WO2019159176A1 - Compositions et méthodes pour le traitement de maladies neurodégénératives - Google Patents

Compositions et méthodes pour le traitement de maladies neurodégénératives Download PDF

Info

Publication number
WO2019159176A1
WO2019159176A1 PCT/IL2019/050188 IL2019050188W WO2019159176A1 WO 2019159176 A1 WO2019159176 A1 WO 2019159176A1 IL 2019050188 W IL2019050188 W IL 2019050188W WO 2019159176 A1 WO2019159176 A1 WO 2019159176A1
Authority
WO
WIPO (PCT)
Prior art keywords
cannabinoid
eucalyptol
composition
combination
cbd
Prior art date
Application number
PCT/IL2019/050188
Other languages
English (en)
Inventor
Zohar KOREN
Original Assignee
Scicann Therapeutics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scicann Therapeutics Inc. filed Critical Scicann Therapeutics Inc.
Publication of WO2019159176A1 publication Critical patent/WO2019159176A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to pharmaceutical compositions and methods for treatment of a neurological or a movement disorder, or an injury to the nervous system.
  • Cannabis plants produce many compounds of possible medical importance such as cannabinoids, which have been shown to be promising agents in treating different neurological and neurodegenerative conditions.
  • Neurological disorders are disorders of the nervous system, where structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Examples of such symptoms include paralysis, muscle weakness, poor coordination, loss of memory, loss of cognitive function, anxiety, loss of spatial orientation, loss of sensation, seizures, confusion, pain, and altered levels of consciousness. There are many recognized neurological disorders, some relatively common, but many rare. A unique subset of neurological disorders includes the group of neurodegenerative diseases, which are generally more frequent in older patients, typically tend to progressive, and characterized by hallmark pathologies of brain tissue inflammation, neuronal cell depletion and sedimentation of toxic malfunctioning misfolded proteins. The latter have drawn a lot of attention due to their irreversibility, lack of effective treatment, as well as their social and economic burdens.
  • CBD cannabidiol
  • AD Alzheimer’s disease
  • Terpenes are naturally occurring compounds found especially in essential oils, resins, and balsam, which have a broad range of biological properties.
  • terpenes are known as skin penetration enhancers, and were found to have cancer chemo- preventive effects as well as anti-inflammatory activities.
  • Eucalyptol a particular natural monoterpene, is known for its mucolytic and spasmolytic action on the respiratory tract, with proven clinical efficacy. Eucalyptol was found to induce apoptosis in certain cancer cells.
  • it has shown therapeutic benefits in inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD); and a therapeutic potency against several neurodegenerative disorders such as AD due to its anti-inflammatory activity.
  • COPD chronic obstructive pulmonary disease
  • US 2017/0273914 discloses a passive inhaler device comprising a composition containing active compounds, for use in treating various diseases including neurodegenerative diseases such as AD or Parkinson’s disease.
  • Particular compositions referred to in this publication comprise a combination of CBD and one or more terpenes selected from mono-terpenes such as inter alia eucalyptol, di-terpenes, and tri-terpenes.
  • US 2018/0169035 discloses various compositions comprising at least one cannabinoid and a terpene, and the uses thereof in treating various medical conditions.
  • a composition comprising CBD and/or tetrahydrocannabinol (THC) and/or tetrahydrocannabinolic acid (THCA), and a terpene selected from limonene, pinene, linalool, beta-caryophyllene, caryophyllene oxide, pulegone, eucalyptol, terpineol, p-cymene, beta-myrcene, and humulene, which is said to be useful in treating a neurodegenerative disease such as AD or Parkinson’s disease.
  • THC tetrahydrocannabinol
  • THCA tetrahydrocannabinolic acid
  • a terpene selected from limonene, pinene, linalool, beta-c
  • a combination e.g., a fixed-dose combination, consisting of a particular cannabinoid compound, more specifically cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof; cannabinol (CBN); or cannabigerol (CBG), and eucalyptol, and a composition, e.g., a pharmaceutical or nutraceutical composition, comprising said combination as the only active agents.
  • CBD cannabidiol
  • CBN cannabinol
  • CBG cannabigerol
  • eucalyptol e.g., a pharmaceutical or nutraceutical composition
  • the cannabinoid-eucalyptol combination disclosed when administered to a subject suffering from a neurological or movement disorder, or an injury to the nervous system, is expected to have a synergistic effect in treatment of said disorder or injury, compared with each one of said active agents when administered separately in a similar amount, and to have a therapeutic efficacy even in cases wherein the dosage of each one of the active agents, when administered alone, has either very low therapeutic effect or no such effect at all.
  • the present invention thus provides a composition
  • a composition comprising as the only active agents a combination consisting of a cannabinoid and eucalyptol, wherein said cannabinoid is selected from CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • the combination of said cannabinoid compound and eucalyptol is a fixed dose combination (FDC) of said active agents.
  • the composition of the present invention may be in the form of a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, and may be used for treatment of a neurological or a movement disorder such as Parkinson’s disease, AD, or amyotrophic lateral sclerosis (ALS), or an injury to the nervous system.
  • a neurological or a movement disorder such as Parkinson’s disease, AD, or amyotrophic lateral sclerosis (ALS), or an injury to the nervous system.
  • the composition may be in the form of a nutraceutical composition formulated, e.g., as a food supplement or comprised within a drink or beverage.
  • the present invention relates to a method for treatment of a neurological or a movement disorder, or an injury to the nervous system, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a combination, e.g., a fixed-dose combination, as defined above, i.e., an optionally fixed-dose combination consisting of a cannabinoid and eucalyptol as the only active agents, wherein said cannabinoid is CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • a combination e.g., a fixed-dose combination, as defined above, i.e., an optionally fixed-dose combination consisting of a cannabinoid and eucalyptol as the only active agents, wherein said cannabinoid is CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • the two active agents i.e., said cannabinoid and said eucalyptol
