WO2022141821A1 - 一种大麻素泡腾制剂及其制备方法 - Google Patents

一种大麻素泡腾制剂及其制备方法 Download PDF

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WO2022141821A1
WO2022141821A1 PCT/CN2021/082031 CN2021082031W WO2022141821A1 WO 2022141821 A1 WO2022141821 A1 WO 2022141821A1 CN 2021082031 W CN2021082031 W CN 2021082031W WO 2022141821 A1 WO2022141821 A1 WO 2022141821A1
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Prior art keywords
effervescent
cannabinoid
preparation
acid
sodium
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PCT/CN2021/082031
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English (en)
French (fr)
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谭昕
王曙宾
范德凯
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汉义生物科技（北京）有限公司
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Priority to CN202180000835.5A priority Critical patent/CN115052587B/zh
Publication of WO2022141821A1 publication Critical patent/WO2022141821A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of medicine, in particular to a cannabinoid effervescent preparation and a preparation method thereof, more particularly to an effervescent preparation containing ultra-micronized cannabinoids and a preparation method thereof.
  • Ultrafine powder usually refers to a substance with a particle size of 20 ⁇ m or less, and a powder substance with micronological characteristics. After the material is ultra-finely pulverized, the formed powder has good surface properties, such as dispersibility and solubility. The newly generated particles have remarkable properties such as good surface effect, quantum size effect, small size effect and quantum tunneling effect.
  • the preparation of ultrafine powder usually has two methods: physical and chemical. Physical methods can be divided into dry and wet methods. In the chemical method, it can be divided into gas phase method and liquid phase method. In the physical method, dry ultrafine pulverizer can be divided into ball mill, vibration mill, jet pulverizer and other methods for pulverization; wet ultrafine pulverization includes liquid flow pulverization, homogenizer pulverization, etc.
  • gas-phase methods include vacuum evaporation method, gas-phase chemical reaction method, plasma method, etc.; in liquid-phase methods, there are mainly precipitation method, oxidative hydrogenation decomposition method, reduction method, spray drying method, freeze-drying method, etc. .
  • ultrafine powder technology has been widely used in metallurgy, ceramics, textiles, food, medicine, cosmetics, aerospace and other fields.
  • Existing cannabinoid foods include CBD water, hemp seed oil, cakes, gummies, etc.
  • cannabinoid products have problems such as unstable cannabinoid content, low bioavailability, and inconvenience to carry.
  • the content of CBD in CBD water currently sold on the market is unstable; liquid cannabinoid food is inconvenient to carry and store; cannabinoids in cakes, gummies, chocolates and other products containing cannabinoids need to be digested and absorbed, and cannabinoids cannot be directly absorbed , low bioavailability.
  • CN110448598A discloses a formulation of a medical water-soluble cannabidiol CBD preparation, which includes that effervescent tablets can be made by adding the effervescent disintegrant, but the specific treatment method of water-soluble cannabidiol is not given.
  • CN109316459A discloses a preparation method of curcumin effervescent tablets, comprising adding curcumin and zein into 40-80% ethanol, stirring and dissolving, dissolving sodium caseinate in water first, and then adding to the above ethanol solution , after stirring evenly, a mixed solution containing curcumin 0.1-1g/L, zein 1-10g/L, and sodium caseinate 1-10g/L was prepared; the mixed solution was freeze-dried and ground into a particle size of 50-500nm ultra-fine powder; add pharmaceutically acceptable auxiliary materials to the ultra-fine powder, and make effervescent tablets according to conventional technology.
  • the active ingredients are first added to the carrier, dried together to form powder, and then micronized.
  • the preparation of cannabinoid effervescent tablets according to the above method easily leads to discoloration of cannabinoids, poor tablet taste, and bioavailability still not tall.
  • the present invention provides a new cannabinoid product.
  • the ultrafine powdered cannabinoid and other pharmaceutically acceptable auxiliary materials are compressed into cannabinoid effervescent preparations.
  • the cannabinoids are evenly dispersed in the water, and the product can mask the bitterness of the cannabinoids themselves and can be taken directly.
  • the invention provides an effervescent preparation of cannabinoids, the cannabinoids are ultra-micronized cannabinoids, and the weight percent of the ultra-micronized cannabinoids in the effervescent preparations is 0.5-10 %, preferably 1%-6%, more preferably 2%-6%, still more preferably 4%-6%.
  • the ultra-micronized cannabinoids are obtained by ball-milling or jet-milling of materials.
  • the effervescent preparations are effervescent preparations or effervescent granules.
  • the cannabinoids are natural or synthetic cannabinoids.
  • the cannabinoid is selected from: one or a combination of two or more of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND.
  • the synthetic cannabinoid is one or a combination of two or more of pure CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND.
  • the natural cannabinoid is a cannabinoid-containing cannabis extract, and the cannabinoid extract contains one or a combination of two or more of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL, and CBND.
  • the cannabinoid-containing cannabis extract is a cannabis plant extract.
  • the hemp plant is industrial hemp, and the THC content of the industrial hemp is less than 0.3%.
  • the cannabis plant extract can be obtained by extracting the husk of the stalk, flower, leaf, root or seed of the cannabis plant.
  • the extraction solvent of the cannabis plant extract of the present invention can be low molecular alcohol (such as methanol, ethanol, butanol or propanol); acetate (such as methyl acetate or ethyl acetate); ketone (such as acetone); ethers (such as methyl ether or diethyl ether); low-boiling aliphatic or aromatic hydrocarbons or chlorinated hydrocarbons.
  • acetate such as methyl acetate or ethyl acetate
  • ketone such as acetone
  • ethers such as methyl ether or diethyl ether
  • low-boiling aliphatic or aromatic hydrocarbons or chlorinated hydrocarbons low molecular alcohol
  • acetate such as methyl acetate or ethyl acetate
  • ketone such as acetone
  • ethers such as methyl ether or diethyl ether
  • the effervescent preparation further comprises pharmaceutically acceptable auxiliary materials.
  • the pharmaceutically acceptable adjuvants comprise organic acids, bicarbonates and/or carbonates and fillers.
  • the organic acid is selected from one or more of citric acid, tartaric acid, citric acid, fumaric acid, adipic acid or malic acid.
  • the weight percentage of the organic acid in the effervescent formulation is 20-40%, preferably 30%.
  • the preferred organic acid is a combination of tartaric acid and citric acid.
  • the weight percentage of the tartaric acid in the effervescent preparation is 2-8%, and the weight percentage of the citric acid in the effervescent preparation is 18-32%.
  • the weight percentage of the tartaric acid in the effervescent preparation is 5%, and the weight percentage of the citric acid in the effervescent preparation is 25% %.
  • the bicarbonate and/or carbonate are selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or calcium carbonate.
  • the weight percentage of the bicarbonate and/or carbonate in the effervescent preparation is 20-40%. In a specific embodiment, the weight percentage of the bicarbonate and/or carbonate in the effervescent formulation is 30%.
  • the bicarbonate is sodium bicarbonate.
  • the carbonate is sodium carbonate.
  • the bicarbonate and/or carbonate is a combination of bicarbonate and carbonate.
  • the weight percentage of the bicarbonate in the effervescent preparation is 18-32%, in a specific embodiment, the bicarbonate in the effervescent preparation The weight percentage is 25%.
  • the weight percentage of the carbonate in the effervescent preparation is 2-8%, in a specific embodiment, the carbonate in the effervescent preparation The weight percentage is 5%.
  • the filler is selected from one or more of starch, sugar, cellulose, inorganic salt or mannitol.
  • starch is selected from starch and/or compressible starch
  • sugar is selected from one or more of powdered sugar, dextrin or lactose
  • cellulose is selected from microcrystalline cellulose
  • inorganic salt is selected from inorganic calcium salt, preferably Calcium sulfate and/or calcium sulfate dihydrate.
  • the lactose is straight-compressed lactose
  • the powdered sugar is powdered sucrose
  • the weight percentage of the filler in the effervescent preparation is 1-15%.
  • the weight percentage of the filler in the effervescent formulation is 8-12%; in a specific embodiment, the filler is in the effervescent formulation
  • the weight percentage in the Teng preparation is 10%.
  • the filler is a combination of straight-compressed lactose and sucrose powder.
  • the weight percentage of the straight-compressed lactose in the effervescent preparation is 4-6%, preferably 5%; the weight percentage of the sucrose powder in the effervescent preparation is 4-6%, preferably 5%.
  • the pharmaceutically acceptable adjuvants in the effervescent preparation may also include one or more of antioxidants, lubricants, sweeteners, essences or colorants.
  • the antioxidant is selected from water-soluble antioxidants.
  • the water-soluble antioxidant is selected from one or more of vitamin C, glutathione or lipoic acid.
