis, and is now also a prescription drug available in several countries.

[0015] Pain Relief

[0016] Traditional pain relief medication includes medicines that can be bought without prescription, including paracetamol, ibuprofen and aspirin. However, these medications are known to have potential side effects which vary amongst individuals, such as those with allergies, chronic illness or that are on any other medicines.

[0017] For cases of mild to moderate pain, Paracetamol (for example Panadol and Panamax) can be effective when used correctly. However, side effects of its use include serious liver damage if taken in high doses.

[0018] Non-steroidal anti-inflammatory (NSAIDs) drugs, such as ibuprofen, are another such non-prescription medication, which are effective against mild to moderate pain. NSAIDs have the potential of serious side-effects and may not be suitable for people with stomach troubles, heart problems, kidney impairment, high blood pressure or asthma. Oral NSAIDs are not recommended for older people. Again, with NSAIDS, overdosing can be dangerous.

[0019] Aspirin has been taken for decades for mild to moderate pain. However, like the other traditional medicines discussed above, those using aspirin must be aware of potential side effects and other risks. Aspirin should be taken with caution if a patient has indigestion, reflux or ulcers, and should not be used in children under 16 years of age. [0020] Once available over the counter, codeine is a type of prescription-only opioid agent related to morphine. Codeine and codeine-containing medicines are may carry with them the potential for severe side effects if abused, and may induce dependency.

[0021] Morphine and morphine-like drugs (for example, oxycodone, fentanyl and buprenorphine) are strong painkillers. They can come in different formulations such as tablets, capsules and patches and will only be prescribed after consultation with a doctor or a pain specialist as part of a long-term plan to manage pain. The dose and response will be closely monitored.

[0022] Although effective in treating pain in patients, the above medications are often accompanied by unpleasant side effects as mentioned above, and a risk of overdosing. It would be beneficial to provide a pain relief medication for use in a patient that has fewer side effects or risks as seen in traditional medication, whilst being highly effective in treating pain.

[0023] Cannabinoids have shown significant promise in basic experiments on pain. Cannabinoids appear to block peripheral nerve pain in experimental animals due to directly targeting cannabinoid receptors on peripheral nerves. Research also appears to suggest that opiates and cannabinoids use different pathways to treat pain, which could lead to the addition of cannabis-based medicines to opiates to increase their efficacy while limiting their side effects.

[0024] Anxiety Medication

[0025] Measurable changes to serotonin, noradrenaline and dopamine levels occur in the brains of people experiencing a severe anxiety event, and thus some types of antidepressant medication, which correct the imbalance of neurotransmitters in the brain, are effective in the treatment of severe anxiety, even where unrelated to symptoms of depression.

[0026] Antidepressants can improve mood, but they do not provide a long-term solution. Side effects are often experienced, and the risks and benefits must be considered. Common side effects of antidepressant medication can include nausea, headaches, anxiety, sweating, dizziness, agitation, weight gain, dry mouth and sexual difficulties.

[0027] Due to the potential of plant cannabinoids to modulate the endocannabinoid system and to act as novel effective medicines without the side effects discussed above for traditional medications, it would be desirable use cannabis to reduce pain and anxiety in a patient. However, some researchers have indicated that cannabis-based medicaments can alter mood, perception and motivation. Unregulated or high doses of cannabis have reportedly led to undesirable reactions, such as anxiety, panic or hallucinations, and may lead to impairment of cognitive functions, perception, reaction time, learning and memory.

[0028] It would therefore be desirable to provide a cannabis based medicine that is effective in the treatment of pain and anxiety while not causing or minimising the side effects indicated above in relation to cannabis use, such as impairment of cognitive functions.

Summary of the invention

[0029] The inventors have now unexpectedly found that certain combinations of cannabinoids are surprisingly useful to treat pain and anxiety in patients in need of such treatment.

