WO2022187295A1 - Compositions de poloxamère et boissons - Google Patents
Compositions de poloxamère et boissons Download PDFInfo
- Publication number
- WO2022187295A1 WO2022187295A1 PCT/US2022/018422 US2022018422W WO2022187295A1 WO 2022187295 A1 WO2022187295 A1 WO 2022187295A1 US 2022018422 W US2022018422 W US 2022018422W WO 2022187295 A1 WO2022187295 A1 WO 2022187295A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- component
- poloxamer
- acid
- weight
- cannabinoid
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 370
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 title claims description 159
- 229920001983 poloxamer Polymers 0.000 title claims description 117
- 229960000502 poloxamer Drugs 0.000 title claims description 108
- 235000013361 beverage Nutrition 0.000 title description 16
- 239000003557 cannabinoid Substances 0.000 claims abstract description 193
- 229930003827 cannabinoid Natural products 0.000 claims abstract description 193
- 239000007787 solid Substances 0.000 claims abstract description 89
- 239000008187 granular material Substances 0.000 claims abstract description 88
- 238000009472 formulation Methods 0.000 claims abstract description 82
- 238000000034 method Methods 0.000 claims abstract description 49
- 229940065144 cannabinoids Drugs 0.000 claims abstract description 39
- 239000004530 micro-emulsion Substances 0.000 claims abstract description 10
- 239000013011 aqueous formulation Substances 0.000 claims description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 84
- 239000007788 liquid Substances 0.000 claims description 43
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 41
- 238000002156 mixing Methods 0.000 claims description 34
- 229920001992 poloxamer 407 Polymers 0.000 claims description 34
- 229940044476 poloxamer 407 Drugs 0.000 claims description 34
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 33
- 235000021355 Stearic acid Nutrition 0.000 claims description 32
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 32
- 239000008117 stearic acid Substances 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 239000003963 antioxidant agent Substances 0.000 claims description 23
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 17
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 14
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- 239000000843 powder Substances 0.000 claims description 13
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 12
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- 230000000087 stabilizing effect Effects 0.000 claims description 12
- 150000007513 acids Chemical class 0.000 claims description 11
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- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 10
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- 230000003078 antioxidant effect Effects 0.000 claims description 10
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- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 9
- 235000011054 acetic acid Nutrition 0.000 claims description 9
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 9
- 239000001630 malic acid Substances 0.000 claims description 9
- 235000011090 malic acid Nutrition 0.000 claims description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 8
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- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 claims description 6
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 claims description 6
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 6
- 239000001530 fumaric acid Substances 0.000 claims description 6
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- 235000010199 sorbic acid Nutrition 0.000 claims description 6
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- 229940075582 sorbic acid Drugs 0.000 claims description 6
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 claims description 5
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 claims description 5
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 5
- 229950006790 adenosine phosphate Drugs 0.000 claims description 5
- 239000001361 adipic acid Substances 0.000 claims description 5
- 235000011037 adipic acid Nutrition 0.000 claims description 5
- 239000000174 gluconic acid Substances 0.000 claims description 5
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- 230000002378 acidificating effect Effects 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 3
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- 238000010348 incorporation Methods 0.000 abstract description 3
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- 229960004242 dronabinol Drugs 0.000 description 80
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 73
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 73
- 229950011318 cannabidiol Drugs 0.000 description 73
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 73
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 73
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 42
- 239000003921 oil Substances 0.000 description 40
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- 239000000523 sample Substances 0.000 description 40
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 28
- 238000009928 pasteurization Methods 0.000 description 24
- 230000003254 anti-foaming effect Effects 0.000 description 23
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 21
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- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 230000000670 limiting effect Effects 0.000 description 19
- -1 THC and CBD Natural products 0.000 description 17
- 229920001993 poloxamer 188 Polymers 0.000 description 16
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- 239000002245 particle Substances 0.000 description 13
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 12
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Definitions
- cannabinoids which are a family of chemical compounds derived from the cannabis plant.
- CBD cannabidiol
- THC tetrahydrocannabinol
- cannabinoids including THC and CBD
- THC and CBD are highly lipophilic and are poorly soluble in water.
- cannabinoids are typically formulated as essential oils, oil-based liquids, or capsules containing the same.
- formulation of cannabinoids into aqueous or water-soluble dosage forms has proven to be challenging.
- an aqueous formulation comprising (1) a cannabinoid component comprising one or more cannabinoids; (2) a poloxamer component comprising a poloxamer that is solid at room temperature; (3) stearic acid; and (4) water.
- an aqueous formulation comprising (1) a cannabinoid component comprising one or more cannabinoids; (2) a poloxamer component comprising a poloxamer that is solid at room temperature; (3) an acidulant component comprising one or more acids selected from the group consisting of acetic acid, adipic acid, citric acid, fumaric acid, gluconic acid, glycolic acid, maleic acid, malic acid, adenylic acid, adenosine triphosphate, phosphoric acid, sorbic acid, and stearic acid; and (4) water.
- a cannabinoid component comprising one or more cannabinoids
- a poloxamer component comprising a poloxamer that is solid at room temperature
- an acidulant component comprising one or more acids selected from the group consisting of acetic acid, adipic acid, citric acid, fumaric acid, gluconic acid, glycolic acid, maleic acid, malic acid, adenylic acid
- an aqueous formulation comprising (1) a cannabinoid component comprising one or more cannabinoids; (2) poloxamer component comprising a poloxamer that is solid at room temperature; (3) an acidulant component; and (4) water; wherein the aqueous formulation does not comprise an antioxidant; and wherein the aqueous formulation is in the form of a clear liquid solution or microemulsion that is physically stable at room temperature.
- a solid granulate composition comprising (1) a cannabinoid component comprising one or more cannabinoids; (2) a poloxamer component comprising a poloxamer that is solid at room temperature; and (3) stearic acid.
- a solid granulate composition comprising (1) a cannabinoid component comprising one or more cannabinoids; (2) a poloxamer component comprising a poloxamer that is solid at room temperature; and (3) an acidulant component comprising one or more acids selected from the group consisting of acetic acid, adipic acid, citric acid, fumaric acid, gluconic acid, glycolic acid, maleic acid, malic acid, adenylic acid, adenosine triphosphate, phosphoric acid, sorbic acid, and stearic acid; wherein the weight ratio of the poloxamer component to the cannabinoid component is at least about 2:1.
- a solid granulate composition comprising (1) a cannabinoid component comprising one or more cannabinoids; (2) poloxamer component comprising a poloxamer that is solid at room temperature; and (3) an acidulant component; wherein the granulate composition does not comprise an antioxidant.
- Also provided herein is a method of preparing a solid granulate composition comprising a blending step wherein a cannabinoid component comprising one or more cannabinoids is mixed with a poloxamer component and stearic acid, thereby forming a liquid blend composition; a cooling step wherein the liquid blend composition is cooled to a solid state, thereby forming a solid blend composition; and a granulation step wherein the solid blend composition is milled to form a solid granulate composition; wherein the granulate composition comprises the poloxamer component in an amount of at least about 70% by weight.
- a solid granulate composition comprising a cannabinoid component comprising one or more cannabinoids, and a poloxamer, wherein the blend composition comprises the poloxamer in an amount of at least about 50% by weight.
- Also provided herein is a method of preparing a liquid blend composition comprising a cannabinoid component and a poloxamer, the method comprising a blending step wherein a cannabinoid component comprising one or more cannabinoids is mixed with a poloxamer, thereby forming a liquid blend composition, wherein the blend composition comprises the poloxamer in an amount of at least about 70% by weight.
- Also provided herein is a method of preparing a granulate composition comprising a cannabinoid component and a poloxamer comprising a blending step wherein a cannabinoid component comprising one or more cannabinoids is mixed with a poloxamer, thereby forming a liquid blend composition; a cooling step wherein the liquid blend composition is cooled to a solid state, thereby forming a solid blend composition; and a granulation step wherein the blend composition is milled to form a granulate composition; wherein the granulate composition comprises the poloxamer in an amount of at least about 70% by weight.