  • the antioxidant is vitamin C.
  • the weight percentage of the antioxidant in the effervescent preparation is 7-15%, preferably 12%.
  • the lubricant is selected from polyethylene glycol, sodium lauryl sulfate, lauryl sulfide, leucine, sodium benzoate, sodium oleate, sodium chloride, sodium acetate, boric acid, stearin One or more of magnesium acid, talc, micropowder silica gel, sucrose fatty acid ester or sodium fumarate.
  • the weight percentage of the lubricant in the effervescent formulation is 5-15%, preferably 9%-10%.
  • the lubricant is a combination of sodium chloride, leucine, polyethylene glycol and sodium fumarate, wherein the weight percent of the sodium chloride in the effervescent preparation is 1- 3%, preferably 2%; the weight percentage of the polyethylene glycol in the effervescent preparation is 2.5-7%, preferably 4-5%; the leucine in the effervescent preparation
  • the weight percentage of the sodium fumarate is 0.5-2%, preferably 1%; the weight percentage of the sodium fumarate in the effervescent preparation is 1-3%, preferably 2%.
  • the sweetener is selected from sodium cyclamate, acesulfame potassium, sucralose, aspartame, sucrose, sodium saccharin, protein sugar, glucose, steviol, stevioside, glycyrrhizin, thomastin , one or more of citric acid, tartaric acid, malic acid or lactic acid.
  • the weight percentage of the sweetener in the effervescent preparation is 0.5-3%. In a specific embodiment, the weight percentage of the sweetener in the effervescent preparation is 1.5%.
  • the sweetener is a combination of aspartame and sucralose, wherein the weight percentage of the aspartame in the effervescent preparation is 0.1-1%, preferably 0.5% ; The weight percentage of the sucralose in the effervescent preparation is 0.4-2%, preferably 1%.
  • the fragrance is selected from one or more of rose essence, lemon essence, vanilla essence, banana essence, apple essence, mint essence, almond essence or orange essence.
  • the weight percentage of the essence in the effervescent preparation is 1-3%, preferably 2%.
  • the colorant is selected from shellac pigment, safflower yellow pigment, beet red, capsanthin, red yeast rice, turmeric, apocarotene aldehyde, beta-carotene or copper chlorophyllin sodium salt one or more of them.
  • the weight percentage of the colorant in the effervescent preparation is 1-5%. In a specific embodiment, the weight percentage of the colorant in the effervescent formulation is 3.5%.
  • the coloring agent is a combination of apocarotene aldehyde and ⁇ -carotene, wherein the weight percentage of the apocarotene aldehyde in the effervescent preparation is 0.9-4%, preferably 3% by weight. %; the weight percentage of the beta carotene in the effervescent preparation is 0.1-1%, preferably 0.5%.
  • the effervescent formulation comprises by weight percentage: 0.5-10% ultra-micronized cannabinoid, 20-40% organic acid, 18-32% bicarbonate, 2-8% carbonates, 5-15% fillers, 7-15% antioxidants, 5-15% lubricants, 0.5-3% sweeteners, 1-3% flavors, 1 -5% colorants. Or consist of the above-mentioned components.
  • the effervescent preparation comprises by weight percentage: 0.5-10% ultra-micronized cannabinoids, 2-8% tartaric acid, 18-32% citric acid, 18-32% sodium bicarbonate , 2-8% sodium carbonate, 4-6% straight-compressed lactose, 4-6% sucrose powder, 1-3% sodium chloride, 7-15% vitamin C, 2.5-7% polyethylene Diol, 1-3% sodium fumarate, 0.5-2% leucine, 0.1-1% aspartame, 0.4-2% sucralose, 1-3% flavor, 0.9- 4% apocarotene, 0.1-1% beta carotene. Or consist of the above-mentioned components.
  • the effervescent formulation comprises by weight percentage: 1% ultra-micronized cannabinoid, 5% tartaric acid, 25% citric acid, 25% sodium bicarbonate, 5% Sodium Carbonate, 5% Direct Compressed Lactose, 5% Powdered Sucrose, 2% Sodium Chloride, 12% Vitamin C, 5% Polyethylene Glycol, 2% Sodium Fumarate, 1% Leucine Acid, 0.5% aspartame, 1% sucralose, 2% flavor, 3% apocarotene, 0.5% beta carotene.
  • the effervescent formulation comprises by weight percentage: 2% ultra-micronized cannabinoids, 5% tartaric acid, 25% citric acid, 25% sodium bicarbonate, 5% Sodium Carbonate, 5% Direct Compressed Lactose, 5% Powdered Sucrose, 2% Sodium Chloride, 12% Vitamin C, 4% Polyethylene Glycol, 2% Sodium Fumarate, 1% Leucine Acid, 0.5% aspartame, 1% sucralose, 2% flavor, 3% apocarotene, 0.5% beta carotene.
  • the effervescent formulation includes by weight: 4% ultra-micronized cannabinoids,
  • the effervescent formulation comprises by weight percentage: 6% ultra-micronized cannabinoids, 5% tartaric acid, 25% citric acid, 25% sodium bicarbonate, 5% Sodium carbonate, 4% straight-compressed lactose, 5% powdered sucrose, 2% sodium chloride, 10% vitamin C, 3% polyethylene glycol, 2% sodium fumarate, 1% leucine Acid, 0.5% aspartame, 1% sucralose, 2% flavor, 3% apocarotene, 0.5% beta carotene.
  • the effervescent formulation comprises by weight percentage: 10% ultra-micronized cannabinoids, 4% tartaric acid, 24% citric acid, 24% sodium bicarbonate, 4% Sodium carbonate, 4% straight-compressed lactose, 5% powdered sucrose, 2% sodium chloride, 10% vitamin C, 3% polyethylene glycol, 2% sodium fumarate, 1% leucine Acid, 0.5% aspartame, 1% sucralose, 2% flavor, 3% apocarotene, 0.5% beta carotene.
  • the present invention also provides a method for preparing the effervescent preparation, the method comprising: taking ultrafinely powdered cannabinoids, organic acids, bicarbonates, carbonates, fillers, antioxidants, lubricants in proportion , sweeteners, flavors, colorants, directly mixed, and pressed into effervescent preparations.
  • the tablet weight of the effervescent tablet is controlled at 0.5-5g.
  • the ultra-micronized cannabinoid is obtained by ball-milling a material, the material includes a cannabinoid and an emulsifier, and the weight percentage of the cannabinoid in the material is 95-99.8%.
  • the weight percentage of the cannabinoid in the material is 98%, 99% or 99.5%.
  • the cannabinoid is a substantially pure combination of one or more cannabinoids or a cannabinoid-containing cannabis extract.
  • the cannabinoid is: CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND pure product in one or a combination of two or more; or, the cannabis extract contains CBD, CBDV , CBG, CBC, CBN, CBDB, CBE, CBL and CBND in one or a combination of two or more.
  • the emulsifier is Tween 80.
  • the ball milling method also needs to add 20-30 times of purified water to the material.
  • the ball milling speed of the ball milling method is 300rpm-500rpm
  • the time of each ball milling is 20-30min
  • the interval time between two ball millings is 3-5min
  • the total grinding time is 2-3h.
  • the described ball milling method prepares the steps of ultra-micronized cannabinoids as follows:
  • Ball milling add the mixture of a) and 20-30 times of water to the tank, add zirconia balls for grinding, the speed of ball milling is 300rpm-500rpm or 400rpm, and the time of each ball milling is 20- 30min or 25min, the interval time between each two ball milling is 3-5min or 4min, and the grinding is 2-3h or 2.5h in total.
  • the ultra-micronized cannabinoid is obtained by jet pulverizing the material, and the material contains cannabinoids and pharmaceutically acceptable excipients, and the excipients are selected from lactose, silicon dioxide Or one or more of magnesium stearate.
  • the weight percentage of cannabinoids in the material is 80-99%.
  • the proportion of the cannabinoid in the mixture is 90%, 95% or 98%.
  • the cannabinoid is a substantially pure combination of one or more cannabinoids or a cannabinoid-containing cannabis extract.
  • the cannabinoid is: CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND pure product in one or a combination of two or more; or, the cannabis extract contains CBD, CBDV , CBG, CBC, CBN, CBDB, CBE, CBL and CBND in one or a combination of two or more.
  • the weight percentage of lactose in the material is 0.1-15%
  • the weight percentage of lactose in the material is 0.5%, 4% or 9%,
  • the weight percentage of silica in the material is 0.1%-1%.
  • the weight percentage of silica in the material is 0.1% or 0.5%.
  • the weight percentage of magnesium stearate in the material is 0.1%-2%.
