CN113842367A - Cannabidiol premix and preparation method thereof - Google Patents
Cannabidiol premix and preparation method thereof Download PDFInfo
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- CN113842367A CN113842367A CN202111164907.8A CN202111164907A CN113842367A CN 113842367 A CN113842367 A CN 113842367A CN 202111164907 A CN202111164907 A CN 202111164907A CN 113842367 A CN113842367 A CN 113842367A
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- cannabidiol
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- 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 title claims abstract description 109
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 229950011318 cannabidiol Drugs 0.000 title claims abstract description 107
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 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 title claims abstract description 107
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000012943 hotmelt Substances 0.000 claims abstract description 24
- 238000002156 mixing Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000004090 dissolution Methods 0.000 claims abstract description 16
- 239000000463 material Substances 0.000 claims abstract description 13
- 229920000642 polymer Polymers 0.000 claims abstract description 13
- 239000000945 filler Substances 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 238000009474 hot melt extrusion Methods 0.000 claims abstract description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 7
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 5
- 229920000578 graft copolymer Polymers 0.000 claims description 5
- 238000002844 melting Methods 0.000 claims description 5
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- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- -1 acetate-polyethylene Chemical group 0.000 claims description 3
- 238000007908 dry granulation Methods 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims description 2
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- 229920003109 sodium starch glycolate Polymers 0.000 claims 1
- 229940079832 sodium starch glycolate Drugs 0.000 claims 1
- 239000008109 sodium starch glycolate Substances 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 25
- 239000000843 powder Substances 0.000 abstract description 12
- 239000003960 organic solvent Substances 0.000 abstract description 9
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 229940079593 drug Drugs 0.000 description 3
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
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- 239000002360 explosive Substances 0.000 description 2
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
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- 230000000049 anti-anxiety effect Effects 0.000 description 1
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- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
The invention discloses a cannabidiol premix and a preparation method thereof, and relates to the field of pharmaceutical preparations, wherein the premix is prepared by carrying out hot melt extrusion on cannabidiol and a high-molecular carrier and then adding a pharmaceutically acceptable filler; the cannabidiol premix has a good dissolution rate, and the dissolution amount of 5min can reach 80% of the marked amount; meanwhile, the powder has good powder properties. The preparation method comprises the following steps: s1, uniformly mixing cannabidiol and a high polymer carrier, adding the mixed material into a hot-melt extruder, carrying out hot-melt extrusion at 120-160 ℃, and then cooling and crushing to obtain a hot-melt extrudate containing cannabidiol; s2, mixing the hot-melt extrudate obtained in the step S1 with a pharmaceutically acceptable filler to obtain the cannabidiol premix. The preparation method does not use organic solvents such as ethanol and the like, does not need special explosion-proof equipment, and has simple process.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a cannabidiol premix and a preparation method thereof.
Background
Cannabidiol (CBD) is a compound extracted from the medicinal plant cannabis sativa, and has pharmacological effects of anti-spasm, anti-anxiety, anti-inflammatory, etc.; however, cannabidiol is white to light yellow solid crystalline powder, the powder has poor powder properties, and is inconvenient to dose, and a pharmaceutical enterprise needs a complex preparation process to prepare cannabidiol into a finished product; in addition, cannabidiol is insoluble in water and soluble in organic solvents such as ethanol, methanol, ether, benzene, chloroform and petroleum ether; because cannabidiol is extremely difficult to dissolve in water, a large amount of cosolvent, excipient and the like are required to be added when the cannabidiol is prepared into a medicament, for example, Epidiolex developed by UK GW pharmaceutical company based on CBD contains 7.9% (w/v) of ethanol, Epidiolex is an oral liquid preparation for treating seizure epilepsy in children, the adaptive population is children, anhydrous ethanol has irritation, certain potential safety hazard is brought to patients intolerant to ethanol, and the safety in vivo is difficult to guarantee; in addition, the ethanol is flammable and explosive, special explosion-proof equipment is required for production, and certain potential safety hazards exist. Therefore, it is very important to develop a cannabidiol drug with good solubility and without ethanol.