- an aqueous formulation comprising a cannabinoid component comprising one or more cannabinoids; a poloxamer; and water; wherein the aqueous formulation is in the form of a clear liquid solution or microemulsion that is physically stable at room temperature.
- an aqueous formulation comprising a cannabinoid component comprising one or more cannabinoids; a poloxamer; and water; wherein the poloxymer comprises a polyoxypropylene component having an average molecular weight of from about from about 1500 g/mol to about 4500 g/mol, and wherein at least about 70% of the total molecular weight of the poloxamer is attributable to polyoxyethylene repeat units.
- Also provided herein is a method of preparing an aqueous formulation comprising combining a liquid blend composition as provided herein and/or a granulate composition as provided herein with water.
- a powder mix formulation comprising a granulate composition as provided herein and one or more additional dry ingredients.
- a semisolid formulation comprising a granulate composition as provided herein, a gelatinous substance, and water.
- compositions comprising a cannabinoid component and a poloxamer.
- the compositions provided herein are suitable for incorporation into aqueous or water-soluble formulations.
- the compositions provided herein can be used to prepare clear aqueous solutions or microemulsions that are physically stable across a wide range of temperatures.
- CBD refers to cannabidiol.
- THC refers to tetrahydrocannabinol, and is inclusive of isomers including but not limited to A 8 -THC and A 9 -THC.
- carboxylic acid refers to an organic acid that comprises at least one carboxyl group.
- carboxylic acids include citric acid, acetic acid, maleic acid, malic acid, tartaric acid, stearic acid, and lactic acid.
- standard conditions “ambient conditions,” and “room temperature” each refer to a temperature of approximately 25°C, a pressure of approximately 1 atm, and a relative humidity of approximately 50% unless otherwise specified.
- food safe or “food-safe” refers to a component that is generally recognized as safe by the United States Food and Drug Administration.
- compositions and formulations provided herein may comprise one or more of a cannabinoid component; a poloxamer; an acidulant component; and additional components as described in further detail below.
- Cannabinoid Components may comprise one or more of a cannabinoid component; a poloxamer; an acidulant component; and additional components as described in further detail below.
- compositions and formulations provided herein may comprise a cannabinoid component comprising one or more cannabinoids.
- the cannabinoid component may be an essential oil.
- Cannabinoids suitable for use in the compositions provided herein include, for example, endocannabinoids, phytocannabinoids, and synthetic cannabinoids.
- the cannabinoid component may comprise one or more phytocannabinoids derived from a Cannabis plant.
- the cannabinoid component may comprise Cannabis plant material (e.g., industrial hemp) or an extract thereof.
- Non-limiting examples of specific cannabinoids that can be incorporated into the compositions, formulations, and methods provided herein include tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabielsoin (CBE), and cannabicitran (CBT).
- cannabinoids that may be present in the cannabinoid component include CBD and THC (including, but not limited
- compositions wherein the cannabinoid component comprises two or more cannabinoids are also within the scope of the present disclosure.
- the cannabinoid component may comprise both THC and CBD.
- the cannabinoid component may comprise a full-spectrum oil extracted from a Cannabis plant (e.g., an essential oil).
- the cannabinoid component may comprise an oil extracted from a Cannabis plant wherein the oil comprises at least about 50% by weight of THC.
- the cannabinoid component may comprise a cannabinoid extract, isolate, or distillate.
- the cannabinoid component may comprise a CBD extract, a CBD isolate, a CBD distillate, or a combination thereof.
- the cannabinoid component may comprise a THC extract, a THC isolate, a THC distillate, or a combination thereof.
- the cannabinoid component may optionally comprise a combination of two or more cannabinoid extracts, isolates, or distillates.
- the cannabinoid component preferably comprises a total cannabinoid content of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the total weight of the cannabinoid component.
- total cannabinoid content refers to the sum of the amount of each cannabinoid species present in the cannabinoid component
- the cannabinoid component may comprise substantially pure CBD.
- the cannabinoid component may comprise CBD in an amount of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% by weight.
- the cannabinoid component may comprise substantially pure THC.
- the cannabinoid component may comprise THC in an amount of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% by weight.
- the cannabinoid component may comprise substantially pure A 8 -THC.
- the cannabinoid component may comprise A 8 -THC in an amount of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% by weight.
- the cannabinoid component may comprise substantially pure A 9 -THC.
- the cannabinoid component may comprise A 9 -THC in an amount of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% by weight.
- compositions and formulations provided herein may comprise a poloxamer component.
- the poloxamer component comprises at least one poloxamer.
- Poloxamers are nonionic triblock copolymers wherein two chains of polyoxyethlene are each bound to a central chain of polyoxypropylene.
- a poloxamer may be represented as a triblock copolymer of the form
- Poloxamer 407 refers to a poloxamer wherein the average molecular weight of the polyoxypropylene component is about 4000 g/mol, and wherein the polyoxyethylene components constitute on average about 70% of the overall molecular weight. Poloxamer 407 generally corresponds to a compound of Formula I wherein y is an average number of about 56, and x and z are each independently average numbers of about 101.
- Non-limiting examples of poloxamers that are suitable for use in the compositions and formulations provided herein include Poloxamer 407, Poloxamer 331, Poloxamer 188, Poloxamer 184, Poloxamer 182, and Poloxamer 124. Poloxamers that are solid at room temperature are preferred. Particularly preferred poloxamers include Poloxamer 407.
- the poloxamer component may comprise a mixture of two or more poloxamers.
- the poloxamer component may comprise Poloxamer 188 and Poloxamer 407.
- the poloxamer comprises a polyoxypropylene component having an average molecular weight of from about 1000 g/mol to about 5000 g/mol, from about 1500 g/mol to about 4500 g/mol, from about 2000 g/mol to about 4500 g/mol, from about 2500 g/mol to about 4500 g/mol, from about 3000 g/mol to about 4500 g/mol, or from about 3500 g/mol to about 4500 g/mol.
- At least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70% of the total molecular weight of the poloxamer is attributable to polyoxyethylene repeat units.
- the poloxamer may be a compound of Formula I, for example, wherein y is an average number of at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, or at least about 55.
- the poloxamer may be a compound of Formula I, for example, wherein x and z are each independently average numbers of at least about 70, at least about 80, at least about 90, or at least about 100.
- the weight ratio of the poloxamer component to the cannabinoid component is preferably greater than 1 : 1.
- the weight ratio of the poloxamer component to the cannabinoid component may be at least about 2: 1, at least about 3: 1, at least about 4: 1, at least about 5: 1, at least about 6: 1, at least about 7: 1, or at least about 8:1.
- compositions and formulations provided herein may comprise an acidulant component comprising one or more food safe acids.
- Cannabinoids are subject to oxidation upon exposure to air or water.
- oxidation of the cannabinoid active ingredient is particularly undesirable, because it can reduce the potency of the cannabinoid and decrease its desired effect upon the user.
- the oxidation products can be strongly colored, which is undesirable in the context of a beverage.
- oxidation of the cannabinoid component can be slowed, or even essentially halted, by decreasing the pH of the composition. Accordingly, an acidulant component can be incorporated into the composition to reduce the rate of oxidation of the cannabinoid component.
- Food safe acids are particularly suitable for use in the compositions described herein, because they can be used to lower the pH of the composition without adversely affecting either the flavor of the beverage or the stability of the aqueous formulation.
- a granulate composition that does not comprise an acidulant component may develop a pink to purple coloration upon storage at room temperature for a period of several weeks. This coloration has not been observed in granulate compositions that comprise an acidulant component as described herein.
- Non-limiting examples of food safe acids include acetic acid, adipic acid, citric acid, fumaric acid, gluconic acid, glycolic acid, maleic acid, malic acid, adenosine monophosphate (adenylic acid), adenosine triphosphate, phosphoric acid, sorbic acid, fatty acids such as stearic acid.