  • the percentage by weight of magnesium stearate in the material is 0.1%, 0.5%, and 0.9%.
  • the feed pressure of the jet pulverization method is 0.1-1.5MP, and the pulverization pressure is 0.1-1.5MP.
  • the feeding pressure is 0.2-0.8MP
  • the pulverizing pressure is 0.3-0.8MP
  • the step of preparing ultrafine cannabinoids by the described jet pulverization method is as follows:
  • step b) Jet milling the mixture of step a) is subjected to jet milling with a feed pressure of 0.1-1.5MP or 0.2-0.8MP and a crushing pressure of 0.1-1.5MP or 0.3-0.8MP.
  • the particle size of the ultra-micronized cannabinoid obtained by the ball milling method or the jet pulverization method of the present invention is below 20um.
  • the particle size of the ultra-micronized cannabinoids of the present invention is 1um, 2um, 3um, 4um, 5um, 6um, 7um, 8um, 9um, 10um, 11um, 12um, 13um, 14um, 15um, 16um, 17um , one or more of 18um, 19um or 20um.
  • the present invention also provides the application of the effervescent preparation containing ultrafine cannabinoids in the preparation of food, medicine, skin care products, and fragrance.
  • CBDV CBDV
  • CBD CBD
  • CBG CBD
  • CBN CBD
  • CBC CBDB
  • CBDB 4-butyl-5'-methyl-2'-( prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-(1,1′-biphenyl)-2,6-diol,Cannabidibutol
  • CBE CannabieLsoin
  • CBL cannabidiol
  • CBND dehydrocannabinol
  • the pure products of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND refer to the pure products of the above compounds, especially the corresponding commercial products, wherein the purity of the compounds is at least 99.5% or more , especially more than 99.9% (the rest are impurities); the content of cannabinoids in the cannabis extract is at least 80% or more, preferably more than 90%, especially more than 95%.
  • effervescent preparation refers to effervescent tablet or effervescent granule, and it has the following beneficial effects:
  • the cannabinoid effervescent tablet adopts the powder direct compression process, the process is simple, the acid-base ratio in the prescription is controlled, and the disintegration is rapid.
  • the cannabinoid effervescent preparation dissolves rapidly in water, the cannabinoid ultrafine powder is uniformly dispersed in water, and the water-soluble cannabinoid can be directly dissolved in water, which can be directly absorbed by drinking, and has high bioavailability.
  • the cannabinoid effervescent preparation is soluble in water, which can cover the bitter taste of cannabinoids when drinking, has excellent taste and is convenient to take.
  • Example 1 Preparation of ultramicronized cannabinoids by ball milling
  • Ball milling add the mixture of a) and 20-30 times of water to the tank body, add zirconia balls for ball milling, the speed of ball milling is 300rpm, the time of each ball milling is 20min, and every two ball milling Intermittent time 3min, a total of 3h grinding.
  • the cannabinoid is cannabidiol, which is derived from industrial hemp mosaic and is prepared by the preparation method disclosed in Example 1 of CN106831353A.
  • Ball milling add the mixture of a) and 20-30 times of water to the tank body, add zirconia balls for grinding, the speed of ball milling is 400rpm, the time of each ball milling is 25min, and every two ball milling The interval time is 4min, and the grinding is 2.5h in total.
  • Ball milling add the mixture of a) and 20-30 times of water to the tank, add zirconia balls for ball milling, the speed of ball milling is 500 rpm, the time of each ball milling is 30 min, and every two ball milling Intermittent time 5min, a total of 2h grinding.
  • the formula of formula 1 it is prepared by direct mixing method: take each component and directly mix it into effervescent granules, the unit weight is controlled at 4g, and the cannabinoid ultrafine powder is prepared by the method of Example 1.
  • the formula of formula 1 it is prepared by one-step granulation method: take each component, dissolve the polyethylene glycol in the auxiliary material in 10-100 times of water as a slurry, and use the remaining raw materials and auxiliary materials as the base material, and the atomization pressure is 0.05-0.2 Mpa, the granulation temperature is 20-70°C, and the effervescent granules are prepared, and the unit weight is controlled at 4g, and the cannabinoid ultrafine powder is prepared by the method of Example 3.
  • the formula of formula 2 it is prepared by one-step granulation method: take each component, dissolve the polyethylene glycol in the auxiliary material in 10-100 times of water as a slurry, and the remaining raw materials and auxiliary materials are used as the base material, and the atomization pressure is 0.05-0.2 Mpa, the granulation temperature is 20-70 ° C, and the effervescent granules are prepared, and the unit weight is controlled at 4 g, and the cannabinoid ultrafine powder is prepared by the method of Example 6.
  • the formula of formula 5 it is prepared by one-step granulation method: take each component, dissolve the polyethylene glycol in the auxiliary material in 10-100 times of water as a slurry, the remaining raw materials and auxiliary materials are used as the base material, and the atomization pressure is 0.05-0.2 Mpa, the granulation temperature is 20-70°C, and the effervescent granules are prepared, and the unit weight is controlled at 4g, and the cannabinoid ultrafine powder is prepared by the method of Example 3.
  • each component was taken and directly mixed into effervescent granules, and the unit weight was controlled at 4g, and the cannabinoid ultrafine powder was prepared by the method of Example 4.
  • the formula of formula 5 it is prepared by one-step granulation method: take each component, dissolve the polyethylene glycol in the auxiliary material in 10-100 times of water as a slurry, and the remaining raw materials and auxiliary materials are used as the base material, and the atomization pressure is 0.05-0.2 Mpa, the granulation temperature is 20-70°C, and the effervescent granules are prepared, and the unit weight is controlled at 4g, and the cannabinoid ultrafine powder is prepared by the method of Example 6.
  • Example 19 Quality comparative study of effervescent granules obtained by different formulations and preparation methods
  • Example disintegration time granularity Solubility Content stability 7 60S qualified qualified Accelerated 6-month content stabilization 8 60S qualified qualified Accelerated 6-month content stabilization 9 60S qualified qualified Accelerated 6-month content stabilization 10 90S qualified qualified Accelerated 6-month content stabilization 11 90S qualified qualified Accelerated 6-month content stabilization 12 90S qualified qualified Accelerated 6-month content stabilization
  • the experimental method is as follows:
  • the inspection method of the disintegration time limit refer to the fourth part of the Chinese Pharmacopoeia 2020 edition, under 0104 granules, effervescent granule inspection method, transfer 4g of granules to a beaker containing 200ml of water, the water temperature is 15 ⁇ 25 °C, should be quickly It produces gas and is effervescent, and the particles should be completely dispersed or dissolved in water within 5 minutes.
  • Inspection methods for particle size and solubility refer to the 2020 edition of the Chinese Pharmacopoeia, under 0104 Granules, particle size and solubility detection methods and requirements.
  • Inspection method for accelerated stability seal the sample into an aluminum-plastic composite bag with a specification of 4g/bag, place the sample in a stability test box at 40°C and a relative humidity of 75%, and test in 0, 3, and 6 months respectively. Particle disintegration time limit, particle size, solubility, content, and sample stability.
  • each component is taken, directly mixed into effervescent granules, and then directly compressed into tablets.
  • the formula of formula 1 take each component, dissolve the polyethylene glycol in the auxiliary material in 10-100 times of water as a slurry, and use the remaining raw materials and auxiliary materials as the primer.
  • the atomization pressure is 0.05-0.2Mpa
  • the granulation temperature is 20- 70° C.
  • the tablet weight was controlled at 0.5 g
  • the cannabinoid ultrafine powder was prepared by the method of Example 3.
  • each component was taken, directly mixed into effervescent granules, and then directly compressed into tablets.
  • the formula of formula 2 take each component, dissolve the polyethylene glycol in the auxiliary material in 10-100 times of water as a slurry, and use the remaining raw materials and auxiliary materials as the base material.
  • the atomization pressure is 0.05-0.2Mpa
  • the granulation temperature is 20- At 70° C., it was prepared into effervescent granules, and then directly compressed into tablets.
  • the tablet weight was controlled at 0.5 g, and the cannabinoid ultrafine powder was prepared by the method of Example 6.
  • each component is taken, directly mixed into effervescent granules, and then directly compressed into tablets.
  • each component is taken, directly mixed into effervescent granules, and then directly compressed into tablets.
  • Embodiment 32 Quality comparative study of effervescent tablets obtained by different formulations and preparation methods
  • Example disintegration time Dispersion uniformity Solution properties Content stability 20 60S qualified Evenly dispersed Tablets accelerate content stability for 6 months twenty one 60S qualified Evenly dispersed Tablets accelerate content stability for 6 months twenty two 60S qualified Evenly dispersed Tablets accelerate content stability for 6 months twenty three 100S qualified Evenly dispersed Tablets accelerate content stability for 6 months twenty four 100S qualified Evenly dispersed Tablets accelerate content stability for 6 months 25 100S qualified Evenly dispersed Tablets accelerate content stability for 6 months
  • the experimental method is as follows:
  • Inspection method for disintegration time limit and dispersion uniformity refer to the fourth part of the 2020 edition of the Chinese Pharmacopoeia, under 0101 Tablets, effervescent tablet inspection method.