[0030] The inventors have also surprisingly found that such combinations are highly effective even at very low doses of the active ingredients. The compositions of the invention have been found to effectively treat pain and anxiety whilst at the same time do not lead to psychoactive effects, impairment of cognitive functions, perception, reaction time, learning or memory. The compositions of the invention are therefore useful alternatives to the traditional medications currently available in the art for such indications.

[0031] According to a first aspect of the present invention there is provided a composition for use in the treatment of pain or anxiety, said composition comprising D ⁹ - tetrahydrocannabinol (A ⁹ -THC) and optionally a pharmaceutically acceptable carrier or excipient.

[0032] The composition may further comprise one or more additional cannabinoid. optionally selected from the group consisting of THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBCA (cannabichromenic acid), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin) and CBT (cannabicitran). [0033] Preferably, said one or more further cannabinoid is selected from the group consisting of CBD and CBG, most preferably CBD.

[0034] In some embodiments, the A ⁹ -THC is present in the composition at at least 0.01 , 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.100, 0.105, 0.110, 0.115, 0.120, 0.130, 0.135, 0.140, 0.145, 0.150, 0.155, 0.160, 0.165, 0.170, 0.175, 0.180, 0.185, 0.190, 0.195, 0.200, 0.205, 0.210,

0.215, 0.220, 0.225, 0.230, 0.235, 0.240, 0.245, 0.250, 0.255, 0.260, 0.265, 0.270, 0.275,

0.280, 0.285, 0.290 or 0.300 percent by volume.

[0035] Preferably, the A9-THC is present in the composition at about 0.120-0.150 percent by volume.

[0036] In some embodiments, the A9-THC-acid is present in the composition at about 0.010, 0.015, 0.020, 0.025, 0.030, 0.035, 0.040, 0.045, 0.050, 0.055, 0.060, 0.065, 0.070,

0.075, 0.080, 0.085, 0.090, 0.095, 0.100, 0.105, 0.110, 0.1 15, 0.120, 0.125, 0.130, 0.135,

0.140, 0.145, or 0.150 percent by volume.

[0037] Preferably the A ⁹ -THC acid is present in the composition at about 0.050-0.100 percent by volume.

[0038] In some embodiments, the composition further comprises one or more terpene, selected from the group consisting of a pinene, limonene, linalool, caryophyllene, caryophyllene oxide, myrcene, humulene, borneol, eucalyptol, terpineol, nerolidol, phytol, geraniol, bisabolol, camphene, beta-amyrin, thujone, citronellol, pulegone, 1 ,8-cineole and cycloartenol.

[0039] According to an embodiment suitable terpenes may be preferably selected from the group consisting of a-Pinene and b-Pinene.

[0040] According to one embodiment, a-Pinene is present in the compositions at about 0.100, 0.105, 0.1 10, 0.1 15, 0.120, 0.130, 0.135, 0.140, 0.145, 0.150, 0.155, 0.160, 0.165, 0.170, 0.175, 0.180, 0.185, 0.190, 0.195, 0.200, 0.205, 0.210, 0.215, 0.220, 0.225, 0.230, 0.235, 0.240, 0.245, 0.250, 0.255, 0.260, 0.265, 0.270, 0.275, 0.280, 0.285, 0.290 or 0.300, 0.305, 0.310, 0.315, 0.320, 0.325, 0.330, 0.335, 0.340, 0.345, 0.350, 0.355, 0.360, 0.365, 0.370, 0.375, 0.380, 0.385, 0.390 or 0.400 percent by volume.

[0041] Preferably a-Pinene is present at about 0.20-0.30 percent by volume.

[0042] According to one embodiment, b-Pinene is present in the compositions at about

0.005, 0.010, 0.015, 0.020, 0.025, 0.030, 0.035, 0.040, 0.045, 0.050, 0.055, 0.060, 0.065, 0.070, 0.075, 0.080, 0.085, 0.090, 0.095, 0.100, 0.105, 0.1 10, 0.115, 0.120, 0.125, 0.130, 0.135, 0.140, 0.145, or 0.150 percent by volume.

