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WO2023214282A1 - Terpènes destinés à être utilisés dans la modulation d'une fonction physiologique - Google Patents

Terpènes destinés à être utilisés dans la modulation d'une fonction physiologique Download PDF

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Publication number
WO2023214282A1
WO2023214282A1 PCT/IB2023/054497 IB2023054497W WO2023214282A1 WO 2023214282 A1 WO2023214282 A1 WO 2023214282A1 IB 2023054497 W IB2023054497 W IB 2023054497W WO 2023214282 A1 WO2023214282 A1 WO 2023214282A1
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Prior art keywords
terpene
thc
cb1r
modulation
administration
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English (en)
Inventor
Noa Raz
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Buzzelet Development and Technologies Ltd
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Buzzelet Development and Technologies Ltd
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Priority to CA3251508A priority Critical patent/CA3251508A1/fr
Priority to AU2023263809A priority patent/AU2023263809A1/en
Publication of WO2023214282A1 publication Critical patent/WO2023214282A1/fr
Priority to US18/931,161 priority patent/US20250099400A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61K31/01—Hydrocarbons
    • 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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • 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
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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)
    • A61K36/348—Cannabaceae
    • A61K36/3482—Cannabis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to the field of medical treatment, and more specifically to use of terpenes for modulation of a physiological function via modulation of activity of a cannabinoid type 1 receptor.
  • the cannabinoid type 1 (CBi) receptor is widely distributed in the brain and peripheral organs where it regulates a wide range of cellular functions and metabolism. Activation and deactivation of the activity of a CB 1 receptor therefore affects a wide range of physiological functions and conditions in the body of a subject, such as a human subject.
  • composition comprising at least one terpene for use in modulation of a physiological function via at least one selected from the group consisting of agonism of a cannabinoid type 1 receptor (CB1R), modulation of agonism of a CB1R, modulation of antagonism of a CB1R and combinations thereof.
  • CB1R cannabinoid type 1 receptor
  • CB1R cannabinoid type 1 receptor
  • FIG. 1 schematically illustrates the experimental design used to establish the effect of the composition of the present invention on activation of CB1 receptors
  • FIGs. 2A-L are dose response curves of CB1 receptor activated GIRK currents by terpenes. Each graph depicts the response to 4 terpene concentrations (each data point represents the mean ⁇ SEM from 4-8 oocytes. Responses were normalized to the response evoked by 10 pM THC at the same oocyte;
  • FIGs. 3A-H are dose response curves of CB1 receptor activated GIRK currents following co-application of THC and terpenes at natural THC/ terpenes w/w ratio.
  • Black symbols and lines represent activation of the receptor by THC alone.
  • Red symbols and lines represent activation of the receptor by co-application of THC and terpene.
  • the w/w ratio between THC and terpene was kept 10:1 throughout (each data point represents mean ⁇ SEM from 6-14 oocytes). Only terpenes with significant modulatory effect, (i.e., significant main effect of condition, two-way ANOVA,p ⁇ 0.05) are presented; and
  • FIGs 4A-E are dose response curves showing responses obtained for compositions comprising THC plus a terpene mixture as compared to those obtained with THC alone.
  • the present invention relates to use of terpenes for modulation of a physiological function related to activation of a cannabinoid type 1 receptor (CB1R).
  • CBD1R cannabinoid type 1 receptor
  • the term “modulating” with regard to a physiological function refers to changing, controlling, affecting, managing or influencing a type or magnitude of a physiological function, and includes increasing or decreasing a magnitude, a frequency and/or a severity of the physiological function.
  • Modulating may be applied to an abnormal physiological function for treating a condition or a symptom thereof arising from such abnormal function, or to a normal healthy physiological function in order to provide a desired change in the function.
  • Modulation of a physiological function may be achieved, for example by modulation of activation of a receptor involved in modulation of the physiological function, such as by increasing or decreasing activation of the receptor by an agonist or antagonist; or by increasing or decreasing availability of THC to the receptor.
  • modulation may be achieved by increasing or decreasing binding of THC to the receptor.
  • Modulation may be additive or synergistic and may involve allosteric or orthosteric interaction of the agonist or antagonist with the receptor.
  • the term “agonist” is intended to encompass both a full and a partial agonist i.e. an agent which fully or partially activates a receptor to which it binds.
  • the agonist or partial agonist may be a natural or synthetic cannabinoid agonist.
  • the agonist is a phytocannabinoid or endocannabinoid.
