CN115052587A - Cannabinoid effervescent formulation and method of making same - Google Patents

Cannabinoid effervescent formulation and method of making same Download PDF

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CN115052587A
CN115052587A CN202180000835.5A CN202180000835A CN115052587A CN 115052587 A CN115052587 A CN 115052587A CN 202180000835 A CN202180000835 A CN 202180000835A CN 115052587 A CN115052587 A CN 115052587A
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cannabinoid
effervescent
preparation
weight
sodium
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CN115052587B (en
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谭昕
王曙宾
范德凯
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Hanyi Bio Technology Beijing Co ltd
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Abstract

An effervescent tablet or granule is prepared from micronized cannabinoid by ball milling or jet milling at a weight ratio of 0.5-10%, preferably 4-6%.

Description

Cannabinoid effervescent formulation and method of making same Technical Field
The invention relates to the field of medicines, in particular to a cannabinoid effervescent preparation and a preparation method thereof, and more particularly relates to an effervescent preparation containing ultra-micronized cannabinoid and a preparation method thereof.
Background
The ultrafine powder is usually a powder having a particle size of 20 μm or less and having a fine particle size. After the material is subjected to superfine grinding, the formed powder has good surface properties such as dispersibility and dissolvability. The newly generated particles have the remarkable characteristics of good surface effect, quantum size effect, small size effect, quantum tunneling effect and the like.
The preparation of ultrafine powders usually involves both physical and chemical methods. The physical methods can be divided into dry methods and wet methods. Chemical processes can be further divided into gas phase processes and liquid phase processes. Among the physical methods, the dry-process ultrafine pulverizer can be divided into a ball mill, a vibration mill, a jet mill and the like for pulverization; the wet superfine grinding comprises liquid flow grinding, homogenizer grinding and the like. Among chemical methods, gas phase methods include vacuum evaporation methods, gas phase chemical reaction methods, plasma methods, and the like; the liquid phase method mainly includes precipitation, oxidative hydrogenation decomposition, reduction, spray drying, and freeze drying.
The superfine powder technology is a new technology and is widely applied to the fields of metallurgy, ceramics, textile, food, medicine, cosmetics, aerospace and the like.
The existing cannabinoid food comprises CBD water, hemp seed oil, cake, soft candy, etc. At present, most of cannabinoid products have the problems of unstable content of the cannabinoid, low bioavailability, inconvenient carrying and the like. For example: the CBD content in the existing commercially available CBD water is unstable; liquid cannabinoid foods are inconvenient to carry and store; the cannabinoid in cake, soft candy, chocolate, etc. containing cannabinoid is absorbed by digestion, and can not be directly absorbed, and has low bioavailability.
CN110448598A discloses a formulation of CBD, a water-soluble cannabidiol for medical use, which comprises effervescent tablets prepared by adding the effervescent disintegrant, but no specific processing method of water-soluble cannabidiol is given.
CN109316459A discloses a method for preparing curcumin effervescent tablets, which comprises the steps of adding curcumin and zein into 40-80% ethanol, stirring for dissolving, dissolving sodium caseinate in water, adding the dissolved sodium caseinate into the ethanol solution, and stirring uniformly to prepare a mixed solution containing 0.1-1g/L curcumin, 1-10g/L zein and 1-10g/L sodium caseinate; freeze drying the mixed solution, and grinding into superfine powder with particle size of 50-500 nm; adding pharmaceutically acceptable adjuvants into the superfine powder, and making into effervescent tablet by conventional process.
However, in the prior art, active ingredients are added into a carrier, dried into powder together and then micronized, and the cannabinoid effervescent tablets prepared by the method easily cause discoloration of the cannabinoid, poor mouthfeel of the tablets and low bioavailability.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a novel cannabinoid product, ultrafine cannabinoid and other pharmaceutically acceptable auxiliary materials are pressed into a cannabinoid effervescent preparation, the process is simple, the cannabinoid is uniformly dispersed in water after being disintegrated by adding water, and the product can cover the bitter taste of the cannabinoid and can be directly taken.
The invention provides an effervescent preparation of cannabinoid, wherein the cannabinoid is micronized cannabinoid, and the weight percentage of the micronized cannabinoid in the effervescent preparation is 0.5-10%, preferably 1% -6%, further preferably 2% -6%, and further preferably 4% -6%. The ultra-micronized cannabinoid is obtained by ball milling or jet milling the material by ball milling or jet milling.
The effervescent preparation is an effervescent preparation or an effervescent granule.
Preferably, the cannabinoid is a natural or synthetic cannabinoid.
The cannabinoid is selected from: one or more of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND.
The synthetic cannabinoids are: one or more of pure CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND products.
The natural cannabinoid is a cannabis extract comprising cannabis, wherein the cannabis extract comprises one or a combination of more than two of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND.
Preferably, the cannabinoid-containing cannabis extract is a cannabis plant extract.
Preferably, the cannabis plant is industrial cannabis, and the content of Tetrahydrocannabinol (THC) in the industrial cannabis is less than 0.3%.
Preferably, the cannabis plant extract may be extracted from the stem core, flower, leaf, root or seed coat of the cannabis plant.
Preferably, the extraction solvent of the cannabis plant extract of the invention may be a low molecular alcohol (such as methanol, ethanol, butanol or propanol); acetates (such as methyl acetate or ethyl acetate); ketones (such as acetone); ethers (e.g., methyl or ethyl ether); aliphatic or aromatic or chlorinated hydrocarbons with a low boiling point.
More preferably, the effervescent preparation further comprises pharmaceutically acceptable auxiliary materials.
