CN113018266A - Preparation method of cannabidiol solid dispersion, cannabidiol solid dispersion prepared by preparation method and application of cannabidiol solid dispersion - Google Patents
Preparation method of cannabidiol solid dispersion, cannabidiol solid dispersion prepared by preparation method and application of cannabidiol solid dispersion Download PDFInfo
- Publication number
- CN113018266A CN113018266A CN201911358071.8A CN201911358071A CN113018266A CN 113018266 A CN113018266 A CN 113018266A CN 201911358071 A CN201911358071 A CN 201911358071A CN 113018266 A CN113018266 A CN 113018266A
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- CN
- China
- Prior art keywords
- cannabidiol
- solid dispersion
- water
- cbd
- emulsifier
- Prior art date
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- Pending
Links
- 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 175
- 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 175
- 229950011318 cannabidiol Drugs 0.000 title claims abstract description 175
- 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 175
- 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 174
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/385—Concentrates of non-alcoholic beverages
- A23L2/39—Dry compositions
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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Abstract
The invention provides a preparation method of a cannabidiol solid dispersion, the solid dispersion prepared by the method and application thereof, which is obtained by forming cannabidiol into a dispersion at a molecular level in a water-soluble solid carrier under the condition of adding an emulsifier, and then cooling or drying. The obtained solid dispersion can solve the problem of water insolubility of cannabidiol, and improve the solubility and bioavailability of cannabidiol. The preparation process of the cannabidiol solid dispersion is simple and convenient for industrial production; the application field of the cannabidiol is expanded, and the obtained cannabidiol solid dispersion can also be used for food, beverage and daily chemical products, and can be combined with a stabilization technology according to the requirement during application.
Description
Technical Field
The invention belongs to the field of preparation and application, and relates to a preparation method of a cannabidiol solid dispersion for improving solubility, the cannabidiol solid dispersion prepared by the method and application of the cannabidiol solid dispersion.
Background
Cannabidiol is a natural active ingredient from the stem, leaf and seed of annual herb plant cannabis sativa L of cannabis of cannabiaceae, has various pharmacological activities, and has anti-tumor, neuroprotective, metabolism and immunoregulatory, cardiovascular, anti-inflammatory and antioxidant, hepatoprotective and antibacterial effects. The cannabidiol has a plurality of pharmacological effects, and can be applied to various aspects such as medicines, foods, skin care products, health care products, pet products and the like to play different effects. However, since cannabidiol is a fat-soluble substance, it is very insoluble in water, usually floats on top of water, and does not form a stable water-soluble solution. And because it is insoluble in water, it is easily destroyed, broken down or cleared by the liver, resulting in reduced delivery to the subject and greatly reduced bioavailability. Therefore, the wide and superior pharmacological properties are difficult to achieve the maximum bioavailability due to the special fat-soluble property, and the application range is limited. Therefore, there is a need for a simple and feasible method for enhancing the solubility, stability and bioavailability of cannabidiol to expand its application range.
Solid dispersion is a method for increasing the solubility of poorly soluble drugs by highly dispersing the active ingredient in the form of a crystallite, an amorphous form or a molecule in a solid dispersion material by a formulation means.
CN201910559038 discloses a preparation method of a water-soluble cannabidiol clathrate (nanocapsule), and CN201910562038 discloses a preparation method of a water-soluble industrial cannabis full spectrum oil clathrate, which respectively refer to the preparation of high-purity cannabidiol crystals and oil of a full spectrum into water-soluble clathrate. CN201910608919 discloses a preparation method of a water-soluble cannabidiol facial mask, wherein the water-soluble cannabidiol is also subjected to inclusion of cannabidiol after a cyclodextrin solution is mixed with a dispersion liquid of cannabidiol, and then a solvent and water are removed. The inclusion compound is mainly combined by utilizing Van der Waals force or hydrogen bond of cyclodextrin and cannabidiol, but the water solubility of the obtained water-soluble cannabidiol and the stability of the obtained water solution are limited, and the simple cyclodextrin inclusion compound is unstable to acid, is easy to acid decomposition and has certain limitation on the application range.
