WO2019128377A1 - 一种含有大麻二酚或大麻提取物和咖啡因的组合物及其应用 - Google Patents

一种含有大麻二酚或大麻提取物和咖啡因的组合物及其应用 Download PDF

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Publication number
WO2019128377A1
WO2019128377A1 PCT/CN2018/109658 CN2018109658W WO2019128377A1 WO 2019128377 A1 WO2019128377 A1 WO 2019128377A1 CN 2018109658 W CN2018109658 W CN 2018109658W WO 2019128377 A1 WO2019128377 A1 WO 2019128377A1
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Prior art keywords
caffeine
cannabidiol
cannabis extract
beverage
pharmaceutical composition
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PCT/CN2018/109658
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English (en)
French (fr)
Inventor
张可
谭昕
于朝晖
常坦然
连萌
金倩
Original Assignee
汉义生物科技（北京）有限公司
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Application filed by 汉义生物科技（北京）有限公司 filed Critical 汉义生物科技（北京）有限公司
Priority to US16/956,129 priority Critical patent/US20210069198A1/en
Priority to CA3087279A priority patent/CA3087279C/en
Priority to JP2020552078A priority patent/JP7008909B2/ja
Priority to EP18896151.0A priority patent/EP3711765A4/en
Priority to AU2018393198A priority patent/AU2018393198A1/en
Publication of WO2019128377A1 publication Critical patent/WO2019128377A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/02—Solvent extraction of solids
    • B01D11/0288—Applications, solvents
    • 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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • 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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/02—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation containing fruit or vegetable juices
    • 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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/385—Concentrates of non-alcoholic beverages
    • A23L2/39—Dry compositions
    • 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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • 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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/54—Mixing with gases
    • 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
    • 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
    • A23L7/00—Cereal-derived products; Malt products; Preparation or treatment thereof
    • 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 
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • 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)
    • A61K36/60—Moraceae (Mulberry family), e.g. breadfruit or fig
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0492—Applications, solvents used
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to the field of medical health, and in particular to a composition containing cannabidiol or cannabis extract and caffeine and application thereof in preparing food or medicine.
  • Caffeine is a methylxanthine alkaloid that excites the heart, skeletal muscles, and central nervous system. It also promotes gastric acid secretion, diuresis, and treatment of migraine. Most of the physiological activities of caffeine are related to promoting intracellular Ca 2+ release and increasing intracellular cAMP concentration to antagonize adenosine A1 and A2A receptors. Long-term chronic or one-time high-dose (>400mg) intake of caffeine can lead to a series of physical and psychological adverse reactions, such as hyperactivity, nervousness, anxiety, insomnia, palpitations, tremors, brain metabolic disorders.
  • CBD Cannabidiol
  • CBD is the main chemical component of medicinal plant cannabis. It is extracted from cannabis plants and is a non-addictive component in cannabis. CBD itself has the function of stimulating adenosine A2A receptor. CBD plays a role in sedation, anticonvulsant and anti-anxiety in the central nervous system; in the cardiovascular system, CBD can relax blood vessels and reduce myocardial contractility by inhibiting L-type Ca 2+ channels.
  • US20160250270A1 discloses a beverage composition which may contain from 0.1 to 10% by weight of CBD, and from 0.015 to 15% by weight of caffeine.
  • Patent US20160324776A1 discloses a caffeine-containing beverage containing cannabinoids, wherein the beverage retains its original taste and appearance, and the content of cannabinoids can be from 0.1 to 5% by weight, while the addition of cannabinoids can calm and alert consumers. .
  • Patent CN201280005750.7 discloses that cold pressed and filtered cannabis juice can be mixed with raw materials such as juice, vegetable juice and/or water, sugar and vanilla and/or caffeine-containing ingredients to make a soft drink.
  • Patent US20170112161A1 discloses a method of making a cannabinoid-containing coffee product extracted from a cannabis plant, comprising extracting cannabinoids from the cannabis plant and mixing the cannabinoids into the coffee product.
  • the present application discloses a composition comprising cannabidiol and caffeine and uses thereof.
  • the present inventors have surprisingly found that caffeine-induced anxiety behavior can be effectively inhibited by combining cannabinol or cannabis extract with caffeine.
  • the present invention provides a composition
  • a composition comprising (1) cannabinol or cannabis extract and (2) caffeine, said cannabis extract containing cannabidiol, cannabinol and coffee in said composition
  • the mass ratio is (1-100): 60.
  • the mass ratio of cannabidiol to caffeine in the composition is (20-80): 60. Further preferably, the mass ratio of cannabidiol to caffeine in the composition is (30-70):60. Most preferably, the mass ratio of cannabidiol to caffeine in the composition is 1:1.
  • the cannabidiol is prepared by chemical synthesis, biosynthesis, plant extraction or other means.
  • the mass percentage of cannabidiol in the cannabis extract is from 10% to 99%.
  • the cannabis extract contains 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% by weight of the cannabisdiol.
  • the extracting site of the cannabis extract of the present invention is the outer shell of the stalk core, flower, leaf, root and/or seed of hemp.
  • the cannabis extract according to the present invention may be a combination of an extract or an extract obtained by separately extracting different plant parts of the cannabis plant, or may be an extract obtained by simultaneously extracting different plant parts of the cannabis plant or a combination thereof. Or a combination of extracts.
  • the extraction site is a cannabis flower and/or a cannabis leaf.
  • the cannabis extract of the present invention is obtained by a conventional extraction method in the pharmaceutical or food field, preferably by solvent extraction.
  • the extraction solvent is selected from the group consisting of water, a low molecular alcohol or an aqueous solution thereof, an acetate, a ketone, an ether or a low boiling hydrocarbon;
  • the low molecular alcohol includes methanol, ethanol, butanol or propanol;
  • the ketone comprises acetone;
  • the ether comprises methyl ether or diethyl ether; and
  • the low boiling hydrocarbons include aliphatic hydrocarbons, aromatic hydrocarbons or chlorinated hydrocarbons.
  • the extraction solvent is selected from the group consisting of water or ethanol solution.
  • the cannabis extract can be obtained by the following method:
  • the cannabis extraction site is heated and refluxed for at least 1 hour using a 3-10 times amount of the extraction solvent or a mixture thereof; and the extraction solvent described in the step 3) of the cannabis extract extraction method is An aqueous sodium hydroxide solution containing 20% by weight of ethanol; the pH adjusting agent in the step 4) is a mixture of an extract and a 5% sulfuric acid solution; and the chromatographic separation described in the step 6) of the method for extracting the cannabis extract
  • the mobile phase mixture used consists of methanol/water and acetic acid or ethanol/water and acetic acid.
  • the cannabis extract can be obtained by the following method:
  • the extract is extracted 2-3 times with 2-8 times, 30%-80% ethanol, 0.5-2 hours each time;
  • the decolorization application in the step 3) is 0.1-1 wt. % activated carbon adsorption decolorization; the concentration is concentrated under reduced pressure at 70 ° C or concentrated at room temperature, and concentrated to a relative density of 1.01-1.03.
  • the cannabis extract of the present invention further comprises one or more of cannabinol CBG, hemp cyclohexanol, tetrahydrocannabinol THCV, and cannabinol ester.
  • the present invention also provides a composition
  • a composition comprising (1) cannabis extract or cannabidiol and (2) caffeine, said cannabis extract containing cannabidiol, said composition of cannabidiol
  • the mass ratio to caffeine is (1-100): 60.
  • composition of the present invention may be a food composition or a pharmaceutical composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) cannabinol or cannabis extract, (2) caffeine, and (3) a pharmaceutical excipient, the cannabis extract containing cannabidiol,
  • the mass ratio of cannabidiol to caffeine in the pharmaceutical composition is (1-100): 60.
  • the mass ratio of cannabidiol to caffeine in the pharmaceutical composition is (20-80): 60.
  • the mass ratio of cannabidiol to caffeine in the pharmaceutical composition is (30-70): 60.
  • the pharmaceutical composition has a mass ratio of cannabidiol to caffeine of 1:1.
  • the mass percentage of cannabidiol in the cannabis extract is from 10% to 99%.
  • the cannabis extract contains 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% by weight of the cannabisdiol.
  • the pharmaceutical composition comprises, by mass percentage, 0.1% to 1% of cannabidiol, 0.06% to 6% of caffeine, and 93% to 99% of pharmaceutically acceptable excipients. Further preferably, the pharmaceutical composition comprises, by mass percentage, from 0.1% to 1% of cannabidiol, from 0.075% to 1.5% of caffeine, and from 97.5% to 99% of pharmaceutically acceptable excipients. Most preferably, the pharmaceutical composition comprises, by mass percentage, 0.6% of cannabidiol, 0.6% of caffeine and 98.8% of pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises 0.1%-10% of the cannabis extract, 0.06%-6% of the caffeine and 84%-99% of the medicinal excipients by mass percentage.