Chinese patent CN 113018266A discloses a preparation method of a cannabidiol solid dispersion, the cannabidiol solid dispersion prepared by the preparation method and application thereof. The preparation method comprises dispersing cannabidiol, emulsifier and water soluble carrier in ethanol, emulsifying, and cooling or drying. However, the preparation method uses a large amount of surfactants such as Tween 80 and poloxamer 188, and as is known, the surfactants have certain toxicity, and the addition of a large amount of surfactants is not beneficial to the safety of medication and even cannot finish the administration in actual clinic; in addition, the preparation method uses an organic solvent ethanol, and the addition of a large amount of ethanol is extremely unfavorable for production, and the ethanol is flammable and explosive, and requires special explosion-proof equipment for production.
Chinese patent No. CN111991444A discloses a solubilizing carrier composition for cannabis oil comprising a surfactant, a polymeric excipient, and optionally an antioxidant, and a solubilized cannabis oil solid dispersion. However, the cannabidiol composition also contains a large amount of surfactant, the surfactant has certain toxicity, and the addition of a large amount of surfactant is not beneficial to the medication safety; in addition, the solubilized hemp oil solid dispersion is prepared using ethanol, an organic solvent.
Therefore, the method for preparing the cannabidiol premix solves the problem that cannabidiol is insoluble in water, and simultaneously avoids using organic solvents and surfactants, and has important significance in practical clinical administration.
Disclosure of Invention
In view of the above disadvantages of the prior art, it is an object of the present invention to provide a cannabidiol premix that does not contain surfactants and organic solvents, has a good dissolution rate in aqueous solution, and has good powdering properties.
In order to achieve the purpose, the specific technical scheme of the invention is as follows:
the cannabidiol premix is prepared by carrying out hot melting extrusion on cannabidiol and a high polymer carrier and then adding a pharmaceutically acceptable filler, wherein the dissolution amount of the cannabidiol premix in an aqueous solution for 5min can reach more than 80% of a marked amount;
the polymer carrier comprises at least one of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone and copovidone.
In the cannabidiol premix, cannabidiol is uniformly dispersed on a polymer carrier, so that the problem that cannabidiol is insoluble in water is solved, and the prepared cannabidiol premix has good powder properties and meets the requirement of subsequent direct tabletting or capsule filling. The cannabidiol premix does not contain a surfactant, so that the safety of taking the cannabidiol premix by a patient is ensured.
Preferably, the weight ratio of the cannabidiol to the polymeric carrier is 1: (1-10).
Preferably, the weight ratio of the cannabidiol to the polymeric carrier to the filler is 1: (1-10): (1.5 to 12).
Preferably, the cannabidiol premix has an angle of repose of less than 42 °; further preferably, the cannabidiol premix has an angle of repose of less than 40 °.
Preferably, the pharmaceutically acceptable filler includes, but is not limited to, one or more of lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, mannitol, hydroxypropylmethyl cellulose E5, povidone, sodium carboxymethyl starch, and calcium hydrogen phosphate.
Preferably, the cannabidiol premix has a tap density of 0.56 to 0.82 g/ml.
The invention also provides a preparation method of the cannabidiol premix, which comprises the following steps:
s1, uniformly mixing cannabidiol and a high polymer carrier, adding the mixed material into a hot-melt extruder, carrying out hot-melt extrusion at 120-160 ℃, and then cooling and crushing to obtain a hot-melt extrudate containing cannabidiol;
s2, mixing the hot-melt extrudate obtained in the step S1 with a pharmaceutically acceptable filler to obtain the cannabidiol premix.
According to the preparation method, a hot-melting extrusion process is adopted, the cannabidiol and the high polymer carrier are mixed and then added into a hot-melting extruder to be extruded at the temperature of 120-160 ℃, the cannabidiol is uniformly dispersed on the high polymer carrier, the problem that the cannabidiol is insoluble in water is solved, and the prepared cannabidiol premix has good powder properties and meets the requirements of subsequent direct tabletting or capsule filling. In addition, the preparation method avoids the use of an organic solvent and a surfactant; the production safety and the safety of taking by patients are ensured.
Preferably, step S2 further includes a granulation step including one of fluid granulation, dry granulation or wet granulation.