  • the present invention relates to use of a combination, e.g., a fixed-dose combination, as defined above, i.e., an optionally fixed-dose combination consisting of a cannabinoid and eucalyptol as the only active agents, in the manufacture of a medicament for treatment of a neurological or a movement disorder, or an injury to the nervous system, wherein said cannabinoid is CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • a combination e.g., a fixed-dose combination, as defined above, i.e., an optionally fixed-dose combination consisting of a cannabinoid and eucalyptol as the only active agents, in the manufacture of a medicament for treatment of a neurological or a movement disorder, or an injury to the nervous system, wherein said cannabinoid is CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • the present invention provides a combination, e.g., a fixed- dose combination, as defined above, i.e., an optionally fixed-dose combination consisting of a cannabinoid and eucalyptol as the only active agents, for use in the treatment of a neurological or a movement disorder, or an injury to the nervous system, wherein said cannabinoid is CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • a fixed- dose combination as defined above, i.e., an optionally fixed-dose combination consisting of a cannabinoid and eucalyptol as the only active agents, for use in the treatment of a neurological or a movement disorder, or an injury to the nervous system, wherein said cannabinoid is CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • the present invention provides a composition comprising as the only active agents a combination consisting of (i) a cannabinoid selected from CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof; and (ii) eucalyptol.
  • cannabinoid refers to a chemical compound acting on cannabinoid receptors, i.e., a cannabinoid type 1 (CB1) or cannabinoid type 2 (CB2) receptor agonist.
  • CB1 cannabinoid type 1
  • CB2 cannabinoid type 2
  • Ligands for these receptor proteins include the endocannabinoids produced naturally in the body; the phytocannabinoids found in Cannabis sativa and some other plants; and synthetic cannabinoids.
  • the cannabinoid compound comprised within the composition of the present invention may be derived from a Cannabis extract, using any suitable extraction and purification procedures known in the art. Alternatively, the cannabinoid compound may be synthesized following any one of the procedures disclosed in the literature.
  • composition of the present invention mean that the cannabinoid and the eucalyptol composing the active agent combination are the only active components, i.e., drugs, comprised within said composition, and that no further active component other than, e.g., carriers, solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, let alone a further cannabinoid compound, is included in said composition.
  • the composition of the present invention comprises, as the only active agents, a combination consisting of CBD (2-[(lR,6R)-6-isopropenyl-3- methylcyclohex-2-en-l-yl]-5-pentylbenzene-l,3-diol), or an enantiomer, diastereomer, or racemate thereof, and eucalyptol.
  • CBD has two stereogenic centers, i.e., at positions 3 and 4 of the cyclohexenyl ring, and may accordingly exist as an enantiomer, i.e., an optical isomer (R or S, which may have an optical purity of 90%, 95%, 99% or more), racemate, i.e., an optically inactive mixture having equal amounts of R and S enantiomers, a diastereoisomer, or a mixture thereof.
  • R or S which may have an optical purity of 90%, 95%, 99% or more
  • racemate i.e., an optically inactive mixture having equal amounts of R and S enantiomers, a diastereoisomer, or a mixture thereof.
  • the present invention encompasses the use of all such enantiomers, isomers and mixtures thereof.
  • CBD may be synthesized following any one of the procedures known in the art, e.g., by acid condensation of p-mentha-2,8-dien-l-ol with olivetol.
  • Optically active forms of CBD may be prepared using any one of the methods disclosed in the art, e.g., by resolution of the racemic form by recrystallization techniques; chiral synthesis; extraction with chiral solvents; or chromatographic separation using a chiral stationary phase.
  • a non limiting example of a method for obtaining optically active materials is transport across chiral membranes, i.e., a technique whereby a racemate is placed in contact with a thin membrane barrier, the concentration or pressure differential causes preferential transport across the membrane barrier, and separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.
  • Chiral chromatography including simulated moving bed chromatography, can also be used.
  • a wide variety of chiral stationary phases are commercially available.
  • CBD effects of CBD were further investigated in transgenic mouse models of AD, as they result from gene mutations that are seen in familial AD (e.g., APP, PS I, and PS2 gene mutations). Based on the pharmacological protocols used, some effects of CBD could be related to a direct effect of the phytocannabinoid on exogenous Ab administration rather than the long-term effects of the accumulated Ab.
  • two studies were conducted to elucidate the remedial and preventative potential of chronic CBD treatment in AD transgenic mice.
  • To assess the remedial effects of CBD adult male APPxPSl mice were treated for three weeks with CBD (20 mg/kg CBD, daily IP injections) post onset of cognitive deficits and AD pathology.
  • CBD treatment was able to reverse cognitive deficits in object recognition memory and social recognition memory without influencing anxiety parameters (Cheng et al, 2014a).
  • male APPxPSl mice at the age of 2.5 months were treated for 8 months with either 20 mg/kg CBD or vehicle pellets using a daily voluntary oral administration protocol. This assessed the long-term effect of CBD prior to“AD onset.”
  • Long-term CBD treatment was able to prevent the development of social recognition memory deficits without affecting anxiety domains in AD transgenic mice. These beneficial effects were not associated with a reduction in Ab load or oxidative damage. There was also no difference in hippocampal or cortical soluble and insoluble levels of Ab 4 o and Ab 42 in the AD transgenic mice regardless of treatment.
  • composition of the present invention comprises, as the only active agents, a combination consisting of CBN (6,6,9-trimethyl-3-pentyl- benzo[c]chromen-l-ol) and eucalyptol.
  • CBN is a non-psychoactive cannabinoid found in trace amounts in Cannabis, mostly in aged Cannabis, and an oxidation artifact of tetrahydrocannabinol (THC) with potential immunosuppressive and anti-inflammatory activities.
  • CBN exerts minimal affinity for CB1 and has a weak effect on the CNS (Rhee et al., 1997).
  • it preferentially binds to the CB2 receptor, which is mainly expressed on a variety of immune cells such as T-cells, B-cells, macrophages and dendritic cells. Stimulation of CB2 receptors by CBN may both trigger apoptosis in these cells and inhibit the production of a variety of cytokines.
  • composition of the present invention comprises, as the only active agents, a combination consisting of CBG (2-[(2£')-3,7-dimethylocta-2,6- dienyl]-5-pentyl-benzene-l,3-diol) and eucalyptol.
  • CBG was the first cannabinoid identified, and its parent molecule cannabigerolic acid (CBGA) was shown to be the first biogenic cannabinoid formed in the plant.
  • CBDA cannabigerolic acid
  • CBG neither binds nor activates the CB1 or CB2 receptor, but has both antioxidant and anti-inflammatory properties. It has been shown that CBG, alone or in combination with other phytocannabinoids or therapies, could be beneficial for the treatment of neurodegenerative diseases such as Huntington’s disease (Valdeolivas et al., 2015).