[0043] Preferably b-Pinene is present in the compositions at about 0.050-0.100 percent by volume.

[0044] In one aspect, the present invention relates to a composition for treating a disorder selected from the group consisting of pain and anxiety, said composition comprising:

• A ⁹ -THC at 0.120-0.150 percent by volume;

• A ⁹ -THC Acid at 0.05-0.1 percent by volume;

• a-Pinene at 0.20-0.30 percent by volume;

• b-Pinene at 0.05-0.1 percent by volume; and

• a pharmaceutically acceptable carrier or excipient.

[0045] The compositions of the invention may be formulated for sublingual or buccal delivery. Optionally, the compositions may be formulated for parenteral delivery.

[0046] Preferably the composition is formulated for oral delivery. In some embodiments, the composition is formulated as a spray.

[0047] Preferably, the composition is formulated as a solid dosage form, such as a gel capsule or a tablet. The composition may also be formulated as a cream, an ointment, a gel, a paste, a powder, a medical patch, a cigarette, a vaporizer liquid or is prepared as a liquid suitable for parenteral administration.

[0048] In some embodiments, where an excipient is present, the excipient may comprise a solvent. In some embodiments, the solvent is an oil. In some embodiments, the solvent comprises an alcohol.

[0049] Optionally, the composition may be formulated as a solution comprising a pharmaceutically effective amount of a cannabinoid of the invention, and optionally a terpene, dispersed in a pharmaceutically acceptable oil-based carrier; and a hard gelatin capsule encapsulating the mixture of the cannabinoid and the oil- based carrier.

[0050] It would be understood by those skilled in the present art that said oil-based carrier may be a triglyceride selected from the group consisting of almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; soy oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof..

[0051] According to an embodiment, the composition additionally contains an additive selected from the group consisting of antioxidants, emulsifiers and texturizers vegetable oils, plant extracts, honey, sucrose, glucose and fructose, pharmaceutical excipients and combinations thereof.

[0052] In another aspect, the present invention provides a method of treating pain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a composition according to the invention. [0053] The pain treated by the present invention includes pain resulting from inflammation, including inflammation from multiple sclerosis, Alzheimer disease, Parkinson disease motor neurone disease and traumatic brain injury. The pain may be acute and/or chronic pain including chronic pain from motor neurone disease, multiple sclerosis, Fibromyalgia, cancer and peripheral neuropathy.

[0054] In another aspect, the present invention provides a method for producing a composition of the invention, comprising providing at least A9-THC and blending it with a terpene. According to an embodiment, the method includes extracting cannabis plant material to form an extract. According to an embodiment, extracting comprises contacting said cannabis plant material with an extractant to form an extract, and said extractant comprises at least A9-THC.

[0055] According to an embodiment, the method comprises synthesizing at least D9- THC and blending said synthesized cannabinoid with a terpene. According to another embodiment, the method comprises blending cannabis plant material with said terpene.

[0056] In one embodiment, the method comprises administering a dose of the composition of 5 mg/kg/day and increased by 2 to 5 mg/kg increments to a maximum dose of 20 mg/kg/day.

[0057] In another aspect, the invention provides a method of treating anxiety in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a composition according to the invention.

[0058] In some embodiments, the anxiety treated by the compositions of the invention is related to a patient having a terminal disease, or having a chronic disease. In some embodiments, the anxiety may be generalised anxiety disorder. In some embodiments, the anxiety may be selected from the group consisting of social anxiety, one or more specific phobias, panic disorder, obsessive compulsive disorder, and post-traumatic stress disorder.

[0059] In some embodiments, the composition is administered at a dose of 5 mg/kg/day and increased by 2 to 5 mg/kg increments to a maximum dose of 20 mg/kg/day. [0060] In embodiments of the invention, the treatment involves administering a plurality of compositions comprising one or more cannabinoids of the invention, wherein said plurality of compositions are administered separately, sequentially or simultaneously to one another, and wherein at least one of the compositions comprises D9 THC.