CN110177543A discloses a method of manufacturing a water soluble composition, the method comprising: isolating a first purified cannabinoid from a cannabis plant material; adding the first purified cannabinoid to vitamin E TPGS to produce a mixture of vitamin E TPGS and the first purified cannabinoid; heating the mixture to a first temperature; adding water to the mixture of vitamin E TPGS and the first purified cannabinoid to produce an aqueous cannabinoid formulation comprising the mixture of vitamin E TPGS and the first purified cannabinoid; and cooling the aqueous formulation to a second temperature, removing water from the aqueous cannabinoid formulation comprising the mixture of vitamin E TPGS and the first purified cannabinoid, to produce a dry powder. CN109833312A discloses a preparation method of a cannabidiol and alkaline cyclodextrin inclusion compound, which is to dissolve alkaline cyclodextrin in water to prepare an alkaline cyclodextrin water solution; dissolving cannabidiol in an organic solvent; adding cannabidiol organic solvent solution into alkaline cyclodextrin water solution, stirring for reaction, filtering, concentrating under reduced pressure at 40 deg.C, and drying to obtain cannabidiol and alkaline cyclodextrin clathrate. The above documents all adopt multi-step processes, and the process flow is complex, which is not favorable for continuous industrial production; and the solubility of the resulting cannabidiol solid powder is to be further improved.
CN107951869A discloses a pharmaceutical preparation, which comprises Cannabidiol (CBD) with unit dose of 25-200mg, and pharmaceutically acceptable adjuvants. The preparation process comprises sieving cannabidiol, mixing with pregelatinized starch, microcrystalline cellulose, polyvinylpyrrolidone and sodium carboxymethyl starch to obtain a uniform mixture, sieving to obtain a mixture, and mixing with magnesium stearate. The resulting powder-type mixture is then compressed into tablets of the desired shape and size, or the mixture is filled into hard gelatin capsules. The process fails to adequately disperse cannabidiol in the solid carrier, resulting in insufficient solubility and the shelf stability of the product is to be improved.
CN201910518640 discloses a method for preparing cannabidiol CBD nanoemulsion freeze-dried powder, which comprises dissolving cannabidiol in an oil phase, adding an emulsifier and an auxiliary emulsifier, then adding water to form an emulsion, then adding an aqueous solution of a freeze-drying protective agent, and then performing the steps of pre-freezing, subliming, resolving and the like to obtain a freeze-dried product, wherein the raw materials have various component types and complex process steps, and the method is not beneficial to realizing industrialization. CN201480066657 discloses a compressed tablet comprising granules comprising: cannabidiol, sucrose fatty acid monoester, lactose and excipient. The granulation is produced by combining a lactose powder with a granulation fluid, the granulation fluid being a granulation produced by removing an organic solvent comprising a solution of cannabidiol, sucrose fatty acid monoesters, an antioxidant and optionally excipients in the organic solvent. Lactose powder is an important essential component, the choice of which plays an important role in the preparation of the granulate. WO2017183011a1 discloses a water-soluble inclusion complex comprising a cannabinoid component and β -cyclodextrin, the inclusion complex being formed into a composition with a pharmaceutically acceptable carrier and optionally a phospholipid or surfactant, for the preparation of the inclusion complex it is disclosed that the cannabinoid is melted and added to the cyclodextrin in liquid form and the two components are mixed until the inclusion complex is formed, cooling gradually will result in solidification into a dry powder, and industrial gas dryers and spray dryers can also be used to obtain solids. Although it is briefly mentioned that a phospholipid or a surfactant may be added to form a composition, the composition is required to be combined with other components after the inclusion compound is formed. The technological process is relatively complex, the final product cannot be directly obtained in one step, the granularity of the cannabidiol in water is relatively large when the cannabidiol is dispersed in the water, and the transmittance of the obtained aqueous solution is limited, so that the application of the cannabidiol in the fields of cosmetics, foods, beverages and the like is limited.
In addition, CN 105395554a discloses a folic acid solid dispersion, which comprises folic acid and a hydrophilic carrier, and comprises the following steps: completely melting the carrier, adding folic acid, and stirring until the carrier is completely melted; rapidly cooling the completely melted folic acid and the hydrophilic carrier to be completely solidified under the ice bath and stirring conditions, and then freezing for 4-12 hours; finally, the frozen material was taken, dried, pulverized and sieved to obtain a folic acid solid dispersion. CN105232489A discloses a preparation method of an allisartan isoproxil solid dispersion, which comprises the following steps: dissolving allisartan isoproxil and a solubilizing carrier in a proper amount of organic solvent, adding a surfactant, and uniformly mixing to prepare a medicinal solution; and then putting the excipient into a fluidized bed, adding the medicine solution in a top spraying mode, and performing fluidized bed spray granulation to obtain the allisartan isoproxil solid dispersion. It can be seen that, although solid dispersions are prepared for various substances in the prior art, specific researches are still needed for how to well disperse specific substances in a certain solid carrier to obtain solid dispersions with good solubility for different specific substances due to the great difference of the solubility characteristics and the temperature sensitivity.