  • Eucalyptol (also known as l,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; 1,8- cineole; and l,8-epoxy-p-menthane) is a naturally occurring terpenoid oxide and a major compound of many plant essential oils, mainly extracted from Eucalyptus globulus oil.
  • Eucalyptol may also be synthesized by, e.g., isomerization of a-terpineol using the heteropoly acid H3PW12O40 as a catalyst. Such isomerization can be carried out in both homogeneous and heterogeneous systems (Lana et al., 2006).
  • eucalyptol Due to its pleasant spicy aroma and taste, eucalyptol is used as a flavoring agent, fragrances and in cosmetics, and is approved by the U.S. Food and Drug Administration (FDA) for adding in food preparation to enhance the odor and taste.
  • FDA U.S. Food and Drug Administration
  • eucalyptol exhibits anti-nociceptive properties and thus has a calmative and depressant action on the central nervous system; enhances blood circulation; and causes vasodilation and bronchodilation (Santos and Rao, 2000).
  • Eucalyptol was found to have therapeutic potency against bronchial asthma, COPD, gastric inflammation, sinusitis, and several neurodegenerative disorders such as AD, due to its anti-inflammatory activity. It is both hepatoprotective and gastroprotective, and also has antibacterial, antimycotic and antitumorogenic activities. Studies have shown that eucalyptol might be effective in treating colorectal cancer due to its antitumorogenic property. (Bhowal and Gopal, 2015).
  • eucalyptol may have a positive effect on AD.
  • eucalyptol may be used in the treatment of neurodegenerative diseases such as AD.
  • Inflammatory process has a fundamental role in the pathogenesis of AD, as insoluble Ab depositis and neurofibrillary tangles, occurring during the progression of AD, are obvious stimuli for inflammation.
  • a study reported in the literature tested the effect of pretreatment with eucalyptol on inflammation induced by Ab in differentiated PC 12 cells.
  • Eucalyptol successfully reduced the mitochondrial membrane potential, reactive oxygen species (ROS) and nitric oxide (NO) levels in Ab treated cells.
  • ROS reactive oxygen species
  • NO nitric oxide
  • Eucalyptol has also lowered the levels of the proinflammatory cytokines TNF-alfa, IL-lbeta and IL-6 in such sells, and managed to lower the expression of NOS-2, COX-2 and NF-kB. These results suggest that eucalyptol may have protective effects on inflammation and may be useful, as anti-inflammatory agent, in treating neurodegenerative diseases (Khan et al., 2014).
  • Eucalyptol is lipid soluble and is quickly absorbed from the gastrointestinal tract. Pharmacokinetic studies have shown that at doses of up to 200 mg/kg, eucalyptol goes through a rapid absorption into the blood, metabolism and conjugation to polar metabolites.
  • the present invention thus suggests that a combination as disclosed herein, consisting as the only active agents of a cannabinoid compound as defined above and eucalyptol, each in an amount having either very little therapeutic effect or no such effect at all when administered alone, has a therapeutic effect that is significantly greater than the expected additive effect.
  • the composition of the present invention comprises, as the only active agents, a combination consisting of said cannabinoid and eucalyptol as defined in any one of the embodiments above, wherein said combination is a fixed dose combination of said cannabinoid and eucalyptol.
  • FDC fixed dose combination
  • the composition of the present invention comprises, as the only active agents, a fixed dose combination of said cannabinoid and eucalyptol, wherein the ratio between the cannabinoid and the eucalyptol in said combination is in a range of 100:1 to 1:100 by weight, respectively.
  • the amount of the cannabinoid in the fixed dose combination is greater than that of the eucalyptol, i.e., the ratio between said cannabinoid and said eucalyptol in said combination is about 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 18:1, 16:1, 14:1, 12:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1, by weight, respectively.
  • the amount of the cannabinoid in the fixed dose combination is lower than that of the eucalyptol, i.e., the ratio between said cannabinoid and said eucalyptol in said combination is about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, or 1:100, by weight, respectively.
  • the amount of the cannabinoid in the fixed dose combination is either equal, or more or less equal, to the amount of the eucalyptol, i.e., the ratio between said cannabinoid and said eucalyptol in said combination is about 1:1 by weight.
  • the composition of the present invention comprises, as the only active agents, a fixed dose combination of CBD, or an enantiomer, diastereomer, or racemate thereof, and eucalyptol, wherein the weight ratio between said CBD, or enantiomer, diastereomer, or racemate thereof, and said eucalyptol in said combination is in a range of 100:1 to 1:100, respectively.
  • the weight ratio between said CBD, or enantiomer, diastereomer, or racemate thereof, and said eucalyptol is about 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 18:1, 16:1, 14:1, 12:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1, respectively.
  • the weight ratio between said CBD, or enantiomer, diastereomer, or racemate thereof, and said eucalyptol is about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, or 1:100, respectively.
  • the weight ratio between said CBD, or enantiomer, diastereomer, or racemate thereof, and said eucalyptol in said combination is about 1:1.
  • the composition of the present invention comprises, as the only active agents, a fixed dose combination of CBN and eucalyptol, wherein the ratio between said CBN and said eucalyptol in said combination is in a range of 100:1 to 1:100 by weight, respectively.
  • the weight ratio between said CBN and said eucalyptol is about 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 18:1, 16:1, 14:1, 12:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1, respectively.
  • the weight ratio between said CBN and said eucalyptol is about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, or 1:100, respectively.
  • the weight ratio between said CBN and said eucalyptol in said combination is about 1:1.
  • the composition of the present invention comprises, as the only active agents, a fixed dose combination of CBG and eucalyptol, wherein the ratio between said CBG and said eucalyptol in said combination is in a range of 100:1 to 1:100 by weight, respectively.
  • the weight ratio between said CBG and said eucalyptol is about 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 18:1, 16:1, 14:1, 12:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1, respectively.
  • the weight ratio between said CBG and said eucalyptol is about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, or 1:100, respectively.
  • the weight ratio between said CBG and said eucalyptol in said combination is about 1:1.
  • compositions disclosed herein may be formulated, e.g., as pharmaceutical compositions, cosmetic compositions, body care compositions, personal hygiene compositions, or nutraceutical compositions, i.e., food products or supplements, were they are mixed with suitable one or more carriers and/or excipients.