  • Inspection method for the properties of the solution after disintegration The shape of the solution is judged according to whether the color of the solution is uniform after effervescence and whether there are obvious large particles.
  • Inspection method for content stability seal the sample into an aluminum-plastic composite bag, place it in a stability test box at 40°C and a relative humidity of 75%, and check the disintegration time limit and uniform dispersion of the particles in 0, 3, and 6 months respectively. properties, solution properties, content, and the stability of the samples.
  • the experimental method is as follows:
  • Test method of bioavailability 12 healthy rats, weighing 20-25g, half male and half male, fasted for 12 hours before the experiment, and had free water. Divided into two groups, the two groups were respectively gavaged with micropowder effervescent solution containing 20mg CBD and oil drops containing 20 mg CBD. Blood was collected at 12h and 16h. Another 8 healthy SD rats, half male and half male, were divided into two groups. The two groups were injected with CBD pure physiological saline solution and full-spectrum cannabis oil physiological saline through tail vein respectively at 0min, 3min, 8min, and 15min after administration.
  • the effervescent tablet containing ultrafine powdered cannabidiol is prepared by the preparation method of Example 20, and the cannabidiol drops are prepared by dissolving cannabidiol in soybean oil.
  • Example 34 Comparison of the stability of effervescent tablets containing ultramicronized cannabidiol with water-soluble cannabidiol powder
  • the effervescent tablet containing ultra-micronized cannabidiol is prepared by the preparation method of Example 20, and the water-soluble powder of cannabidiol is prepared by inclusion of cannabidiol through ⁇ -cyclodextrin.
  • Example 35 Mouthfeel comparison between effervescent tablets containing ultra-micronized cannabidiol and water-soluble cannabidiol powder
  • the effervescent tablet containing ultra-micronized cannabidiol is prepared by the preparation method of Example 20, and the water-soluble powder of cannabidiol is prepared by inclusion of cannabidiol through ⁇ -cyclodextrin.

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Abstract

一种大麻素泡腾制剂及其制备方法，其中泡腾制剂为泡腾片或泡腾颗粒，大麻素是超微粉化大麻素，通过球磨法或气流粉碎法制得，超微粉化大麻素重量百分比为0.5-10%，优选4-6%。

Description

一种大麻素泡腾制剂及其制备方法 技术领域
本发明涉及药物领域，特别是涉及一种大麻素泡腾制剂及其制备方法，更特别是涉及一种含有超微粉化大麻素的泡腾制剂及其制备方法。
背景技术
超微粉通常是指物质粒径在20μm以下的物质，具有微粉学特征的粉体物质。物质经过超微粉碎后，使得形成的粉体具有了良好的表面性能，如可分散性和可溶解性。由于新生成粒子具有良好的表面效应，量子尺寸效应，小尺寸效应及量子隧道效应等显著特性。
超微粉的制备通常有物理和化学两种方法。物理方法中又可分为干法和湿法两种。在化学方法中又可分为气相法和液相法。在物理方法中，干法超微粉碎机又可分为球磨机、振动磨机、气流粉碎机等方法粉碎；湿法超微粉碎包括液流粉碎、均质机粉碎等。在化学方法中，气相法包含真空蒸发法、气相化学反应法、等离子体法等；在液相法中，主要有沉淀法、氧化加氢分解法、还原法、喷雾干燥法、冷冻干燥法等。
超微粉技术作为一种新兴工艺技术，已经广泛应用于冶金、陶瓷、纺织、食品、医药、化妆品及航天航空等领域。
现有大麻素的食品有CBD水、火麻仁油、蛋糕、软糖等。现在多数大麻素产品中存在大麻素含量不稳定，生物利用度低，携带不方便等问题。例如：现有市面上出售的CBD水中CBD含量不稳定；液态大麻素食品携带、贮存不方便；蛋糕、软糖、巧克力等其它含大麻素产品中大麻素需经过消化吸收，大麻素不能直接吸收，生物利用度低。
CN110448598A公开了一种医用水溶性大麻二酚CBD制剂配方，其中包括通过加入所述泡腾崩解剂可以制成泡腾片，但未给出水溶性大麻二酚的具体处理方法。
CN109316459A公开了一种姜黄素泡腾片的制备方法，包括将姜黄素、玉米醇溶蛋白加入到40-80％乙醇中，搅拌溶解，将酪蛋白酸钠先用水溶解，然后加入到上述乙醇溶液中，搅拌均匀后制成含姜黄素0.1-1g/L、玉米醇溶蛋白1-10g/L、酪蛋白酸钠1-10g/L的混合溶液；将混合溶液冷冻干燥后研磨成粒径为50-500nm的超微粉末；向超微粉末中加入药剂学上可接受的辅料，按照常规工艺制成泡腾片。
然而现有技术都是先将活性成分加入载体中，共同干燥成粉末，再进行微粉化，按照上述方法制备大麻素泡腾片容易导致大麻素变色、片剂口感欠佳，而且生物利用度仍然不高。
发明内容
为克服现有技术的缺陷，本发明提供了一种新的大麻素产品，将超微粉化大麻素与其他药剂学上可接受的辅料压制成大麻素泡腾制剂，工艺简单，加水崩解后大麻素均匀分散在水中，所述的产品能够掩盖大麻素本身苦味，直接服用。
本发明提供了一种大麻素的泡腾制剂，所述的大麻素为超微粉化大麻素，所述的超微粉化大麻素在所述的泡腾制剂中所占的重量百分比为0.5-10％，优选1％-6％，进一步优选2％-6％，更进一步优选4％-6％。所述的超微粉化大麻素是通过球磨法或气流粉碎法对物料进行球磨或气流粉碎得到的。