[0061] In another aspect, the present invention provides a product comprising tablets, gel capsules, medical patches, cigarettes and vaporizer liquids containing the composition of the invention.

[0062] In another aspect, the invention provides a use of a therapeutically effective amount of a composition according to the invention for the manufacture of a medicament for treating pain in a subject.

[0063] In yet another aspect, the invention provides a use of a therapeutically effective amount of a composition according to the invention for the manufacture of a medicament for treating anxiety in a subject.

[0064] In one aspect, the invention also provides a composition according to the invention for use as a medicament.

[0065] The invention also provides a composition according to the invention for treating pain in a subject.

[0066] In another aspect, the invention provides a composition according to the invention for treating anxiety in a subject.

Definitions

[0067] Unless the context clearly requires otherwise, throughout the description and the claims, the words“comprise”,“comprising” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0068] Unless indicated otherwise, percent is percent by volume (volume percent) and ratio is weight/weight ratio. Volume percent is defined as v/v % = [(volume of solute)/(volume of solution)] x 100%. Unless indicated otherwise, weight ratio means the ratio between weight content, e.g. in an aqueous solution containing 20% solute and 80% water, the solute to water weight ratio is 20:80 or 1 :4.

[0069] The particulars shown herein are by way of example and for purposes of illustrative discussion of the various embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, the description is intended to make apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

[0070] The present invention will now be described by reference to more detailed embodiments. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for describing particular embodiments only and is not intended to be limiting of the invention. As used herein and in the appended claims, the singular form of“a”,“an”, and“the” may include the plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element.

[0072] As used herein the term“about” can mean within 1 or more standard deviation per the practice in the art. Alternatively,“about” can mean a range of up to 20%, up to 10%, or up to 5%. In certain embodiments,“about” can mean to 5%. When particular values are provided in the specification and claims the meaning of “about” should be assumed to be within an acceptable error range for that particular value.

[0073] Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein. [0074] In one embodiment, said composition comprises at least two cannabinoids, at least three, at least four or at least five. Cannabinoids have an acid form as known in the art, and a non-acid form (which is also referred to as decarboxylated form, since it can be generated by decarboxylating the acid form). The acid form may be indicated herein by the letter (a) at the end of the cannabinoid acronym, e.g. tetrahydrocannabiniolic acid is indicated as THCa, while the decarboxylated form is THC. The acid form may also be indicated herein by the use of the word“acid”, such as THC acid.

[0075] In one embodiment, said cannabinoids are selected from the group consisting of THCa or THC, CBCa or CBC, CBDa or CBD, CBGa or CBG, THCVa or THCV, CBDVa or CBDV and CBNa or CBN.

[0076] At least one of said cannabinoids may be in acid form. In one embodiment, at least one of said cannabinoids is at least partially in decarboxylated form.

[0077] Optionally, said composition comprises both CBD and/or CBDa and THC and/or THCa and the weight/weight ratio between THC and/or THCa and CBD and/or CBDa ((THC+THCa) / (CBD+CBDa)) is at least 10, at least 15, at least 20, at least 25 or at least 30.

[0078] The composition of the invention may comprise a carrier at least at 5%, 10%, 15%, 20%, 25%, 30%, 35% or 40% by volume. The carrier in some embodiments is selected from the group consisting of vegetable oils, such as olive oil, coconut oil or sesame oil, honey, bees wax, cellulose or pharmaceutical excipients, and combinations thereof. As used herein, the term cellulose refers to cellulose, hemicellulose and their combinations.

[0079] Preferably the composition is used in treatment against pain and or anxiety, especially resulting from motor neurone disease, rheumatoid arthritis or Crohn's Disease, sarcoidosis, asthma, Alzheimers disease, multiple sclerosis, psoriasis, ulcerative colitis, osteoarthritis or spondyloarthropathy (erg. ankylosing spondylitis), and pain and or anxiety resulting from terminal disease.