  • the medicinal adjuvant is selected from the group consisting of a binder, a carrier, a pH adjuster, a filler, a disintegrant, a flavoring agent, a stabilizer, a solubilizer, a dispersing agent, a film forming agent, a plasticizer, and a wetting agent.
  • a solvent a solvent, a coating agent, a capsule shell, a coloring agent, a preservative, an antioxidant, and a surfactant.
  • the binder is from 2% to 8% by mass of the pharmaceutical composition; the binder is selected from the group consisting of cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl Cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, starch, micro-silica gel, starch syrup, syrup, sucrose, nectar, polyvinylpyrrolidone, liquid glucose, cellulose One or a combination of two or more of a derivative, sodium alginate, polyethylene glycol, magnesium aluminum silicate, gelatin, and tragacanth.
  • the binder is 5% by mass of the pharmaceutical composition; the binder is selected from the group consisting of microcrystalline cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, aluminum magnesium silicate One or a combination of two or more.
  • the pH adjuster is 0.1%-5% by mass of the pharmaceutical composition, and is selected from the group consisting of lactic acid, citric acid or a salt thereof, sodium hydrogencarbonate, sodium hydroxide, ethanesulfonic acid, tartaric acid, aspartic acid One or a combination of two or more of a salt thereof, a salt thereof, fumaric acid or a salt thereof, and methanesulfonic acid.
  • the pH adjusting agent is selected from the group consisting of lactic acid, citric acid or a salt thereof, fumaric acid or a salt thereof, or a combination of two or more thereof; 2% of the object.
  • the filler is selected from the group consisting of microcrystalline cellulose, glucose, lactose, starch, fumed silica gel, sucrose, sodium carbonate, calcium carbonate, sorbitol, mannitol, dextrose, propylene glycol; The percentage by mass is from 4% to 16% of the pharmaceutical composition. Further preferably, the filler is selected from the group consisting of starch and sorbitol; and the filler accounts for 13% by mass of the pharmaceutical composition.
  • the disintegrant is selected from the group consisting of alginic acid, agar, sodium hydrogencarbonate, tartaric acid, citric acid, and sodium starch glycolate; and the disintegrant accounts for 4% to 16% by mass of the pharmaceutical composition. Further preferably, the disintegrant accounts for 10% by mass of the pharmaceutical composition.
  • the flavoring agent is selected from the group consisting of lactose, glucose, peppermint, menthol, peppermint oil, stevioside, sucralose, xylitol, aspartame, sodium saccharin, sucralose, maple syrup, sorbitol One or a combination of two or more of fennel, clove, lactitol, perfume, maltose, lemon oil; the flavoring agent is 0.02% to 5% by mass of the pharmaceutical composition. Further preferably, the flavoring agent is selected from the group consisting of one or a combination of two or more of lactose, sodium saccharin, and sucralose; and the flavoring agent is 3% by mass of the pharmaceutical composition.
  • the solvent is water or ethanol.
  • the carrier is selected from the group consisting of cyclodextrin or a derivative thereof, polyethylene glycol, microcrystalline cellulose, lactose, polyvinylpyrrolidone or a combination of two or more; the carrier accounts for a percentage by mass Use from 1% to 16% of the composition.
  • the carrier is selected from the group consisting of cyclodextrin or a derivative thereof, microcrystalline cellulose, polyvinylpyrrolidone or a combination of two or more; the carrier is 9% by mass of the pharmaceutical composition .
  • the surfactant is selected from the group consisting of sodium lauryl sulfate, glycerin, sodium oleate, sodium lauroyl sarcosinate, betaine, or a combination of two or more; the surfactant is by mass The percentages range from 0.1% to 5% of the pharmaceutical composition. Further preferably, the surfactant is sodium lauroyl sarcosinate or sodium lauryl sulfate; the surfactant is 2.5% by mass of the pharmaceutical composition.
  • the preservative is selected from one or a combination of two or more of a benzoate, ascorbic acid, chlorphenone or paraben.
  • the preservative comprises from 0.08% to 0.15% by mass of the total amount of the pharmaceutical composition.
  • the benzoate is sodium benzoate, potassium benzoate or calcium benzoate; further preferably sodium benzoate.
  • the paraben is methylparaben, ethylparaben, propylparaben or a mixture of sodium nepaltone; further preferably methylparaben.
  • the preservative is 0.12% by mass of the total amount of the pharmaceutical composition.
  • the lubricant is selected from one or more of stearic acid, sodium stearate, calcium stearate, potassium stearate, polyethylene glycol, talc, and hydrogenated vegetable oil.
  • the film forming agent is selected from the group consisting of sodium alginate, carrageenan, maltodextrin, chitosan, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, trehalose, pectin, konjac One or a combination of two or more of gum, gum arabic, guar gum, pullulan, and locust bean gum.
  • the film former is 70%-85% by mass of the total amount of the pharmaceutical composition. More preferably, the film former is from 80% to 85% by mass based on the total amount of the pharmaceutical composition.
  • the film forming agent is sodium alginate.
  • the plasticizer is selected from one or a combination of two or more of glycerin, propylene glycol, sorbitol, mannitol, and ethylene glycol.
  • the plasticizer is from 10% to 20% by mass based on the total amount of the pharmaceutical composition. More preferably, the plasticizer is from 10% to 15% by mass based on the total amount of the pharmaceutical composition.
  • the plasticizer is glycerin or mannitol.
  • the pharmaceutical composition may be in any conventional dosage form such as a tablet, a film, a powder, a capsule, a granule, a powder, a pill, a topical lotion, a plaster, a solution or an injection.
  • the present invention also provides a food composition
  • a food composition comprising (1) cannabinol or cannabis extract and (2) caffeine, the cannabis extract containing cannabidiol, the food composition of the cannabis
  • the mass ratio of phenol to caffeine is (1-100): 60.
  • the mass ratio of cannabidiol to caffeine in the food composition is (20-80): 60.
  • the mass ratio of cannabidiol to caffeine in the food composition is (30-70): 60.
  • the mass ratio of cannabidiol to caffeine in the food composition is 1:1.
  • the mass percentage of cannabidiol in the cannabis extract is from 10% to 99%.
  • the cannabis extract contains 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% by weight of the cannabisdiol.
  • the food may be a beverage, a pasta, a rice, an edible oil, a dairy product, a protein powder, a porridge, a soup, a paste, a meat, a soy product, a chocolate, a candy, and a jelly.
  • the pasta is selected from the group consisting of flour, noodles, bread, twist, biscuits, and hazelnuts.
  • the rice is selected from rice flour.
  • the edible oil is selected from the group consisting of blended oils.
  • the dairy product is selected from the group consisting of milk, yogurt, and curd.
  • the meat is selected from the group consisting of sausages.
  • the bean product is selected from the group consisting of tofu and yuba.
  • the food composition is a beverage.
  • the beverage of the present invention further comprises a nutritional supplement, and more preferably, the mass percentage of the nutritional supplement in the beverage is 0.001%-70%, and the nutritional supplement is selected from the group consisting of vitamins and trace elements.
  • a nutritional supplement is selected from the group consisting of vitamins and trace elements.
  • the vitamin is selected from the group consisting of vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, vitamin C, vitamin E, inositol or a combination of two or more;
  • the amino acid is selected from the group consisting of tea One or a combination of two or more of L, tyrosine, glycine, and glutamic acid;
  • the trace element is one or more selected from the group consisting of iron, zinc, calcium, magnesium, copper, and the like.
  • the plant extract is selected from the group consisting of guarana extract, black pepper extract, maca extract, ginseng extract, Cistanche extract, puerarin extract, turmeric extract, ginkgo extract, medlar extract One or a combination of two or more of acai berry extract, cranberry extract, coconut extract, and Prunella vulgaris extract.
  • the nutritional supplement is selected from the group consisting of theanine, guarana extract, L-tyrosine, ⁇ -aminobutyric acid, taurine, black pepper extract, vitamin C, vitamin E, and beta.
  • the beverage according to the present invention further contains an additive. More preferably, the beverage has a content of 0.1%-50% by mass of the additive, and the additive is selected from the group consisting of spices, fruit and vegetable juices, and tea juice.
  • the additive is selected from the group consisting of spices, fruit and vegetable juices, and tea juice.
  • the juice is selected from the group consisting of apple juice, grape juice, lychee juice, peach juice, longan juice, orange juice, pineapple juice, mulberry juice, pomegranate juice, carrot juice, watermelon juice, passion fruit juice, tomato juice.
  • mango juice sugar cane juice, coconut juice, cantaloupe juice, rambutan juice, lemon juice, strawberry juice, passion fruit juice, tamarind juice, hairy basil juice, cocoa juice, pandanus juice, kiwi juice, winter melon juice
  • beetroot juice, blueberry juice, Sydney juice, cherry juice, betel nut juice, bitter gourd juice and plum juice, and other edible juices are selected from the group consisting of apple juice, grape juice, lychee juice, peach juice, longan juice, orange juice, pineapple juice, mulberry juice, pomegranate juice, carrot juice, watermelon juice, passion fruit juice, tomato juice.