所述的泡腾制剂为泡腾制剂或泡腾颗粒。
优选的，所述的大麻素为天然的或合成的大麻素。
所述大麻素选自：CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND中的一种或两种以上的组合。
所述合成大麻素为：CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND纯品中的一种或两种以上的组合。
所述天然的大麻素为包含大麻素的大麻提取物，所述的大麻提取物包含CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND中的一种或两种以上的组合。
优选的，所述的含有大麻素的大麻提取物为大麻植物提取物。
优选的，所述的大麻植物为工业大麻，所述的工业大麻中四氢大麻酚THC含量小于0.3％。
优选的，所述的大麻植物提取物可以为大麻植物的秆芯、花、叶、根或籽的外壳提取得到的。
优选的，本发明所述的大麻植物提取物的提取溶剂可以为低分子醇(如甲醇、乙醇、丁醇或者丙醇)；乙酸酯(如乙酸甲酯或者乙酸乙酯)；酮(如丙酮)；醚(如甲醚或者乙醚)；低沸点的脂肪烃或者芳香烃或者氯化烃。
更优选的，所述的泡腾制剂还包含药剂学上可以接受的辅料。
优选的，所述的药剂学上可以接受的辅料包含有机酸、碳酸氢盐和/或碳酸盐以及填充剂。
优选的，所述的有机酸选自柠檬酸、酒石酸、枸橼酸、富马酸、己二酸或苹果酸的一种或几种。
优选的，在一个具体的实施方案中，所述的有机酸在所述的泡腾制剂中所占的重量 百分比为20-40％，优选为30％。
优选的所述的有机酸为酒石酸和枸橼酸的组合。所述的酒石酸在所述的泡腾制剂中所占的重量百分比为2-8％，所述的枸橼酸在所述的泡腾制剂中所占的重量百分比为18-32％。在一个具体的实施方案中，所述的酒石酸在所述的泡腾制剂中所占的重量百分比为5％，所述的枸橼酸在所述的泡腾制剂中所占的重量百分比为25％。
优选的，所述的碳酸氢盐和/或碳酸盐选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾或碳酸钙的一种或几种。
优选的，所述的碳酸氢盐和/或碳酸盐在所述的泡腾制剂中所占的重量百分比为20-40％。在一个具体的实施方案中，所述的碳酸氢盐和/或碳酸盐在所述的泡腾制剂中所占的重量百分比为30％。
优选的，所述的碳酸氢盐为碳酸氢钠。
优选的，所述的碳酸盐为碳酸钠。
优选的，所述的碳酸氢盐和/或碳酸盐为碳酸氢盐和碳酸盐的组合。所述的碳酸氢盐在所述的泡腾制剂中所占的重量百分比为18-32％，在一个具体的实施方案中，所述的碳酸氢盐在所述的泡腾制剂中所占的重量百分比为25％。所述的碳酸盐在所述的泡腾制剂中所占的重量百分比为2-8％，在一个具体的实施方案中，所述的碳酸盐在所述的泡腾制剂中所占的重量百分比为5％。
优选的，所述的填充剂选自淀粉、糖、纤维素、无机盐或甘露醇的一种或几种。其中淀粉选自淀粉和/或可压性淀粉；糖选自糖粉、糊精或乳糖中的一种或几种；纤维素选自微晶纤维素；无机盐选自无机钙盐，优选为硫酸钙和/或二水硫酸钙。
优选的，所述的乳糖为直压乳糖，所述的糖粉为蔗糖粉。
优选的，所述的填充剂在所述的泡腾制剂中所占的重量百分比为1-15％。在一个具体的实施方案中，所述的填充剂在所述的泡腾制剂中所占的重量百分比为8-12％；在一个具体的实施方案中，所述的填充剂在所述的泡腾制剂中所占的重量百分比为10％。
在一个具体实施例中，所述的填充剂为直压乳糖和蔗糖粉的组合。其中，所述的直压乳糖在所述的泡腾制剂中所占的重量百分比为4-6％，优选5％；所述的蔗糖粉在所述的泡腾制剂中所占的重量百分比为4-6％，优选5％。
优选的，所述的泡腾制剂中药剂学上可以接受的辅料还可以包括抗氧化剂、润滑剂、甜味剂、香精或着色剂的一种或几种。
优选的，所述的抗氧化剂选自水溶性的抗氧化剂。
进一步优选的，所述的水溶性的抗氧化剂选自维生素C、谷胱甘肽或硫辛酸中的一种或几种。
更优选的，所述的抗氧化剂为维生素C。
优选的，所述的抗氧化剂在所述的泡腾制剂中所占的重量百分比为7-15％，优选为12％。
优选的，所述的润滑剂选自聚乙二醇、十二烷基硫酸钠、十二烷基硫、亮氨酸、苯甲酸钠、油酸钠、氯化钠、醋酸钠、硼酸、硬脂酸镁、滑石粉、微粉硅胶、蔗糖脂肪酸酯或富马酸钠的一种或几种。
优选的，所述的润滑剂在所述的泡腾制剂中的重量百分比为5-15％，优选9％-10％。
优选的，所述的润滑剂为氯化钠、亮氨酸、聚乙二醇和富马酸钠的组合，其中，所述的氯化钠在所述的泡腾制剂中的重量百分比为1-3％，优选2％；所述的聚乙二醇在所述的泡腾制剂中的重量百分比为2.5-7％，优选4-5％；所述的亮氨酸在所述的泡腾制剂中的重量百分比为0.5-2％，优选1％；所述的富马酸钠在所述的泡腾制剂中的重量百分比为1-3％，优选2％。
优选的，所述的甜味剂选自甜蜜素、安赛蜜、三氯蔗糖、阿司帕坦、蔗糖、糖精钠、蛋白糖、葡萄糖、甜菊素、甜菊苷、甘草甜素、索马甜、枸橼酸、酒石酸、苹果酸或乳酸的一种或几种。
优选的，所述的甜味剂在所述的泡腾制剂中的重量百分比为0.5-3％。在一个具体的实施方案中，所述的甜味剂在所述的泡腾制剂中所占的重量百分比为1.5％。
优选的，所述的甜味剂为阿斯巴坦和三氯蔗糖的组合，其中，所述的阿斯巴坦在所述的泡腾制剂中的重量百分比为0.1-1％，优选0.5％；所述的三氯蔗糖在所述的泡腾制剂中的重量百分比为0.4-2％，优选1％。
优选的，所述的香精选自玫瑰香精、柠檬香精、香草香精、香蕉香精、苹果香精、薄荷香精、杏仁香精或桔子香精的一种或几种。
优选的，所述的香精在所述的泡腾制剂中的重量百分比为1-3％，优选2％。
优选的，所述的着色剂选自有虫胶色素、红花黄色素、甜菜红、辣椒红素、红曲米、姜黄、阿朴胡萝卜素醛、β-胡萝卜素或叶绿酸铜钠盐中的一种或几种。
优选的，所述的着色剂在所述的泡腾制剂中的重量百分比为1-5％。在一个具体的实施方案中，所述的着色剂在所述的泡腾制剂中的重量百分比为3.5％。
优选的，所述的着色剂为阿朴胡萝卜素醛和β胡萝卜素的组合，其中，所述的阿朴 胡萝卜素醛在所述的泡腾制剂中的重量百分比为0.9-4％，优选3％；所述的β胡萝卜素在所述的泡腾制剂中的重量百分比为0.1-1％，优选0.5％。
在本发明的一个具体实施方式中，所述的泡腾制剂中按重量百分比包括：0.5-10％的超微粉化大麻素、20-40％的有机酸、18-32％的碳酸氢盐、2-8％的碳酸盐、5-15％的填充剂、7-15％的抗氧化剂、5-15％的润滑剂、0.5-3％的甜味剂、1-3％的香精、1-5％的着色剂。或者由上述组分组成。
优选的，所述的泡腾制剂中按重量百分比包括：0.5-10％的超微粉化大麻素、2-8％的酒石酸、18-32％的枸橼酸、18-32％的碳酸氢钠、2-8％的碳酸钠、4-6％的直压乳糖、4-6％的蔗糖粉、1-3％的氯化钠、7-15％的维生素C、2.5-7％的聚乙二醇、1-3％的富马酸钠、0.5-2％的亮氨酸、0.1-1％的阿斯巴坦、0.4-2％的三氯蔗糖、1-3％的香精、0.9-4％的阿朴胡萝卜素、0.1-1％的β胡萝卜素。或者由上述组分组成。
在一个具体实施例中，所述的泡腾制剂中按重量百分比包括：1％的超微粉化大麻素、5％的酒石酸、25％的枸橼酸、25％的碳酸氢钠、5％的碳酸钠、5％的直压乳糖、5％的蔗糖粉、2％的氯化钠、12％的维生素C、5％的聚乙二醇、2％的富马酸钠、1％的亮氨酸、0.5％的阿斯巴坦、1％的三氯蔗糖、2％的香精、3％的阿朴胡萝卜素、0.5％的β胡萝卜素。
在一个具体实施例中，所述的泡腾制剂中按重量百分比包括：2％的超微粉化大麻素、5％的酒石酸、25％的枸橼酸、25％的碳酸氢钠、5％的碳酸钠、5％的直压乳糖、5％的蔗糖粉、2％的氯化钠、12％的维生素C、4％的聚乙二醇、2％的富马酸钠、1％的亮氨酸、0.5％的阿斯巴坦、1％的三氯蔗糖、2％的香精、3％的阿朴胡萝卜素、0.5％的β胡萝卜素。
在一个具体实施例中，所述的泡腾制剂中按重量百分比包括：4％的超微粉化大麻素、
5％的酒石酸、25％的枸橼酸、25％的碳酸氢钠、5％的碳酸钠、5％的直压乳糖、5％的蔗糖粉、2％的氯化钠、10％的维生素C、4％的聚乙二醇、2％的富马酸钠、1％的亮氨酸、0.5％的阿斯巴坦、1％的三氯蔗糖、2％的香精、3％的阿朴胡萝卜素、0.5％的β胡萝卜素。