In summary, there is still a need for cannabidiol based on the above prior art to further simplify the process flow and further improve the solubility. The invention aims to improve the solubility and stability of cannabidiol, expand the application range of cannabidiol, and prepare products which can be applied to various application directions such as food, beverage, daily chemical products, medicines and the like by combining with a stabilization technology.
Disclosure of Invention
In view of the technical problems still existing in the prior art, the inventors of the present invention have found that, by using the method for preparing a cannabidiol solid dispersion described in the present application, the cannabidiol is dispersed in a water-soluble solid carrier, and an emulsifier is added to promote the dispersion of the cannabidiol in the carrier, so as to form a molecular-level dispersion, and then the dispersion is cooled or dried to obtain the solid dispersion, so that the problem that the cannabidiol is insoluble in water can be solved, and the solubility and bioavailability of the cannabidiol can be improved. The obtained cannabidiol solid dispersion can be directly applied to a medicinal preparation, is beneficial to targeted administration, prolongs the retention time of the medicament in vivo, and has the advantages of high medicament-loading rate and the like. The obtained cannabidiol solid dispersion can also be used in food, beverage, daily chemical products, and can be combined with stabilization technology according to requirements in application.
The "cannabidiol solid dispersion" described herein is a "solid dispersion" obtained by dispersing cannabidiol in a certain solid carrier medium, wherein the cannabidiol solid dispersion is a dispersion material of full spectrum cannabis oil or high purity cannabidiol (having a mass percentage concentration of 95% or more). The cannabidiol in the cannabidiol solid dispersion is a cannabinoids compound with the content of the cannabidiol of more than 50 wt%; that is, it contains cannabinoids in addition to Cannabidiol (CBD). The "cannabidiol oil" refers to an oily mixture of cannabinoids including Cannabidiol (CBD), wherein the content of cannabidiol in the "cannabidiol oil" is 50 wt% or more.
The aqueous solution obtained from the cannabidiol solid dispersion described herein, or the dispersion formed by dispersing the cannabidiol solid dispersion in water, means that the resulting dispersion is "clear", i.e., does not contain macroscopic particles (e.g., undissolved lipophilic compound particles) therein, or does not include visible large micelles (macroscopic micelles) in water ". "Cannabidiol (CBD)" refers to a cannabidiol compound. The resulting solution can be visually inspected for colloids or particles to determine the extent of dissolution of the compound. Alternatively, the solution may be filtered and analyzed to determine solubility. For example, a spectrophotometer may be used to determine the concentration of a compound present in the filtered solution. Typically, the test solution is compared to a positive control containing a series of known amounts of a pre-filtered lipophilic natural compound solution to obtain a standard concentration versus UV/VIS absorbance curve. Alternatively, the amount of compound in solution can be determined using high performance liquid chromatography.
Specifically, the method is realized by the following technical scheme:
a preparation method of a solid dispersion, which is prepared from cannabidiol oil or Cannabidiol (CBD) crystals, an emulsifier and a biologically acceptable water-soluble carrier, comprises the following preparation processes:
the method comprises the following steps:
melting and mixing cannabidiol oil or Cannabidiol (CBD) crystals, an emulsifier and a water-soluble carrier to form a uniform molten mixed solution; then, directly placing the molten mixed solution at-40-4 ℃ for cooling to form a solid dispersion; or
The second method comprises the following steps:
dispersing cannabidiol oil or Cannabidiol (CBD) crystals, an emulsifier and a water-soluble carrier in ethanol, and fully mixing to form a uniform mixed solution; step (2), after the step (1), drying the mixed solution to remove the solvent to obtain a solid dispersion; or
The third method comprises the following steps:
dissolving cannabidiol oil or Cannabidiol (CBD) crystals in ethanol to form a uniform dispersion; step (2), melting and blending the emulsifier and the biologically acceptable carrier to form a uniform mixed solution; step (3), uniformly mixing the dispersion liquid obtained in the step (1) with the mixed liquid obtained in the step (2), and drying the mixed liquid to remove the solvent to obtain a solid dispersion;
in the first method, the water-soluble carrier is selected from one or more than two of polyethylene glycol and poloxamer; the water-soluble carrier in the second method or the third method is selected from one or more than two of polyvinylpyrrolidone, polyethylene glycol, poloxamer, hydroxypropyl cellulose, hydroxypropyl methylcellulose and phthalate;
the order of steps (1) and (2) in method three can be switched.