- Further examples include salts of polyacids such as monobasic sodium phosphate and monosodium citrate, where their aqueous pH is less than 7.
- acidic cannabinoids is also contemplated, such as the addition of 1% CBDA just before cooling the liquid blend.
- the acidulant component may comprise one or more carboxylic acids.
- suitable carboxylic acids include citric acid, acetic acid, maleic acid, ascorbic acid, malic acid, tartaric acid, and lactic acid.
- the acidulant component may comprise citric acid.
- the acidulant component may comprise one or more of stearic acid, acetic acid, phosphoric acid, malic acid, and maleic acid.
- the acidulant component preferably comprises stearic acid.
- the acidulant component may comprise a combination of two or more food safe acids.
- the acidulant component may comprise citric acid and stearic acid.
- the acidulant component comprises an acid that is not an antioxidant.
- the acidulant component may comprise a carboxylic acid that is not an antioxidant.
- the weight ratio of the cannabinoid component to the acidulant component is preferably no greater than about 50: 1.
- the weight ratio of the cannabinoid component to the acidulant component may be no greater than about 40: 1, no greater than about 35: 1, no greater than about 30: 1, no greater than about 25: 1, no greater than about 20: 1, no greater than about 15 : 1 , or no greater than about 12:1.
- the weight ratio of the cannabinoid component to the acidulant component is preferably at least about 5: 1, at least about 6: 1, at least about 8:1, or at least about 10:1.
- the weight ratio of the cannabinoid component to the acidulant component may fall within a range defined by an upper limit and a lower limit as set forth above. As non-limiting examples, the weight ratio of the cannabinoid component to the acidulant component may fall within a range of from about 5:1 to about 50: 1, from about 5:1 to about 30: 1, from about 8:1 to about 25: 1, or from about 10: 1 to about 25: 1.
- compositions and formulations provided herein may comprise an antifoaming component.
- an aqueous formulation comprising a cannabinoid component and a poloxamer component, as generally described herein, will generate significant amounts of foam when agitated (including normal handling that occurs during the beverage preparation process). It is therefore desirable to include an antifoaming component in compositions and formulations provided herein, and particularly in the context of aqueous beverages and aqueous concentrates. While small amounts of foam may be acceptable or even desirable for consumers of cannabis beverages, excessive foaming is undesirable. Excessive foaming also makes canning and carbonation of reproduceable volumes a difficult process.
- Non-limiting examples of antifoaming components include silicone-based antifoaming agents that are generally recognized as safe for use in food and beverages.
- the antifoaming component may comprise stearic acid. Surprisingly, it has been discovered that stearic acid functions as both a pH adjustment component and an antifoaming component when it is present in the composition. The ability of a single species to function as both an acidulant and an antifoaming component is advantageous.
- stearic acid as both an acidulant and an antifoaming component simplifies the method of making the beverages described herein; reduces the number of ingredients present in the beverage, which is appealing to consumers; and lowers the overall cost of materials by reducing the number of components that must be purchased and stored.
- the weight ratio of the poloxamer component to the antifoaming component is typically no greater than about 200: 1.
- the weight ratio of the poloxamer component to the antifoaming component may be no greater than about 150: 1, no greater than about 125: 1, no greater than about 100: 1, no greater than about 80: 1, or no greater than about 50: 1.
- the weight ratio of the poloxamer component to the antifoaming component is typically at least about 20: 1, at least about 25: 1, at least about 30: 1, at least about 35:1, or at least about 40:1.
- the weight ratio of the poloxamer component to the antifoaming component may fall within a range defined by an upper limit and a lower limit as set forth above. As non-limiting examples, the weight ratio of the poloxamer component to the antifoaming component may fall within a range of from about 25: 1 to about 150: 1, or from about 25: 1 to about 100:1.
- the weight ratio of the cannabinoid component to the antifoaming component is typically no greater than about 50: 1.
- the weight ratio of the cannabinoid component to the antifoaming component may be no greater than about 40: 1, no greater than about 30:1, or no greater than about 25:1.
- the weight ratio of the cannabinoid component to the antifoaming component is typically at least about 5:1, at least about 6:1, at least about 7:1, at least about 8 : 1 , or at least about 10:1.
- the weight ratio of the cannabinoid component to the antifoaming component may fall within a range defined by an upper limit and a lower limit as set forth above. As non-limiting examples, the weight ratio of the cannabinoid component to the antifoaming component may fall within a range of from about 5:1 to about 50: 1, or from about 8: 1 to about 25:1. [0070] Antioxidants
- compositions and formulations provided herein may comprise an acidulant component that acts to prevent undesirable oxidation of the cannabinoid.
- an acidulant component that acts to prevent undesirable oxidation of the cannabinoid.
- the presence of an acidulant component makes it unnecessary to include an antioxidant.
- Non-limiting examples of antioxidants include ascorbic acid, butylated hydroxy toluene, butylated hydroxy anisole, tocopherols, propyl gallate, tertiary butylhydroquinone, sorbic acid, sodium sorbate and sorbates, benzoic acid and benzoates, parabens, sulfur dioxide and sulfites, nitrites, nitrates, lactic acid, propionic acid and propionates.
- antioxidants are heavily regulated in many states, and products that include added antioxidants may be subject to additional regulatory burdens. Antioxidants are often expensive, particularly compared to acidulants such as citric or stearic acid. And among consumers of cannabis products, certain antioxidants — particularly Vitamin E — are viewed with skepticism or concern due to recent accusations of harm caused by their presence in electronic cigarettes.
- antioxidants provide only limited effectiveness at preventing oxidation of the cannabinoid component. Additionally, antioxidants are sacrificial, and their ability to prevent oxidation therefore degrades over time. In contrast, an acidulant component as described herein is not sacrificial and is more effective at preventing oxidation of the cannabinoid component, over both the short and long term.
- compositions and formulations provided herein preferably comprise no greater than 5% by weight of an antioxidant.
- the composition may comprise less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, less than about 0.5% by weight of an antioxidant.
- the compositions and formulations provided herein do not comprise an antioxidant.
- compositions and formulations provided herein may optionally comprise one or more flavoring components commonly used to improve the taste or palatability of beverages and/or pharmaceutical formulations.
- suitable flavoring components include flavorings, sweeteners, and coloring agents.
- the composition or formulation may comprise one or more flavorings.
- suitable flavorings include natural and synthetic sources of vanillin, hexyl acetate, ethyl vanillin, ethyl methylphenylglycidate, manzanate, diacetyl, acetylpropionate, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, myrcene, pinenes, plant terpenes, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethylvanillin, peppermint oil, methyl salicylate, glutamic acid salts, glycine salts, guanylic acid salts, inosinic acid salts
- the composition or formulation may comprise one or more sweeteners.
- suitable sweeteners include aspartame, saccharin, cyclamate, sucralose, monk fruit extract, stevia, com syrup, honey, table sugar, dextrose, fructose, maple syrup, neotame, acesulfame potassium, sorbitol, xylitol, lactitol, maltitol, allulose, and erythritol.
- a solid granulate composition comprising one or more of (1) a cannabinoid component, (2) a poloxamer component, (3) an acidulant component, and (4) an antifoaming component.
- the granulate composition may optionally comprise further components, including but not limited to a solid carrier.
- the granulate composition is preferably a solid, free flowing powder. It has been discovered that a granulate composition as provided herein is highly homogeneous with respect to the concentration of cannabinoid. Because the granulate composition can be easily divided and weighed, it can be used to precisely control the amount of cannabinoid introduced into a desired dosage form or cannabinoid formulation. This provides a significant advantage relative to prior art compositions, which often resulted in widely inconsistent concentrations of cannabinoids across different product batches, or even across individual products prepared as part of a single batch.
- the granulate composition may comprise a cannabinoid component as described above.
- the granulate composition may comprise the cannabinoid component in an amount of no greater than about 50% by weight, no greater than about 40% by weight, no greater than about 30% by weight, no greater than about 25% by weight, no greater than about 20% by weight, no greater than about 15% by weight, no greater than about 10% by weight, no greater than about 5% by weight, no greater than about 2% by weight, or no greater than about 1% by weight of the composition.