  • mango juice sugar cane juice, coconut juice, cantaloupe juice, rambutan juice, lemon juice,
  • the flower tea juice according to the present invention is selected from one or a combination of two or more of green tea juice, rosacea juice, jasmine tea juice, lemon grass juice, chrysanthemum juice, and safflower juice.
  • the juice of the present invention may be a juice stock solution or a concentrate. Further preferably, the juice of the present invention is selected from the group consisting of concentrated cherry juice, concentrated apple juice, concentrated passion fruit juice, concentrated kiwi juice, concentrated Sydney juice, or a combination of two or more.
  • the fragrance is phenethylamine.
  • the sweetener is selected from the group consisting of white sugar, fructose syrup, sorbitol, aspartame, sucralose, xylitol, acesulfame potassium, maltitol, erythritol, isomalt One or a combination of two or more of ketitol, lactitol, lactose, maltose, mannose, trehalose, arabitol, saccharin, stevioside, maple syrup, and ganin. Further preferably, the sweetener is selected from one or a combination of two or more of fructose syrup, sorbitol, aspartame, saccharin, and stevioside.
  • the coloring agent is selected from one or a combination of two or more of bright blue, sunset yellow, chlorophyll, chlorophyll copper sodium salt, plausible red, iron oxide, amaranth or carmine.
  • the colorant is iron oxide or chlorophyll or a mixture thereof.
  • the acidity regulator is selected from the group consisting of citric acid or a salt thereof, malic acid or a salt thereof, fumaric acid or a salt thereof, adipic acid or a salt thereof, phosphoric acid or a salt thereof, gluconic acid or a salt thereof, tartaric acid or A combination of one or a mixture of a salt thereof, ascorbic acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof.
  • the acidity adjusting agent is selected from the group consisting of citric acid or a salt thereof, malic acid or a salt thereof, ascorbic acid or a salt thereof, or a combination of two or more thereof.
  • the preservative is selected from the group consisting of sodium benzoate, calcium benzoate, potassium benzoate, sodium sorbate, calcium sorbate, potassium sorbate, ascorbic acid, SHMP, BHA, BHT, TBHQ, dehydroacetic acid, hydrogen carbonate One or a combination of two or more of a base ester, ethoxyquine, and heptyl p-hydroxybenzoate. Further preferably, the preservative is selected from the group consisting of sodium benzoate, sodium sorbate or heptyl p-hydroxybenzoate.
  • the chelating agent is selected from the group consisting of sodium acetate or EDTA.
  • the stabilizer is selected from the group consisting of modified starch, carrageenan, pectin, konjac gum, xanthan gum, sodium carboxymethylcellulose, sodium alginate, sodium caseinate, and microcrystalline cellulose. Or a combination of two or more.
  • the beverage of the present invention may be a liquid beverage or a solid beverage.
  • the beverage according to the present invention may contain CO 2 (carbonated beverage) or may contain no CO 2 (no steamed beverage).
  • CO 2 carbonated beverage
  • no CO 2 no steamed beverage
  • the amount of CO 2 gas dissolved in the beverage is 2-2.5 times that of the beverage solvent (measured at 20 ° C).
  • the beverage of the present invention may be a non-alcoholic beverage, and the raw material of the beverage further includes water.
  • the beverage according to the present invention may be a beverage wine, wherein the beverage has an alcohol content of 0.5% to 60% (V/V), preferably 0.5% to 10% (V/V), and the beverage is
  • the raw material further includes one or a combination of two or more selected from the group consisting of alcohol, wine, rice wine, beer, fruit wine, white wine, brandy, whiskey, vodka, rum, gin, milk wine, or other distilled spirits.
  • the invention further provides a method for preparing a beverage, comprising the steps of:
  • step b) heating the vessel in step a), stirring and mixing to obtain a mixed liquid
  • step b) The mixed liquid obtained in the step b) is sequentially subjected to constant volume, filling, sterilization, and cooling to obtain a beverage.
  • the liquid used in the constant volume in the step c) is selected from the group consisting of water, alcohol, wine, rice wine, beer, fruit wine, white wine, brandy, whiskey, vodka, rum, gin, milk wine or other distilled spirits.
  • the sterilization temperature is from 75 ° C to 130 ° C.
  • the preparation method further comprises filling the container with CO 2 .
  • the present invention still further provides the use of cannabidiol or cannabis extract for the preparation of a product for preventing and/or improving caffeine adverse reactions.
  • the active ingredient in the cannabis extract is cannabinol.
  • the preventing and/or improving caffeine adverse reactions is to prevent and/or ameliorate caffeine-induced anxiety behavior;
  • the product may be a pharmaceutical, food or health supplement.
  • the "X-fold amount” and the like in the present invention means that the volume of the extraction solvent used is X times the mass of the extraction site, for example, in the "3-10 times amount", if the mass of the cannabis extraction portion is 1 g.
  • the amount of the extraction solvent is from 3 mL to 10 mL.
  • the "ethanol” described in the present invention is a mixture of pure ethanol and water or pure ethanol, wherein the concentration is a volume percentage (v/v%), such as 30% ethanol is a mixture of ethanol and water, which contains 30% pure Ethanol and 70% water, 100% ethanol is anhydrous ethanol.
  • the cannabis extract contains 50% of the mass of cannabidiol.
  • step (2) heating the cannabis leaf dried in step (1) with a 9-fold amount of 60% ethanol for 1 hour;
  • the mobile phase mixture consists of ethanol/water and acetic acid, ie, cannabis extract,
  • the cannabis extract contains 90% of the mass of cannabidiol.
  • step (2) heating the cannabis leaf dried in step (1) with a 7-fold amount of 80% ethanol for 1.5 hours;
  • the mobile phase mixture consists of ethanol/water and acetic acid, ie, cannabis extract,
  • the cannabis extract contains 99% of the mass of cannabidiol.
  • the cannabis extract contains 10% of the mass of cannabidiol.
  • Cannabis extract obtained in Example 1 0.2%, caffeine 6%, dextrin 84%, sodium carboxymethyl starch 7%, magnesium stearate 2.8%.
  • the cannabis extract and caffeine are sieved and mixed with dextrin and sodium carboxymethyl starch until a homogeneous mixture is formed, which is sieved to obtain a mixture and mixed with magnesium stearate.
  • the resulting powder form mixture is then compressed into tablets of the desired shape and size to obtain a medicinal tablet.
  • Cannabis extract obtained in Example 2 0.66%, caffeine 0.36%, maltodextrin 85%, mannitol 10%, sodium benzoate 0.08%, sucralose 1.79%, citric acid 0.11%, microcrystalline cellulose 2 %.
  • step b) adding the cannabis extract, caffeine, sodium benzoate, sucralose, citric acid, microcrystalline cellulose, mannitol to the colloidal maltodextrin obtained in step a) to obtain a colloidal mixture;
  • step c) obtaining a colloidal mixture in step b) by a doctor blade method to form a film
  • Cannabis extract obtained in Example 3 2%, caffeine 2%, microcrystalline cellulose 42%, pregelatinized starch 42%, croscarmellose 10%, magnesium stearate 2%.
  • the cannabis extract and caffeine are sieved and mixed with other excipients, and the mixture is filled into a hard gelatin capsule to obtain a medicinal capsule.
  • Cannabis extract obtained in Example 4 2%, caffeine 0.2%, microcrystalline cellulose 42.9%, pregelatinized starch 42.9%, croscarmellose 10%, magnesium stearate 2%.
  • the cannabis extract and caffeine are sieved and mixed with other excipients, and the mixture is filled into a hard gelatin capsule to obtain a medicinal capsule.
  • Cannabidiol (purity >99%) 0.1%, caffeine 0.06%, ⁇ -aminobutyric acid 0.2%, guarana extract 4%, theanine 0.2%, L-tyrosine 60%, taurine 0.6%, vitamin E 0.1%, concentrated apple juice 20%, stevioside 0.4%, chlorophyll 2%, malic acid 0.14%, water balance.
  • step b) heating the vessel in step a), stirring and mixing to obtain a mixed liquid
  • the mixed solution obtained in the step b) was made up to a volume of 100 mL, filled, sterilized at 100 ° C, and cooled to obtain a beverage.
  • Cannabidiol (purity >99%) 0.1%, caffeine 6%, vitamin C 0.05%, niacin 0.1%, concentrated cherry juice 40%, sorbitol 3%, chlorophyll 0.4%, iron oxide 0.1%, ascorbic acid 0.15 %, water balance.
  • step b) heating the vessel in step a), stirring and mixing to obtain a mixed liquid
  • step b) The mixture obtained in step b) is sequentially added with water to a constant volume of 100 mL, filled, sterilized at 75 ° C, and cooled to room temperature;
  • Cannabinol (purity >99%) 1%, caffeine 0.6%, ⁇ -carotene 0.15%, phenethylamine 0.08%, aspartame 4%, citric acid 0.1%, calcium benzoate 0.12%, milk wine margin.