The invention also provides a preparation method of the solid dispersion, which comprises the following steps:
melting and mixing cannabidiol oil or Cannabidiol (CBD) crystal, poloxamer 188 and one or two of PEG4000 and PEG6000 to form uniform melt mixed solution; and then directly placing the molten mixed solution at-40-4 ℃ for cooling to form a solid dispersion, wherein the total amount of poloxamer 188 and one or two of PEG4000 and PEG6000 is added in an amount enough to disperse the cannabidiol oil or Cannabidiol (CBD) crystals to form the solid dispersion, and the mass ratio of poloxamer 188 to one or two of PEG4000 and PEG6000 is 1:1-1: 5. In the method, the inventor finds that when poloxamer 188 and one or two of PEG4000 and PEG6000 are added for matching, poloxamer 188 can simultaneously play the dual functions of a carrier and an emulsifier, no additional emulsifier is required to be added, water solubility similar to that of the method I to method III can be obtained, and the process flow is simplified.
The step of drying to remove the solvent to obtain the solid dispersion according to the second method or the third method can be realized by one or a combination of the following methods: drying under reduced pressure, heating to evaporate solvent, and cooling to solidify.
Removing the solvent by adopting a decompression drying mode to obtain a solid dispersion; removing the solvent by heating to evaporate the solvent and then cooling and solidifying to obtain a solid dispersion; the cooling temperature is-40 ℃ to 10 ℃, preferably-30 ℃ to 4 ℃, and most preferably-20 ℃ to 0 ℃.
The cannabidiol oil is from full spectrum cannabidiol oil, the content of Cannabidiol (CBD) is more than or equal to 50 wt%, and the content of Cannabidivarin (CBDV) is less than or equal to 40 wt%; or the purity of the Cannabidiol (CBD) crystal is more than 98 wt%.
The emulsifier comprises: one or more of sucrose ester, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, mono-diglycerol fatty acid ester and phospholipid; preferably, the emulsifier is selected from one or more of polyvinyl alcohol and polyoxyethylene sorbitan fatty acid ester.
The polyethylene glycol is selected from one or two of PEG4000 and PEG 6000; the poloxamer is selected from poloxamer 188.
The addition amount of the water-soluble carrier is 35 wt% -94 wt%, preferably 40 wt% -90 wt%, more preferably 50 wt% -85 wt%, most preferably 60 wt% -80 wt% based on the total mass of the cannabidiol oil or cannabidiol crystals, the emulsifier and the water-soluble carrier.
The addition amount of the emulsifier is 1 wt% -50 wt%, preferably 2 wt% -30 wt%, more preferably 3 wt% -15 wt%, and most preferably 5 wt% -10 wt% based on the total mass of the cannabidiol oil or cannabidiol crystal, the emulsifier and the water-soluble carrier.
The solid dispersion obtained by the preparation has a Cannabidiol (CBD) content of 3% -30%, preferably 4-20%, more preferably 5-15%, and most preferably 6-12%.
The method further comprises the step of pulverizing the resulting solid dispersion; optionally, a step of sieving the crushed dispersion is included.
Further, the present invention relates to a solid dispersion obtained by the above method for producing a solid dispersion.
In another aspect, the invention also relates to a composition containing the solid dispersion, which further contains one or more than two of proteins, carbohydrates, hydrophilic colloid substances and pharmaceutical excipients besides the solid dispersion.
The protein is selected from one or more of soybean protein isolate, gelatin, zein, casein and salts thereof, and is preferably gelatin;
the carbohydrate is selected from one or more of corn starch, sodium starch octenylsuccinate, maltodextrin, sucrose and cyclodextrin, and is preferably one or more of sodium starch octenylsuccinate and maltodextrin;
the hydrophilic colloid substance is one or more than two of acacia, carrageenan and xanthan gum, and preferably the acacia is selected.
The pharmaceutic adjuvant is selected from one or more of sorbitol, mannitol, magnesium stearate and microcrystalline cellulose.
A product made from either the solid dispersion or the composition, made by a process comprising:
dissolving cannabidiol solid dispersion in water, optionally adding the above proteins, carbohydrates, hydrophilic colloids or medicinal adjuvants, shearing, emulsifying, and spray drying to obtain powder.
The product is powder, microcapsule, tablet or capsule.
Wherein, the microcapsule is used for preparing capsules.
In another aspect, the present invention also relates to the use of any one of the solid dispersion and the composition in food, beverages, skin care products, cleaning products, daily chemical products, and pharmaceutical products.