  • treating includes ameliorating, mitigating, and reducing the instances of a disease or condition, or the symptoms of a disease or condition.
  • administering includes any mode of administration, such as oral, subcutaneous, sublingual, transmucosal, parenteral, intravenous, intra-arterial, buccal, topical, vaginal, rectal, ophthalmic, otic, nasal, inhaled, intramuscular, intraosseous, intrathecal, and transdermal, or combinations thereof.
  • administering can also include providing a different compound that when ingested or delivered as above will necessarily transform into the compound that is desired to be administered, this type of “different compound” is often being referred to as a “Prodrug”.
  • administering can also include prescribing or filling a prescription for a dosage form comprising a particular compound.
  • administeristering can also include providing directions to carry out a method involving a particular compound or a dosage form comprising the compound or compounds.
  • the term "therapeutically effective amount” means the amount of an active substance that, when administered to a subject for treating a disease, disorder, or other undesirable medical condition, is sufficient to have a beneficial effect with respect to that disease, disorder, or condition.
  • the therapeutically effective amount will vary depending on the chemical identity and formulation form of the active substance, the disease or condition and its severity, and the age, weight, and other relevant characteristics of the patient to be treated. Determining the therapeutically effective amount of a given active substance is within the ordinary skill of the art and typically requires no more than routine experimentation.
  • percent is weight percent and ratio is weight/weight ratio.
  • composition comprising at least one terpene for use in modulation of a physiological function via at least one selected from the group consisting of agonism of a cannabinoid type 1 receptor (CB1R), modulation of agonism of a CB1R, modulation of antagonism of a CB1R and combinations thereof.
  • CB1R cannabinoid type 1 receptor
  • modulation of agonism of the CB1R, and/or modulation of antagonism of the CB1R comprises modulation of an interaction between the CB1R and an agonist or an antagonist of the CB1R.
  • the composition further comprises at least one CB1R agonist or at least one CB1R antagonist, at a total terpene to total agonist or antagonist weight/ weight ratio in the range between about 0.05:1 and 1:1, such as about 0.05:1, about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1 or about 1:1.
  • the composition is for co-administration with at least one CB1R agonist or at least one CB1R antagonist, at a total terpene to total agonist or antagonist weight/ weight ratio in the range between 0.05:1 and 1:1.
  • the agonist comprises tetrahydrocannabinol (THC).
  • THC tetrahydrocannabinol
  • the THC is present at a dosage of from about 1 to about 100 mg, such as about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg.
  • the terpene is for administration to a subject at a dosage resulting in a concentration of up to about lOpM of said terpene in the plasma and or serum of the subject, such as about 0.5pM, about IpM, about 2pM, about 3pM, about 4pM, about 5pM, about 6pM, about 7pM, about 8pM, about 9pM, or about lOpM.
  • the terpene is selected from the group consisting of alpha pinene, beta pinene, limonene, terpineol, geraniol, myrcene, ocimene, terpinolene, borneol, linalool, sabinene, eucalyptol and combinations thereof.
  • the terpene is an agonist or partial agonist of the CB1R.
  • the at least one terpene comprises one terpene, two terpenes, three terpenes, four terpenes, five terpenes, six terpene, seven terpenes, eight terpenes or nine terpenes.
  • the agonism or modulation of the CB 1 receptor results in increased activation, such as an increase of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 300% increase in activation as compared to that obtained with THC in the absence of a terpene.
  • the agonism or modulation of the CB 1 receptor is decreased activation, such as partial activation, partial or total deactivation, such as a deactivation of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.
  • the modulation of a physiological function comprises modulation of a pathological function.
  • the modulation of the physiological function provides treating of a condition relating to the pathological function, or a symptom thereof.
  • a terpene for use in treating a condition related to activation of CB1R receptor is provided.
  • the agonist comprises tetrahydrocannabinol (THC).
  • the at least one terpene is for administration together with tetrahydrocannabinol (THC) at a terpene to THC weight/ weight ratio in the range between about 0.05:1 and about 1:1, wherein the modulation of the CB1R receptor is via modulation of an interaction of the THC with the CB1R.
  • administration of the terpene together with THC provides a synergistic effect as compared to administration of either the terpene or THC alone.
  • administration of the terpene together with THC provides an additive effect, wherein the combined effect is similar to the sum of the individual effects of the terpene in the absence of THC and THC in the absence of terpene.
  • the at least one terpene is selected from the group consisting of beta pinene, linalool, limonene, geraniol, ocimene, borneol, terpineol, sabinene and combinations thereof.