  • step b) heating the vessel in step a), stirring and mixing to obtain a mixed liquid
  • step b) The mixed liquid obtained in the step b) is sequentially subjected to a constant volume of 100 mL of milk wine, filled, sterilized at 130 ° C, and cooled to obtain a beverage.
  • Cannabis extract obtained in Example 3 0.1%, caffeine 0.2%, vitamin E 0.1%, inositol 0.05%, glycine 0.08%, L-tyrosine 50%, grape juice 25%, phenethylamine 0.08% , sorbitol 4%, amaranth 0.09%, malic acid 0.2%, p-hydroxybenzoic acid heptyl ester 0.1%, water balance.
  • step b) heating the vessel in step a), stirring and mixing to obtain a mixed liquid
  • step b) The mixed liquid obtained in the step b) was sequentially subjected to water to a volume of 100 mL, filled, sterilized at 130 ° C, and cooled to obtain a beverage.
  • Cannabis extract obtained in Example 4 10%, caffeine 1%, ⁇ -carotene 0.15%, vitamin C 0.09, phenethylamine 0.08%, guarana extract 4%, mango juice 30%, maltitol 3%, sodium citrate 0.1%, sodium benzoate 0.12%, water balance.
  • step b) heating the vessel in step a), stirring and mixing to obtain a mixed liquid
  • step b) The mixed liquid obtained in the step b) was sequentially subjected to water to a volume of 100 mL, filled, sterilized at 130 ° C, and cooled to obtain a beverage.
  • Example 14 Cannabidiol (CBD) improves caffeine-induced anxiety behavior
  • Test animals 50 male Wistar rats of SPF grade, 180-200 g.
  • Breeding environment SPF animal room, free feeding, 12h light / 12h dark.
  • Test group After one week of adaptive feeding, rats were randomly divided into 5 groups according to body weight: normal control group, caffeine model group, CBD-1 mg/kg group, CBD-10 mg/kg group, CBD-100 mg/kg group. . Except the normal control group, each group of animals was intragastrically administered with 60 mg/kg caffeine physiological saline solution; each CBD group was intragastrically administered with the corresponding dose of CBD soybean oil solution, and the elevated plus maze test was performed 30 minutes after administration.
  • Elevated Cross Maze (EMP) Test The maze consists of two open arms (OA), two closed arms (CA), and a central platform. The labyrinth was fixed on the bracket, 50 cm from the ground, and a camera was placed above the central platform, and the behavior of the rat was analyzed by computer recording. The test was carried out under quiet, shading conditions. Before the test, the rats to be tested were placed in a squirrel cage, and they were quickly placed on the central platform of the EMP after 5 minutes of free exploration. Immediately after the release, the observation test was started, and each rat was tested for five minutes. After the end of each rat test, the maze was thoroughly cleaned with a towel dampened with water and a low concentration of ethanol. After the volatilization and diffusion, the next rat was tested.
  • Open arm entry the number of times to enter any open arm, which is based on the fact that all four paws of the rat enter the arm, and one paw in the middle withdraws completely from the arm. The second entry activity is completed.
  • Open arm residence time ratio (OT%), ie OT/(OT+CT) ⁇ 100%.
  • OE% and OT% were used as indicators for evaluating the anxiety state of rats.
  • CBD has a significant inhibition on anxiety behavior in rats
  • the OE% of the caffeine model group is 21.21%, which is a large slope for the gavage of rats from CBD-1 mg/kg to CBD-10 mg/kg.
  • the improvement was obvious.
  • the slope of CBD-10mg/kg and CBD-100mg/kg was slightly smaller than before, and the anxiety behavior was improved.
  • Test animals 100 male Wistar rats of SPF grade, 180-200 g.
  • Breeding environment SPF animal room, free feeding, 12h light / 12h dark.