Preferably, the pharmaceutically acceptable excipients comprise organic acid, bicarbonate and/or carbonate and filler.
Preferably, the organic acid is selected from one or more of citric acid, tartaric acid, citric acid, fumaric acid, adipic acid and malic acid.
Preferably, in a specific embodiment, the organic acid accounts for 20-40% by weight of the effervescent preparation, and is preferably 30%.
Preferably the organic acid is a combination of tartaric acid and citric acid. The tartaric acid accounts for 2-8% of the effervescent preparation, and the citric acid accounts for 18-32% of the effervescent preparation. In a specific embodiment, the tartaric acid accounts for 5% by weight of the effervescent preparation, and the citric acid accounts for 25% by weight of the effervescent preparation.
Preferably, the bicarbonate and/or carbonate is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or calcium carbonate.
Preferably, the bicarbonate and/or carbonate accounts for 20-40% of the effervescent preparation by weight. In a specific embodiment, the bicarbonate and/or carbonate is present in the effervescent formulation in an amount of 30% by weight.
Preferably, the bicarbonate is sodium bicarbonate.
Preferably, the carbonate is sodium carbonate.
Preferably, the bicarbonate and/or carbonate is a combination of bicarbonate and carbonate. The bicarbonate is present in the effervescent formulation in an amount of 18-32% by weight, and in one embodiment the bicarbonate is present in the effervescent formulation in an amount of 25% by weight. The carbonate accounts for 2-8% of the effervescent preparation, and in a specific embodiment, the carbonate accounts for 5% of the effervescent preparation.
Preferably, the filler is selected from one or more of starch, sugar, cellulose, inorganic salt or mannitol. Wherein the starch is selected from starch and/or compressible starch; the sugar is selected from one or more of sugar powder, dextrin or lactose; the cellulose is selected from microcrystalline cellulose; the inorganic salt is selected from inorganic calcium salts, preferably calcium sulfate and/or calcium sulfate dihydrate.
Preferably, the lactose is direct compression lactose, and the powdered sugar is sucrose powder.
Preferably, the filling agent accounts for 1 to 15 percent of the effervescent preparation by weight. In a specific embodiment, the bulking agent is present in the effervescent formulation in an amount of 8 to 12% by weight; in a specific embodiment, the bulking agent is present in the effervescent formulation in an amount of 10% by weight.
In one embodiment, the bulking agent is a combination of direct compression lactose and sucrose powder. Wherein, the weight percentage of the direct compression lactose in the effervescent preparation is 4-6%, preferably 5%; the sucrose powder accounts for 4-6% by weight of the effervescent preparation, and preferably accounts for 5% by weight of the effervescent preparation.
Preferably, the pharmaceutically acceptable auxiliary materials in the effervescent preparation can also comprise one or more of an antioxidant, a lubricant, a sweetener, an essence or a coloring agent.
Preferably, the antioxidant is selected from water-soluble antioxidants.
Further preferably, the water-soluble antioxidant is selected from one or more of vitamin C, glutathione or lipoic acid.
More preferably, the antioxidant is vitamin C.
Preferably, the antioxidant accounts for 7-15% by weight of the effervescent preparation, and is preferably 12%.
Preferably, the lubricant is selected from one or more of polyethylene glycol, sodium dodecyl sulfate, dodecyl sulfur, leucine, sodium benzoate, sodium oleate, sodium chloride, sodium acetate, boric acid, magnesium stearate, talcum powder, superfine silica gel powder, sucrose fatty acid ester or sodium fumarate.
Preferably, the lubricant is present in the effervescent formulation in an amount of 5-15% by weight, preferably 9-10%.
Preferably, the lubricant is a combination of sodium chloride, leucine, polyethylene glycol and sodium fumarate, wherein the weight percentage 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 weight percentage of the leucine in the effervescent preparation is 0.5-2%, preferably 1%; the weight percentage of the sodium fumarate in the effervescent preparation is 1-3%, preferably 2%.
Preferably, the sweetener is one or more selected from sodium cyclamate, acesulfame, sucralose, aspartame, sucrose, saccharin sodium, aspartame, glucose, steviosin, stevioside, glycyrrhizin, thaumatin, citric acid, tartaric acid, malic acid or lactic acid.
Preferably, the sweetener is present in the effervescent formulation in an amount of 0.5 to 3% by weight. In a specific embodiment, the sweetener is present in the effervescent formulation in an amount of 1.5% by weight.
Preferably, the sweetening agent is a combination of aspartame and sucralose, wherein the weight percentage of 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%.
Preferably, the essence is selected from one or more of rose essence, lemon essence, vanilla essence, banana essence, apple essence, mint essence, almond essence or orange essence.
Preferably, the weight percentage of the essence in the effervescent preparation is 1-3%, preferably 2%.
Preferably, the coloring agent is selected from one or more of shellac pigment, safflower yellow, beet red, capsorubin, red yeast rice, turmeric, apocarotene aldehyde, beta-carotene or copper sodium chlorophyllin.
Preferably, the colorant is present in the effervescent formulation in an amount of 1-5% by weight. In a specific embodiment, the colorant is present in the effervescent formulation in an amount of 3.5% by weight.
Preferably, the coloring agent is a combination of apocarotene aldehyde and beta-carotene, wherein the apocarotene aldehyde accounts for 0.9 to 4 percent by weight, preferably 3 percent by weight, of the effervescent preparation; the weight percentage of the beta carotene in the effervescent preparation is 0.1-1%, and preferably 0.5%.