  • the at least one terpene comprises one terpene, two terpenes, three terpenes, four terpenes, five terpenes, six terpene or seven terpenes.
  • the terpene to THC weight/weight ratio is about 0.05:1, about 0.06:1, about 0.07:1, about 0.08:1, about 0.09:1, about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, or about 1:1. According to some embodiments, the terpene to THC weight/weight ratio is in the range of from about 0.05:1 to about 0.5:1.
  • the THC is provided in a form suitable for sublingual administration.
  • the THC is provided in a form suitable for administration by a route selected from the group consisting of inhalation, oral and transdermal administration.
  • the terpene is for administration together with THC at a dosage of from about 1 to about 100 mg THC, ,such as about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg.
  • modulation of the interaction between the CB1R and the agonist or antagonist of the CB 1R is selected from the group consisting of an allosteric interaction, an orthosteric interaction, and a combination thereof.
  • the terpene is for co-administration together with THC in a single dosage form.
  • the terpene is for administration in a separate dosage form from said THC, wherein the administration is performed independently, sequentially, simultaneously or concomitantly.
  • the separate dosage forms may be dosage forms configured for administration by different delivery routes, or dosage forms configured for separate administration by a same delivery route.
  • the terpene is for administration within 2 hours of administration of the THC.
  • the terpene is for administration prior to administration of the THC. According to some such embodiments, the terpene is for administration substantially immediately prior to administration of the THC. According to some embodiments, the terpene is for administration about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 1 hour or about 2 hours prior to administration of the THC.
  • the terpene is for administration subsequent to administration of the THC. According to some embodiments, the terpene is for administration substantially immediately subsequent to administration of the THC. According to some embodiments, the terpene is for administration about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 1 hour or about 2 hours subsequent to administration of the THC.
  • the THC is provided in a form selected from the group consisting of a solid, a vapor, an aerosol and a liquid.
  • the terpene is provided in a form selected from the group consisting of a solid, a vapor, an aerosol and a liquid.
  • the terpene is for administration together with a CB1R agonist other than tetrahydrocannabinol (THC) at a terpene to CB1R agonist weight/ weight ratio in the range between about 0.05:1 and about 1:1, wherein the modulation of activation of the CB 1R is via modulation of an interaction of the non-THC CB 1R agonist with the CB1R.
  • THC tetrahydrocannabinol
  • the physiological function is selected from the group consisting of pain, sleep, appetite, anxiety, depression, memory, movement, inflammation, excitatory neuronal activity, neurodegeneration, neurotransmitter release, stress, cardiovascular function, motivation, mood, sedation, cognitive function, muscle tension, cramps and combinations thereof.
  • CB1R cannabinoid type 1 receptor
  • modulation of agonism of the CB1R, and/or modulation of antagonism of the CB1R comprises modulation of an interaction between the CB1R and an agonist or an antagonist of the CB1R.
  • the method further comprises administration of at least one CB 1R agonist or at least one CB 1R antagonist, at a total terpene to total agonist or antagonist weight/ weight ratio in the range between about 0.05: 1 and 1:1, such as about 0.05 : 1 , about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1 or about 1:1.
  • the agonist comprises tetrahydrocannabinol (THC).
  • the THC is administered at a dosage of from about 1 to about 100 mg THC, such as about Img, about 5mg, about lOmg, about 15 mg, about 20mg, about 25 mg, about 30mg, about 35 mg, about 40mg, about 45 mg, about 50mg, about 55 mg, about 60mg, about 65 mg, about 70mg, about 75 mg, about 80mg, about 85 mg, about 90mg, about 95 mg or about lOOmg.
  • THC is administered at a dosage of from about 1 to about 100 mg THC, such as about Img, about 5mg, about lOmg, about 15 mg, about 20mg, about 25 mg, about 30mg, about 35 mg, about 40mg, about 45 mg, about 50mg, about 55 mg, about 60mg, about 65 mg, about 70mg, about 75 mg, about 80mg, about 85 mg, about 90mg, about 95 mg or about lOOmg.
  • the terpene is administered at a dosage resulting in a concentration of up to about lOpM of said terpene in the plasma and or serum of said subject, such as about 0.5pM, about IpM, about 2pM, about 3pM, about 4pM, about 5pM, about 6pM, about 7pM, about 8pM, about 9pM, or about lOpM.