  • Test group After one week of adaptive feeding, rats were randomly divided into 10 groups according to body weight: normal control group, group A (obtained in Example 5), group B (obtained in Example 6), and group C (example) 7 Preparation), Group D (obtained in Example 9), Group E (obtained in Example 10), Group F (obtained in Example 11), Group G (obtained in Example 8), H (Example 12) Preparation obtained) and I (obtained in Preparation of Example 13). Except the normal control group (administered saline), each drug-administered group was administered with a pharmaceutical composition or a 50 mL beverage at the same time. After 30 minutes of administration, the elevated plus maze test was performed, and the blood pressure of the rats was measured by non-invasive method after the behavioral test.
  • the ratio of the number of times of entering the open arms and the time ratio of the rats to which the products of Examples 5-13 (AI group) were applied were similar to those in the normal case, that is, substantially no production was observed in the rats compared with the normal control group.
  • Anxiety behavior At the same time, according to the caffeine model group in Experiment 1, the OE% was 21.21%, and the anxiety effect was obvious. That is to say, the administration of the pharmaceutical composition or the beverage prepared by the embodiment of the invention does not produce an anxiety behavior, and the cannabis extract or cannabidiol is reflected from the side to inhibit the anxiety behavior caused by caffeine in rats, especially group B and F. Rats in group and group D had no excessive anxiety behavior, and blood pressure in the AI group was in the normal range after the test.

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Abstract

本发明提供了一种包括大麻二酚或大麻提取物和咖啡因的组合物，所述的大麻提取物中大麻二酚的质量百分比为10％-99％，所述的组合物中大麻二酚和咖啡因的质量比为(1-100)：60，所述的组合物可以为食品组合物或药用组合物，所述的大麻二酚或大麻提取物能够预防和/或改善咖啡因不良反应，特别是预防和/或改善咖啡因诱导的焦虑行为。

Description

一种含有大麻二酚或大麻提取物和咖啡因的组合物及其应用 技术领域
本发明涉及医药健康领域，具体涉及一种含有大麻二酚或大麻提取物和咖啡因的组合物及其在制备食品或药品中的应用。
背景技术
咖啡因属甲基黄嘌呤生物碱，可兴奋心脏、骨骼肌和中枢神经系统，还能促进胃酸分泌、利尿和治疗偏头痛等疾病。咖啡因的生理活性机制多数与促进细胞内Ca 2+释放，提高细胞内cAMP浓度拮抗腺苷A1和A2A受体相关。长期慢性或一次性大剂量(>400mg)摄取咖啡因会出现一系列的身体与心理的不良反应，比如兴奋过度，神经过敏、焦躁、失眠、心悸、震颤、脑代谢紊乱等。
大麻二酚(CBD)是药用植物大麻中的主要化学成分，提取自大麻植株，是大麻中的非成瘾性成分，CBD自身具有激动腺苷A2A受体的作用。CBD在中枢神经系统发挥镇静、抗惊厥、抗焦虑等作用；在心血管系统，CBD可舒张血管，并通过抑制L型Ca 2+通道降低心肌收缩力。
专利US20160250270A1公开了一种饮料组合物，所述的饮料组合物中可以含有0.1-10wt％的CBD，以及0.015-15wt％的咖啡因。
专利US20160324776A1公开了一种含有大麻素的含咖啡因的饮料，其中饮料保持其原有的味道和外观，大麻素的含量可以为0.1-5wt％，而大麻素的添加可以使消费者冷静而警觉。
专利CN201280005750.7公开了经冷榨并过滤的大麻汁液可与果汁、蔬菜汁和/或水、糖和香草和/或含咖啡因成分等原料进行混合以制成软饮料。
专利US20170112161A1公开了制造从大麻植物提取的含有大麻素的咖啡产品的方法，包括从大麻植物中提取大麻素和将大麻素混入咖啡产品中。
综上所述，尽管现有技术中已经报道了含有大麻素(例如是大麻二酚)和咖啡因的饮品，但是还没有对CBD对咖啡因诱导的焦虑行为的改善作用研究，也没有报道CBD和咖 啡因组合物的剂量比例。
因此，为克服现有技术的缺陷，本申请公开了一种含有大麻二酚和咖啡因的组合物及其应用。
发明内容
本发明令人惊讶的发现，通过将大麻二酚或大麻提取物和咖啡因组合使用后可以有效抑制咖啡因导致的焦虑行为。
本发明提供了一种组合物，包括(1)大麻二酚或大麻提取物和(2)咖啡因，所述的大麻提取物中含有大麻二酚，所述组合物中的大麻二酚和咖啡因的质量比为(1-100)：60。
优选的，所述的组合物中大麻二酚和咖啡因的质量比为(20-80)：60。进一步优选的，所述的组合物中大麻二酚和咖啡因的质量比为(30-70)：60。最优选的，所述的组合物中大麻二酚和咖啡因的质量比为1：1。
优选的，所述的大麻二酚采用化学合成、生物合成、植物提取或其他方式制备得到。
优选的，所述的大麻提取物中大麻二酚的质量百分比为10％-99％。例如，所述的大麻提取物中按质量百分比含有大麻二酚为10％、20％、30％、40％、50％、60％、70％、80％、90％、95％、99％。
本发明所述的大麻提取物的提取部位为大麻的秆芯、花、叶、根和/或籽的外壳。本发明所述的大麻提取物，可以是将大麻植株不同的植物部位分别提取形成的提取物或提取物的组合，也可以是将大麻植株不同的植物部位或其组合同时提取，得到的提取物或提取物的组合。优选的，所述的提取部位为大麻花和/或大麻叶。
本发明所述的大麻提取物是通过药学或食品领域常规提取方法提取得到，优选通过溶剂提取得到。提取溶剂选自水、低分子醇或其水溶液、乙酸酯、酮、醚或低沸点的烃；所述的低分子醇包括甲醇、乙醇、丁醇或丙醇；所述的乙酸酯包括乙酸甲酯或乙酸乙酯；所述的酮包括丙酮；所述的醚包括甲醚或乙醚；所述的低沸点的烃包括脂肪烃、芳香烃或氯化烃。优选的，所述的提取溶剂选自水或乙醇溶液。
在本发明的一个具体实施方式中，所述的大麻提取物可以通过以下方法得到：
1)使用提取溶剂或其混合物对原材料加热回流；
2)过滤除去残余物；
3)萃取；
4)调节pH值为2-4；
5)用提取溶剂提取，随后除去溶剂；
6)进行色谱分离，获得大麻提取物。
优选的，所述步骤1)中使用3-10倍量的提取溶剂或其混合物对大麻提取部位加热回流至少1小时；所述的大麻提取物提取方法中步骤3)中所述的萃取溶剂为含有20wt％的乙醇的氢氧化钠水溶液；所述步骤4)中pH调节剂为萃取液与5％硫酸溶液的混合液；所述的大麻提取物提取方法中步骤6)中所述的色谱分离应用的流动相混合物由甲醇/水和乙酸或乙醇/水和乙酸组成。
在本发明的一个具体实施方式中，所述的大麻提取物可以通过以下方法得到：
1)将原材料粉碎至10-40目，得到粉末；
2)将所得粉末用提取溶剂冷浸提取，得到提取液；
3)将所得的提取液脱色；
4)浓缩，即得大麻提取物浸膏。
优选的，所述步骤2)中，用2-8倍量、30％-80％的乙醇冷浸提取1-3次，每次0.5-2小时；所述步骤3)中脱色应用0.1-1wt％活性炭吸附脱色；所述浓缩在70℃条件下减压浓缩或室温下浓缩，浓缩到相对密度为1.01-1.03。
本发明所述的大麻提取物还包括大麻萜酚CBG、大麻环萜酚、四氢次大麻酚THCV、大麻萜酚酯中的一种或两种以上。
本发明还提供了一种组合物，由(1)大麻提取物或大麻二酚和(2)咖啡因组成，所述的大麻提取物中含有大麻二酚，所述的组合物中大麻二酚和咖啡因的质量比为(1-100)：60。