In one embodiment of the invention, the effervescent preparation comprises the following components in percentage by weight: 0.5-10% of superfine powder cannabinoid, 20-40% of organic acid, 18-32% of bicarbonate, 2-8% of carbonate, 5-15% of filler, 7-15% of antioxidant, 5-15% of lubricant, 0.5-3% of sweetener, 1-3% of essence and 1-5% of colorant. Or consist of the above components.
Preferably, the effervescent preparation comprises the following components in percentage by weight: 0.5-10% of superfine pulverization cannabinoid, 2-8% of tartaric acid, 18-32% of citric acid, 18-32% of sodium bicarbonate, 2-8% of sodium carbonate, 4-6% of lactose, 4-6% of sucrose powder, 1-3% of sodium chloride, 7-15% of vitamin C, 2.5-7% of polyethylene glycol, 1-3% of sodium fumarate, 0.5-2% of leucine, 0.1-1% of aspartame, 0.4-2% of sucralose, 1-3% of essence, 0.9-4% of apocarotene and 0.1-1% of beta carotene. Or consist of the components.
In one embodiment, the effervescent formulation comprises, by weight: 1% of superfine pulverization cannabinoid, 5% of tartaric acid, 25% of citric acid, 25% of sodium bicarbonate, 5% of sodium carbonate, 5% of direct compression lactose, 5% of sucrose powder, 2% of sodium chloride, 12% of vitamin C, 5% of polyethylene glycol, 2% of sodium fumarate, 1% of leucine, 0.5% of aspartame, 1% of sucralose, 2% of essence, 3% of apocarotene and 0.5% of beta carotene.
In one embodiment, the effervescent formulation comprises, by weight: 2% of superfine pulverization cannabinoid, 5% of tartaric acid, 25% of citric acid, 25% of sodium bicarbonate, 5% of sodium carbonate, 5% of direct compression lactose, 5% of sucrose powder, 2% of sodium chloride, 12% of vitamin C, 4% of polyethylene glycol, 2% of sodium fumarate, 1% of leucine, 0.5% of aspartame, 1% of sucralose, 2% of essence, 3% of apocarotene and 0.5% of beta carotene.
In one embodiment, the effervescent formulation comprises, by weight: 4% of micronized cannabinoid,
5% of tartaric acid, 25% of citric acid, 25% of sodium bicarbonate, 5% of sodium carbonate, 5% of direct compression lactose, 5% of sucrose powder, 2% of sodium chloride, 10% of vitamin C, 4% of polyethylene glycol, 2% of sodium fumarate, 1% of leucine, 0.5% of aspartame, 1% of sucralose, 2% of essence, 3% of apocarotene and 0.5% of beta carotene.
In one embodiment, the effervescent formulation comprises, by weight: 6% of superfine pulverization cannabinoid, 5% of tartaric acid, 25% of citric acid, 25% of sodium bicarbonate, 5% of sodium carbonate, 4% of direct compression lactose, 5% of sucrose powder, 2% of sodium chloride, 10% of vitamin C, 3% of polyethylene glycol, 2% of sodium fumarate, 1% of leucine, 0.5% of aspartame, 1% of sucralose, 2% of essence, 3% of apocarotene and 0.5% of beta carotene.
In one embodiment, the effervescent formulation comprises, by weight: 10% of superfine pulverization cannabinoid, 4% of tartaric acid, 24% of citric acid, 24% of sodium bicarbonate, 4% of sodium carbonate, 4% of direct compression lactose, 5% of sucrose powder, 2% of sodium chloride, 10% of vitamin C, 3% of polyethylene glycol, 2% of sodium fumarate, 1% of leucine, 0.5% of aspartame, 1% of sucralose, 2% of essence, 3% of apocarotene and 0.5% of beta carotene.
The invention also provides a preparation method of the effervescent preparation, which comprises the following steps: mixing the superfine powder cannabinoid, organic acid, bicarbonate, carbonate, bulking agent, antioxidant, lubricant, sweetener, essence, and colorant at a certain proportion, directly mixing, and making into effervescent preparation.
Preferably, the weight of the effervescent tablet is controlled to be 0.5-5 g.
Preferably, the ultra-micronized cannabinoid is obtained by ball milling a material by a ball milling method, wherein the material comprises the cannabinoid and an emulsifier, and the weight percentage of the cannabinoid in the material is 95-99.8%.
Preferably, the cannabinoid is present in the material in an amount of 98%, 99% or 99.5% by weight.
Preferably, the cannabinoid is one or more combination of substantially pure cannabinoids or a cannabis extract containing the cannabinoid.
In particular, the cannabinoids are: one or more of pure products of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND; or, the cannabis extract comprises one or a combination of two or more of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND.
Preferably, the emulsifier is tween 80.
Preferably, the ball milling method also requires 20-30 times of purified water to be added to the material.
Preferably, the ball milling speed of the ball milling method is 300rpm-500rpm, each ball milling time is 20-30min, the interval time between two ball milling times is 3-5min, and the total milling time is 2-3 h.
Preferably, the ball milling process for preparing ultra-micronized cannabinoids comprises the steps of:
a) mixing materials: mixing cannabinoid and Tween 80 at a certain ratio;
b) ball milling: adding the mixture of a) and water of which the amount is 20-30 times that of the mixture into a tank, adding zirconia balls for grinding at the speed of 300-500 rpm or 400rpm for 20-30min or 25min each time, and carrying out batch time of 3-5min or 4min between every two ball grindings for 2-3h or 2.5h in total grinding.