  • the at least one terpene comprises one terpene, two terpenes, three terpenes, four terpenes, five terpenes, six terpene or seven terpenes.
  • the terpene is selected from the group consisting of beta pinene, linalool, limonene, geraniol, ocimene, borneol, terpineol, sabinene and combinations thereof.
  • the modulation of the CB1 receptor comprises an agonistic or antagonistic interaction with the receptor.
  • the modulation of the CB 1 receptor results in increased activation, such as an increase of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 300% increase in activation as compared to that obtained with THC in the absence of a terpene.
  • the modulation of the CB1 receptor results in decreased activation, such as partial or total deactivation, such as a deactivation of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.
  • the modulation of a physiological function comprises modulation of a pathological function.
  • the modulation of the physiological function provides treating of a condition relating to the pathological function, or a symptom thereof.
  • the method further comprises administering tetrahydrocannabinol (THC) at a terpene to THC weight/ weight ratio in the range between 0.05:1 and 1:1, wherein modulation of the CB1 receptor is via modulation of an interaction of the THC with the CB 1 receptor.
  • THC tetrahydrocannabinol
  • administration of the terpene together with THC provides a synergistic effect as compared to administration of either the terpene or THC alone.
  • the terpene is selected from the group consisting of Beta Pinene, Linalool, Limonene, Geraniol, Ocimene, Borneol, Terpineol, Sabinene and combinations thereof.
  • the terpene to THC weight/weight ratio is about 0.05:1, about 0.06:1, about 0.07:1, about 0.08:1, about 0.09:1, about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, or about 1:1.
  • the terpene to THC weight/weight ratio is in the range of from about 0.05:1 to about 0.5:1.
  • the THC is administered sublingually.
  • modulation of the interaction between the CB1R and the agonist or antagonist of the CB1R is selected from the group consisting of an allosteric modulation, an orthosteric modulation and a combination thereof.
  • the terpene and the THC are administered in a single dosage form.
  • the terpene and the THC are administered in separate dosage forms, wherein the administration is performed independently, sequentially, simultaneously or concomitantly.
  • the separate dosage forms are administered by different delivery routes, or in dosage forms by a same delivery route.
  • the terpene is administered within 2 hours of administration of the THC.
  • the terpene is administered prior to administration of the THC.
  • the terpene is administered substantially immediately prior to administration of the THC.
  • the terpene is administered about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 1 hour or about 2 hours prior to administration of the THC.
  • the terpene is administered subsequent to administration of the THC.
  • the terpene is administered substantially immediately subsequent to administration of the THC.
  • the terpene is administered about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 1 hour or about 2 hours subsequent to administration of the THC.
  • the THC is administered in the form of a solid, a vapor, an aerosol or a liquid form.
  • the terpene is administered in a form selected from the group consisting of a solid, a vapor, an aerosol and a liquid.
  • the method further comprises administering a CB1 agonist other than Tetrahydrocannabinol (THC) at a terpene to CB1 agonist weight/ weight ratio in the range between about 0.05:1 and about 1:1, wherein the modulation of activation of the CB 1 receptor is via modulation of an interaction of the THC with the CB 1 receptor.
  • THC Tetrahydrocannabinol
  • the physiological function is selected from the group consisting of pain, sleep, appetite, anxiety, depression, memory, movement, inflammation, excitatory neuronal activity, neurodegeneration, neurotransmitter release, stress, cardiovascular function, motivation, mood, sedation, cognitive function, muscle tension, cramps and combinations thereof.
  • THC was extracted from a THC -rich cannabis chemovar, using an authorized IGMP (Israeli Good Manufactory Practice) extraction process at Bazelet manufacturing plant (Or Akiva, Israel) and verified by a validated High Performance Liquid Chromatography (HPLC) analysis (HPLC Waters PDA 2996, equipped with a pump, autosampler, column-oven, and a Photodiode Array detector (PDA) detector).
  • HPLC High Performance Liquid Chromatography
  • terpenes were purchased from Vigon International Inc. (Pennsylvania, USA. a-pinene (natural, 98.2%), P-pinene (natural, 94%) limonene-D (natural, 99%), myrcene (natural, 95.5%), ocimene (Trans, natural, 69.3%) sabinene (natural, 76.67%), terpinolene (natural, 92.6%), borneol (natural, 59.9%), eucalyptol (natural, 100%), geraniol natural (97%), linalool (racemic mixture, 100%), terpineol (natural, 98%), P-caryophyllene (natural, 88.4%), humulene (natural, 91.6%), bisabolol (natural, 98.5%) and nerolidol (natural, 99%).