本发明所述的组合物，可以为食品组合物或药用组合物。
本发明还提供了一种药用组合物，包括(1)大麻二酚或大麻提取物、(2)咖啡因以及(3)药用辅料，所述的大麻提取物含有大麻二酚，所述的药用组合物中大麻二酚和咖啡因的质量比为(1-100)：60。优选的，所述的药用组合物中大麻二酚和咖啡因的质量比为(20-80)：60。进一步优选的，所述的药用组合物中大麻二酚和咖啡因的质量比为(30-70)：60。最优选的，所述的药用组合物中大麻二酚和咖啡因的质量比为1：1。
优选的，所述的大麻提取物中大麻二酚的质量百分比为10％-99％。例如，所述的大麻提取物中按质量百分比含有大麻二酚为10％、20％、30％、40％、50％、60％、70％、80％、90％、95％、99％。
优选的，所述药用组合物中按质量百分比包括大麻二酚0.1％-1％，咖啡因0.06％-6％和药用辅料93％-99％。进一步优选的，所述药用组合物中按质量百分比包括大麻二酚为0.1％-1％，咖啡因0.075％-1.5％和药用辅料97.5％-99％。最优选的，所述药用组合物中按质量百分比包括大麻二酚为0.6％，咖啡因0.6％和药用辅料98.8％。
优选的，所述的药物组合物中按质量百分比包括大麻提取物0.1％-10％，咖啡因0.06％-6％和药用辅料84％-99％。
优选的，所述的药用辅料选自粘合剂、载体、pH调节剂、填充剂、崩解剂、调味剂、稳定剂、增溶剂、分散剂、成膜剂、增塑剂、润湿剂、溶剂、包衣剂、胶囊剂壳、着色剂、防腐剂、抗氧化剂、表面活性剂中的一种或两种以上的组合。
优选的，所述的粘合剂按质量百分比占药用组合物的2％-8％；所述粘合剂选自纤维素、微晶纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟乙基纤维素、乙基纤维素、甲基纤维素、羟甲基纤维素钠、淀粉、微粉硅胶、淀粉浆、糖浆、饴糖、炼蜜、聚乙烯吡咯烷酮、液状葡萄糖、纤维素衍生物、海藻酸钠、聚乙二醇、硅酸铝镁、明胶、西黄蓍胶中的一种或两种以上的组合。进一步优选的，所述的粘合剂按质量百分比占药用组合物的5％；所述粘合剂选自微晶纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、硅酸铝镁中的一种或两种以上的组合。
优选的，所述的pH调节剂按质量百分比占药用组合物的0.1％-5％，选自乳酸、柠檬 酸或其盐、碳酸氢钠、氢氧化钠、乙磺酸、酒石酸、天冬氨酸或其盐、富马酸或其盐、甲磺酸中的一种或两种以上的组合。进一步优选的，所述的pH调节剂选自乳酸、柠檬酸或其盐、富马酸或其盐中的一种或两种以上的组合；所述的pH调节剂按质量百分比占药用组合物的2％。
优选的，所述的填充剂选自微晶纤维素、葡萄糖、乳糖、淀粉、烟雾硅胶、蔗糖、碳酸钠、碳酸钙、山梨醇、甘露醇、右旋糖、丙二醇；所述的填充剂按质量百分比占药用组合物的4％-16％。进一步优选的，所述的填充剂选自淀粉、山梨醇；所述的填充剂按质量百分比占药用组合物的13％。
优选的，所述的崩解剂选自海藻酸、琼脂、碳酸氢钠、酒石酸、柠檬酸、淀粉羟乙酸钠；所述崩解剂按质量百分比占药用组合物的4％-16％。进一步优选的，所述崩解剂按质量百分比占药用组合物的10％。
优选的，所述的调味剂选自乳糖、葡萄糖、薄荷、薄荷醇、薄荷油、甜菊糖、蔗糖素、木糖醇、阿斯巴甜、糖精钠、三氯蔗糖、枫糖浆、山梨糖醇、茴香脑、丁香、乳糖醇、香精、麦芽糖、柠檬油中的一种或两种以上的组合；所述调味剂按质量百分比占药用组合物的0.02％-5％。进一步优选的，所述的调味剂选自乳糖、糖精钠、三氯蔗糖中的一种或两种以上的组合；所述调味剂按质量百分比占药用组合物的3％。
优选的，所述溶剂为水或乙醇。
优选的，所述载体选自环糊精或其衍生物、聚乙二醇、微晶纤维素、乳糖、聚乙烯吡咯烷酮中的一种或两种以上的组合；所述载体按质量百分比占药用组合物的1％-16％。进一步优选的，所述载体选自环糊精或其衍生物、微晶纤维素、聚乙烯吡咯烷酮中的一种或两种以上的组合；所述载体按质量百分比占药用组合物的9％。
优选的，所述表面活性剂选自十二烷基硫酸钠、甘油、油酸钠、月桂酰肌氨酸钠、甜菜碱中的一种或两种以上的组合；所述表面活性剂按质量百分比占药用组合物的0.1％-5％。进一步优选的，所述表面活性剂为月桂酰肌氨酸钠或十二烷基硫酸钠；所述表面活性剂按质量百分比占药用组合物的2.5％。
优选的，所述防腐剂选自苯甲酸盐、抗坏血酸、氯苯甘醚或尼泊金酯类中的一种或两种以上的组合。优选的，所述防腐剂按质量百分比占药用组合物总量的0.08％-0.15％。优选的，所述苯甲酸盐为苯甲酸钠、苯甲酸钾或苯甲酸钙；进一步优选为苯甲酸钠。所述尼泊金酯类为尼泊金甲酯、尼泊金乙酯、尼泊金丙酯或尼泊金混合脂钠；进一步优选为尼泊金甲酯。所述防腐剂按质量百分比占药用组合物总量的0.12％。
优选的，所述润滑剂选自硬脂酸、硬脂酸钠、硬脂酸钙、硬脂酸钾、聚乙二醇、滑石粉、氢化植物油中的一种或两种以上。
优选的，所述成膜剂选自海藻酸钠、卡拉胶、麦芽糊精、壳聚糖、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻糖、果胶、魔芋胶、阿拉伯胶、瓜尔胶、普鲁兰、刺槐豆胶中的一种或两种以上的组合。优选的，所述的成膜剂按质量百分比占药用组合物总量为70％-85％。更优选的，所述的成膜剂按质量百分比占药用组合物总量为80％-85％。优选的，所述的成膜剂为海藻酸钠。
优选的，所述的增塑剂选自甘油、丙二醇、山梨醇、甘露醇、乙二醇中的一种或两种以上的组合。优选的，所述的增塑剂按质量百分比占药用组合物总量为10％-20％。更优选的，所述的增塑剂按质量百分比占药用组合物总量为10％-15％。优选的，所述的增塑剂为甘油或甘露醇。
优选的，所述药用组合物可以为任意常规剂型，如片剂、膜剂、散剂、胶囊剂、颗粒、粉剂、丸剂、外用涂剂、膏药、溶液剂或注射剂。
本发明还提供了一种食品组合物，包括(1)大麻二酚或大麻提取物和(2)咖啡因，所述的大麻提取物中含有大麻二酚，所述的食品组合物中大麻二酚和咖啡因的质量比为(1-100)：60。优选的，所述的食品组合物中大麻二酚和咖啡因的质量比为(20-80)：60。进一步优选的，所述的食品组合物中大麻二酚和咖啡因的质量比为(30-70)：60。最优选的，所述的食品组合物中大麻二酚和咖啡因的质量比为1：1。
优选的，所述的大麻提取物中大麻二酚的质量百分比为10％-99％。例如，所述的大麻提取物中按质量百分比含有大麻二酚为10％、20％、30％、40％、50％、60％、70％、80％、 90％、95％、99％。
优选的，所述的食品可以为饮料、面食、米、食用油、奶制品、蛋白粉、粥、汤、糊、肉食、豆制品、巧克力、糖果、果冻。
进一步优选的，所述的面食选自面粉、面条、面包、麻花、饼干、粽子。所述的米选自米粉。所述的食用油选自调和油。所述的奶制品选自牛奶、酸奶、凝乳。所述的肉食选自香肠。所述的豆制品选自豆腐、腐竹。
最优选的，所述的食品组合物为饮料。
优选的，本发明所述饮料中还包括营养补充物质，更优选的，所述的饮料中营养补充物质的质量百分比为0.001％-70％，所述的营养补充物质选自维生素、微量元素、β-胡萝卜素、氨基酸、γ-氨基丁酸、牛磺酸和植物提取物中的一种或两种以上的组合。
优选的，所述的维生素选自维生素B1、维生素B2、烟酸、维生素B6、维生素B12、维生素C、维生素E、肌醇中的一种或两种以上的组合；所述的氨基酸选自茶氨酸，L-酪氨酸，甘氨酸，谷氨酸中的一种或两种以上的组合；所述的微量元素选自铁、锌、钙、镁、铜等中的一种或两种以上的组合；所述的植物提取物选自瓜拉纳提取物、黑胡椒提取物、玛卡提取物、人参提取物、肉苁蓉提取物、葛根提取物、姜黄提取物、银杏提取物、枸杞提取物、巴西莓提取物、越橘提取物、椰子提取物、夏枯草提取物中的一种或两种以上的组合。进一步优选的，所述的营养补充物质选自茶氨酸、瓜拉纳提取物、L-酪氨酸、γ-氨基丁酸、牛磺酸、黑胡椒提取物、维生素C、维生素E、β-胡萝卜素、烟酸、维生素B6、维生素B12、肌醇中的一种或两种以上的组合。
优选的，本发明所述的饮料中还含有添加剂，更优选的，所述的饮料中按质量百分比添加剂的含量为0.1％-50％，所述的添加剂选自香料、果蔬汁、花茶汁、着色剂、酸度调节剂、防腐剂、乳化剂、抗氧化剂、增稠剂、螯合剂、稳定剂、甜味剂中的一种或两种以上的组合。
优选的，所述的果蔬汁选自苹果汁、葡萄汁、荔枝汁、桃汁、龙眼汁、桔汁、菠萝汁、桑椹汁、石榴汁、胡萝卜汁、西瓜汁、西番莲汁、西红柿汁、芒果汁、甘蔗汁、椰子汁、 哈密瓜汁、红毛丹果汁、柠檬汁、草莓汁、西番莲果汁、罗望子汁、毛罗勒汁、可可汁、露兜树果汁、猕猴桃汁、冬瓜汁、甜菜根汁、蓝莓汁、雪梨汁、樱桃汁、槟榔汁、苦瓜汁和李子汁以及其他可食用果汁中的一种或两种以上的组合。本发明所述的花茶汁选自绿茶汁、洛神花汁、茉莉花茶汁、柠檬草汁、菊花汁、红花汁中的一种或两种以上的组合。本发明所述的果蔬汁可以是果汁原液也可以是浓缩液。进一步优选的，本发明所述的果蔬汁选自浓缩樱桃汁、浓缩苹果汁、浓缩西番莲汁、浓缩猕猴桃汁、浓缩雪梨汁中的一种或两种以上的组合。
优选的，所述的香料为苯乙胺。
优选的，所述的甜味剂选自白砂糖、果葡糖浆、山梨糖醇、阿斯巴甜糖、三氯蔗糖、木糖醇、乙酰磺胺酸钾、麦芽糖醇、赤藓糖醇、异麦芽酮糖醇、乳糖醇、乳糖、麦芽糖、甘露糖、海藻糖、阿拉伯糖醇、糖精、甜菊苷、枫糖浆和甘精中的一种或两种以上的组合。进一步优选的，所述的甜味剂选自果葡糖浆、山梨糖醇、阿斯巴甜糖、糖精、甜菊苷中的一种或两种以上的组合。