  • the composition of the present invention as defined in any one of the embodiments above is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, i.e., a pharmaceutical composition comprising as the only active agents a combination consisting of one of CBD, CBN and CBG, or an enantiomer, diastereomer, or racemate thereof; and eucalyptol, herein also referred to as the active agent combination or drug combination, e.g., such a composition comprising a fixed-dose combination of said active components.
  • a pharmaceutically acceptable carrier i.e., a pharmaceutical composition comprising as the only active agents a combination consisting of one of CBD, CBN and CBG, or an enantiomer, diastereomer, or racemate thereof
  • eucalyptol herein also referred to as the active agent combination or drug combination, e.g., such a composition comprising a fixed-dose combination of said active components.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein interchangeably refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.
  • the pharmaceutically acceptable carrier may further comprise ingredients aimed at enhancing the activity of the active agents or modulating the bioavailability thereof.
  • compositions should meet sterility, pyrogenicity, and general safety and purity standards as required by, e.g., the U.S. FDA or the European Medicines Agency (EMA).
  • the pharmaceutical composition disclosed herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 19* Ed., 1995.
  • the compositions can be prepared, e.g., by uniformly and intimately bringing the active agents into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.
  • the compositions may be in the form of a liquid (e.g., solution, emulsion, or suspension), gel, cream, solid, semisolid, film, lyophilisate, or aerosol, and may further include pharmaceutically acceptable fillers, carriers, diluents or adjuvants, and other inert ingredients and excipients.
  • the pharmaceutical composition of the present invention is formulated as nanoparticles.
  • the pharmaceutical composition of the present invention may be formulated for any suitable route of administration, e.g., for oral, buccal, sublingual, or parenteral, e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, or topical, administration, as well as for inhalation, but is preferably formulated for oral or sublingual administration, or for inhalation.
  • suitable route of administration e.g., for oral, buccal, sublingual, or parenteral, e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, or topical, administration, as well as for inhalation, but is preferably formulated for oral or sublingual administration, or for inhalation.
  • compositions of the invention when formulated for oral administration, may be in any suitable form, e.g., tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • said tablets are in the form of matrix tablets in which the release of a soluble active is controlled by having the active diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid ⁇ in vitro ) or gastro-intestinal fluid ⁇ in vivo).
  • the tablets are formulated as bi- or multi-layer tablets, made up of two or more distinct layers of granulation compressed together with the individual layers lying one on top of another, with each separate layer containing a different active agent. Bilayer tablets have the appearance of a sandwich since the edge of each layer or zone is exposed.
  • compositions for oral administration might be formulated so as to inhibit the release of one or both of the active agents in the stomach, i.e., delay the release of one or both of the active agents until at least a portion of the dosage form has traversed the stomach, in order to avoid the acidity of the gastric contents from hydrolyzing the active agent.
  • Particular such compositions are those wherein the active agent is coated by a pH-dependent enteric-coating polymer.
  • pH-dependent enteric-coating polymer examples include, without being limited to, Eudragit ® S (poly(methacrylicacid, methylmethacrylate), 1:2), Eudragit ® L 55 (poly (methacrylicacid, ethylacrylate), 1:1), Kollicoat ® (poly(methacrylicacid, ethylacrylate), 1:1), hydroxypropyl methylcellulose phthalate (HPMCP), alginates, carboxymethylcellulose, and combinations thereof.
  • the pH- dependent enteric-coating polymer may be present in the composition in an amount from about 10% to about 95% by weight of the entire composition.
  • the invention provides a pharmaceutical composition for oral administration, which is solid and may be in the form of granulate, granules, grains, beads or pellets, mixed and filled into capsules or sachets, or compressed to tablets by conventional methods.
  • the pharmaceutical composition is in the form of a bi- or multilayer tablet, in which each one of the layers comprise one of the two active agents, and the layers are optionally separated by an intermediate, inactive layer, e.g., a layer comprising one or more disintegrants.
  • Another contemplated formulation is depot systems, based on biodegradable polymers. As the polymer degrades, the active agent(s) is slowly released.
  • the most common class of biodegradable polymers is the hydrolytically labile polyesters prepared from lactic acid, glycolic acid, or combinations of these two molecules. Polymers prepared from these individual monomers include poly (D,L-lactide) (PLA), poly (glycolide) (PGA), and the copolymer poly (D,L-lactide-co-glycolide) (PLG).
  • compositions for oral administration may be prepared according to any method known to the art and may further comprise one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active agents in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients may be, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, e.g., corn starch or alginic acid; binding agents, e.g., starch, gelatin or acacia; and lubricating agents, e.g., magnesium stearate, stearic acid, or talc.
  • the tablets may be either uncoated or coated utilizing known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated using the techniques described in the US Patent Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
  • the pharmaceutical composition of the invention may also be in the form of oil-in-water emulsion.
  • Useful dosage forms of the pharmaceutical compositions include orally disintegrating systems including, but not limited to, solid, semi-solid and liquid systems including disintegrating or dissolving tablets, soft or hard capsules, gels, fast dispersing dosage forms, controlled dispersing dosage forms, caplets, films, wafers, ovules, granules, buccal/mucoadhesive patches, powders, freeze dried (lyophilized) wafers, chewable tablets which disintegrate with saliva in the buccal/mouth cavity and combinations thereof.
  • Useful films include, but are not limited to, single layer stand-alone films and dry multiple layer stand-alone films.
  • the pharmaceutical composition of the invention may comprise one or more pharmaceutically acceptable excipients.
  • a tablet may comprise at least one filler, e.g., lactose, ethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose; at least one disintegrant, e.g., cross-linked polyvinylpyrrolidinone; at least one binder, e.g., polyvinylpyridone, hydroxypropylmethyl cellulose; at least one surfactant, e.g., sodium laurylsulfate; at least one glidant, e.g., colloidal silicon dioxide; and at least one lubricant, e.g., magnesium stearate.