- the granulate composition may comprise the cannabinoid component in an amount, for example, of at least about 0.1% by weight, at least about 0.5% by weight, at least about 1% by weight, at least about 2% by weight, at least about 5% by weight, or at least about 10% by weight of the composition.
- the granulate composition may comprise the cannabinoid component in a concentration that falls within a range defined by an upper limit and a lower limit as set forth above.
- the granulate composition may comprise the cannabinoid component in an amount of from about 1% by weight to about 50% by weight, from about 1% by weight to about 40% by weight, from about 1% by weight to about 30% by weight, or from about 1% by weight to about 20% by weight of the composition.
- the granulate composition may comprise a poloxamer component as described above.
- the granulate composition may comprise the poloxamer component in an amount of at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 75% by weight, at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, at least about 95% by weight, at least about 98% by weight, or at least about 99% by weight of the composition.
- the poloxamer concentration will not exceed about 99% by weight due to the presence of other components (such as the cannabinoid) in the granulate composition.
- the granulate composition may comprise the poloxamer component in an amount of from about 50% by weight to about 99% by weight, from about 60% by weight to about 99% by weight, from about 70% by weight to about 99% by weight, or from about 80% by weight to about 99% by weight of the composition.
- the granulate composition may comprise an acidulant component as described above.
- the granulate composition may comprise the acidulant component in an amount of at least about 0.1% by weight, at least about 0.2% by weight, at least about 0.3% by weight, at least about 0.4% by weight, at least about 0.5% by weight, at least about 0.6% by weight, at least about 0.7% by weight, at least about 0.8% by weight, at least about 0.9% by weight, or at least about 1.0% by weight of the composition.
- the granulate composition may comprise the acidulant component, for example, in an amount of at least about 1.1% by weight, at least about 1.2% by weight, at least about 1.3% by weight, at least about 1.4% by weight, or at least about 1.5% by weight of the composition.
- the granulate composition may comprise the acidulant component in an amount, for example, of no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2.5% by weight, no greater than about 2% by weight, or no greater than about 1.5% by weight of the composition.
- the granulate composition may comprise the acidulant component in a concentration that falls within a range defined by an upper limit and a lower limit as set forth above.
- the granulate composition may comprise the acidulant component in an amount of from about 0.1% by weight to about 5% by weight, from about 0.5% by weight to about 4% by weight, from about 0.5% by weight to about 3% by weight, or from about 0.5% by weight to about 2% by weight of the composition.
- the granulate composition may comprise a solid carrier component.
- Non-limiting examples of solid carriers include calcium phosphate, sodium phosphate, polyvinyl pyrrobdone, povidone, polyvinyl alcohol, dextrose, lactose, mannitol, sorbitol, maltitol, xylitol, polyethylene oxides, starch, methylcellulose, hydroxy propyl methyl cellulose, polymethacrylates, microcrystalline cellulose, sodium carboxy methyl cellulose, methylcellulose, ethyl cellulose, carbomers, silica, alumina, magnesium aluminum silicate, crosslinked polystyrene, and poly lactic acid.
- the composition or formulation may comprise dextrose, lactose, or a combination thereof.
- the composition or formulation may comprise microcrystalline cellulose.
- the method may comprise one or more of: (1) a blending step wherein a cannabinoid component is mixed with a poloxamer component, thereby forming a liquid blend composition; (2) a carrier addition step wherein a solid carrier is added to the liquid blend composition; (3) a cooling step wherein the liquid blend composition is cooled to form a solid blend composition; and (4) a granulation step wherein the liquid blend composition is milled to form a granulate composition.
- a blending step wherein a cannabinoid component is mixed with a poloxamer component, thereby forming a liquid blend composition
- a carrier addition step wherein a solid carrier is added to the liquid blend composition
- a cooling step wherein the liquid blend composition is cooled to form a solid blend composition
- (4) a granulation step wherein the liquid blend composition is milled to form a granulate composition.
- the method may comprise a blending step wherein a cannabinoid component is mixed with a poloxamer component, thereby forming a liquid blend composition.
- the liquid blend composition may comprise, consist essentially of, or consist of a cannabinoid component and a poloxamer component.
- the cannabinoid component is preferably heated above its melting point (i.e., to form a liquid) prior to mixing with the poloxamer component.
- the cannabinoid component may be heated, for example, to a temperature of at least about 30°C, at least about 40°C, at least about 50°C, or at least about 60°C.
- the cannabinoid component may be heated to a temperature of from about 30°C to about 100°C, from about 50°C to about 90°C, from about 55°C to about 80°C, or from about 60°C to about 70°C prior to mixing with the poloxamer.
- the poloxamer component may be heated prior to mixing with the cannabinoid component. If the poloxamer component is a solid at room temperature, it is preferably heated above its melting point (i.e., to form a liquid) prior to mixing.
- the poloxamer component may be heated, for example, to a temperature of at least about 30°C, at least about 40°C, at least about 50°C, or at least about 60°C.
- the poloxamer component may be heated to a temperature of from about 30°C to about 100°C, from about 50°C to about 90°C, from about 55°C to about 80°C, or from about 60°C to about 70°C.
- the cannabinoid component, and the poloxamer component may be added to a mixing vessel in either order, or simultaneously.
- Other components such as the acidulant component and/or antifoaming component, may be added to the mixing vessel prior to, subsequent to, or simultaneously with the cannabinoid component and the poloxamer component.
- the blend composition may be stirred (e.g., using a stir bar) to facilitate complete mixing of the cannabinoid component, the poloxamer component, and any other components of the blend (e.g., the acidulant component and/or antifoaming component).
- the blending step therefore provides a liquid blend composition that comprises a homogeneous mixture of the cannabinoid component and the poloxamer component.
- the blending step does not require the use of a solvent.
- solvents include diacetin, propylene glycol, triacetin, monoacetin, propylene glycol diacetate, and triethyl citrate.
- the blend composition preferably comprises no greater than about 10% by weight, no greater than about 9% by weight, no greater than about 8% by weight, no greater than about 7% by weight, no greater than about 6% by weight, no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2% by weight, or no greater than about 1% by weight of a solvent.
- the blend composition does not comprise a solvent.
- the blending step does not require the use of a stabilizing oil.
- stabilizing oil refers to a non-cannabinoid oil that serves to stabilize an emulsion of the cannabinoid component in water.
- Non-limiting examples of stabilizing oils include triglycerides, diglycerides or monoglycerides or mixtures thereof derived from glycerol and at least one fatty acid selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid and mixtures thereof; hydrogenated vegetable oils, nut oils, anise oil, soybean oil, hydrogenated soybean oil, apricot kernel oil, com oil, olive oil, peanut oil, almond oil, walnut oil
- the blend composition preferably comprises no greater than about 10% by weight, no greater than about 9% by weight, no greater than about 8% by weight, no greater than about 7% by weight, no greater than about 6% by weight, no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2% by weight, or no greater than about 1% by weight of a stabilizing oil.
- the blend composition does not comprise a stabilizing oil.
- the method may comprise a solid carrier addition step wherein a solid carrier is added to the blend composition.
- the solid carrier addition step may be carried out after the blending step or simultaneously with the blending step.
- a solid carrier is optional. It may be desirable, for example, when the desired concentration of cannabinoid in the final product is relatively low.
- the solid carrier serves to reduce the concentration of cannabinoid in the granulate composition, which may make it easier to achieve a desired concentration of cannabinoid in the final product.
- the solid carrier may be added to the blend composition using repeated geometric addition (for example, where the blend composition and solid carrier are repeatedly mixed in a 1:1 ratio).
- the repeated geometric addition may comprise combining 1 part of a blend composition with 1 part of a solid carrier, then combining the resulting mixture with 2 parts of a solid carrier, and then combining the resulting mixture with 4 parts of a solid carrier, and so on.