[0080] The patient is preferably a mammal such as a human.

[0081] The term“active ingredient" as used herein is used interchangeably with the term “active agent” and refers to an agent or a mixture of agents that causes a desired therapeutic effect. Preferably, in compositions of the invention, the active ingredient is a cannabinoid and/or a terpene. [0082] The term“cannabinoid” as used herein means chemical compounds of a class able to act on cannabinoid receptors in cells that alter neurotransmitter release in the brain. Cannabinoids may be endocannabinoids (produced in the body of animals), phytocannabinoids (produced in cannabis and some other plants), and synthetically manufactured cannabinoids.

[0083] Cannabinoids useful in the compositions of the invention comprise one or more cannabinoid selected from the following group consisting of:

[0084] THC (tetrahydrocannabinol); THCA (tetrahydrocannabinolic acid); CBD (cannabidiol); CBDA (cannabidiolic acid); CBN (cannabinol); CBG (cannabigerol); CBC (cannabichromene); CBL (cannabicyclol); CBV (cannabivarin); THCV (tetrahydrocannabivarin); CBDV (cannabidivarin); CBCV (cannabichromevarin); CBGV (cannabigerovarin); CBGM (cannabigerol monomethyl ether); CBE (cannabielsoin); and CBT (cannabicitran).

[0085] Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Forms include Delta-9-tetrahydrocannabinol (A9-THC, THC) and delta-8- tetrahydrocannabinol (Dd-THC). These cannabinoids bind to the CB1 cannabinoid receptors in the brain.

[0086] Cannabidiol (CBD) is a non-psychotropic cannabinoid. Cannabidiol does not bind strongly to CB1 and CB2 receptors but appears to act as an indirect antagonist of cannabinoid agonists. CBD is though to be an antagonist of the GPR55 receptor, expressed in the caudate nucleus and putamen. Cannabidiol is however an agonist of the 5-HT1 A receptor. CBD may inhibit with the uptake of adenosine, and may play a role in promoting sleep and suppressing arousal. CBD may prevent the short-term memory loss associated with THC.

[0087] CBD has shown promise as a treatment for chronic pain, and is currently used as a topical oil treatment.

[0088] Cannabinol (CBN) is produced by THC degradation, but is only mildly psychoactive. It has higher affinity to the CB2 receptor than the CB1 receptor.

[0089] Cannabigerol (CBG) is thought to be non-psychoactive. CBG binds to the CB2 receptor and has been shown in animal studies to promote apoptosis in cancer cells and lead to inhibition of tumour growth. CBG is an agonist of a2-adrenergic receptor, and is a 5-HT1A and CB1 receptor antagonist.

[0090] Tetrahydrocannabivarin (THCV) antagonises THC at CB1 receptors and is prevalent in certain central Asian and southern African strains of Cannabis.

[0091] Cannabidivarin (CBDV) is found in small quantities in cannabis, although little is known at the present date of its properties..

[0092] Cannabichromene (CBC) is a non-psychoactive agonist of TRPV1 and TRPA1 receptors, and appears to inhibit with their ability to break down endocannabinoids. CBC has shown promising antitumor effects in animal breast cancer models.

[0093] "Synthetic cannabinoids" are compounds that have a cannabinoid or cannabinoid- like structure and are artificially manufactured using chemical means rather than produced naturally by an animal or by a plant.

[0094] The term “terpene” as used herein, refers to a class of hydrocarbon organic compounds, produced for chemical protection by many plants and insects. Terpenes may have a strong odor and when modified to have additional functional groups are known as “terpenoids (or isoprenoids)”.

[0095] The term“isolated” is intended to include a naturally occurring substance that has been purified from its natural source or has been chemically synthesised.