  • filler e.g., lactose, ethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose
  • disintegrant e.g., cross-linked polyvinylpyrrolidinone
  • binder e.g., polyvinylpyri
  • the pharmaceutical composition of the invention may be in the form of a sterile injectable aqueous or oleagenous suspension, which may be formulated according to the known art using suitable dispersing, wetting or suspending agents.
  • the sterile injectable preparation may also be an injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Acceptable vehicles and solvents that may be employed include, without limiting, water, Ringer's solution, polyethylene glycol (PEG), 2- h yd o x y p o p y 1 - b - c y c 1 o dc x t r i n (HPCD), a surfactant such as Tween-80, and isotonic sodium chloride solution.
  • PEG polyethylene glycol
  • HPCD 2- h yd o x y p o p y 1 - b - c y c 1 o dc x t r i n
  • surfactant such as Tween-80
  • isotonic sodium chloride solution isotonic sodium chloride solution.
  • compositions according to the invention when formulated for inhalation, may be in any suitable form, e.g., liquid or fine powder, and may be administered utilizing any suitable device known in the art, such as pressurized metered dose inhalers, liquid nebulizers, dry powder inhalers, sprayers, thermal vaporizers, electrohydrodynamic aerosolizers, and the like.
  • compositions of the invention may be formulated for controlled release of one or both of the active agents.
  • Such compositions may be formulated as controlled-release matrix, e.g., as controlled-release matrix tablets in which the release of a soluble active agent is controlled by having the active diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid ⁇ in vitro ) or gastro-intestinal fluid ⁇ in vivo).
  • compositions comprise the active agent formulated for controlled release in microencapsulated dosage form, in which small droplets of the active agent are surrounded by a coating or a membrane to form particles in the range of a few micrometers to a few millimeters.
  • the pharmaceutical compositions of the present invention are useful in treatment of a neurological or a movement disorder, or an injury to the nervous system.
  • neurological or movement disorder include, without being limited to, neurodegenerative diseases such as Parkinson’s disease, secondary parkinsonism, Parkinson’s like syndrome, AD, Huntington disease, ALS, restless leg syndrome, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and Shy-Drager syndrome, as well as spatial orientation loss, memory loss, deterioration of cognitive function, dementia, and anxiety.
  • the injury to the nervous system might be, e.g., acute brain damage, such as stroke, or traumatic brain injury.
  • compositions of the present invention are used for treatment of Parkinson’s disease, AD, or ALS, wherein each one of these diseases/disorders represents a separate embodiment.
  • Pharmaceutical compositions according to the present invention when used for treatment of a neurological or a movement disorder, or an injury to the nervous system, may be administered once a day, twice a day, or more, wherein the daily dosage of said cannabinoid is, e.g., in a range of 1 mg to 1000 mg (for example, about 1 to about 10 mg, about 10 to about 25 mg, about 25 to about 50 mg, about 50 to about 100 mg, about 100 to about 200 mg, about 200 to about 300 mg, about 300 to about 500 mg, or about 500 to about 1000 mg); and the daily dosage of said eucalyptol is in a range of from about 100 times less- to about 100 times more than the daily dosage of the cannabinoid.
  • the composition of the present invention as defined in any one of the embodiments above is in the form of a nutraceutical composition, i.e., a nutraceutical composition comprising as the only active agents a combination consisting of one of CBD, CBN and CBG, or an enantiomer, diastereomer, or racemate thereof; and eucalyptol, e.g., such a composition comprising a fixed-dose combination of said active agents.
  • the nutraceutical composition disclosed herein may be formulated as a tablet, capsule, pill and powder, or as a liquid dosage form such as syrup and elixir, and may be prepared by conventional techniques known in the art. Particular such nutraceutical compositions are formulated for oral, buccal or sublingual administration, or for inhalation.
  • the nutraceutical composition disclosed herein has a physiological benefit and may thus be used for enhancement of cognitive functions, improvement of memory capabilities, promoting feeling of alertness and well-being, improvement of spatial orientation, reduction of stress and anxiety.
  • the present invention thus provides a drink or beverage, comprising a nutraceutical composition as defined in any one of the embodiments above, i.e., a nutraceutical composition comprising as the only active agents a combination, e.g., a fixed-dose combination, consisting of one of CBD, CBN, and CBG, or an enantiomer, diastereomer, or racemate thereof; and eucalyptol.
  • a nutraceutical composition comprising as the only active agents a combination, e.g., a fixed-dose combination, consisting of one of CBD, CBN, and CBG, or an enantiomer, diastereomer, or racemate thereof; and eucalyptol.
  • the present invention relates to a method for treatment of a neurological or a movement disorder, or an injury to the nervous system, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a combination consisting of a cannabinoid and eucalyptol as the only active agents, wherein said cannabinoid is selected from CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • Particular combinations for administering according to the method of the present invention are fixed dose combination of said cannabinoid and eucalyptol, as defined in any one of the embodiments above.
  • the active agent combination administered according to the method of the invention is a combination of CBD, or an enantiomer, diastereomer, or racemate thereof, and eucalyptol, e.g., a fixed dose combination of said drugs wherein the ratio between said CBD, or enantiomer, diastereomer, or racemate thereof, and said eucalyptol in said fixed dose combination is in a range of 100:1 to 1:100 by weight, respectively.
  • the active agent combination administered according to the method of the invention is a combination of CBG and eucalyptol, e.g., a fixed dose combination of said drugs wherein the ratio between said CBG and said eucalyptol in said fixed dose combination is in a range of 100:1 to 1:100 by weight, respectively.
  • the active agent combination administered according to the method of the invention is a combination of CBN and eucalyptol, e.g., a fixed dose combination of said drugs wherein the ratio between said CBN and said eucalyptol in said fixed dose combination is in a range of 100:1 to 1:100 by weight, respectively.
  • subject refers to any mammal, e.g., a human, non human primate, horse, ferret, dog, cat, cow, and goat. In a preferred embodiment, the term “subject” denotes a human, i.e., an individual.