Compared with the prior art, the invention has the advantages that:
(1) according to the cannabidiol premix disclosed by the invention, the cannabidiol is uniformly dispersed in the high polymer carrier, so that the solubility and dissolution rate of the cannabidiol are improved, and the dissolution amount of the cannabidiol premix in 5min can reach more than 80% of the marked amount.
(2) The cannabidiol premix provided by the invention has good powder properties and good content uniformity.
(3) The cannabidiol premix does not contain a surfactant, so that the safety of taking the cannabidiol premix by a patient is ensured.
(4) The preparation method of the cannabidiol premix does not use organic solvents such as ethanol and the like, does not need special explosion-proof equipment, has simple process and is suitable for mass production and preparation.
(5) The cannabidiol premix can be directly supplied to enterprises for subsequent tabletting, capsule filling and the like, the enterprises do not need additional related equipment for mixing, granulating and the like, the operation is simple, the process flow is greatly shortened, and the enterprise cost is saved.
Drawings
FIG. 1 is a graph showing the dissolution profile in water of cannabidiol premixes of examples 1-3 of the invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, 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 derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The type of the hot-melting extruder used in the embodiment of the invention is ZE-16, and the manufacturer is ATS; the model of the fluidized bed is Mini Glatt, and the manufacturer is Glatt; the model of the dry granulator is TF-Lab, and the manufacturer is Japanese friendship; the model of the wet granulator is HLSH2-6A, and the manufacturer is the research institute of aviation manufacturing engineering in Beijing of the Zhonghang industry.
In the embodiment of the invention, the determination of the repose angle is carried out by adopting a fixed conical bottom method, a culture dish with a diameter D cm is arranged on a chassis, two glass funnels are overlapped in a vertically staggered manner and fixed on an iron support, the distance between the outlet of a lower funnel and the chassis is 3.5-6.0cm, a plurality of powder to be determined is taken and slowly added from an upper funnel, so that a sample is gradually accumulated on the chassis through the buffering of the two funnels to form a cone until the highest cone is obtained, the height H of the cone is determined, the cone is parallelly determined for three times, the average value is taken, and the repose angle is calculated according to the following formula: α ═ arctg (H/R) where α is the angle of repose and R is the chassis radius.
The content uniformity in the embodiment of the invention is measured according to the general rules of the four parts of the 2015 version of Chinese pharmacopoeia0941 (content uniformity test), weighing 10 samples, and measuring the relative content X of each single agent with index amount of 100 according to the method specified in each varietyiTo the content XiCalculating the mean value thereof
And the standard deviation S, and the absolute value A of the difference between the indicated quantity and the mean
If A +2.2S is less than or equal to 15, the content uniformity of the sample meets the specification. Wherein the calculation formula of the standard deviation S is as follows:
in the test of the dissolution amount in the embodiment of the invention, according to the second method (paddle method) of the dissolution amount and release degree determination method in Chinese pharmacopoeia (2015 edition four parts general rule 0931), the dissolution medium is 600ml of aqueous solution, the temperature is 37 ℃ plus or minus 0.5 ℃, the rotating speed is 75 revolutions per minute, and a sample of powder is put into a dissolution cup for dissolution test.
The formula for calculating the amount of elution is as follows:
in the formula, X is the elution amount,%;
mto pairWeighing the reference substance;
Afor supplying toThe peak area of the test solution is shown;
mamount of sampleWeighing the sample amount of the test sample;
Ato pairAs the peak area of the control solution.
Example 1
In this example, using copovidone as the polymeric carrier, a cannabidiol-copovidone hot melt extrudate was prepared and further a cannabidiol premix was prepared, and the formulation of this example is shown in table 1.
Table 1 shows the recipe of example 1
The method of preparing the cannabidiol premix of this example comprises the steps of:
s1, weighing cannabidiol, micropowder silica gel and copovidone (S630) according to the formula amount, uniformly mixing, adding the mixed materials into a double-screw hot-melt extruder, and performing melt extrusion at 120 ℃; cooling, crushing and sieving the melt extrudate by a 40-mesh sieve to obtain a hot melt extrudate containing cannabidiol;
s2, uniformly mixing the hot-melt extruded material obtained in the step S1 with lactose, microcrystalline cellulose and croscarmellose sodium in the prescribed amount; adding the mixed materials into a fluidized bed, and performing fluidization granulation by taking povidone K30 water solution with the mass concentration of 10% as an adhesive;
s3, after granulation is finished, setting the air inlet temperature of the fluidized bed to be 60 ℃ to dry the particles, and controlling the moisture of the particles to be less than 2%; then adding magnesium stearate, and mixing for 3min to obtain cannabidiol premix.