- the repeated geometric addition may be carried out until the desired concentration of cannabinoid in the blend composition has been achieved.
- the method may comprise a cooling step wherein the liquid blend composition is cooled to a solid state, thereby forming a solid blend composition that is suitable for milling.
- the blend composition may be cooled to a temperature of less than about 40°C, less about 30°C, or about 25°C (i.e., room temperature) or lower.
- the blend composition freezes at a temperature of at least about 5°C, at least about 10°C, at least about 15°C, at least about 20°C, at least about 25°C, at least about 30°C, or at least about 35°C.
- the method may comprise a granulation step wherein the solid blend composition is milled to produce a solid powder, which is referred to herein as the granulate composition.
- the solid blend composition may be milled using methods and equipment generally known to those skilled in the art.
- equipment that may be utilized in the milling step include a hammer mill, a cone mill, a communiting mill, a sieve mill, a burr mill, a ball mill, a high shear granulator, and a food processor.
- the granulation step may optionally comprise cryogenic milling of the solid blend composition, for example using liquid nitrogen.
- the solid blend composition may be cooled to a temperature, for example, of less than -100°C, less than -120°C, less than -140°C, less than -160°C, less than -180°C, or less than -195°C.
- the granulate composition may optionally be filtered to obtain smaller particles with a more uniform particle size distribution.
- the granulate composition may be filtered using a screen of at least about 10 mesh, at least about 12 mesh, at least about 15 mesh, at least about 18 mesh, or at least about 20 mesh.
- a granulate composition produced using this method may comprise the same components (e.g., the cannabinoid component, poloxamer component, acidulant component, and optionally other components) in the same proportions as described above.
- the granulate composition may be substantially free of solvents and/or stabilizing oils as generally described above.
- the granulate composition and/or liquid blend composition may be incorporated into a consumable formulation (e.g., food or drink).
- a consumable formulation e.g., food or drink
- suitable dosage forms include aqueous formulations, powder mix formulations, and semisolid formulations, each of which is discussed in further detail below.
- aqueous formulations may comprise one or more of (1) a cannabinoid component, (2) a poloxamer component, and (3) an acidulant component, and (4) water. Additionally, the cannabinoid formulations may comprise (5) an antifoaming component and/or (6) one or more additional excipients (e.g., flavoring agents).
- the aqueous formulation is preferably in the form of a clear liquid solution or microemulsion.
- Clear liquid solutions are particularly preferred.
- an aqueous formulation comprising Poloxamer 407 will form a clear liquid solution when prepared as described herein. This represents a significant advantage, particularly with respect to the preparation of drink formulations. Clear solutions are palatable, aesthetically pleasing, and familiar to consumers, and avoid the downfalls of emulsion-based drinks discussed in detail above.
- the aqueous formulation may be in the form of a clear microemulsion.
- the aqueous formulation may be a microemulsion having an average micelle size of no greater than about 1 micron. At micelle sizes greater than about 1 micron, the aqueous formulation will become cloudy and suffer from the downfalls of emulsion-based drinks discussed above.
- poloxamers that can be used to prepare a clear microemulsion include Poloxamer 188.
- the clear liquid solutions and microemulsions provided herein can be prepared without the use of high shear mixing or sonication.
- a liquid blend composition or granulate composition as described above may be combined with water to form an aqueous formulation.
- the aqueous formulation is sprayable using conventional spray equipment.
- the aqueous formulation can be sprayed to create a cannabinoid-containing coating or layer on a substrate (e.g, an edible substrate).
- a substrate e.g, an edible substrate
- the aqueous formulation maintains physical stability (i.e., avoids phase separation or cloudiness) at temperatures of about 30°C or higher. This represents a significant advantage over prior art formulations, which must be stored under cool conditions to maintain the physical stability of the emulsion.
- the aqueous formulation may maintain physical stability at a temperature of at least about 40°C, at least about 50°C, at least about 60°C, at least about 70°C, at least about 80°C, at least about 90°C, or at least about 100°C.
- the aqueous formulation may have a cloud point, for example, of at least about 40°C, at least about 50°C, at least about 60°C, at least about 70°C, at least about 80°C, at least about 90°C, or at least about 100°C.
- the aqueous formulation maintains physical stability for a period of at least about 1 day, at least about 1 week, at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks when stored at a temperature of at least about 25°C, at least about 30°C, at least about 40°C, or at least about 50°C.
- the aqueous formulation may maintain physical stability for a period of at least about 4 weeks when stored at a temperature of at least about 50°C.
- an additional advantage of the aqueous formulation is that it may be pasteurized.
- the aqueous formulation may be a pasteurized formulation.
- the aqueous formulation may be pasteurized, for example, at a temperature of at least about 40°C, at least about 50°C, at least about 60°C, at least about 70°C, at least about 80°C, at least about 90°C, or at least about 100°C.
- the aqueous formulations will maintain physical stability upon storage at temperatures between 0°C and about 15°C (i.e., conventional refrigeration temperatures).
- the aqueous formulation may maintain physical stability at a temperature of less than about 15°C, less than about 10°C, or less than about 5°C.
- the aqueous formulation comprises a total poloxamer concentration of no greater than about 20% by weight.
- total poloxamer concentration refers to the sum of the concentration of each poloxamer species present in the formulation.
- the aqueous formulation preferably has a viscosity comparable to that of water.
- the aqueous formulation may have a viscosity at room temperature of less than about 2 mPa-s, less than about 1.5 mPa-s, less than about 1.4 mPa-s, less than about 1.3 mPa-s, less than about 1.2 mPa-s, less than about 1.1 mPa-s, or less than about 1 mPa-s.
- the aqueous formulation may comprise a total poloxamer concentration of no greater than about 15% by weight, no greater than about 14% by weight, no greater than about 13% by weight, no greater than about 12% by weight, no greater than about 11% by weight, no greater than about 10% by weight, no greater than about 9% by weight, no greater than about 8% by weight, no greater than about 7% by weight, no greater than about 6% by weight, no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2% by weight, or no greater than about 1% by weight.
- the aqueous formulation may have less physical stability at cannabinoid concentrations above about 4% by weight. Accordingly, in preferred embodiments the aqueous formulation comprises a total cannabinoid concentration of no greater than about 4% by weight. As used herein, the term “total cannabinoid concentration” refers to the sum of the concentration of each cannabinoid species present in the formulation.
- the aqueous formulation may comprise a total cannabinoid concentration of no greater than about 3% by weight, no greater than about 2.5% by weight, no greater than about 2% by weight, no greater than about 1.5% by weight, or no greater than about 1% by weight.
- the aqueous formulation may comprise a total cannabinoid concentration of, for example, from about 0.1% by weight to about 2% by weight, from about 0.2% by weight to about 1% by weight, from about 0.25% by weight to about 1% by weight, or from about 0.3% by weight to about 0.8% by weight.
- the aqueous formulation may be a drink, for example a flavored drink.
- a total cannabinoid concentration of about 1 mg to about 10 mg per serving.
- the aqueous formulation may comprise a total cannabinoid concentration of at least about 1 mg/L, at least about 2 mg/L, at least about 3 mg/L, at least about 4 mg/L, at least about 5 mg/L, at least about 6 mg/L, at least about 7 mg/L, or at least about 8 mg/L.
- the aqueous formulation may comprise a total cannabinoid concentration of no greater than about 40 mg/L, no greater than about 35 mg/L, no greater than about 30 mg/L, no greater than about 25 mg/L, no greater than about 20 mg/L, no greater than about 15 mg/L, no greater than about 10 mg/L, or no greater than about 8 mg/L.
- the aqueous formulation may comprise the cannabinoid component in a concentration that falls within a range defined by an upper limit and a lower limit as set forth above.
- the aqueous formulation may comprise a total cannabinoid concentration of from about 2 mg/L to about 40 mg/L, from about 2 mg/L to about 35 mg/L, from about 5 mg/L to about 35 mg/L, or from about 5 mg/L to about 25 mg/L.