Preferably, the ultrafine powder cannabinoid is obtained by carrying out airflow pulverization on a material through an airflow pulverization method, wherein the material comprises the cannabinoid and pharmaceutically acceptable auxiliary materials, and the auxiliary materials are selected from one or more of lactose, silicon dioxide and magnesium stearate.
Preferably, the weight percentage of the cannabinoid in the material is 80-99%.
More preferably, the cannabinoid is present in the mixture in an amount of 90%, 95% or 98%.
Preferably, the cannabinoid is one or more combination of substantially pure cannabinoids or a cannabis extract containing the cannabinoid.
In particular, the cannabinoids are: one or more of pure products of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND; or, the cannabis extract comprises one or a combination of two or more of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND.
Preferably, the lactose in the material accounts for 0.1-15% by weight
In some specific embodiments, the lactose in the material accounts for 0.5%, 4% or 9% by weight,
Preferably, the weight percentage of the silicon dioxide in the material is 0.1-1%.
In some specific embodiments, the silica accounts for 0.1% or 0.5% by weight of the material.
Preferably, the weight percentage of magnesium stearate in the material is 0.1% -2%.
In some embodiments, the magnesium stearate in the material is 0.1%, 0.5%, 0.9% by weight.
Further preferably, the feeding pressure of the jet milling method is 0.1-1.5MP, and the milling pressure is 0.1-1.5 MP.
In one embodiment, the feeding pressure is 0.2-0.8MP and the crushing pressure is 0.3-0.8 MP.
Preferably, the process for preparing ultra-micronized cannabinoids by jet milling comprises the steps of:
a) mixing materials: mixing cannabinoid with lactose, silicon dioxide and magnesium stearate in proportion;
b) airflow crushing: jet milling the mixture of step a) at a feed pressure of 0.1-1.5MP or 0.2-0.8MP, a milling pressure of 0.1-1.5MP or 0.3-0.8 MP.
Preferably, the particle size of the ultra-micronized cannabinoid obtained by the ball milling method or the jet milling method of the present invention is less than 20 um.
Further preferably, the particle size of the ultra-micronized cannabinoid is 1um, 2um, 3um, 4um, 5um, 6um, 7um, 8um, 9um, 10um, 11um, 12um, 13um, 14um, 15um, 16um, 17um, 18um, 19um or 20um or more.
The invention also provides application of the effervescent preparation containing the ultra-micronized cannabinoid in preparation of foods, medicines, skin care products and perfumes.
Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains, as the following abbreviations and their counterparts appear in the present invention: CBDV (cannabidiol), CBD (cannabidiol), CBG (cannabigerol), CBN (cannabinol), CBC (cannabichromene), CBDB (4-butyl-5 ' -methyl-2 ' - (prop-1-en-2-yl) -1 ', 2 ', 3 ', 4 ' -tetrahydrol- (1,1 ' -biphenol) -2,6-diol, canabidibutol), cbe (canabie lsoin), CBL (cannabicyclol), CBND (dehydrocannabidiol).
In the present invention, the pure products of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND refer to pure products of the above compounds, in particular to corresponding commercial products, wherein the purity of the compounds is at least 99.5% or more, in particular 99.9% or more (the remainder being impurities); the content of cannabinoid in the Cannabis sativa extract is at least 80%, preferably 90%, especially 95%.
The preparation method of the invention is adopted to obtain a novel cannabinoid effervescent preparation, which refers to effervescent tablets or effervescent granules and has the following beneficial effects:
a) the cannabinoid effervescent tablet adopts a powder direct compression process, has simple process, controls the acid-base ratio in the prescription, and has rapid disintegration.
b) The cannabinoid effervescent preparation has high content of cannabinoid, high stability, convenient carrying and storage.
c) The cannabinoid effervescent preparation can dissolve in water quickly, the cannabinoid micropowder can be dispersed in water uniformly, the water-soluble cannabinoid can be dissolved in water directly, and can be absorbed by drinking directly, and the bioavailability is high.
d) The effervescent cannabinoid preparation is soluble in water, and can mask the bitter taste of cannabinoid when drinking, and has good taste and convenient administration.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
Example 1 preparation of ultra-micronized cannabinoid Using a ball milling Process
a) Mixing materials: mixing 99.5% cannabinoid with 0.5% tween 80;
b) ball milling: adding the mixture of a) and water which is 20-30 times of the mixture into a tank, adding zirconia balls for ball milling at the speed of 300rpm for 20min each time, and milling for 3h in total with the intermittent time between each two ball mills.
Wherein the cannabinoid is cannabidiol, is derived from industrial cannabis sativa flower and leaf, and is prepared by the preparation method disclosed in example 1 of CN 106831353A.
Example 2: preparation of ultra-micronized cannabinoids by ball milling
a) Mixing materials: mixing 99% cannabinoid 1% tween 80;
b) ball milling: adding the mixture of a) and water which is 20-30 times of the mixture into a tank, adding zirconia balls for grinding, wherein the speed of ball grinding is 400rpm, the time of each ball grinding is 25min, the interval time between every two ball grinding is 4min, and the total grinding time is 2.5 h.
Wherein the source and preparation method of cannabinoid are the same as in example 1.
Example 3: preparation of ultra-micronized cannabinoids by ball milling
a) Mixing materials: mixing 98% cannabinoid with 2% tween 80;
b) ball milling: adding the mixture of a) and water which is 20-30 times of the mixture into a tank, adding zirconia balls for ball milling at the speed of 500rpm for 30min, and milling for 2h in total with the interval time between every two ball mills of 5 min.
Wherein the source and preparation method of cannabinoid are the same as in example 1.