优选的，所述的着色剂选自亮蓝、日落黄、叶绿素、叶绿素铜钠盐、诱惑红、氧化铁、苋菜红或胭脂红中的一种或两种以上的组合。进一步优选的，所述的着色剂为氧化铁或叶绿素或他们的混合。
优选的，所述的酸度调节剂选自柠檬酸或其盐、苹果酸或其盐、富马酸或其盐、己二酸或其盐、磷酸或其盐、葡萄糖酸或其盐、酒石酸或其盐、抗坏血酸或其盐、乙酸或其盐、磷酸或其盐中的一种或两种以上的组合。进一步优选的，所述的酸度调节剂选自柠檬酸或其盐、苹果酸或其盐、抗坏血酸或其盐中的一种或两种以上的组合。
优选的，所述防腐剂选自苯甲酸钠、苯甲酸钙、苯甲酸钾、山梨酸钠、山梨酸钙、山梨酸钾、抗坏血酸、SHMP、BHA、BHT、TBHQ、脱氢乙酸、碳酸氢二甲基酯、乙氧基喹、对羟基苯甲酸庚酯中的一种或两种以上的组合。进一步优选的，所述防腐剂选自苯甲酸钠、山梨酸钠或对羟基苯甲酸庚酯。
优选的，所述的螯合剂选自乙酸钠或EDTA。
优选的，所述的稳定剂选自变性淀粉、卡拉胶、果胶、魔芋胶、黄原胶、羧甲基纤维素钠、海藻酸钠、酪朊酸钠、微晶纤维素中的一种或两种以上的组合。
本发明所述的饮料可以为液体饮料或固体饮料。
本发明所述的饮料中可以含有CO 2(碳酸饮料)，也可以不含有CO 2(无汽饮料)。优选的，当本发明所述的饮料为碳酸饮料时，所述的饮料中CO 2气溶量为饮料溶剂的2-2.5倍(20℃时测量)。
本发明所述的饮料可以为非酒精饮料，则所述的饮料中原料还包括水。
本发明所述的饮料可以为饮料酒，所述的饮料酒中酒精含量为0.5％-60％(V/V)，优选为0.5％-10％(V/V)，则所述的饮料的原料还包括选自酒精、葡萄酒、黄酒、啤酒、果酒、白酒、白兰地、威士忌、伏特加、朗姆酒、杜松子酒、奶酒或其他蒸馏酒中的一种或两种以上的组合。
本发明进一步提供了一种饮料的制备方法，包括如下步骤：
a)按比例称取原料，放置在容器中，所述的容器中加入适量的水；
b)加热步骤a)中的容器，搅拌混合，获得混合液；
c)将步骤b)中获得的混合液依次进行定容、灌装、灭菌、冷却，获得饮料。
优选的，所述步骤c)中的定容所用液体选自水、酒精、葡萄酒、黄酒、啤酒、果酒、白酒、白兰地、威士忌、伏特加、朗姆酒、杜松子酒、奶酒或其他蒸馏酒中的一种或两种以上的组合；所述的灭菌的温度为75℃-130℃。
优选的，当所述的饮料为碳酸饮料时，所述的制备方法还包括向容器中填充CO 2。
本发明又进一步提供了大麻二酚或大麻提取物在制备预防和/或改善咖啡因不良反应的产品中的应用。优选的，所述的大麻提取物中有效成分为大麻二酚。
优选的，所述预防和/或改善咖啡因不良反应为预防和/或改善咖啡因诱导的焦虑行为；所述的产品可以为药品、食品或保健品。
除非特别说明，本发明中的“X倍量”等描述，是指采用的提取溶剂的体积是提取部位质量的X倍，比如，“3-10倍量”中，若大麻提取部位质量为1g，提取溶剂的用量为 3mL-10mL。
本发明中所述的“乙醇”，为纯乙醇与水的混合物或纯乙醇，其中浓度为体积百分比(v/v％)，如30％乙醇为乙醇和水的混合物，其含30％的纯乙醇和70％的水，100％乙醇为无水乙醇。
具体实施方式
下面将结合本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明的部分实施例，而不是全部。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1 大麻提取物的制备
(1)将原材料大麻叶洗净风干；
(2)将上述风干后的原材料粉碎，后过40目筛；
(3)将所得粉末，用6倍量、45％的乙醇冷浸提取2次，每次1.5小时；
(4)合并提取液，经0.5wt％活性炭吸附脱色；
(5)70℃温度条件下，减压浓缩至相对密度1.02，即得大麻提取物，
其中，大麻提取物中含有大麻二酚质量含量为50％。
实施例2 大麻提取物的制备
(1)将原材料大麻叶洗净风干；
(2)使用9倍量的60％乙醇对步骤(1)中风干的大麻叶加热回流1小时；
(3)过滤除去残余物，真空条件下除去溶剂；
(4)将获得的浸膏在温度约125℃加热约40分钟；
(5)随后进行色谱分离，其中流动相混合物由乙醇/水和乙酸组成，即得大麻提取物，
其中，大麻提取物中含有大麻二酚质量含量为90％。
实施例3 大麻提取物的制备
(1)将原材料大麻叶洗净风干；
(2)使用7倍量的80％乙醇对步骤(1)中风干的大麻叶加热回流1.5小时；
(3)过滤除去残余物；
(4)用5wt％的氢氧化钠水溶液至少萃取两次，其中氢氧化钠水溶液中含有20wt％的乙醇；
(5)将萃取液与5wt％的硫酸溶液混合以使pH值约3；
(6)然后使用脂肪烃提取两次，低温真空下除去溶剂；
(7)随后进行色谱分离，其中流动相混合物由乙醇/水和乙酸组成，即得大麻提取物，
其中，大麻提取物中含有大麻二酚质量含量为99％。
实施例4 大麻提取物的制备
(1)将原材料大麻叶洗净风干；
(2)将上述风干后的原材料粉碎，后过10目筛；
(3)将所得粉末，用2倍量、30％的乙醇冷浸提取2次，每次1小时；
(4)合并提取液，经0.5wt％活性炭吸附脱色；
(5)室温条件下，减压浓缩至相对密度1.02，即得大麻提取物，
其中，大麻提取物中含有大麻二酚质量含量为10％。
实施例5 药用组合物片剂的制备
一、原料(质量百分比)
大麻提取物(实施例1制备获得)0.2％，咖啡因6％，糊精84％，羧甲基淀粉钠7％，硬脂酸镁2.8％。
二、制备方法
将所述大麻提取物和咖啡因过筛，并与糊精和羧甲基淀粉钠混合直至形成均匀的混合物，过筛得到混合物，并与硬脂酸镁混合。然后将所得的粉型混合物压制成需要形状和大小的药片，获得药用片剂。
实施例6 药用组合物膜剂的制备
一、原料(质量百分比)
大麻提取物(实施例2制备获得)0.66％，咖啡因0.36％，麦芽糊精85％，甘露醇10％， 苯甲酸钠0.08％，三氯蔗糖1.79％，柠檬酸0.11％，微晶纤维素2％。
二、制备方法
a)将所述的麦芽糊精进行溶胀，获得胶状麦芽糊精；
b)在步骤a)获得的胶状麦芽糊精中加入大麻提取物，咖啡因，苯甲酸钠，三氯蔗糖，柠檬酸，微晶纤维素，甘露醇，获得胶体混合物；
c)将步骤b)获得胶体混合物采用刮浆法形成薄膜；
d)将步骤c)获得的薄膜进行烘干，获得药用膜剂。
实施例7 药用组合物胶囊剂的制备
一、原料(质量百分比)
大麻提取物(实施例3制备获得)2％，咖啡因2％，微晶纤维素42％，预胶凝淀粉42％，交联羧甲基纤维素10％，硬脂酸镁2％。
二、制备方法
将所述大麻提取物和咖啡因过筛，并与其他辅料混合，将混合物装入硬明胶胶囊中，获得药用胶囊剂。
实施例8 药用组合物胶囊剂的制备
一、原料(质量百分比)
大麻提取物(实施例4制备获得)2％，咖啡因0.2％，微晶纤维素42.9％，预胶凝淀粉42.9％，交联羧甲基纤维素10％，硬脂酸镁2％。
二、制备方法
将所述大麻提取物和咖啡因过筛，并与其他辅料混合，将混合物装入硬明胶胶囊中，获得药用胶囊剂。
实施例9 饮料的制备
一、原料(质量百分比)
大麻二酚(纯度>99％)0.1％，咖啡因0.06％，γ-氨基丁酸0.2％、瓜拉纳提取物4％、茶氨酸0.2％、L-酪氨酸60％，牛磺酸0.6％，维生素E 0.1％，浓缩苹果汁20％，甜菊苷0.4％， 叶绿素2％，苹果酸0.14％，水余量。
二、制备方法
a)按比例称取原料，放置在容器中，所述的容器中加入适量的水；
b)加热步骤a)中的容器，搅拌混合，获得混合液；
c)将步骤b)中获得的混合液定容100mL、灌装、100℃灭菌、冷却，获得饮料。
实施例10 饮料的制备
一、原料(质量百分比)
大麻二酚(纯度>99％)0.1％，咖啡因6％，维生素C 0.05％，烟酸0.1％，浓缩樱桃汁40％，山梨糖醇3％，叶绿素0.4％，氧化铁0.1％，抗坏血酸0.15％，水余量。
二、制备方法
a)按比例称取原料，放置在容器中，所述的容器中加入适量的水；
b)加热步骤a)中的容器，搅拌混合，获得混合液；
c)将步骤b)中获得的混合液依次进行加水定容100mL、灌装、75℃灭菌、冷却至室温；
d)填充二氧化碳，使得产品的气溶量为饮料的2.0倍(20℃)，获得饮料。
实施例11 饮料的制备
一、原料(质量百分比)
大麻二酚(纯度>99％)1％，咖啡因0.6％，β-胡萝卜素0.15％，苯乙胺0.08％，阿斯巴甜糖4％，柠檬酸0.1％，苯甲酸钙0.12％，奶酒余量。
二、制备方法
a)按比例称取原料，放置在容器中，所述的容器中加入适量的水；
b)加热步骤a)中的容器，搅拌混合，获得混合液；
c)将步骤b)中获得的混合液依次进行奶酒定容100mL、灌装、130℃灭菌、冷却，获得饮料。
实施例12 饮料的制备
一、原料(质量百分比)
大麻提取物(实施例3制备获得)0.1％，咖啡因0.2％，维生素E 0.1％，肌醇0.05％，甘氨酸0.08％，L-酪氨酸50％，葡萄汁25％，苯乙胺0.08％，山梨糖醇4％，苋菜红0.09％，苹果酸0.2％，对羟基苯甲酸庚酯0.1％，水余量。
二、制备方法
a)按比例称取原料，放置在容器中，所述的容器中加入适量的水；
b)加热步骤a)中的容器，搅拌混合，获得混合液；
c)将步骤b)中获得的混合液依次进行水定容100mL、灌装、130℃灭菌、冷却，获得饮料。