  • treatment refers to the administering of a therapeutic amount of a drug combination as described above, which is effective to ameliorate undesired symptoms associated with said medical condition; prevent the manifestation of such symptoms before they occur; slow down the progression of said medical condition; slow down the deterioration of symptoms; enhance the onset of remission period; slow down the irreversible damage caused in the progressive chronic stage of said medical condition; delay the onset of said progressive stage; lessen the severity or cure said medical condition; improve survival rate or more rapid recovery; and/or prevent said medical condition form occurring.
  • terapéuticaally effective amount means an amount of said drug combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought.
  • the amount must be effective to achieve the desired therapeutic effect as described above, depending inter alia on the type and severity of the condition to be treated and the treatment regime.
  • the effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials to determine the effective amount.
  • an effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half-life in the body, on undesired side effects, if any, on factors such as age and gender, etc.
  • the cannabinoid and eucalyptol administered according to the method of the present invention are formulated as two separate pharmaceutical compositions for administration either concurrently or sequentially at any order.
  • each one of the compositions administered may be independently formulated for any suitable administration route as defined above, but is preferably formulated for oral, or sublingual administration, or for inhalation.
  • the cannabinoid and eucalyptol administered according to the method of the present invention are formulated as a sole pharmaceutical composition.
  • a composition may be formulated for any suitable administration route as defined above, but is preferably formulated for oral, or sublingual administration, or for inhalation.
  • the dose of the cannabinoid administered to said subject according to the method of the invention is in a range of about 1 mg to about 1000 mg per day, and the dose of the eucalyptol is in a range of from about 100 times less- to about 100 times more than the dose of the cannabinoid, i.e., in a range of about 0.01 to about 100000 mg, per day.
  • the daily dose of the cannabinoid is about 10 mg
  • the daily dose of the eucalyptol is in a range of about 0.1 to about 0.2 mg, about 0.2 to about 1 mg, about 1 to about 2 mg, about 2 to 5 mg, about 5 to about 10 mg, about 10 to about 20 mg, about 20 to about 50 mg, or higher than 50 mg.
  • the daily dose of the cannabinoid is about 25 mg
  • the daily dose of the eucalyptol is in a range of about 0.25 to about 0.5 mg, about 0.5 to about 2.5 mg, about 2.5 to about 5 mg, about 5 to 12.5 mg, about 12.5 to about 25 mg, about 25 to about 50 mg, about 50 to about 125 mg, or higher than 125 mg.
  • the daily dose of the cannabinoid is about 50 mg
  • the daily dose of the eucalyptol is in a range of about 0.5 to about 1.0 mg, about 1 to about 5 mg, about 5 to about 10 mg, about 10 to about 25 mg, or about 25 to about 50 mg, about 50 to about 100 mg, about 100 to about 250 mg, or higher than 250 mg.
  • the daily dose of the cannabinoid is about 100 mg
  • the daily dose of the eucalyptol is in a range of about 1 to about 2 mg, about 2 to about 10 mg, about 10 to about 20 mg, about 20 to about 50 mg, or about 50 to about 100 mg, about 100 to about 200 mg, about 200 to about 500 mg, or higher than 500 mg.
  • the daily dose of the cannabinoid is about 200 mg
  • the daily dose of the eucalyptol is in a range of about 2 to about 4 mg, about 4 to about 20 mg, about 20 to about 40 mg, about 40 to about 100 mg, or about 100 to about 200 mg, about 200 to about 400 mg, about 400 to about 1000 mg, or higher than 1000 mg.
  • the daily dose of the cannabinoid is about 300 mg
  • the daily dose of the eucalyptol is in a range of about 3 to about 6 mg, about 6 to about 30 mg, about 30 to about 60 mg, about 60 to about 150 mg, or about 150 to about 300 mg, about 300 to about 600 mg, about 600 to about 1500 mg, or higher than 1500 mg.
  • the daily dose of the cannabinoid is about 500 mg
  • the daily dose of the eucalyptol is in a range of about 5 to about 10 mg, about 10 to about 50 mg, about 50 to about 100 mg, about 100 to about 250 mg, or about 250 to about 500 mg, about 500 to about 1000 mg, about 1000 to about 2500 mg, or higher than 2500 mg.
  • the daily dose of the cannabinoid is about 1000 mg
  • the daily dose of the eucalyptol is in a range of about 10 to about 20 mg, about 20 to about 100 mg, about 100 to about 200 mg, about 200 to about 500 mg, or about 500 to about 1000 mg, about 1000 to about 2000 mg, about 2000 to about 5000 mg, or higher than 5000 mg.
  • the pharmaceutical composition(s) can be administered to subject treated over a time period of, e.g., days, weeks, months, years, or more.
  • the weight ratio of the two active agents, i.e., the cannabinoid and the eucalyptol, contained within the composition of the present invention is precisely calibrated and the two active agents are preferably formulated in a single dosage form designed for optimal pharmacokinetic performance and efficacy and for patient’s compliance.
  • the synergistic effects between the drugs in the combination may depend on the time they have to act together in the body, i.e., on the relative release profile of the drugs determined by the formulation of each one of the drugs in the combination.
  • the present invention relates to use of a combination, e.g., a fixed-dose combination, as defined in any one of the embodiments above, i.e., an optionally fixed-dose combination consisting of a cannabinoid and eucalyptol as the only active agents, in the manufacture of a medicament for treatment of a neurological or a movement disorder, or an injury to the nervous system, wherein said cannabinoid is selected from CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • the present invention provides a combination, e.g., a fixed- dose combination, as defined in any one of the embodiments above, i.e., an optionally fixed-dose combination consisting of a cannabinoid and eucalyptol as the only active agents, for use in the treatment of a neurological or a movement disorder, or an injury to the nervous system, wherein said cannabinoid is selected from CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • a fixed- dose combination as defined in any one of the embodiments above, i.e., an optionally fixed-dose combination consisting of a cannabinoid and eucalyptol as the only active agents, for use in the treatment of a neurological or a movement disorder, or an injury to the nervous system, wherein said cannabinoid is selected from CBD, CBN, CBG, or an enantiomer, diastereomer, or racemate thereof.
  • AD mouse models for use in the testing of the potential therapeutic effect of the combination of a cannabinoid (CBD, CBG or CBN) and eucalyptol are, e.g., (i) APP/PS1 mice: double transgenic mice expressing both the human amyloid precursor protein (APP) (K670M/N671L) and presenilin-l (PS1) (M146L) mutations.
  • APP human amyloid precursor protein
  • PS1 presenilin-l
  • mice display impaired long term potentiation (LTP), spatial working memory, and contextual learning as early as three to four months of age, and they show deficits in basal synaptic transmission (BST) and spatial reference memory after five to six months of age;