[0096] The compositions of the invention can be used alone or in combination with other pharmaceutically active agents. Examples of such other pharmaceutically active agents include, but are not limited to, anti-inflammatory agents (e.g., NSAIDS, bradykinin receptor antagonists, hormones and autacoids such as corticosteroids), anti-depressant agents, anti viral agents, antiseptic agents (e.g., antibacterials), local anaesthetics, anti-migraine agents, opioids, and other pain relieving medication.

[0097] In some embodiments, the invention provides pharmaceutical compositions of any of the foregoing cannabinoids and/or terpenes. Exemplary pharmaceutical compositions are formulated in a pharmaceutically acceptable carrier.

[0098] The compositions of the invention may optionally be used alone or as part of a therapeutic regimen together with other treatments, therapies, or interventions prescribed for the particular disease, condition, injury or disorder being treated. In some embodiments, the compositions may be used together with a treatment modalities selected from the group consisting of administration of cannabinoid pharmaceuticals, chemotherapy, radiotherapy, homeopathic therapy, diet, stress management, and surgery.

[0099] In some embodiments, the compositions of the invention are administered to treat a particular primary disease, injury, disorder, or condition. Additionally or alternatively, the the compositions of the invention may be administered to treat pain associated with a disease, injury, disorder, or condition. In other embodiments, compositions of the invention may be administered to treat symptoms secondary to the primary disease, injury, disorder, or conditions.

[00100] The term "preventing" is art-recognized to include administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of pain or anxiety includes, for example, reducing the degree of, or delaying, pain or anxiety sensations experienced by subjects in a treated population versus an untreated control population.

[00101] The term "treating" as used herein includes prophylactic and/or therapeutic treatments. The term "prophylactic or therapeutic" treatment is recognized in the art and comprises administration to a subject one or more of the compositions of the invention. The treatment is prophylactic if it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) as it protects the host against developing the unwanted condition. The treatment is therapeutic if it is administered after manifestation of the unwanted condition, as it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof.

[00102] Pain may be chronic pain or acute pain. Chronic pain or acute pain differ in duration, and underlying mechanism. Chronic pain is persistent and often does not respond well to treatment with currently available analgesics, non-steroidal anti-inflammatory drugs, and opioids.

[00103] Neuropathic pain and cancer pain are subcategories of chronic pain known in the art (Wang and Wang (2003) Advanced Drug Delivery Reviews 55: 949-965). Neuropathic pain results from damage (e.g., from disease, injury, age) to the nervous system (e.g., nerves, spinal cord, CNS, PNS). Cancer-related pain can be related to the particular treatment regimen (e.g., radiation, chemotherapeutics, surgery) undertaken or to tumour infiltration, compression of nerves and substances secreted by tumours.

[00104] Pain treated by the compositions of the invention may be nociceptive, inflammatory, or neuropathic. Nociceptive pain is pain experienced following, for example, changes or extremes in temperature, exposure to acids, exposure to chemical agents, exposure to force, and exposure to pressure. Inflammation results from the immune system's response to injury or disease and the recruitment of macrophages, mast cells, neutrophils, and other cells of the immune system. Which along with the release of cytokines and other factors (e.g., histamine, serotonin, bradykinin, prostaglandins, ATP, H+, nerve growth factor, TNFa, endothelins, interleukins), can cause fever, swelling, and pain. Standard therapy for the pain of inflammation include Cox2 inhibitors and opioids. Neuropathic pain results from damage (e.g., from disease, injury, age) to the nervous system- (e.g., nerves, spinal cord, CNS, PNS). Tricyclic antidepressants, anticonvulsants, Na+ channel blockers, NMDA receptor antagonists, and opioids are useful in the treatment of neuropathic pain.