Example 4: ultra-micronized cannabinoids by jet milling
a) Mixing materials: mixing 98% cannabinoid, 0.5% lactose, 0.5% silicon dioxide and 0.1% magnesium stearate;
b) airflow crushing: jet milling the mixture of step a) at a feed pressure of 0.2MP and a milling pressure of 0.3 MP.
Wherein the source and preparation method of cannabinoid are the same as in example 1.
Example 5: ultra-micronized cannabinoids by jet milling
Mixing materials: mixing 95% cannabinoid, 4% lactose, 0.5% silicon dioxide, and 0.5% magnesium stearate;
b) airflow crushing: jet milling the mixture of step a) at a feed pressure of 0.5MP, a milling pressure of 0.5 MP.
Wherein the source and preparation method of cannabinoid are the same as in example 1.
Example 6: ultra-micronized cannabinoids by jet milling
a) Mixing materials: mixing 90% cannabinoid, 9% lactose, 0.1% silicon dioxide, and 0.9% magnesium stearate;
b) airflow crushing: jet milling the mixture of step a) at a feed pressure of 0.8MP, a milling pressure of 0.8 MP.
Wherein the source and preparation method of cannabinoid are the same as in example 1.
The following table is a table of formulations used in examples 7-18, 20-31 for the preparation of cannabinoid effervescent formulations:
TABLE 1 cannabinoid effervescent formulation Table
Component (percentage by weight) Formulation 1 Formulation 2 Formulation 3 Formulation 4 Formulation 5
Cannabinoid ultra-fine powder% 1 2 4 6 10
Sodium bicarbonate% 25 25 25 25 24
Sodium carbonate% 5 5 5 5 4
Tartaric acid% 5 5 5 5 4
Citric acid% 25 25 25 25 24
Aspartame% 0.5 0.5 0.5 0.5 0.5
Lactose% by direct compression 5 5 5 4 4
Sodium chloride% 2 2 2 2 2
Polyethylene glycol% 5 4 4 3 3
Vitamin C% 12 12 10 10 10
Fine particles of sucrose% 5 5 5 5 5
Apocarotene aldehyde% 3 3 3 3 3
Beta carotene% 0.5 0.5 0.5 0.5 0.5
Sucralose% 1 1 1 1 1
Essence% 2 2 2 2 2
Sodium fumarate% 2 2 2 2 2
Leucine% 1 1 1 1 1
Example 7: preparation of cannabinoid effervescent granules
The formulation according to formulation 1 was prepared by direct mixing: the ingredients were mixed directly into effervescent granules, the unit weight was controlled at 4g, where the cannabinoid micropowder was prepared using the method of example 1.
Example 8: preparation of cannabinoid effervescent granules
The formula of formula 1 is prepared by a dry granulation method: the ingredients were mixed directly and pressed into granules using a dry granulator with a unit weight controlled at 4g and a roller pressure controlled at 4-60bar, where the cannabinoid micropowder was prepared using the method of example 2.
Example 9: preparation of cannabinoid effervescent tablets
The formulation according to formulation 1 was prepared by a one-step granulation method: taking the components, dissolving polyethylene glycol in auxiliary materials into water with the volume of 10-100 times of that of the components to be used as slurry, using the rest raw materials and auxiliary materials as base materials, preparing into effervescent granules with the atomizing pressure of 0.05-0.2Mpa and the granulating temperature of 20-70 ℃, and controlling the unit weight to be 4g, wherein the cannabinoid ultrafine powder is prepared by the method of the embodiment 3.
Example 10: preparation of cannabinoid effervescent granules
The formulation according to formulation 2 was prepared by direct mixing: the ingredients were mixed directly into effervescent granules, the unit weight was controlled at 4g, where the cannabinoid micropowder was prepared using the method of example 4.
Example 11: preparation of cannabinoid effervescent granules
The formula according to formula 2 is prepared by a dry granulation method: the ingredients were mixed directly and pressed into granules using a dry granulator with a unit weight controlled at 4g and a roller pressure controlled at 4-60bar, where the cannabinoid micropowder was prepared using the method of example 5.
Example 12: preparation of cannabinoid effervescent granules
The formulation according to formulation 2 was prepared by a one-step granulation method: taking the components, dissolving polyethylene glycol in auxiliary materials into water with the volume of 10-100 times of that of the components to be used as slurry, using the rest raw materials and the auxiliary materials as base materials, preparing into effervescent granules with the atomizing pressure of 0.05-0.2Mpa and the granulating temperature of 20-70 ℃, and controlling the unit weight to be 4g, wherein the cannabinoid ultrafine powder is prepared by the method of the embodiment 6.
Example 13: preparation of cannabinoid effervescent granules
The formulation according to formulation 3 was prepared by direct mixing: the ingredients were mixed directly into effervescent granules, the unit weight was controlled at 4g, where the cannabinoid micropowder was prepared using the method of example 1.
Example 14: preparation of cannabinoid effervescent granules
The formula according to formula 4 is prepared by a dry granulation method: mixing the above components directly, granulating with dry granulator to obtain granule with unit weight of 4g and compression pressure of 4-60bar, wherein the superfine powder is prepared by the method of example 2.
Example 15: preparation of cannabinoid effervescent granules
The formulation according to formulation 5 was prepared by a one-step granulation method: taking the components, dissolving polyethylene glycol in auxiliary materials into water with the volume of 10-100 times of that of the components to be used as slurry, using the rest raw materials and auxiliary materials as base materials, preparing into effervescent granules with the atomizing pressure of 0.05-0.2Mpa and the granulating temperature of 20-70 ℃, and controlling the unit weight to be 4g, wherein the cannabinoid ultrafine powder is prepared by the method of the embodiment 3.