- the aqueous formulation may be a liquid concentrate.
- the aqueous formulation may be a liquid concentrate, it may be desirable to provide a total cannabinoid concentration of 1 mg/ml (i.e., 1000 mg/L) or greater.
- the aqueous formulation may comprise a total cannabinoid concentration of at least about 1 mg/ml, at least about 2 mg/ml, at least about 5 mg/ml, at least about 10 mg/ml, at least about 20 mg/ml, or even at least about 30 mg/ml.
- the total cannabinoid concentration is typically no greater than about 45 mg/ml, no greater than about 40 mg/ml, or no greater than about 35 mg/ml.
- the aqueous formulation may comprise the cannabinoid component in a concentration that falls within a range defined by an upper limit and a lower limit as set forth above.
- the aqueous formulation may comprise a total cannabinoid concentration of from about 1 mg/ml to about 40 mg/ml, from about 2 mg/ml to about 20 mg/ml, from about 3 mg/ml to about 15 mg/ml, or from about 5 mg/ml to about 10 mg/ml.
- the aqueous formulation may comprise a desired amount of a specific cannabinoid (e.g., CBD or THC).
- a specific cannabinoid e.g., CBD or THC.
- the aqueous formulation may comprise a specific cannabinoid in the amounts and concentrations described above with respect to the total cannabinoid concentration.
- the aqueous formulation when the aqueous formulation is a drink, it may be desirable to provide THC in a concentration of about 1 mg to about 5 mg per serving.
- the aqueous formulation may comprise THC in a concentration of at least about 1 mg/L, at least about 2 mg/L, at least about 3 mg/L, at least about 4 mg/L, at least about 5 mg/L, at least about 6 mg/L, at least about 7 mg/L, or at least about 8 mg/L.
- the aqueous formulation may comprise THC in a concentration of no greater than about 40 mg/L, no greater than about 35 mg/L, no greater than about 30 mg/L, no greater than about 25 mg/L, no greater than about 20 mg/L, no greater than about 15 mg/L, no greater than about 10 mg/L, or no greater than about 8 mg/L.
- the aqueous formulation may comprise THC in a concentration that falls within a range defined by an upper limit and a lower limit as set forth above.
- the aqueous formulation may comprise THC in a concentration of from about 2 mg/L to about 40 mg/L, from about 2 mg/L to about 35 mg/L, from about 5 mg/L to about 35 mg/L, or from about 5 mg/L to about 25 mg/L.
- the aqueous formulation when the aqueous formulation is a liquid concentrate, it may be desirable to provide THC in a concentration of 1 mg/ml (i.e., 1000 mg/L) or greater.
- the aqueous formulation may comprise THC in a concentration of at least about 1 mg/ml, at least about 2 mg/ml, at least about 5 mg/ml, at least about 10 mg/ml, at least about 20 mg/ml, or even at least about 30 mg/ml.
- the THC concentration is typically no greater than about 45 mg/ml, no greater than about 40 mg/ml, or no greater than about 35 mg/ml.
- the aqueous formulation may comprise THC in a concentration that falls within a range defined by an upper limit and a lower limit as set forth above.
- the aqueous formulation may comprise THC in a concentration of from about 1 mg/ml to about 40 mg/ml, from about 2 mg/ml to about 20 mg/ml, from about 3 mg/ml to about 15 mg/ml, or from about 5 mg/ml to about 10 mg/ml.
- the aqueous formulations provided herein do not require the use of a solvent.
- the aqueous formulation preferably comprises no greater than about 10% by weight, no greater than about 9% by weight, no greater than about 8% by weight, no greater than about 7% by weight, no greater than about 6% by weight, no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2% by weight, or no greater than about 1% by weight of a solvent.
- the aqueous formulation is essentially free of solvent.
- the aqueous formulations provided herein do not require the use of a stabilizing oil.
- the aqueous formulation preferably comprises no greater than about 10% by weight, no greater than about 9% by weight, no greater than about 8% by weight, no greater than about 7% by weight, no greater than about 6% by weight, no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2% by weight, or no greater than about 1% by weight of a stabilizing oil.
- the aqueous formulation is essentially free of a stabilizing oil.
- the aqueous formulation may comprise one or more additional ingredients, including but not limited to one or more flavorings, sweeteners, antioxidants, or preservatives.
- additional ingredients including but not limited to one or more flavorings, sweeteners, antioxidants, or preservatives.
- the aqueous formulation when it is a drink formulation, it preferably comprises one or more flavorings or sweeteners.
- the aqueous formulation may comprise carbonari on.
- the water may be in the form of carbonated water or seltzer.
- the aqueous formulation comprises the one or more excipients in an amount of no greater than about 10% by weight, no greater than about 8% by weight, no greater than about 6% by weight, no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2% by weight, no greater than about 1.5% by weight, no greater than about 1% by weight, or no greater than about 0.5% by weight.
- the aqueous formulation may comprise the one or more excipients in an amount, for example, of at least about 0.1% by weight, at least about 0.5% by weight, at least about 1% by weight, or at least about 2% by weight.
- the aqueous formulation may comprise the one or more excipients in a concentration that falls within a range defined by an upper limit and a lower limit as set forth above.
- the aqueous formulation may comprise the one or more excipients in an amount of from about 0.1% by weight to about 10% by weight, from about 0.1% by weight to about 5% by weight, from about 0.1% by weight to about 2% by weight, or from about 0.1% by weight to about 1% by weight.
- a granulate composition as provided herein may be combined with one or more additional dry ingredients to form a powder mix formulation.
- powder mix formulations include dry mixes for baked goods (including brownies and cakes), tablets, and water-dispersible powder packets.
- the powder mix formulation may further comprise one or more sweeteners, flavorings, antioxidants, stabilizers, or other ingredients generally known in the art.
- a granulate composition as provided herein may be combined with water and one or more additional ingredients to form a semisobd formulation.
- the granulate composition may be combined with water and a gelatinous component in order to form edible “gummies” having a desired cannabinoid content.
- gelatinous components include gelatin, gums, agar, carrageenan, and pectin.
- the semisobd formulation may further comprise one or more sweeteners, flavorings, antioxidants, stabilizers, or other ingredients generally known in the art.
- the granulate composition provided herein provides a significant advantage in semisobd formulations, in that it enables the amount of cannabinoid in the formulation to be precisely controlled. Additionally, to prepare a semisobd formulation as described herein, it is not necessary for the granulate composition to be fully dissolved in water. For example, the granulate composition will form a homogenous suspension that is readily dispersible, and can be mixed thoroughly with the remaining ingredients in the formulation.
- HPLC was performed on a Waters 2796 equipped with a column compartment and Waters 2487 Dual Wavelength Detector. HPLC conditions used were as described in Dedicated Cannabinoid Potency Testing in Cannabis or Hemp Products Using the Agilent 1220 Infinity II LC System, Agilient Technologies, Inc., published on May 22, 2020. CBD isolate (99%) was used as a standard with a RRF of 1.1 versus A 9 -tetrahydrocannabinol. Solutions of analytes were prepared at concentrations between 0.03 and 3 mg/ml by dilution with water.
- Particle size measurements were performed with a Malvern Mastersizer 3000 with Hydro MV accessory.
- the cell was filled with tap water and the system initialized and a background measurement taken. The cell was then drained. The sample was then prepared by dilution in water to 100 ml and added to the cell. A set of 25 measurements was then taken, and the average laser obscuration and particle size reported.
- a granulate composition comprising Poloxamer 407 was prepared using the following procedure.
- a granulate composition comprising Poloxamer 407 was prepared using the following procedure.
- a granulate composition comprising Poloxamer 188 was prepared using the following procedure.
- a granulate composition comprising Poloxamer 407 was prepared using the following procedure.