[00105] Pain is typically studied in one of many animal models understood by those with skill in the present art. Such models use a variety of agents or procedures to simulate pain resulting from injuries, diseases, or other conditions (Blackburn-Munro (2004) Trends in Pharmacological Sciences 25: 299-305). Compounds or procedures that are found to reduce pain in the animals can be advance for further research in humans using procedures understood by those with skill in the present art.

[00106] As used herein, the term “composition” is intended to encompass a product comprising the specified active and optionally other (i.e. , non-active) ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[00107] The phrase "therapeutically effective amount" as used herein means that amount of an active ingredient, or composition of the present invention that is effective for producing some desired therapeutic effect in an animal, at a reasonable benefit/risk ratio applicable to any medical treatment. In particular, the term describes an amount of an active ingredient or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect desired. [00108] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[00109] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, suitable for carrying the active ingredients of the invention. "Acceptable" means being compatible with the other ingredients of the formulation and not harmful to the patient. Potentially useful pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[00110] Lubricants, wetting agents, and emulsifiers, including sodium lauryl sulfate and magnesium stearate, as well as coating agents, colouring agents, release agents, sweetening, flavouring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[00111] Antioxidants that are considered pharmaceutically acceptable in the present invention include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and similar antioxidents which would be understood as useful by one having skill in the present art. [00112] The compositions of the present invention may be formulated for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may be provided in unit dosage form by any methods well known to those skilled in the art of pharmacy. Depending on the subject and method of administration, the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will change. The quantity of active ingredient that can be combined with a carrier material to produce a single dosage form for the invention will usually be an amount of the active ingredient sufficient to produce a therapeutic effect.

[00113] The compositions of the invention may be prepared by bringing into association an active ingredient of the present invention with the carrier and, optionally, one or more accessory ingredients. Usually an active ingredient of the present invention is brought into intimate association with a liquid carrier, and/or a finely divided solid carrier, and then, if necessary, the product is shaped.

[00114] Compositions of the invention may be prepared for oral administration as capsules, pills, tablets, cachets, granules, lozenges, powders, or may be formulated as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as a syrup, bolus, electuary or paste, or a mouth wash, or an elixir, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes or other useful form known to the art, each containing a predetermined amount of an active ingredient of the present invention.

[00115] Pharmaceutically acceptable carriers for solid dose forms include sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato, or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) colouring agents. Buffering agents may be included. Compositions of the invention may also be formulated as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [001 16] Compressed or moulded tablets can be prepared with additional binder (such as, gelatin or hydroxypropyl methyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.

[001 17] The solid dosage forms of the invention may optionally be provided with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical- formulating art so as to provide slow or controlled release of the active ingredient therein. Examples include using hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.

[001 18] The invention may be formulated as a liquid dosage form for oral administration. Preferably, these include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs, including inert diluents known in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, oils including cottonseed, groundnut, corn, germ, olive, castor and sesame oils, glycerol, tetra hydrofury I alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[001 19] Optionally, adjuvants can be included, such as wetting agents, emulsifying and suspending agents, sweetening, flavouring, colouring, perfuming and preservative agents.

[00120] Suspending agents suitable for use with suspensions of the present invention include aluminum metahydroxide, bentonite, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, tragacanth and agar-agar and mixtures thereof.

[00121] The invention also contemplates the administration of the compositions via catheter, stent, wire, or other intraluminal device. Administration of such devices may include administering to the bladder, urethra, ureter, rectum, or intestine.

[00122] When formulated as a topical or transdermal product, the compositions of the present invention can be prepared as a powder, a spray, an ointment, a paste, a cream, a lotion, a gel, a solution, a patch and an inhalant. The formulation of such products would be well within the skill of a skilled person in the art. [00123] "Parenteral administration" as used herein refers to means other than enteral and topical administration. Such means may include intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[00124] Compositions of this invention may be formulated to comprise one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstitutable into sterile injectable solutions or dispersions before using as understood by those skilled in the art.

[00125] Aqueous and nonaqueous carriers useful in formulations of the compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.