Example 2
In this example, polyvinylpyrrolidone is used as a polymer carrier to prepare a cannabidiol-polyvinylpyrrolidone hot melt extrudate, and further prepare a cannabidiol premix, and the formula of this example is shown in table 2.
Table 2 shows the recipe of example 2
The method of preparing the cannabidiol premix of this example comprises the steps of:
s1, weighing cannabidiol, micropowder silica gel and polyvinylpyrrolidone K12 in the formula amount, uniformly mixing, adding the mixed materials into a double-screw hot-melt extruder, and performing melt extrusion at 150 ℃; cooling, crushing and sieving the melt extrudate by a 40-mesh sieve to obtain a hot melt extrudate containing cannabidiol;
s2, uniformly mixing the hot-melt extruded material obtained in the step S1 with the microcrystalline cellulose and the croscarmellose sodium in the prescribed amount; adding the mixed materials into a dry granulating machine, and performing dry granulation (main parameters: pressure of a pressing wheel: 5MPa, and a whole-grain screen: 1.0 mm); then adding sodium stearyl fumarate, and mixing for 3min to obtain cannabidiol premix.
Example 3
In this example, a hot melt extrusion of a cannabidiol-polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus) was prepared using a polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer as a polymeric carrier, and a cannabidiol premix was further prepared, as shown in table 3.
Table 3 shows the recipe of example 3
The method of preparing the cannabidiol premix of this example comprises the steps of:
s1, weighing cannabidiol, micropowder silica gel and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer according to the formula amount, uniformly mixing, adding the mixed materials into a double-screw hot-melt extruder, and performing melt extrusion at 130 ℃; cooling, crushing and sieving the melt extrudate by a 40-mesh sieve to obtain a hot melt extrudate containing cannabidiol;
s2, uniformly mixing the hot-melt extrudate obtained in the step S1 with mannitol, microcrystalline cellulose, sodium carboxymethyl starch and hydroxypropyl methyl cellulose E5 in a prescribed amount; adding the mixed materials into a wet granulating machine, wetting with purified water, and performing wet granulation (main parameters: stirring speed: 400 rpm; cutting speed: 1200 rpm); drying at 60 deg.C, and controlling water content of the granule to be less than 2%; then adding sodium stearyl fumarate, and mixing for 3min to obtain cannabidiol premix.
Example 4
In this example, hydroxypropyl cellulose was used as the polymeric carrier to prepare a cannabidiol-hydroxypropyl cellulose hot melt extrudate and further prepare a cannabidiol premix, which is formulated as shown in table 4.
Table 4 shows the recipe of example 4
The method of preparing the cannabidiol premix of this example comprises the steps of:
s1, weighing cannabidiol, micropowder silica gel and hydroxypropyl cellulose in the formula amount, uniformly mixing, adding the mixed materials into a double-screw hot-melt extruder, and performing melt extrusion at 160 ℃; cooling, crushing and sieving the melt extrudate by a 40-mesh sieve to obtain a hot melt extrudate containing cannabidiol;
s2, uniformly mixing the hot-melt extruded material obtained in the step S1 with a prescribed amount of microcrystalline cellulose, sodium carboxymethyl starch, calcium hydrophosphate and sodium stearyl fumarate; thus obtaining the cannabidiol premix.
The cannabidiol premixes prepared in examples 1-4 were subjected to angle of repose, tap density, content uniformity, and elution amount measurements, and the test results are shown in table 5.