  • Tg2576 mice overexpress the APP (isoform 695) mutation (K670M/N671L), resulting in elevated levels of Ab and ultimately amyloid plaques. Hemizygous mice develop extensive amyloid pathology and cognitive deficits; or
  • 3xTgAPP mice contain three mutations associated with familial AD (APP K670M, N671L, microtubule-associated protein tau (MAPT) P301L, and PS1 M146V).
  • mice are viable, fertile, and display no initial gross physical or behavioral abnormalities. Translation of the overexpressed transgenes appears restricted to the central nervous system, including the hippocampus and cerebral cortex. These mice display both plaque and tangle pathology. Ab deposition is progressive, with intracellular immunoreactivity detected in some brain regions as early as three to four months of age. Extracellular Ab deposits appear by six months in the frontal cortex and become more extensive by twelve months.
  • Non-transgenic (NonTg) mouse models could also be used for testing the potential therapeutic effect of the combination of a cannabinoid (CBD, CBG or CBN) and eucalyptol.
  • CBD cannabinoid
  • CBG cannabinoid
  • eucalyptol e.g., oligomeric Ab directly infused into the ventricles or hippocampi of adult animals provide an acute Ab pathology model.
  • the Ab can be infused via pre-implanted cannulas, which facilitate direct delivery and help avoid issues related to the blood brain barrier.
  • Experiments described in the literature have shown that Ab per se is capable of impairing different types of memory including associative and reference memory, suggesting that the peptide plays a direct role in memory impairment in general.
  • Transgenic mice APP/PS1, Tg2576, or 3xTgAPP mice, or non-transgenic (NonTg) littermates of the appropriate genetic background and age are orally administered with a cannabinoid (CBD, CBG or CBN); eucalyptol; a combination of said cannabinoid and eucalyptol; or a vehicle (e.g., water).
  • CBD cannabinoid
  • eucalyptol a combination of said cannabinoid and eucalyptol
  • vehicle e.g., water
  • Different drug combinations having various cannabinoid and eucalyptol dosages and hence various cannabinoid- eucalyptol weight ratios are administered, e.g., drug combinations as shown in Table 1.
  • PCR Polymerase chain reaction
  • Behavioral studies Behavioral studies that might reflect defects in humans affected by AD are e.g., (i) the fear conditioning (FC) test which studies associative memory that is affected in AD patients; (ii) the radial arm water maze (RAWM) test which studies short-term memory (STM), a type of memory that is affected early in the disease; and/or (iii) the Morrison water maze (MWM) test which studies long-term memory (LTM) which is affected at late stages of the disease.
  • FC fear conditioning
  • RAWM radial arm water maze
  • STM short-term memory
  • MLM Morrison water maze
  • LTM long-term memory
  • RAWM test The RAWM test has been previously described (Trinchese et al., 2004). Briefly, the RAWM consists of a white tank filled with water (24-25°C) and made opaque by the addition of nontoxic white paint. Within the tank, walls are positioned so as to produce six arms, radiating from a central area. Spatial cues are presented on the walls of the testing room. At the end of one of the arms is positioned a clear 10 cm submerged platform that is remain in the same location for every trial in one day but is moved approximately randomly from day to day. On each trial, the mouse starts the task from a different randomly chosen arm.
  • the mouse is not using its long-term memory of the location of the platform on previous days but relies on the short-term memory of its location on the day in question based on spatial cues that are present in the room.
  • Each trial lasts one min, and errors are counted each time the mouse enters the wrong arm or needs 20s to reach the platform. After each error, the mouse is pulled back to the start arm for that trial. After four consecutive acquisition trials, the mouse is placed in its home cage for 30 min, then returns to the maze and is administered a fifth retention trial. Testing is considered completed as the WT mice make the same number of errors at the fourth and fifth trial. The scores for each mouse on the last third day of testing are averaged and used for statistical analysis.
  • MWM test The Morris water maze test has been previously described (Trinchese et al., 2004). Briefly, mice are trained in two daily sessions (4 h apart), each consisting of three trials (1 min each), for three days, so that mice has to rely on long-term memory of platform location of previous days. Time required to reach the hidden platform is recorded. To test the retention of the spatial memory, four probe trials are performed after the training with the platform moved. The maze is divided into four quadrants. The percentage of time spent in the quadrant that previously contained the platform is recorded and analyzed with a video tracking system.
  • FC test The test has been previously described (Bourtchuladze et al., 1994).
  • a conditioning chamber located within a sound-attenuating box and containing a 36-bar insulated shock grid removable floor is used.
  • mice are placed in the conditioning chamber for 2 min before the onset of a discrete tone (CS) (a sound that lasted 30 sec at 2800 Hz and 85 dB).
  • CS discrete tone
  • FTS foot shock
  • Freezing behavior defined as the absence of all movement except for that necessitated by breathing, and scored using the Freezeview software.
  • freezing is measured for 5 min in the chamber in which the mice are trained 24 hours after training.
  • cued fear learning following contextual testing, mice are placed in a novel context (triangular cage with smooth flat floor and with vanilla odorant) for 2 min (pre-CS test), after which they are exposed to the CS for 3 min (CS test), and freezing is measured.
  • Sensory perception of the shock was determined through threshold assessment. A threshold to flinching, jumping, and screaming is quantified for each animal by averaging of the shock intensity at which each animal manifested a behavioral response of that type to the foot shock.
  • mice treated with a combination of CBD and eucalyptol will show synergistic improvement of their behavioral performance in the relevant behavioral test, as compared to mice that treated with only the cannabinoid or eucalyptol.
  • a chosen set of cognitive performance tasks and anxiety related questionnaires are used to measure the improvement of the healthy volunteers/patients in the different treatment groups. These tasks may include, but not limited to, (1) arithmetic tasks (such as serial sevens subtraction tasks etc.); (2) rapid visual information processing tasks; (3) various memory tasks (short term and long term); (4) spatial orientation tasks; and (5) anxiety and quality of life related questionnaires.
  • the treatment with the drug combination is expected to show a synergistic effect compared to the treatment with either the cannabinoid or eucalyptol alone, in the efficacy of enhancement of memory and cognitive performance and reduction in general anxiety of the healthy volunteers/patients under these tests and tasks.
  • Valdeolivas S. Navarrete C., Cantarero L, Bellido M. L., Munoz E., Sagredo O., Neuroprotective properties of carmabigeroi in Huntington’s disease: studies in R6/2 mice and 3-nitropropionate-lesioned mice. N eurotherapeutics , 2015, 12, 185- 199