实施例13 饮料的制备
一、原料(质量百分比)
大麻提取物(实施例4制备获得)10％，咖啡因1％，β-胡萝卜素0.15％，维生素C 0.09，苯乙胺0.08％，瓜拉纳提取物4％，芒果汁30％，麦芽糖醇3％，柠檬酸钠0.1％，苯甲酸钠0.12％，水余量。
二、制备方法
a)按比例称取原料，放置在容器中，所述的容器中加入适量的水；
b)加热步骤a)中的容器，搅拌混合，获得混合液；
c)将步骤b)中获得的混合液依次进行水定容100mL、灌装、130℃灭菌、冷却，获得饮料。
实施例14 大麻二酚(CBD)改善咖啡因导致的焦虑行为
试验一
一、目的
研究不同剂量CBD对高剂量咖啡因摄入诱发的大鼠焦虑行为的防治作用。
二、试验动物及组别
试验动物：SPF级雄性wistar大鼠50只，180-200g。饲养环境：SPF级动物房，自由摄食，12h光照/12h黑暗。
试验组别：适应性饲养一周后，根据体重将大鼠随机分为5组：正常对照组、咖啡因模型组、CBD-1mg/kg组、CBD-10mg/kg组、CBD-100mg/kg组。除正常对照组外，各组动物均灌胃给予60mg/kg咖啡因生理盐水溶液；各CBD给药组同时灌胃给予相应剂量的CBD大豆油溶液，给药30min后进行高架十字迷宫测试。
三、试验方法
高架十字迷宫(EMP)测试:迷宫由2个开放臂(open arm,OA)、两个封闭臂(closed arm，CA)及中央平台组成，呈十字形。迷宫固定于支架上，离地面50cm，中央平台上方安置摄像头，通过电脑记录分析大鼠行为。测试于安静、遮光条件下进行。测试前，将待测大鼠放于一个鼠笼内，待其自由探究5min后迅速置于EMP的中央平台处，释放后立刻开始观察测试，每只大鼠测试五分钟。每只大鼠检测结束后，用毛巾蘸清水及低浓度乙醇彻底清理迷宫，待其挥发扩散后，再进行下一只大鼠的测试。
测试内容：
(1)进入开放臂次数(open arm entry，OE)：进入到任一开放臂的次数，以大鼠四个爪子均进入到臂内为准，中途一个爪子从该臂中完全退出则为该次进入活动完成。
(2)进入开放臂时间(open arm time，OT)：单位：s。
(3)进入封闭臂次数(closed arm entry，CE)：进入到任一封闭臂的次数，判断标准同OE。
(4)进入封闭臂时间(closed arm time，CT)：单位：s。
(5)计算出进入开放臂次数比例(OE％)：即OE/(OE+CE)×100％。
(6)开放臂停留时间比例(OT％)，即OT/(OT+CT)×100％。以OE％和OT％作为评价大鼠焦虑状态的指标。
统计方法：
数据以
Figure PCTCN2018109658-appb-000001
表示，多样本均数比较采用单因素方差分析(one way ANOVA)，两组间比较采用t检验。
四、结果
进臂次数、时间及其比率见表1。
表1 进臂次数、时间及其比率
  OE(次) OT(s) OE％ OT％ CE(次) CT(s)
正常对照 5.3±0.48 105±4.52 52.94 34.4 4.8±0.68 200±1.24
咖啡因模型 2.1±0.78 42.9±1.89 21.21 14.50 7.8±0.11 253±5.09
CBD-1mg/kg 3.2±0.45 58.1±3.30 31.37 19.24 7.0±0.92 244±5.14
CBD-10mg/kg 4.8±0.91 85±2.07 47.52 28.43 5.3±1.07 214±4.01
CBD-100mg/kg 5.4±0.25 100±1.32 54.00 33.22 4.5±0.91 201±3.05
由表1可知，CBD对大鼠焦虑行为抑制明显，咖啡因模型组的OE％为21.21％，为大鼠灌胃从CBD-1mg/kg到CBD-10mg/kg斜率较大，对焦虑行为的改善明显，然而灌胃CBD-10mg/kg与CBD-100mg/kg斜率较之前稍小，对焦虑行为具有一定的改善。
试验二
一、试验动物及组别
试验动物：SPF级雄性wistar大鼠100只，180-200g。饲养环境：SPF级动物房，自由摄食，12h光照/12h黑暗。
试验组别：适应性饲养一周后，根据体重将大鼠随机分为10组：正常对照组、A组(实施例5制备获得)、B组(实施例6制备获得)、C组(实施例7制备获得)、D组(实施例9制备获得)、E组(实施例10制备获得)、F组(实施例11制备获得)、G组(实施例8制备获得)、H(实施例12制备获得)和I(实施例13制备获得)。除正常对照组(灌胃生理盐水)外，各给药组同时灌胃给予药用组合物或50mL饮料，给药30min后进行高架十字迷宫测试，行为学测试结束后无创法测定大鼠血压。
二、试验方法与试验一同
三、试验结果
进臂次数、时间及其比率见表2。
表2 进开放臂次数比率及其时间比率结果
Figure PCTCN2018109658-appb-000002
由表2可知，施用实施例5-13的产品(A-I组)的大鼠的进入开放臂次数比率及其时间比率均与正常情况下相近，即与正常对照组相比对大鼠基本没有产生焦虑行为。同时根据试验一中咖啡因模型组显示OE％为21.21％，焦虑作用明显。也就是说施用本发明实施例制备的药物组合物或饮料不会产生焦虑行为，从侧面反映大麻提取物或大麻二酚对抑制大鼠因咖啡因导致的焦虑行为作用明显，尤其B组、F组、D组大鼠基本没有过多焦虑行为的产生，并且A-I组的大鼠试验后血压均处于正常范围。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。

Claims (17)

  1. 一种组合物，其特征在于，包括(1)大麻二酚或大麻提取物和(2)咖啡因；其中，所述的大麻提取物中含有大麻二酚，所述的组合物中大麻二酚和咖啡因的质量比为(1-100)：60。
  2. 根据权利要求1所述的组合物，其特征在于，所述的大麻提取物中大麻二酚的质量百分比为10％-99％。
  3. 根据权利要求1或2所述的组合物，其特征在于，所述的组合物为食品组合物或药用组合物。
  4. 一种药用组合物，其特征在于，包括(1)大麻二酚或大麻提取物和(2)咖啡因以及(3)药用辅料，所述的大麻提取物中含有大麻二酚，所述的药用组合物中大麻二酚和咖啡因的质量比为(1-100)：60。
  5. 根据权利要求4所述的药用组合物，其特征在于，所述的大麻提取物中大麻二酚的质量百分比为10％-99％。
  6. 根据权利要求4或5所述的药用组合物，其特征在于，所述药用组合物中按质量百分比包括大麻二酚0.1％-1％，咖啡因0.06％-6％和药用辅料93％-99％。
  7. 根据权利要求4-6任一所述的药用组合物，其特征在于，所述的药用辅料选自粘合剂、载体、pH调节剂、填充剂、崩解剂、调味剂、稳定剂、成膜剂、增塑剂、增溶剂、分散剂、润湿剂、溶剂、包衣剂、胶囊剂壳、着色剂、防腐剂、抗氧化剂、表面活性剂中的一种或两种以上的组合。
  8. 根据权利要求4-7任一所述的药用组合物，其特征在于，所述的药用组合物为片剂、散剂、胶囊剂、颗粒、粉剂、丸剂、外用涂剂、膏药、膜剂、溶液剂或注射剂。
  9. 一种食品组合物，其特征在于，包括(1)大麻二酚或大麻提取物和(2)咖啡因；所述的大麻提取物中含有大麻二酚，所述的食品组合物中大麻二酚和咖啡因的质量比为(1-100)：60。
  10. 根据权利要求9所述的食品组合物，其特征在于，所述的大麻提取物中大麻二酚的质量百分比为10％-99％。
  11. 根据权利要求9或10所述的食品组合物，其特征在于，所述的食品选自饮料、面食、米、食用油、奶制品、蛋白粉、粥、汤、糊、肉食、豆制品、巧克力、糖果或果冻。
  12. 根据权利要求11所述的食品组合物，其特征在于，所述的食品为饮料，所述饮料中还包括营养补充物质，所述的营养补充物质选自维生素、微量元素、β-胡萝卜素、氨基酸、γ-氨基丁酸、牛磺酸和植物提取物中的一种或两种以上的组合。
  13. 根据权利要求12所述的食品组合物，其特征在于，所述的饮料中还含有添加剂，所述的添加剂选自香料、果蔬汁、花茶汁、着色剂、酸度调节剂、防腐剂、乳化剂、抗氧化剂、增稠剂、螯合剂、稳定剂、甜味剂中的一种或两种以上的组合。
  14. 根据权利要求13所述的食品组合物，其特征在于，所述的饮料为液体饮料或固体饮料。
  15. 根据权利要求13所述的食品组合物，其特征在于，所述的饮料为碳酸饮料或无汽饮料。
  16. 大麻二酚或大麻提取物在制备预防和/或改善咖啡因不良反应的产品中的应用。
  17. 权利要求16所述的大麻二酚或大麻提取物在制备预防和/或改善咖啡因不良反应的产品中的应用，所述预防和/或改善咖啡因不良反应为预防和/或改善咖啡因诱导的焦虑行为。
PCT/CN2018/109658 2017-12-29 2018-10-10 一种含有大麻二酚或大麻提取物和咖啡因的组合物及其应用 WO2019128377A1 (zh)

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JP2020552078A JP7008909B2 (ja) 2017-12-29 2018-10-10 カンナビジオール又は大麻抽出物とカフェインを含む組成物及びその応用
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