Table 5 shows the results of the cannabidiol premix of examples 1-4
| Group of | Angle of reposeα | Tap density (g/ml) | Content uniformity | Elution quantity (5min) |
| Limit requirements | Less than 42 ° | 0.3～1 | Less than 15 | More than 80 percent |
| Example 1 | 36° | 0.56 | A+2.2S＝5.5 | 99.6％ |
| Example 2 | 38° | 0.78 | A+2.2S＝4.6 | 98.9％ |
| Example 3 | 38° | 0.74 | A+2.2S＝6.1 | 99.7％ |
| Example 4 | 40° | 0.82 | A+2.2S＝7.3 | 100％ |
The test results show that the dissolution amount of the cannabidiol premix in the aqueous solution for 5min can reach 98.9-100% of the marked amount. The cannabidiol premix has an angle of repose of 36 ° to 40 °. The cannabidiol premix prepared by the preparation method has good solubility and dissolution rate, and the dissolution amount of 5min can be completely released; the cannabidiol premix has good powder properties, and the content uniformity accords with the Chinese pharmacopoeia standard.
According to the preparation method, the cannabidiol is melted and dispersed in the high polymer carrier, so that the dissolution rate of the cannabidiol is improved, and the dissolution amount of the prepared cannabidiol premix in 5min can reach 100% of the marked amount; the cannabidiol premix has good powder properties; in addition, the cannabidiol premix prepared by the preparation method does not contain a surfactant, so that the safety of taking by patients is ensured. The preparation method of the invention does not use organic solvent, has simple process, does not need special explosion-proof equipment and is suitable for mass production and preparation. The cannabidiol premix can be directly supplied to enterprises for subsequent tabletting, capsule filling and the like as a product, the enterprises do not need additional related equipment for mixing, granulating and the like, the operation is simple, the process flow is greatly shortened, and the enterprise cost is saved; meanwhile, the cannabidiol premix has reliable quality and good content uniformity and meets pharmacopoeia standards.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. The cannabidiol premix is characterized by being prepared by hot-melting and extruding cannabidiol and a high polymer carrier and adding a pharmaceutically acceptable filler, wherein the dissolution amount of the cannabidiol premix in an aqueous solution for 5min can reach more than 80% of a marked amount;
the polymer carrier comprises at least one of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone and copovidone.
2. A cannabidiol premix according to claim 1 wherein the weight ratio of cannabidiol to polymeric carrier is 1: (1-10).
3. A cannabidiol premix according to claim 1 wherein the cannabidiol premix has an angle of repose of less than 42 °.
4. A cannabidiol premix according to claim 3 wherein the cannabidiol premix has an angle of repose of less than 40 °.
5. A cannabidiol premix according to claim 1 wherein the pharmaceutically acceptable fillers include, but are not limited to, one or more of lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, mannitol, hydroxypropylmethylcellulose E5, povidone, sodium starch glycolate, calcium hydrogen phosphate.
6. A cannabidiol premix according to claim 1, wherein the cannabidiol premix has a tap density of from 0.56 to 0.82 g/ml.
7. A process for the preparation of a cannabidiol premix as claimed in any one of claims 1 to 6 comprising the steps of:
s1, uniformly mixing cannabidiol and a high polymer carrier, adding the mixed material into a hot-melt extruder, carrying out hot-melt extrusion at 120-160 ℃, and then cooling and crushing to obtain a hot-melt extrudate containing cannabidiol;
s2, mixing the hot-melt extrudate obtained in the step S1 with a pharmaceutically acceptable filler to obtain the cannabidiol premix.
8. The method of preparing a cannabidiol premix as recited in claim 7, wherein step S2 further comprises a granulation step comprising one of fluid granulation, dry granulation, or wet granulation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103202811A (en) * | 2013-03-22 | 2013-07-17 | 中山大学 | Diflunisal solid dispersion and preparation method thereof |
| US20210196637A1 (en) * | 2019-06-13 | 2021-07-01 | Imbucanna, Inc. | Compressible Cannabinoid Pharmaceutical Composition |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103202811A (en) * | 2013-03-22 | 2013-07-17 | 中山大学 | Diflunisal solid dispersion and preparation method thereof |
| US20210196637A1 (en) * | 2019-06-13 | 2021-07-01 | Imbucanna, Inc. | Compressible Cannabinoid Pharmaceutical Composition |
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Application publication date: 20211228 |