Example 16: preparation of cannabinoid effervescent granules
The formulation according to formulation 3 was prepared by direct mixing: the ingredients were mixed directly into effervescent granules, the unit weight was controlled at 4g, where the cannabinoid micropowder was prepared using the method of example 4.
Example 17: preparation of cannabinoid effervescent granules
The formula according to formula 4 is prepared by a dry granulation method: the ingredients were mixed directly and pressed into granules using a dry granulator with a unit weight controlled at 4g and a roller pressure controlled at 4-60bar, where the cannabinoid micropowder was prepared using the method of example 5.
Example 18: preparation of cannabinoid effervescent granules
The formulation according to formulation 5 was prepared by a one-step granulation method: taking the components, dissolving polyethylene glycol in auxiliary materials into water with the volume of 10-100 times of that of the components to be used as slurry, using the rest raw materials and the auxiliary materials as base materials, preparing into effervescent granules with the atomizing pressure of 0.05-0.2Mpa and the granulating temperature of 20-70 ℃, and controlling the unit weight to be 4g, wherein the cannabinoid ultrafine powder is prepared by the method of the embodiment 6.
Example 19: quality comparison research of effervescent granules obtained by different formulas and preparation methods
Examples Disintegration time Particle size Solubility in water Content stability
7 60S Qualified Qualified Accelerating the content stabilization for 6 months
8 60S Qualified Qualified Accelerating the content stabilization for 6 months
9 60S Qualified Qualified Accelerated for 6 months and has stable content
10 90S Qualified Qualified Accelerating the content stabilization for 6 months
11 90S Qualified Qualified Accelerating the content stabilization for 6 months
12 90S Qualified Qualified Accelerating the content stabilization for 6 months
The experimental method is as follows:
1. method for checking disintegration time limit, comprising: referring to the item of 0104 granules in the fourth pharmacopoeia of 2020 edition, an effervescent granule inspection method is adopted, wherein 4g of granules are transferred to a beaker filled with 200ml of water, the water temperature is 15-25 ℃, gas is rapidly generated to form effervescence, and the granules are completely dispersed or dissolved in the water within 5 min.
2. Particle size and solubility test methods: see 2020 version of Chinese pharmacopoeia, 0104 granule, particle size and solubility detection method and requirements.
3. The method for checking the acceleration stability comprises the following steps: sealing the sample into an aluminum-plastic composite bag with the specification of 4 g/bag, placing the sample in a stability experiment box with the relative humidity of 75% at 40 ℃, detecting the disintegration time limit, the particle size, the dissolubility and the content of the particles at 0, 3 and 6 months respectively, and inspecting the stability of the sample.
Example 20: preparation of cannabinoid effervescent tablets
The components are taken according to the formula of the formula 1, are directly mixed into effervescent granules and are directly pressed into tablets, the weight of the tablets is controlled to be 0.5g, and the cannabinoid submicron powder is prepared by the method of the example 1.
Example 21: preparation of cannabinoid effervescent tablets
The components are taken according to the formula of the formula 1 and directly mixed, and are firstly granulated by a dry granulating machine, the pressure of a compression roller is controlled to be 4-60bar, and then the components are directly compressed into tablets, the tablet amount is controlled to be 0.5g, wherein the cannabinoid ultrafine powder is prepared by the method of the embodiment 2.
Example 22: preparation of cannabinoid effervescent tablets
Taking the components according to the formula of the formula 1, dissolving polyethylene glycol in auxiliary materials in 10-100 times of water to serve as slurry, using the rest raw materials and auxiliary materials as base materials, atomizing under the pressure of 0.05-0.2Mpa, granulating at the temperature of 20-70 ℃, preparing effervescent granules, and directly pressing into tablets, wherein the weight of the tablets is controlled to be 0.5g, and the cannabinoid submicron powder is prepared by the method of the embodiment 3.
Example 23: preparation of cannabinoid effervescent tablets
The ingredients are taken according to the formula of the formula 2, directly mixed into effervescent granules and directly compressed into tablets, the weight of the tablets is controlled to be 0.5g, and the cannabinoid submicron powder is prepared by the method of the example 4.
Example 24: preparation of cannabinoid effervescent tablets
The ingredients were mixed directly according to formulation 2 and compressed into granules using a dry granulator with a roller pressure controlled at 4-60bar and directly compressed into tablets with a tablet weight controlled at 0.5g, wherein the cannabinoid micropowder was prepared using the method of example 5.
EXAMPLE 25 preparation of cannabinoid effervescent tablets
Taking the components according to the formula of the formula 2, dissolving polyethylene glycol in auxiliary materials in 10-100 times of water to be used as slurry, using the rest raw materials and auxiliary materials as base materials, atomizing under the pressure of 0.05-0.2Mpa, granulating at the temperature of 20-70 ℃, preparing effervescent granules, and directly pressing into tablets, wherein the weight of the tablets is controlled to be 0.5g, and the cannabinoid ultrafine powder is prepared by the method of the embodiment 6.
Example 26: preparation of cannabinoid effervescent tablets
The components are taken according to the formula of the formula 3, are directly mixed into effervescent granules and are directly pressed into tablets, the weight of the tablets is controlled to be 0.5g, and the cannabinoid submicron powder is prepared by the method of the example 1.
Example 27: preparation of cannabinoid effervescent tablets
Taking the components according to the formula of the formula 4, directly mixing, granulating by using a dry granulating machine, controlling the pressure of a compression roller to be 4-60bar, and directly compressing into tablets, wherein the tablet amount is controlled to be 0.5g, and the cannabinoid ultrafine powder is prepared by the method of the example 2.