- a drink concentrate or sublingual formulation comprising Poloxamer 182 was prepared using the following procedure. [0177] Combined 0.22 grams cannabidiol isolate, 0.21 grams D 8 - tetrahydrocannabinol, and 4.4 grams Poloxamer 182 (liquid). The components were warmed at 60°C until the poloxamer, CBD, and oil were all molten and well mixed. With mixing, 50 ml of water was added to obtain a milky suspension.
- the formulation contained CBD in a concentration of 4.2 mg/ml and D 8 - tetrahydrocannabinol in a concentration of 4.4 mg/ml.
- Assay using HPLC 103% CBD and 86% D 8 -tetrahydrocannabinol versus theoretical calculations.
- the formulation had a sufficiently low viscosity to be used in a dropper bottle or breath spray device, and would be suitable for, e.g., sublingual use.
- a drink concentrate or sublingual formulation comprising Poloxamer 188 was prepared using the following procedure.
- a granulate composition prepared as described in Example 3 (4.04 grams) was placed in 39.7 ml of room temperature water and mixed. The solid rapidly dissolved, producing a milky emulsion. The emulsion was warmed to 50°C to yield a clear formulation. Storge in a refrigerator increased the opacity of the formulation.
- the formulation contained CBD in a concentration of 4.5 mg/ml and D 8 - tetrahydrocannabinol in a concentration of 4.5 mg/ml.
- Assay using HPLC 95% CBD and 89% A 8 -tetrahydrocannabinol versus theoretical calculations.
- the formulation had a sufficiently low viscosity to be used in a dropper bottle or breath spray device, and would be suitable for, e.g., sublingual use.
- a drink concentrate or sublingual formulation comprising Poloxamer 407 was prepared using the following procedure.
- a granulate composition prepared as described in Example 3 (4.04 grams) was placed in 44.1 ml of room temperature water and mixed. The solid rapidly dissolved, producing a clear solution. Warming the solution to 50°C did not affect the solution. Storge in a refrigerator did not affect the solution. The solution was observed to remain visibly clear over a wide temperature range.
- the formulation contained CBD in a concentration of 4.1 mg/ml and D 8 - tetrahydrocannabinol in a concentration of 3.8 mg/ml. Assay using HPLC: 105% CBD and 99% A 8 -tetrahydrocannabinol versus theoretical calculations. [0189] The formulation had a sufficiently low viscosity to be used in a dropper bottle or breath spray device, and would be suitable for, e.g., sublingual use.
- a water-based drink comprising Poloxamer 182 was prepared using the following procedure.
- Example 5 One milliliter of a formulation prepared as described in Example 5 was added to a graduated cylinder and water (99 ml) was added. The resulting mixture remained slightly opaque but homogeneous, and contained approximately 0.04 mg/ml of CBD and D 8 - tetrahydrocannabinol. No high shear blending or sonication was required to obtain a homogeneous mixture. Particle size measurement yielded an average laser obscuration of 33.76% and an average particle size of 0.594 microns.
- a water-based drink comprising Poloxamer 188 was prepared using the following procedure. [0195] One milliliter of a formulation prepared as described in Example 6 was added to a graduated cylinder and water (99 ml) was added. The resulting mixture was slightly opaque but homogeneous, and contained approximately 0.04 mg/ml of CBD and D 8 - tetrahydrocannabinol. No high shear blending or sonication was required to obtain a homogeneous mixture. Particle size measurement yielded an average laser obscuration of 7.23% and an average particle size of 0.251 microns.
- a water-based drink comprising Poloxamer 407 was prepared using the following procedure.
- Example 11 One milliliter of a formulation prepared as described in Example 7 was added to a graduated cylinder and water (99 ml) was added. The resulting mixture remained clear and homogeneous, and contained approximately 0.04 mg/ml of CBD and D 8 - tetrahydrocannabinol. Note no high shear blending or sonication was required. Particle size measurement yielded an average laser obscuration of 0.66% and was below the range required for accurate particle size measurement. [0199] Example 11
- a water-based drink comprising Poloxamer 188 was prepared using the following procedure, and was used to conduct an assay test.
- a water-based drink comprising Poloxamer 407 was prepared using the following procedure, and was used to conduct an assay test.
- Example 7 One hundred microliters of a formulation prepared as described in Example 7 was added to 10 ml of water. The resulting mixture remained clear and homogeneous and contains approximately 0.04 mg/ml of CBD and A 8 -tetrahydrocannabinol. Assay using HPLC: 110% CBD and 93% A 8 -tetrahydrocannabinol versus theoretical calculations.
- Gummies comprising Poloxamer 407 were prepared using the following procedure.
- a gummy mixture was formed by warming 10 grams water, 4 grams gelatin, 2 grams collagen, 1 gram glycerin, 4.5 grams sugar solution, 5.5 grams artificial sweetener, 30 mg mold inhibitor, 1.2 grams flavoring solution and 0.6 grams citric acid. The mixture was stirred warm, and 3 grams of a granulate composition prepared as described in Example 4 was mixed in.
- the resulting bulk mixture contained approximately 10 mg of cannabinoids per gram.
- the mixture was dosed into cubes that had an average weight of 0.75 g.
- Table 1 the resulting gummies were highly homogeneous with respect to the amount of cannabinoid in each individual gummy.
- Assay using HPLC 104% CBD and 102% A 8 -tetrahydrocannabinol versus theoretical calculations.
- Average assay 7.7 mg cannabinoid per gummy, Standard Deviation 0.2 mg, % RSD 2.6%.
- Tablets comprising Poloxamer 407 were prepared using the following procedure. [0211] D 8 -tetrahydrocannabinol oil (5 g) and Poloxamer 407 (45 g) were melted together at 60°C and mixed until homogeneous. The resulting solution was poured onto a plastic sheet and cooled to room temperature. The solid was broken up, milled and screened using an 18 mesh screen. Compressible dextrates (420 g) were charged to a 3 L ribbon blender. The mixing was activated and peppermint oil (10 g) was slowly added. The poloxamer pre-blend was added, followed by sodium starch glycolate (60 g) and finally polyethylene glycol 8000 (60 g).
- the blend was mixed about 5 minutes then charged to the hopper of a TDP-5 benchtop tablet press. Tablets weighing approximately 600 mg were produced with a target dose of about 5 mg of D 8 -tetrahydrocannabinol. Four tablets were randomly selected and individually assayed. As shown in Table 2 below, the D 8 - tetrahydrocannabinol Assay average was 5.5 mg with a standard deviation of 0.156 mg and a
- a pasteurized water-based concentrate comprising Poloxamer 188 was prepared using the following procedure.
- One gram of a formulation prepared as described in Example 3 was added to 9 ml of water. The resulting mixture remained slightly opaque but pale yellow and homogeneous and contained approximately 4.9 mg per ml of CBD and D 8 - tetrahydrocannabinol. Measured concentration before pasteurization using HPLC: 4.5 mg per ml CBD and 4.4 mg per ml D 8 -tetrahydrocannabinol.
- a pasteurized water-based drink comprising Poloxamer 188 was prepared using the following procedure.
- a pasteurized water-based concentrate comprising Poloxamer 407 was prepared using the following procedure.
- a pasteurized water-based drink comprising Poloxamer 407 was prepared using the following procedure.
- a pasteurized water-based concentrate comprising Poloxamer 182 was prepared using the following procedure.
- Poloxamer 182 (0.8 g) and 0.1 g each of CBD and A -tetrahydrocannabinol were mixed at 60°C briefly until homogeneous, cooled and 9 ml water was added. The resulting mixture was milky and opaque but homogeneous and contained approximately 10 mg per ml of CBD and D 8 -tetrahydrocannabinol. Measured concentration before pasteurization using HPLC: 8.1 mg per ml CBD and 8.1 mg per ml A 8 -tetrahydrocannabinol.
- a pasteurized water-based drink comprising Poloxamer 182 was prepared using the following procedure.
- Example 19 One hundred microliters of a formulation prepared as described in Example 19 was added to 9.9 ml of water. The resulting mixture remained opaque but homogeneous and contained approximately 0.1 mg per ml of CBD and A 8 -tetrahydrocannabinol. Measured concentration before pasteurization using HPLC: 0.06 mg per ml CBD and 0.06 mg per ml D 8 -tetrahydrocannabinol.