[00126] Dosage levels of the active ingredients in the compositions of the invention will depend upon numerous factors including the particular cannabinoid(s) used, the mode and time of administration, the rate of excretion of the particular cannabinoid being used, the treatment duration, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and other factors well known in the medical arts such as whether other pharmaceutically active compounds are to be used in combination with the particular active ingredient employed.

[00127] The required dose can be readily determined by a physician or veterinarian of skill in the art based on the factors above. The physician or veterinarian may determine the correct dose by administering a very low dose of the active ingredients followed by gradually increasing the dosage until the desired effect is achieved.

[00128] It is preferable that the lowest dose effective to produce a therapeutic effect is given on a recurring basis, and this can be readily determined by one skilled in the relevant art.

[00129] The dose of the active ingredient of the invention may optionally be separated into two, three, four, five, six or more sub-doses for separate administration throughout the day.

[00130] It is contemplated that the compositions of the present invention may be useful to treat mammals such as pets or livestock, and primates, in particular humans. [00131] As used herein, a“subject” is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

Brief Description of the Figures

[00132] Embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings as follows.

[00133] Figure 1 shows the results of HPLC analysis indicating the level of cannabinoids in a representative composition of the invention.

[00134] Figure 2 shows the results of GCMS analysis indicating the level of terpenes in a representative composition of the invention.

[00135] All references cited herein, including patents, patent applications, publications, and databases, are hereby incorporated by reference in their entireties, whether previously specifically incorporated or not.

Detailed description of preferred embodiments

[00136] Preferred embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings.

[00137] Example 1

[00138] Efficacy of a Composition of the Invention in the Treatment of Pain in

Adult Subjects With Motor Neurone Disease (MND)

[00139] Materials and Methods

[00140] A single-centre, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial is held for 20 patients having MND and central pain states (including dysesthetic and/or painful spasms) of a composition of the invention (CCC), containing delta-9-tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oil in clear gel-capsule of 1 ml, as adjunctive analgesic treatment. Each capsule delivers 0.130 percent by volume of THC, THC Acid cannabinoid at 0.05-0.1 percent by volume, alpha- pinene at 0.21% percent by volume and beta-pinene, at 0.05% percent by volume. Patients can gradually self-titrate to a maximum of 12 tablets in 24 hours.

[00141] Results:

[00142] 20 patients complete the trial, 10 receive CCC. Pain and sleep disturbance are recorded daily on an 11 -point numerical rating scale. The CCC is superior to placebo in reducing the mean intensity of pain at a 95% Cl and sleep disturbance at a 95% Cl: CCC is generally well tolerated, with no or negligible reported side effects.

[00143] Conclusions:

[00144] CCC is effective in reducing pain and sleep disturbance in patients with motor neurone disease related central neuropathic pain and is well tolerated.

[00145] Example 2

[00146] Efficacy of a Composition of the Invention in the Treatment of Anxiety in

Adult Subjects

[00147] A single-centre, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial is held for 20 patients having chronic anxiety of a composition of the invention (CCC), containing delta-9- tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oil in clear gel-capsule of 1 ml, as adjunctive analgesic treatment. Each capsule delivers 0.130 percent by volume of THC, THC Acid cannabinoid at 0.05-0.1 percent by volume, alpha-pinene at 0.21% percent by volume and beta-pinene, at 0.05% percent by volume. Patients can gradually self-titrate to a maximum of 12 tablets in 24 hours.

[00148] Results:

[00149] 20 patients complete the trial, 10 receive CCC. Levels of anxiety are recorded daily on an 11-point numerical rating scale. The CCC is superior to placebo in reducing the mean intensity of anxiety at a 95% Cl and sleep disturbance at a 95% Cl: CCC is generally well tolerated, with no or negligible reported side effects. [00150] Conclusions:

[00151] CCC is effective in reducing anxiety and sleep disturbance in patients with chronic anxiety central neuropathic pain and is well tolerated.