在一个具体实施例中，所述的泡腾制剂中按重量百分比包括：6％的超微粉化大麻素、5％的酒石酸、25％的枸橼酸、25％的碳酸氢钠、5％的碳酸钠、4％的直压乳糖、5％的蔗糖粉、2％的氯化钠、10％的维生素C、3％的聚乙二醇、2％的富马酸钠、1％的亮氨酸、0.5％的阿斯巴坦、1％的三氯蔗糖、2％的香精、3％的阿朴胡萝卜素、0.5％的β胡萝卜素。
在一个具体实施例中，所述的泡腾制剂中按重量百分比包括：10％的超微粉化大麻素、4％的酒石酸、24％的枸橼酸、24％的碳酸氢钠、4％的碳酸钠、4％的直压乳糖、5％的蔗糖粉、2％的氯化钠、10％的维生素C、3％的聚乙二醇、2％的富马酸钠、1％的亮氨酸、0.5％ 的阿斯巴坦、1％的三氯蔗糖、2％的香精、3％的阿朴胡萝卜素、0.5％的β胡萝卜素。
本发明还提供了一种所述的泡腾制剂的制备方法，所述方法包括：按比例取超微粉化大麻素、有机酸、碳酸氢盐、碳酸盐、填充剂、抗氧化剂、润滑剂、甜味剂、香精、着色剂，直接混匀，压制成泡腾制剂。
优选，所述的泡腾片的片重控制在0.5-5g。
优选的，所述的超微粉化大麻素是通过球磨法对物料进行球磨得到，所述的物料包括大麻素和乳化剂，所述的大麻素在物料中的重量百分比为95-99.8％。
优选的，所述的大麻素在物料中的重量百分比为98％、99％或99.5％。
优选的，所述的大麻素为基本上纯的大麻素的一种或多种的组合或含有大麻素的大麻提取物。
具体地，所述大麻素为：CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND纯品中的一种或两种以上的组合；或，所述大麻提取物包含CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND中的一种或两种以上的组合。
优选的，所述的乳化剂为吐温80。
优选的，所述的球磨法还需要向物料中添加20-30倍的纯化水。
优选的，所述的球磨法的球磨速度为300rpm-500rpm，每次球磨时间为20-30min，两次球磨之间的间歇时间为3-5min，共研磨2-3h。
优选的，所述的球磨法制备超微粉化大麻素的步骤如下：
a)物料的混合：按比例取大麻素与吐温80进行混合；
b)球磨：将a)的混合物与20-30倍于所述混合物的水加至罐体，加入氧化锆球进行研磨，球磨的速为300rpm-500rpm或400rpm，每次球磨的时间为20-30min或25min，每两次球磨之间间歇时间3-5min或4min，一共研磨2-3h或2.5h。
优选的，所述的超微粉化大麻素通过气流粉碎法对物料进行气流粉碎得到，所述的物料中包含大麻素和药剂学上可接受的辅料，所述的辅料选自乳糖、二氧化硅或硬脂酸镁的一种或几种。
优选的，所述的物料中大麻素的重量百分比为80-99％。
更优选的，所述的大麻素在所述的混合物中的占比为90％、95％或98％。
优选的，所述的大麻素为基本上纯的大麻素的一种或多种的组合或含有大麻素的大麻提取物。
具体地，所述大麻素为：CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和 CBND纯品中的一种或两种以上的组合；或，所述大麻提取物包含CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND中的一种或两种以上的组合。
优选的，所述的物料中乳糖所占的重量百分比为0.1-15％
在一些具体的实施例中，所述的物料中乳糖所占的重量百分比为0.5％、4％或9％、
优选的，所述的物料中二氧化硅所占的重量百分比为0.1％-1％。
在一些具体的实施例中，所述的物料中二氧化硅所占的重量百分比为0.1％或0.5％。
优选的，所述的物料中硬脂酸镁所占的重量百分比为0.1％-2％。
在一些具体的实施例中，所述的物料中硬脂酸镁所占的重量百分比为0.1％、0.5％、0.9％。
进一步优选的，所述的气流粉碎法的进料压力为0.1-1.5MP，粉碎压力为0.1-1.5MP。
在一个具体的实施例中，所述的进料压力为0.2-0.8MP，所述的粉碎压力为0.3-0.8MP。
优选的，所述的气流粉碎法制备超微粉化大麻素的步骤如下：
a)物料的混合：按比例取大麻素与乳糖、二氧化硅和硬脂酸镁混合；
b)气流粉碎：以0.1-1.5MP或0.2-0.8MP的进料压力，0.1-1.5MP或0.3-0.8MP的粉碎压力对步骤a)的混合物进行气流粉碎。
优选的，本发明所述的球磨法或气流粉碎法得到的超微粉化大麻素粒径在20um以下。
进一步优选的，本发明所述的超微粉化大麻素粒径为1um、2um、3um、4um、5um、6um、7um、8um、9um、10um、11um、12um、13um、14um、15um、16um、17um、18um、19um或20um的一种或几种。
本发明还提供了一种所述的含有超微粉化大麻素的泡腾制剂在制备食品、药品、护肤品、香料的制备中的应用。
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义，如在本发明中出现的以下缩写及其对应的物质为：CBDV(次大麻二酚)、CBD(大麻二酚)、CBG(大麻萜酚)、CBN(大麻酚)、CBC(大麻色原烯)、CBDB(4-butyl-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-(1,1′-biphenyl)-2,6-diol,Cannabidibutol)、CBE(cannabieLsoin)、CBL(大麻环酚)、CBND(脱氢大麻二酚)。
在本发明中，CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL以及CBND的纯品是指上述化合物的纯净物产品，特别是相应的市售产品，其中化合物纯度至少为 99.5％以上，特别是99.9％以上(其余为杂质)；所述的大麻提取物中大麻素的含量至少为80％以上，优选为90％以上，特别是95％以上。
采用本发明的制备方法得到的是一种新的大麻素泡腾制剂，所述的泡腾制剂指泡腾片或泡腾颗粒，其具有以下有益效果：
a)大麻素泡腾片采用粉末直压工艺，工艺简单，控制处方中酸碱比例，崩解迅速。
b)大麻素泡腾制剂中大麻素量高，稳定性强，携带方便以及存贮。
c)大麻素泡腾制剂溶水迅速，大麻素超细粉在水中均匀分散，水溶性大麻素可直接溶于水，均可直接饮用吸收，生物利用度高。
d)大麻素泡腾制剂溶于水，饮用时可遮盖大麻素的苦味，口味极佳，方便服用。
具体实施方式
下面将结合本发明实施例，对本发明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一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作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:用球磨法制备超微粉化大麻素
a)物料的混合：将99.5％大麻素与0.5％的吐温80混合；
b)球磨：将a)的混合物与20-30倍于所述混合物的水加至罐体，加入氧化锆球进行球磨，球磨的速为300rpm，每次球磨的时间为20min，每两次球磨之间间歇时间3min，一共研磨3h。
其中，所述的大麻素为大麻二酚，来源于工业大麻花叶，采用CN106831353A的实施例1公开的制备方法制得。
实施例2：用球磨法制备超微粉化大麻素
a)物料的混合：将99％的大麻素1％吐温80进行混合；
b)球磨：将a)的混合物与20-30倍于所述混合物的水加至罐体，加入氧化锆球进行研磨，球磨的速为400rpm，每次球磨的时间为25min，每两次球磨之间间歇时间4min，一共研磨2.5h。
其中大麻素的来源和制备方法与实施例1相同。
实施例3：用球磨法制备超微粉化大麻素
a)物料的混合：将98％的大麻素与2％吐温80进行混合；
b)球磨：将a)的混合物与20-30倍于所述混合物的水加至罐体，加入氧化锆球进 行球磨，球磨的速为500rpm，每次球磨的时间为30min，每两次球磨之间间歇时间5min，一共研磨2h。
其中大麻素的来源和制备方法与实施例1相同。
实施例4：用气流粉碎法制备超微粉化大麻素
a)物料的混合：将98％的大麻素、0.5％的乳糖、0.5％的二氧化硅和0.1％的硬脂酸镁混合；
b)气流粉碎：以0.2MP的进料压力，0.3MP的粉碎压力对步骤a)的混合物进行气流粉碎。
其中大麻素的来源和制备方法与实施例1相同。
实施例5：用气流粉碎法制备超微粉化大麻素