- Poloxamer 407 (7.5 grams), CBD isolate (1.5 grams), and propylene glycol (1.0 grams) were mixed at 70°C until they formed a homogeneous liquid. The liquid was cooled, and a gummy, purple semisold was obtained. The semisold had a consistency similar to that of used chewing gum, and was not capable of being milled.
- the liquid was cooled, and a gummy, purple semisold was obtained.
- the semisold had a consistency similar to that of used chewing gum, and was not capable of being milled.
- a water-based drink comprising Poloxamer 182 was prepared using the procedure described in Example 8; a water-based drink comprising Poloxamer 188 was prepared using the procedure described in Example 9; and water-based drink comprising Poloxamer 407 was prepared using the procedure described in Example 10.
- the three water-based drinks were then stored at a consistent temperature of 50°C for a period of four weeks to test their physical stability. After 4 weeks, the water-based drink comprising Poloxamer 182 had separated into an organic phase and an aqueous phase; the water-based drink comprising Poloxamer 188 was still a homogeneous aqueous mixture; and the water-based drink comprising Poloxamer 407 was still a homogeneous aqueous mixture.
- a Comparative Composition #1 was prepared by combining 3.40 grams of poloxamer 124, 1.50 grams of poloxamer 188, 2.60 grams of propylene glycol and 2.50 grams of cannabidiol. Post cooling, the formulation remained a yellow viscous oil. After sitting about 24 hours two phases had formed. A solid was present on the bottom of the vial, but an oil layer remained on top. When ten grams of water was added to a vial containing 1 gram of the pre-blend, a milky mixture formed. To ensure good mixing, a magnetic stir bar was placed in the vial and mixed at 1000 rpm until all the oil was dispersed. Throughout the procedure the mixture remailed milky and opaque. The vial was allowed to sit at room temperature. At 24 hours the solution remained milky and opaque. At one week a thin layer of white powder had formed on the bottom of the vial and solids collected on the sides of the vial.
- a Comparative Composition #2 was prepared by combining 2.50 grams of poloxamer 124, 2.50 grams of poloxamer 407, 2.50 grams of propylene glycol and 2.50 grams of cannabidiol. Post cooling, the formulation remained a yellow viscous oil. After sitting 24 hours a second phase formed indicated by a few grains of solid formed on the bottom of the oil, but a substantial oil layer remained. When ten grams of water was added to one gram of the pre-blend in a vial, a milky mixture formed and much of the formulation remaining stuck on the side of the glass. To ensure good mixing, a magnetic stir bar was placed in the vial and mixed at 1000 rpm until all the oil was dispersed.
- a Comparative Composition #3 was prepared by combining 3.50 grams of poloxamer 124, 2.00 grams of poloxamer 188, 2.00 grams of triethyl citrate and 2.50 grams of cannabidiol. Post cooling, the formulation remained a yellow viscous oil. After sitting about 1 hour the mixture became an oily grainy semi-solid. After 24 hours two phases were present but the sample was primarily a grainy solid with a thin layer of oil. When ten grams of water was added to a vial containing one gram of the pre-blend, a milky mixture formed. To ensure good mixing, a magnetic stir bar was placed in the vial and mixed at 1000 rpm until all the oil was dispersed.
- Sample compositions comprising Poloxamer 407, cannabidiol, and an acidulant component were prepared as listed in Table 4 below.
- the sample weights listed in Table 4 were calculated based on the area of the Petri dish used so the resulting films were the same thickness.
- the solid cannabinoid (approximately 20 wt%), poloxamer (approximately 80 wt%) and acidulant were combined in a petri dish and placed on a hot plate set to 130°C.
- the samples were mixed with a spatula until homogeneous, then held for about 10 minutes and cooled.
- the samples were held at room temperature for 1 to 5 days to assess color.
- ASTM Color refers to ASTM D1500 color scale. Pink or purple are not present on the ASTM D1500 scale and were listed for individual samples if required.
- CBD was used as the cannabinoid, as it shows discoloration the fastest; however, similar discoloration is also evident in samples containing THC.
- the ideal color for the composition would be light gold to amber, which are the colors typically seen in cannabinoid oils.
- Control A formulation containing 3.49 grams of poloxamer 407 and 0.71 grams of CBD was mixed with warming until homogeneous. A 99 mg portion was dissolved in 16.8 oz of water to create a beverage sample. The sample was shaken vigorously. A fine, dense foam was formed with small bubble size. The sample was allowed to rest and monitored until the collapse exposed a liquid surface approximately 1” in diameter.
- Silicone Anti-foamant A formulation containing 3.74 grams of poloxamer 407 and 0.70 grams of CBD and 0.08 g of silicone 100 oil was mixed with warming until homogeneous. A 103 mg portion was dissolved in 16.8 oz of water to create a beverage sample. The sample was shaken vigorously. A fine, dense foam was formed with small bubble size. The sample was allowed to rest and monitored until the collapse exposed a liquid surface approximately 1” in diameter.
- Stearic Acid ⁇ % A formulation containing 4.93 grams of poloxamer 407 and 1.24 grams of CBD and 0.06 g of stearic acid was mixed with warming until homogeneous.
- a 98 mg portion was dissolved in 16.8 oz of water to create a beverage sample.
- the sample was shaken vigorously. A coarse foam was formed with much larger bubble size.
- the sample was allowed to rest and monitored until the collapse exposed a liquid surface approximately 1” in diameter.
- Stearic Acid -1.5% A formulation containing 3.77 grams of poloxamer 407 and 0.89 grams of CBD and 0.08 g of stearic acid was mixed with warming until homogeneous. A 102 mg portion was dissolved in 16.8 oz of water to create a beverage sample. The sample was shaken vigorously. A coarse foam was formed with much larger bubble size. The sample was allowed to rest and monitored until the collapse exposed a liquid surface approximately 1” in diameter. Table 5
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Abstract
L'invention concerne des compositions de cannabinoïdes et des procédés de fabrication de telles compositions. Les compositions de granulés solides de l'invention sont appropriées pour être incorporées dans des formulations aqueuses ou solubles dans l'eau. L'invention concerne également des solutions aqueuses claires ou des microémulsions de cannabinoïdes qui sont physiquement stables sur une large plage de températures.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US20180071210A1 (en) * | 2016-07-01 | 2018-03-15 | GW Research Limited | Cannabinoid formulations |
WO2019159174A1 (fr) * | 2018-02-16 | 2019-08-22 | Icdpharma Ltd. | Administration, dans le côlon, de cannabinoïdes dans des compositions de solution solide |
US20200222360A1 (en) * | 2017-07-07 | 2020-07-16 | Solmic Research Gmbh | Stable cannabinoid compositions |
US10842758B1 (en) * | 2019-06-18 | 2020-11-24 | Ampersand Biopharmaceuticals, Inc. | Transdermal penetrant formulations containing cannabidiol |
WO2020240184A1 (fr) * | 2019-05-31 | 2020-12-03 | GW Research Limited | Formulations de cannabinoïdes |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20180071210A1 (en) * | 2016-07-01 | 2018-03-15 | GW Research Limited | Cannabinoid formulations |
US20200222360A1 (en) * | 2017-07-07 | 2020-07-16 | Solmic Research Gmbh | Stable cannabinoid compositions |
WO2019159174A1 (fr) * | 2018-02-16 | 2019-08-22 | Icdpharma Ltd. | Administration, dans le côlon, de cannabinoïdes dans des compositions de solution solide |
WO2020240184A1 (fr) * | 2019-05-31 | 2020-12-03 | GW Research Limited | Formulations de cannabinoïdes |
US10842758B1 (en) * | 2019-06-18 | 2020-11-24 | Ampersand Biopharmaceuticals, Inc. | Transdermal penetrant formulations containing cannabidiol |
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