Example 28: preparation of cannabinoid effervescent tablets
Taking the components according to the formula of the formula 5, dissolving polyethylene glycol in auxiliary materials in 10-100 times of water to serve as slurry, using the rest raw materials and auxiliary materials as base materials, atomizing under the pressure of 0.05-0.2Mpa, granulating at the temperature of 20-70 ℃, preparing effervescent granules, and directly pressing into tablets, wherein the weight of the tablets is controlled to be 0.5g, and the cannabinoid submicron powder is prepared by the method of the embodiment 3.
Example 29: preparation of cannabinoid effervescent tablets
The ingredients are taken according to the formula of the formula 3, directly mixed into effervescent granules and directly compressed into tablets, the weight of the tablets is controlled to be 0.5g, and the cannabinoid submicron powder is prepared by the method of the example 4.
Example 30: preparation of cannabinoid effervescent tablets
The ingredients were mixed directly according to formula 4 and granulated using a dry granulator under a pressure of 4-60bar and directly tabletted at 0.5g, wherein the cannabinoid micropowder was prepared using the method of example 5.
Example 31: preparation of cannabinoid effervescent tablets
Taking the components according to the formula of the formula 5, dissolving polyethylene glycol in auxiliary materials in 10-100 times of water to serve as slurry, using the rest raw materials and auxiliary materials as base materials, atomizing under the pressure of 0.05-0.2Mpa, granulating at the temperature of 20-70 ℃, preparing effervescent granules, and directly pressing into tablets, wherein the weight of the tablets is controlled to be 0.5g, and the cannabinoid submicron powder is prepared by the method of the embodiment 6.
Example 32: quality comparison research of effervescent tablets obtained by different formulas and preparation methods
Examples Disintegration time Uniformity of dispersion Solution behavior Content stability
20 60S Qualified Is uniformly dispersed The tablet has stable content for 6 months
21 60S Qualified Is uniformly dispersed The tablet has stable content for 6 months
22 60S Qualified Is uniformly dispersed The tablet has stable content for 6 months
23 100S Qualified Is uniformly dispersed The tablet has stable content for 6 months
24 100S Qualified Uniformly disperse The tablet has stable content after accelerated for 6 months
25 100S Qualified Uniformly disperse The tablet has stable content after accelerated for 6 months
The experimental method is as follows:
1. the method for checking disintegration time limit and dispersion uniformity comprises the following steps: refer to the inspection method of effervescent tablets under the item of 0101 tablets in the fourth pharmacopoeia of China, 2020 edition.
2. The method for inspecting the properties of the solution after disintegration comprises the following steps: the shape of the solution is judged according to whether the solution is uniform in color after effervescence and whether obvious large particles exist.
3. The content stability inspection method comprises the following steps: sealing the sample into an aluminum-plastic composite bag, placing the bag in a stability experiment box with the relative humidity of 75% at 40 ℃, detecting the disintegration time limit, the dispersion uniformity, the solution property and the content of the particles at 0, 3 and 6 months respectively, and inspecting the stability of the sample.
And (4) analyzing results: the effervescent tablets prepared by the methods of examples 20-25 all meet the quality standard requirements of effervescent tablets.
Example 33: the bioavailability of effervescent tablet containing superfine cannabidiol powder and drop is compared
Figure PCTCN2021082031-APPB-000001
The experimental method is as follows:
1. method for checking sedation onset time: 20 male mice, weighing 20-25g, were selected and animals were raised in an artificially controlled environment using a circadian rhythm of 12h, with food and water ad libitum. The injection is subcutaneously injected with pentylenetetrazol, 20 mice have remarkable clonic convulsion, wherein ten of the mice are administered with 20 mgCBD/tablet ultramicro-pulverization cannabidiol effervescent tablet after effervescence and are intragastrically administered, and the other ten mice are administered with 1ml cannabidiol drop of 20 mgCBD/ml. Wherein the average clonic convulsion of mice in the micronized effervescent tablet group is obviously improved by 10min, and the average clonic convulsion of the drop group is obviously improved by 30 min.
2. Method for checking bioavailability: 12 healthy rats with weight of 20-25g and half of male and female are taken, fasted for 12 hours before the experiment and free to drink water. The two groups are divided into two groups, wherein the two groups are respectively intragastric micro powder effervescent solution containing 20mgCBD and oil drop agent containing 20mgCBD, and blood is respectively taken at the time points of 0min, 1.5h, 3h, 4h, 5h, 6h, 7h, 8h, 10h, 12h and 16h after administration. Taking 8 healthy SD rats with half of male and female, dividing into two groups, and respectively injecting CBD pure normal saline solution and full spectrum hemp oil normal saline into tail vein of two groups, and taking blood at 0min, 3min, 8min, 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 16h after administration. Both groups of samples were bled 50. mu.L from the periocular venous plexus and placed in 1.5mL heparin EP tubes. Centrifuging the collected blood sample at 4 deg.C and 4500rpm for 10min, and collecting supernatant to detect content. And calculating AUC 0- ∞ofthe CBD micro powder effervescent tablet group and the CBD oil drop group in a fitting manner, and AUC 0- ∞ofthe intravenous injection group, wherein the bioavailability of the CBD effervescent tablet group is calculated to be 20.2%, and the bioavailability of the CBD drop group is calculated to be 3.1%.
The effervescent tablet containing the ultra-micronized cannabidiol is prepared by the preparation method of the embodiment 20, and the cannabidiol drops are prepared by dissolving cannabidiol in soybean oil.