物料的混合：将95％的大麻素、4％的乳糖、0.5％的二氧化硅和0.5％的硬脂酸镁混合；
b)气流粉碎：以0.5MP的进料压力，0.5MP的粉碎压力对步骤a)的混合物进行气流粉碎。
其中大麻素的来源和制备方法与实施例1相同。
实施例6：用气流粉碎法制备超微粉化大麻素
a)物料的混合：将90％的大麻素、9％的乳糖、0.1％的二氧化硅和0.9％的硬脂酸镁混合；
b)气流粉碎：以0.8MP的进料压力，0.8MP的粉碎压力对步骤a)的混合物进行气流粉碎。
其中大麻素的来源和制备方法与实施例1相同。
下表是制备大麻素泡腾制剂的实施例7-18、20-31采用的配方表：
表1大麻素泡腾制剂配方表
组分(重量百分比) 配方1 配方2 配方3 配方4 配方5
大麻素超微粉％ 1 2 4 6 10
碳酸氢钠％ 25 25 25 25 24
碳酸钠％ 5 5 5 5 4
酒石酸％ 5 5 5 5 4
枸橼酸％ 25 25 25 25 24
阿斯巴坦％ 0.5 0.5 0.5 0.5 0.5
直压乳糖％ 5 5 5 4 4
氯化钠％ 2 2 2 2 2
聚乙二醇％ 5 4 4 3 3
维生素C％ 12 12 10 10 10
蔗糖细颗粒％ 5 5 5 5 5
阿朴胡萝卜素醛％ 3 3 3 3 3
β胡萝卜素％ 0.5 0.5 0.5 0.5 0.5
三氯蔗糖％ 1 1 1 1 1
香精％ 2 2 2 2 2
富马酸钠％ 2 2 2 2 2
亮氨酸％ 1 1 1 1 1
实施例7：制备大麻素泡腾颗粒
按照配方1的配方用直接混合法制备：取各组分，直接混合成泡腾颗粒，单位重量控制在4g，其中的大麻素超微粉是用实施例1的方法制得的。
实施例8：制备大麻素泡腾颗粒
按照配方1的配方用干法制粒法制备：取各组分，直接混合，用干法制粒机压制成颗粒，单位重量控制在4g，压辊压力控制在4-60bar，其中的大麻素超微粉是用实施例2的方法制得的。
实施例9：制备大麻素泡腾片
按照配方1的配方用一步制粒法制备：取各组分，将辅料中的聚乙二醇溶于10-100倍水作为浆料，剩余原、辅料做底料，雾化压力0.05-0.2Mpa，制粒温度20-70℃，制备成泡腾颗粒，单位重量控制在4g，其中的大麻素超微粉是用实施例3的方法制得的。
实施例10：制备大麻素泡腾颗粒
按照配方2的配方用直接混合法制备：取各组分，直接混合成泡腾颗粒，单位重量控制在4g，其中的大麻素超微粉是用实施例4的方法制得的。
实施例11：制备大麻素泡腾颗粒
按照配方2的配方用干法制粒法制备：取各组分，直接混合，用干法制粒机压制成颗粒，单位重量控制在4g，压辊压力控制在4-60bar，其中的大麻素超微粉是用实施例5的方法制得的。
实施例12：制备大麻素泡腾颗粒
按照配方2的配方用一步制粒法制备：取各组分，将辅料中的聚乙二醇溶于10-100倍水作为浆料，剩余原、辅料做底料，雾化压力0.05-0.2Mpa，制粒温度20-70℃，制备成泡腾颗粒，单位重量控制在4g，其中的大麻素超微粉是用实施例6的方法制得的。
实施例13：制备大麻素泡腾颗粒
按照配方3的配方用直接混合法制备：取各组分，直接混合成泡腾颗粒，单位重量 控制在4g，其中的大麻素超微粉是用实施例1的方法制得的。
实施例14：制备大麻素泡腾颗粒
按照配方4的配方用干法制粒法制备：取各组分，直接混合，用干法制粒机压制成颗粒，单位重量控制在4g，压辊压力控制在4-60bar，其中的大麻素超微粉是用实施例2的方法制得的。
实施例15：制备大麻素泡腾颗粒
按照配方5的配方用一步制粒法制备：取各组分，将辅料中的聚乙二醇溶于10-100倍水作为浆料，剩余原、辅料做底料，雾化压力0.05-0.2Mpa，制粒温度20-70℃，制备成泡腾颗粒，单位重量控制在4g，其中的大麻素超微粉是用实施例3的方法制得的。
实施例16：制备大麻素泡腾颗粒
按照配方3的配方用直接混合法制备：取各组分，直接混合成泡腾颗粒，单位重量控制在4g，其中的大麻素超微粉是用实施例4的方法制得的。
实施例17：制备大麻素泡腾颗粒
按照配方4的配方用干法制粒法制备：取各组分，直接混合，用干法制粒机压制成颗粒，单位重量控制在4g，压辊压力控制在4-60bar，其中的大麻素超微粉是用实施例5的方法制得的。
实施例18：制备大麻素泡腾颗粒
按照配方5的配方用一步制粒法制备：取各组分，将辅料中的聚乙二醇溶于10-100倍水作为浆料，剩余原、辅料做底料，雾化压力0.05-0.2Mpa，制粒温度20-70℃，制备成泡腾颗粒，单位重量控制在4g，其中的大麻素超微粉是用实施例6的方法制得的。
实施例19：不同配方和制备方法得到的泡腾颗粒的质量对比研究
实施例 崩解时间 粒度 溶化性 含量稳定性
7 60S 合格 合格 加速6个月含量稳定
8 60S 合格 合格 加速6个月含量稳定
9 60S 合格 合格 加速6个月含量稳定
10 90S 合格 合格 加速6个月含量稳定
11 90S 合格 合格 加速6个月含量稳定
12 90S 合格 合格 加速6个月含量稳定
实验方法如下：
1、崩解时限的检查方法，：参照2020版中国药典四部，0104颗粒剂项下，泡腾颗 粒检查法，将4g颗粒转移至盛有200ml水的烧杯中，水温15～25℃，应迅速产生气体而呈泡腾状，5min内颗粒应完全分散或溶解在水中。
2、粒度、溶化性的检查方法：参见2020版中国药典，0104颗粒剂项下，粒度、溶化性检测方法及要求。
3、加速稳定性的检查方法：将样品密封至铝塑复合袋内，规格4g/袋，将样品放置于40℃，相对湿度75％稳定性实验箱内，分别于0、3、6月检测颗粒崩解时限、粒度、溶化性、含量，考察样品稳定性。
实施例20：制备大麻素泡腾片
按照配方1的配方取各组分，直接混合成泡腾颗粒，再直接压制成片，片重控制在0.5g，其中的大麻素超微粉是用实施例1的方法制得的。
实施例21：制备大麻素泡腾片
按照配方1的配方取各组分，直接混合，用干法制粒机压先制成颗粒，压辊压力控制在4-60bar，再直接压制成片，片量控制在0.5g，其中的大麻素超微粉是用实施例2的方法制得的。
实施例22：制备大麻素泡腾片
按照配方1的配方取各组分，将辅料中的聚乙二醇溶于10-100倍水作为浆料，剩余原、辅料做底料，雾化压力0.05-0.2Mpa，制粒温度20-70℃，制备成泡腾颗粒，再直接压制成片，片重控制在0.5g，其中的大麻素超微粉是用实施例3的方法制得的。
实施例23：制备大麻素泡腾片
按照配方2的配方取各组分，直接混合成泡腾颗粒，再直接压制成片，片重控制在0.5g，其中的大麻素超微粉是用实施例4的方法制得的。
实施例24：制备大麻素泡腾片
按照配方2的配方取各组分，直接混合，用干法制粒机压制成颗粒，压辊压力控制在4-60bar，再直接压制成片，片重控制在0.5g，其中的大麻素超微粉是用实施例5的方法制得的。
实施例25制备大麻素泡腾片
按照配方2的配方取各组分，将辅料中的聚乙二醇溶于10-100倍水作为浆料，剩余原、辅料做底料，雾化压力0.05-0.2Mpa，制粒温度20-70℃，制备成泡腾颗粒，再直接压制成片，片重控制在0.5g，其中的大麻素超微粉是用实施例6的方法制得的。
实施例26：制备大麻素泡腾片
按照配方3的配方取各组分，直接混合成泡腾颗粒，再直接压制成片，片重控制在0.5g，其中的大麻素超微粉是用实施例1的方法制得的。
实施例27：制备大麻素泡腾片
按照配方4的配方取各组分，直接混合，用干法制粒机压先制成颗粒，压辊压力控制在4-60bar，再直接压制成片，片量控制在0.5g，其中的大麻素超微粉是用实施例2的方法制得的。
实施例28：制备大麻素泡腾片
按照配方5的配方取各组分，将辅料中的聚乙二醇溶于10-100倍水作为浆料，剩余原、辅料做底料，雾化压力0.05-0.2Mpa，制粒温度20-70℃，制备成泡腾颗粒，再直接压制成片，片重控制在0.5g，其中的大麻素超微粉是用实施例3的方法制得的。
实施例29：制备大麻素泡腾片
按照配方3的配方取各组分，直接混合成泡腾颗粒，再直接压制成片，片重控制在0.5g，其中的大麻素超微粉是用实施例4的方法制得的。
实施例30：制备大麻素泡腾片
按照配方4的配方取各组分，直接混合，用干法制粒机压先制成颗粒，压辊压力控制在4-60bar，再直接压制成片，片量控制在0.5g，其中的大麻素超微粉是用实施例5的方法制得的。
实施例31：制备大麻素泡腾片