  • cDNA plasmids of the two subunits of the G protein-activated inwardly rectifying K + channel (GIRK) (GIRK1 and GIRK2), the CB1 receptor, and the a subunit of the G-protein (Gai3) were linearized with the appropriate restriction enzymes.
  • the linearized plasmids were transcribed in vitro using a standard procedure.
  • Oocytes were isolated from female adult X. laevis anesthetized (with Ig/L MS -222) and incubated in NDE96 solution composed of ND96 (in mM: 96 NaCl, 2 KC1, 1 CaCh, 1 MgCh, 5 Hepes, with pH adjusted to 7.5 with NaOH) with the addition of 2.5 mM Na + pyruvate, 100 units/ml penicillin, and 100 pg/ml streptomycin (16).
  • the isolated oocytes were injected with the relevant cRNAs: cRNAs of CB1 receptor (2 ng) and GIRK1 and GIRK2 (200 pg each) were injected.
  • cRNA of Gai3 1000 pg was injected to decrease the basal GIRK current (IK) and to improve the relative activation by the agonist.
  • Each oocyte was placed in a recording bath containing ND96 solution and was impaled with two electrodes pulled from 1.5-mm Clark capillaries (Warner instruments, Hamden, CT). Both electrodes were filled with a 3M KC1 solution and the electrode resistance was between 1 and 5 MQ.
  • the CB1 receptor-mediated GIRK currents were measured in 24 mM K + solution (in mM: 72 NaCl, 24 KC1, 1 CaC12, 1 MgC12, 5 Hepes, with pH adjusted to 7.5 with KOH) .
  • Ba +2 (1 mM) was used to block the currents in order to verify that the measured currents were indeed mediated by GIRK channels.
  • pCLAMPIO software (Axon Instruments, Molecular Devices, San Jose, CA) was used for data acquisition and analysis.
  • Y Bottom + X*(Top-Bottom)/(EC5o + X), where Y is the normalized response, X is the concentration of THC, Bottom and Top are the lowest and highest points of the curve and EC50 is the THC concentration that gives the half- maximal response.
  • 10 pM was taken as the highest THC concentration, as dictated by solubility limit Therefore, at the end of the recording from each oocyte, the response to 10 pM was measured as a reference value.
  • Two-way ANOVA was used to evaluate terpenes effects on THC-derived CB1 responses (FIG. 3), analyzing the two main effects of (1) Condition, i.e., the CB1 response obtained by application of THC alone vs. the response obtained by co-application of THC and a terpene, and (2) THC concentration levels (0.01, 0.1, 1 and 5 pM THC). An interaction between the main effects was also assessed.
  • Condition i.e., the CB1 response obtained by application of THC alone vs. the response obtained by co-application of THC and a terpene
  • THC concentration levels 0.01, 0.1, 1 and 5 pM THC
  • the Xenopus oocytes functional expression system was used to test the possibility that the presence of various terpenes affects the activation of the CB1 receptor, as depicted schematically in FIG. 1A.
  • Xenopus oocytes were injected with cRNAs of proteins involved in the pathway leading to activation of K + currents by CB1 receptor via Py subunits of the G-proteins: The CB1 receptor, the two subunits of the GIRK channel (GIRK1 and GIRK2), and the Gai3 subunit .
  • ITHC THC-induced K + current
  • the oocyte was voltage-clamped to-80 mV in a low K + (2 mM K + ) solution, ND96.
  • Basal GIRK current (IK) was developed upon replacement of the ND96 by the 24 mM K + solution. This current represents the basal activation of GIRK channel by endogenous Py subunits present in the oocytes.
  • five different concentrations of THC were applied sequentially in ascending order giving rise to ITHC. This current was terminated upon washout of THC.
  • a full DR curve was constructed. A representative recording is shown in FIG. IB.
  • ITHC at any particular THC concentration was normalized to ITHC obtained at a 10 pM THC, defined as the reference response, at this same oocyte.
  • terpenes The effects of terpenes on CB1 receptor activation and on THC-induced CB1 receptor activation were next assessed.