Abstract

La présente invention concerne une composition comprenant, en tant que seuls agents actifs, une combinaison constituée d'un cannabinoïde et de l'eucalyptol, par exemple, une telle combinaison à dose fixe, qui est utile pour le traitement d'un trouble neurologique ou d'un trouble du mouvement tel que la maladie de Parkinson, la maladie d'Alzheimer, ou la sclérose latérale amyotrophique (SLA), ou une lésion du système nerveux; et ses utilisations.
PCT/IL2019/050188 2018-02-18 2019-02-17 Compositions et méthodes pour le traitement de maladies neurodégénératives WO2019159176A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862631806P 2018-02-18 2018-02-18
US62/631,806 2018-02-18

Publications (1)

Publication Number Publication Date
WO2019159176A1 true WO2019159176A1 (fr) 2019-08-22

Family

ID=67618541

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2019/050188 WO2019159176A1 (fr) 2018-02-18 2019-02-17 Compositions et méthodes pour le traitement de maladies neurodégénératives

Country Status (1)

Country Link
WO (1) WO2019159176A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3842039A1 (fr) * 2019-12-24 2021-06-30 Folium Biosciences Europe B.V. Complément alimentaire comprenant des cannbinoïdes et des phytostérols pour la maladie d'alzheimer
WO2021130002A1 (fr) 2019-12-24 2021-07-01 Folium Biosciences Europe B.V. Complément alimentaire pour la maladie d'alzheimer
WO2022178008A1 (fr) * 2021-02-16 2022-08-25 Augusta University Research Institute, Inc. Cannabidiol permettant de traiter des maladies neurodégénératives
US11712456B2 (en) 2018-04-09 2023-08-01 Portland Technology Holdings Llc Hemp extract for treatment of pain in animals

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160039591A1 (en) * 2014-07-22 2016-02-11 Craig E. Kinzer Packaging systems, devices, methods, and composition including cannabinoid unit dose forms
AU2016225026A1 (en) * 2015-02-27 2017-09-07 Canopy Growth Corporation Compositions comprising combinations of purified cannabinoids, with at least one flavonoid, terpene, or mineral
WO2017158839A1 (fr) * 2016-03-18 2017-09-21 Ｋｂセーレン株式会社 Fil de nettoyage pour outil de nettoyage de connecteur, et procédé de fabrication de celui-ci
US20170273914A1 (en) * 2014-08-25 2017-09-28 Janing Holding Aps Device with compositions for delivery to the lungs, the oral mucosa and the brain
WO2017218845A1 (fr) * 2016-06-15 2017-12-21 Ojai Energetics Pbc Procédés et compositions pour réduire le stress oxydatif

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160039591A1 (en) * 2014-07-22 2016-02-11 Craig E. Kinzer Packaging systems, devices, methods, and composition including cannabinoid unit dose forms
US20170273914A1 (en) * 2014-08-25 2017-09-28 Janing Holding Aps Device with compositions for delivery to the lungs, the oral mucosa and the brain
AU2016225026A1 (en) * 2015-02-27 2017-09-07 Canopy Growth Corporation Compositions comprising combinations of purified cannabinoids, with at least one flavonoid, terpene, or mineral
WO2017158839A1 (fr) * 2016-03-18 2017-09-21 Ｋｂセーレン株式会社 Fil de nettoyage pour outil de nettoyage de connecteur, et procédé de fabrication de celui-ci
WO2017218845A1 (fr) * 2016-06-15 2017-12-21 Ojai Energetics Pbc Procédés et compositions pour réduire le stress oxydatif

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11712456B2 (en) 2018-04-09 2023-08-01 Portland Technology Holdings Llc Hemp extract for treatment of pain in animals
EP3842039A1 (fr) * 2019-12-24 2021-06-30 Folium Biosciences Europe B.V. Complément alimentaire comprenant des cannbinoïdes et des phytostérols pour la maladie d'alzheimer
WO2021130002A1 (fr) 2019-12-24 2021-07-01 Folium Biosciences Europe B.V. Complément alimentaire pour la maladie d'alzheimer
WO2022178008A1 (fr) * 2021-02-16 2022-08-25 Augusta University Research Institute, Inc. Cannabidiol permettant de traiter des maladies neurodégénératives

Similar Documents

Publication Publication Date Title
WO2019159176A1 (fr) Compositions et méthodes pour le traitement de maladies neurodégénératives
AU2019297198B2 (en) Composition and method for treating pain
JP2022075675A (ja) タンニン酸を含有する組成物及びその使用
WO2020188568A1 (fr) Méthodes et compositions pour le traitement du trouble du spectre autistique et de troubles associés
US20240024340A1 (en) Compositions and Methods For Treating Migraine
WO2019180706A1 (fr) Méthodes et compositions pour le traitement de l'épilepsie et des troubles associés
RU2336870C2 (ru) Применение l-бутилфталида для изготовления лекарственного средства для профилактики и лечения церебрального инфаркта
AU2516201A (en) Drug combination for the treatment of depression and related disorders comprising mirtazapine and gepirone
EP4251181A1 (fr) Compositions et méthodes de traitement de pathologies neurologiques
JP2011530543A (ja) 感覚欠損を治療するための組成物および方法
US10675269B2 (en) Compositions comprising melatonin
WO2020183456A1 (fr) Combinaisons de cannabinoïdes pour le traitement de la douleur chronique chez des patients sous dialyse
WO2020183455A1 (fr) Combinaisons de cannabinoïdes pour le traitement des douleurs lombaires
RU2559088C2 (ru) Растительные экстраты для лечения нейродегенеративных заболеваний
JP2002507211A (ja) ジヒドロホノキオール組成物の合成
US20230218566A1 (en) Composition and Method for Treating Chronic Pain
CN109562089A (zh) 苯甲酸锂用于治疗中枢神经系统疾病的用途
WO2020183457A1 (fr) Combinaisons de cannabinoïdes pour traiter une neuropathie diabétique
WO2020188569A1 (fr) Méthodes et compositions pour prévenir ou traiter un gain de poids provoqué par des médicaments utilisés en psychiatrie
CN112691102A (zh) 黄芩素在防治帕金森病/帕金森综合征抑郁症状中的应用
AU2021390590B2 (en) Antiinflammatory compositions comprising cannabidiol, delta-9- tetrahydrocannabinol and linalool
WO2020075170A1 (fr) Compositions comprenant un extrait de pissenlit officinal et leurs utilisations
EP2830641B1 (fr) Nouveaux extraits de valeriane et leurs utilisations
US8828453B2 (en) Herbal-based compositions for alleviating symptoms associated with autism
AU2021106137B4 (en) Composition and method for treating chronic pain

Legal Events

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

Ref document number: 19754585

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19754585

Country of ref document: EP

Kind code of ref document: A1