Example 34: stability comparison of effervescent tablets containing micronized cannabidiol with Water soluble cannabidiol powder
Dosage forms Specification of Room temperature for 30 days
Effervescent tablet containing superfine cannabidiol powder 20 mg/tablet Does not change color
Water soluble cannabidiol powder 20mg/g Changing into pink
The investigation method comprises the following steps: the two samples were left open at room temperature for 30 days, the ultra-micro cannabinoid did not change color, and the water-soluble cannabinoid powder was oxidized to a pale pink color.
The effervescent tablet containing ultra-micronized cannabidiol is prepared by the preparation method of embodiment 20, and the cannabidiol water-soluble powder is prepared by performing inclusion on cannabidiol by beta-cyclodextrin.
Example 35: the effervescent tablet containing superfine cannabidiol powder has a taste comparable to that of water soluble cannabidiol powder
Dosage forms Taste of the product
Effervescent tablet containing superfine cannabidiol powder Has good taste and no bitter taste
Water soluble cannabidiol powder Bitter taste
The effervescent tablet containing ultra-micronized cannabidiol is prepared by the preparation method of embodiment 20, and the cannabidiol water-soluble powder is prepared by performing inclusion on cannabidiol by beta-cyclodextrin.

Claims (13)

  1. An effervescent cannabinoid formulation, said cannabinoid being an ultra micronized cannabinoid, said ultra micronized cannabinoid being present in an amount of from about 0.5% to about 10% by weight, preferably from about 4% to about 6% by weight, said ultra micronized cannabinoid being produced by a ball milling process or a jet milling process.
  2. The effervescent formulation of claim 1, further comprising pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise an organic acid, bicarbonate and/or carbonate salt, and a bulking agent.
  3. The effervescent preparation of claim 2, wherein the organic acid is selected from one or more of citric acid, tartaric acid, citric acid, fumaric acid, adipic acid or malic acid, and the organic acid accounts for 20-40% of the effervescent preparation; the bicarbonate and/or carbonate is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or calcium carbonate, and the bicarbonate and/or carbonate accounts for 20-40% of the effervescent preparation by weight; the filling agent is selected from one or more of starch, sugar, cellulose or mannitol, and the filling agent accounts for 1-15% of the effervescent preparation by weight.
  4. The effervescent formulation of claim 3, wherein the pharmaceutically acceptable excipients further comprise one or more of an antioxidant, a lubricant, a sweetener, a fragrance, or a colorant.
  5. The effervescent preparation of claim 4, wherein the antioxidant is selected from one or more of vitamin C, glutathione or lipoic acid, and the antioxidant accounts for 7-15% by weight of the effervescent preparation; the lubricant is selected from one or more of polyethylene glycol, sodium dodecyl sulfate, dodecyl sulfur, leucine, sodium benzoate, sodium oleate, sodium chloride, sodium acetate, boric acid, magnesium stearate, talcum powder, superfine silica gel powder, sucrose fatty acid ester or sodium fumarate, and accounts for 5-15% of the effervescent preparation by weight; the sweetening agent is selected from one or more of sodium cyclamate, acesulfame potassium, sucralose, aspartame, sucrose, saccharin sodium, aspartame, glucose, steviosin, stevioside, glycyrrhizin, thaumatin, citric acid, tartaric acid, malic acid or lactic acid, and the sweetening agent accounts for 0.5-3% of the effervescent preparation by weight percent; the weight percentage of the essence in the effervescent preparation is 1-3%; the coloring agent is selected from one or more of shellac pigment, safflower yellow, beet red, capsorubin, red yeast rice, turmeric, apocarotene aldehyde, beta-carotene or copper sodium chlorophyllin, and the weight percentage of the coloring agent in the effervescent preparation is 1-5%.
  6. An effervescent formulation as claimed in claim 1, wherein the micronized cannabinoid is obtained by ball milling a material comprising 95-99.8%, preferably 98%, 99% or 99.5% by weight of the cannabinoid in the material, and an emulsifier, the cannabinoid being: one or more of pure products of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND; or the cannabinoid is a cannabis extract comprising one or a combination of two or more of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND.
  7. The effervescent formulation of claim 6, wherein the emulsifier is tween 80.
  8. The effervescent preparation of claim 6 or 7, wherein the ball milling process is carried out at a ball milling speed of 300rpm to 500rpm for 20 to 30min each time, and a time interval between ball milling is 3 to 5min for 2 to 3 hours.
  9. The effervescent formulation of claim 1, wherein the micronized cannabinoid is obtained by jet milling a material comprising the cannabinoid and a pharmaceutically acceptable excipient selected from one or more of lactose, silicon dioxide, or magnesium stearate by jet milling, wherein the cannabinoid is: one or more of pure products of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND; or the cannabinoid is a cannabis extract comprising one or a combination of two or more of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND.
  10. The effervescent formulation of claim 9, wherein the amount of cannabinoid present in the composition is from 80% to 99% by weight, preferably 90%, 95% or 98%.
  11. An effervescent formulation as claimed in claim 9 or claim 10 wherein the jet milling process is carried out at a feed pressure of 0.1 to 1.5MP, preferably 0.2 to 0.8 MP; the pulverizing pressure is 0.1-1.5MP, preferably 0.3-0.8 MP.
  12. An effervescent formulation as claimed in any of claims 1-11, wherein the micronized cannabinoid has a particle size of less than 20 um.
  13. The effervescent formulation of any one of claims 1-12, wherein the effervescent formulation is an effervescent formulation or effervescent granule.
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