  • Sixteen cannabis terpenes were studied, including: a- pinene, P-pinene, limonene, myrcene, ocimene, sabinene and terpinolene (monoterpenes, hydrocarbons consisting of two isoprene units, having the molecular formula of C10H16), borneol, eucalyptol, geraniol, linalool and terpineol, (monoterpenoids, oxygen-containing monoterpenes, C10H18O), P-caryophyllene and humulene (sesquiterpenes, hydrocarbons consisting of three isoprene units, C15H24), bisabolol and nerolidol (sesquiterpenoids, oxygen-containing sesquiterpenes, C
  • FIG. 1 depicting DR curves of the various terpenes. Twelve out of the 16 terpenes were tested (P-caryophyllene, bisabolol, humulene and nerolidol were excluded from analysis as their solubility is below the tested concentration range). The responses to each of the terpene in each experiment was normalized to the response evoked by 10 pM THC in the same oocyte, taken to be 1. As seen, CBi receptor activity is detected for all terpenes. The response to 10 pM terpene ranged between 10% and 48% of the response amplitude obtained by the reference 10 pM THC.
  • compositions A-E were prepared comprising THC and a terpene mixture as specified below, wherein the concentration ratio of THC to total terpene mixture was 1:10:
  • A THC, alpha pinene, sabinene, limonene, terpinolene, eucalyptol, borneol, caryophyllene
  • B THC, myrcene, ocimene, linalool, terpineol, caryophyllene, nerolidol, bisabolol
  • C THC, alpha pinene, beta pinene, eucalyptol, linalool, terpineol, borneol, caryophyllene, nerolidol
  • E THC, alpha pinene, beta pinene, limonene, terpinolene, geraniol, caryophyllene, bisabolol
  • Results are presented in Figs. 4A-E, showing that a greater response was obtained for a composition comprising THC plus a terpene mixture as compared to that obtained with THC alone.

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Abstract

L'invention concerne une composition comprenant au moins un terpène destiné à être utilisé dans la modulation d'une fonction physiologique par l'intermédiaire d'au moins l'un choisi dans le groupe consistant en l'agonisme d'un récepteur cannabinoïde de type 1 (CB1R), la modulation de l'agonisme d'un CB1R, la modulation de l'antagonisme d'un CB1R et les combinaisons de ceux-ci. L'invention concerne également des procédés d'utilisation de la composition.
PCT/IB2023/054497 2022-05-01 2023-04-30 Terpènes destinés à être utilisés dans la modulation d'une fonction physiologique Ceased WO2023214282A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025141443A1 (fr) * 2023-12-25 2025-07-03 Buzzelet Development And Technologies Ltd. Terpènes destinés à être utilisés dans la modulation d'une fonction physiologique ou psychologique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170266153A1 (en) * 2015-02-27 2017-09-21 Ebbu, LLC Compositions purposefully selected comprising purified cannabinoids and/or purified terpenes
US20210322367A1 (en) * 2018-12-29 2021-10-21 Buzzelet Development And Technologies Ltd. Isolated or synthetic cannabinoid compositions with selected terpene blend and methods of use thereof
WO2023031862A1 (fr) * 2021-09-03 2023-03-09 Buzzelet Development And Technologies Ltd. Procédés pour le traitement d'états dépendant de cb1-, trpa1- et trpv1-

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170266153A1 (en) * 2015-02-27 2017-09-21 Ebbu, LLC Compositions purposefully selected comprising purified cannabinoids and/or purified terpenes
US20210322367A1 (en) * 2018-12-29 2021-10-21 Buzzelet Development And Technologies Ltd. Isolated or synthetic cannabinoid compositions with selected terpene blend and methods of use thereof
WO2023031862A1 (fr) * 2021-09-03 2023-03-09 Buzzelet Development And Technologies Ltd. Procédés pour le traitement d'états dépendant de cb1-, trpa1- et trpv1-

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ETHAN B RUSSO: "Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects", BRITISH JOURNAL OF PHARMACOLOGY, WILEY-BLACKWELL, UK, vol. 163, no. 7, 12 July 2011 (2011-07-12), UK , pages 1344 - 1364, XP071102687, ISSN: 0007-1188, DOI: 10.1111/j.1476-5381.2011.01238.x *
LAVIGNE JUSTIN E., HECKSEL RYAN, KERESZTES ATTILA, STREICHER JOHN M.: "Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity", SCIENTIFIC REPORTS, vol. 11, no. 1, 15 April 2021 (2021-04-15), XP093043341, DOI: 10.1038/s41598-021-87740-8 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025141443A1 (fr) * 2023-12-25 2025-07-03 Buzzelet Development And Technologies Ltd. Terpènes destinés à être utilisés dans la modulation d'une fonction physiologique ou psychologique

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