按照配方5的配方取各组分，将辅料中的聚乙二醇溶于10-100倍水作为浆料，剩余原、辅料做底料，雾化压力0.05-0.2Mpa，制粒温度20-70℃，制备成泡腾颗粒，再直接压制成片，片重控制在0.5g，其中的大麻素超微粉是用实施例6的方法制得的。
实施例32：不同配方和制备方法得到的泡腾片的质量对比研究
实施例 崩解时间 分散均匀性 溶液性状 含量稳定性
20 60S 合格 均匀分散 片剂加速6个月含量稳定
21 60S 合格 均匀分散 片剂加速6个月含量稳定
22 60S 合格 均匀分散 片剂加速6个月含量稳定
23 100S 合格 均匀分散 片剂加速6个月含量稳定
24 100S 合格 均匀分散 片剂加速6个月含量稳定
25 100S 合格 均匀分散 片剂加速6个月含量稳定
实验方法如下：
1、崩解时限、分散均匀性的检查方法：参照2020版中国药典四部，0101片剂项下，泡腾片检查法。
2、崩解后溶液性状的检查方法：根据泡腾后溶液是否颜色均一，是否存在明显大颗粒来判断溶液形状。
3、含量稳定性的检查方法：将样品密封至铝塑复合袋内，放置于40℃，相对湿度75％稳定性实验箱内，分别于0、3、6月检测颗粒崩解时限、分散均匀性、溶液性状、含量，考察样品稳定性。
结果分析：以实施例20-25的方法制备得到的泡腾片均符合泡腾片质量标准要求。
实施例33：含有超微粉化大麻二酚的泡腾片与滴剂生物利用度比较
Figure PCTCN2021082031-appb-000001
实验方法如下：
1、镇静起效时间的检查方法：选取20只体重20-25g雄性小鼠，动物饲养在人工调控的环境，使用12h的昼夜节律，随意取食食物和水。用戊四唑皮下注射给药，20只小鼠阵挛性惊厥明显，其中十只将20mgCBD/片超微粉化大麻二酚的泡腾片泡腾后灌胃给入，另外十只给入1ml，20mgCBD/ml的大麻二酚滴剂。其中微粉化泡腾片组平均10min小鼠阵挛性惊厥明显改善，滴剂组平均30min阵挛性惊厥明显改善。
2、生物利用度的检查方法：取健康大鼠12只，体重20-25g，雌雄各半，实验前12h禁食，饮水自由。分为两组，两组分别灌胃含20mgCBD的微粉泡腾溶液和含20mgCBD量的油滴剂，分别于给药后0min、1.5h、3h、4h、5h、6h、7h、8h、10h、12h、16h时间点取血。另取取健康SD大鼠8只，雌雄各半，分为两组，两组分别尾静脉注射CBD纯品生理盐水溶液和全谱系大麻油生理盐水分别于给药后0min、3min、8min、15min、30min、1h、2h、3h、4h、6h、8h、10h、12h、16h时间点取血。两组样品均均从眼缘静脉丛取血50μL置于1.5mL肝素EP管中。将采集得的血液样品以4℃、4500rpm离心10min，取上清血浆检测含量。拟合计算CBD微粉泡腾片组、CBD油滴剂组的AUC 0-∞，计算静脉注射组的AUC 0-∞，计算得CBD泡腾片组的生物利用度为20.2％，CBD滴剂组的生物利用度为3.1％。
其中，所述的含有超微粉化大麻二酚的泡腾片由实施例20的制备方法制得，所述的大麻二酚滴剂为大豆油溶解大麻二酚制得。
实施例34：含有超微粉化大麻二酚的泡腾片与水溶性大麻二酚粉末稳定性比较
剂型 规格 室温30天
含有超微粉化大麻二酚的泡腾片 20mg/片 不变色
水溶性大麻二酚粉末 20mg/g 变粉色
考察方法：将两组样品在室温下敞口放置30天，超微粉大麻素未变色，水溶性大麻素粉末被氧化为淡粉色。
其中，所述的含有超微粉化大麻二酚的泡腾片由实施例20的制备方法制得，所述的大麻二酚水溶性粉末为大麻二酚经β-环糊精包合制得。
实施例35：含有超微粉化大麻二酚的泡腾片与水溶性大麻二酚粉末口感比较
剂型 口感
含有超微粉化大麻二酚的泡腾片 口感好，不苦
水溶性大麻二酚粉末 苦
其中，所述的含有超微粉化大麻二酚的泡腾片由实施例20的制备方法制得，所述的大麻二酚水溶性粉末为大麻二酚经β-环糊精包合制得。

Claims (13)

  1. 一种大麻素泡腾制剂，所述的大麻素为超微粉化大麻素，所述的超微粉化大麻素按照重量百分比为0.5-10％，优选为4％-6％，所述的超微粉化大麻素通过球磨法或气流粉碎法得到。
  2. 权利要求1所述的泡腾制剂，其特征在于，所述的泡腾制剂中还包含药剂学上可以接受的辅料，所述的药剂学上可以接受的辅料包含有机酸、碳酸氢盐和/或碳酸盐以及填充剂。
  3. 权利要求2所述的泡腾制剂，其特征在于，所述的有机酸选自柠檬酸、酒石酸、枸橼酸、富马酸、己二酸或苹果酸的一种或几种，所述的有机酸在所述的泡腾制剂中所占的重量百分比为20-40％；所述的碳酸氢盐和/或碳酸盐选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾或碳酸钙的一种或几种，所述的碳酸氢盐和/或碳酸盐在所述的泡腾制剂中所占的重量百分比为20-40％；所述的填充剂选自淀粉、糖、纤维素或甘露醇中的一种或几种，所述的填充剂在所述的泡腾制剂中所占的重量百分比为1-15％。
  4. 权利要求3所述的泡腾制剂，其特征在于，所述的药剂学上可以接受的辅料还包括抗氧化剂、润滑剂、甜味剂、香精或着色剂中的一种或几种。
  5. 权利要求4所述的泡腾制剂，其特征在于，所述的抗氧化剂选自维生素C、谷胱甘肽或硫辛酸中的一种或几种，所述的抗氧化剂在所述的泡腾制剂中所占的重量百分比为7-15％；所述的润滑剂选自聚乙二醇、十二烷基硫酸钠、十二烷基硫、亮氨酸、苯甲酸钠、油酸钠、氯化钠、醋酸钠、硼酸、硬脂酸镁、滑石粉、微粉硅胶、蔗糖脂肪酸酯或富马酸钠的一种或几种，所述的润滑剂在所述的泡腾制剂中所占的重量百分比为5-15％；所述的甜味剂选自甜蜜素、安赛蜜、三氯蔗糖、阿司帕坦、蔗糖、糖精钠、蛋白糖、葡萄糖、甜菊素、甜菊苷、甘草甜素、索马甜、枸橼酸、酒石酸、苹果酸或乳酸的一种或几种，所述的甜味剂在所述的泡腾制剂中所占的重量百分比为0.5-3％；所述的香精在所述的泡腾制剂中的重量百分比为1-3％；所述的着色剂选自有虫胶色素、红花黄色素、甜菜红、辣椒红素、红曲米、姜黄、阿朴胡萝卜素醛、β-胡萝卜素或叶绿酸铜钠盐中的一种或几种，所述的着色剂在所述的泡腾制剂中的重量百分比为1-5％。
  6. 权利要求1所述的泡腾制剂，其特征在于，所述的超微粉化大麻素是通过球磨法对物料进行球磨得到，所述的物料包括大麻素和乳化剂，所述的大麻素在物料中的重量百分比为95-99.8％，优选98％、99％或99.5％，所述的大麻素为：CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND纯品中的一种或两种以上的组合；或，所述大麻素为大麻提取物，所述的大麻提取物包含CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND中 的一种或两种以上的组合。
  7. 权利要求6所述的泡腾制剂，其特征在于，所述的乳化剂为吐温80。
  8. 权利要求6或7所述的泡腾制剂，其特征在于，所述的球磨法中球磨速度为300rpm-500rpm，每次球磨时间为20-30min，两次球磨之间的间歇时间为3-5min，共研磨2-3h。
  9. 权利要求1所述的泡腾制剂，其特征在于，所述的超微粉化大麻素通过气流粉碎法对物料进行气流粉碎得到，所述的物料中包含大麻素和药剂学上可接受的辅料，所述的药剂学上可接受的辅料选自乳糖、二氧化硅或硬脂酸镁的一种或几种，所述的大麻素为：CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND纯品中的一种或两种以上的组合；或，所述大麻素为大麻提取物，所述的大麻提取物包含CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND中的一种或两种以上的组合。
  10. 权利要求9所述的泡腾制剂，其特征在于，所述的物料中大麻素的重量百分比为80-99％，优选90％、95％或98％。
  11. 权利要求9或10所述的泡腾制剂，其特征在于，所述的气流粉碎法中进料压力为0.1-1.5MP，优选为0.2-0.8MP；粉碎压力为0.1-1.5MP，优选为0.3-0.8MP。
  12. 权利要求1-11任一所述的泡腾制剂，其特征在于，所述的超微粉化大麻素粒径在20um以下。
  13. 如权利要求1-12任一所述的泡腾制剂，其特征在于，所述的泡腾制剂为泡腾制剂或泡腾颗粒。
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