The application comprises adding Cannabidiol (CBD) in an amount of 5-5000ppm into the solid dispersion; alternatively, 0.01 to 50 wt% of a solid dispersant is added based on the total mass of the obtained product.
In some embodiments, Cannabidiol (CBD) may be present in the solid dispersion at a concentration of at least 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 4.0%, 5.0%, 6.0%, 8.0%, 10.0%, 12.0%, 15.0%, 18.0%, or 20.0% by weight. In some embodiments, the cannabidiol solid dispersion may be added to the food, beverage, skin care product, cleaning product, daily chemical product and pharmaceutical product in an amount of, for example, 0.01% to 50%, 0.1% to 30%, 1% to 20%, 2% to 15%, 3% to 10% or 5% to 12% (by weight), based on the total mass of the product.
At least 0.5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg or 1g of the Cannabidiol (CBD) is present in a water-based food, beverage, skin care product or pharmaceutical product. The Cannabidiol (CBD) is introduced by adding the cannabidiol solid dispersion or an aqueous dispersion of the cannabidiol solid dispersion.
The invention aims to solve the problem that the cannabidiol is insoluble in water, and the solubility of the cannabidiol is obviously improved by using a water-soluble carrier and matching with a certain surfactant. And different carriers can be matched with different preparation processes to achieve the optimal effects of simplifying the process and saving energy, thereby being more beneficial to the effective development and utilization of the cannabidiol. The invention has the following beneficial effects:
(1) the method has simple process and lower cost and is convenient for realizing industrial production;
(2) the solubility of the cannabidiol in water is increased, the solid dispersing agent forms an aqueous dispersion with good transmittance when dispersed in water, and the particle size of the cannabidiol in the aqueous dispersion is less than 100 nm;
(3) the obtained product has better stability and is convenient to store and transport;
(4) the application direction of the cannabidiol product is expanded, and the obtained cannabidiol solid dispersing agent can be applied to the fields of food, beverage, skin care products, cleaning products, daily chemical products, medicines and the like;
(5) the obtained cannabidiol product has various application modes, can be directly added and used, and can also be used as an intermediate to be prepared into powder, capsules, tablets and the like; for example, the method can be combined with a microcapsule embedding technology, so that the bioavailability of the cannabidiol is greatly improved and the effect is exerted.
Detailed Description
The present invention is further illustrated by the following specific examples, but the present invention is not limited to these examples, and the examples should not be construed as limiting the present invention.
And (3) detecting the water solubility of the product:
sample pretreatment: accurately weighing 0.02g of cannabidiol solid dispersion, and fully and uniformly dispersing in 100ml of purified water.
The instrument comprises the following steps: zetasizer (Malvern, model Nano-ZS); turbidimeter (HACH Corp., model: DR 900).
Particle size and PDI value (Polymer dispersion index): the particle size of cannabidiol powder in aqueous solution was measured using Nano-ZS, and the average particle size and PDI value were recorded, the PDI value representing the polydispersity index of the sample, the smaller the detected value of the polydispersity index PDI of the sample, the more uniform the sample was dispersed, PDI <0.05, the very uniform the monodispersion of the sample, 0.05< PDI <0.08, approximately monodispersion, 0.08< PDI <0.7, moderate dispersion, PDI >0.7, not suitable for detection.
Transmittance of aqueous solution: the transmittance was measured by a turbidimeter using pure water as a control, and the greater the transmittance, the more transparent the aqueous solution.
Example 1:
weighing 10g cannabidiol crystal (with purity of 99%), 100g PEG4000 and 50g poloxamer 188, melting in 70 deg.C water bath condition to obtain uniform liquid, and directly freezing in-19 deg.C refrigerator for 24h to obtain solid dispersion 1.
Comparative example 1a
Same as example 1 except that poloxamer 188 was replaced with polyethylene glycol 4000.
Comparative example 1b
Same as example 1 except that poloxamer 188 was replaced with a mono-diglycerol fatty acid ester.
Example 2:
weighing 20g of whole lineage oil (with the content of CBD being 80 percent), 120g of PVP K30 and 10g of Tween 80, dissolving in 200mL of absolute ethanol together, dissolving uniformly by ultrasonic, reacting for 5h at 60 ℃, drying the mixed solution under reduced pressure to obtain a cannabidiol solid dispersion 2, and grinding the prepared solid dispersion into a powder product.
Example 3:
weighing 20g of full spectrum oil (CBD content 56%, CBDV content 40%) and dissolving in 20mL of absolute ethanol, uniformly mixing 120g of PEG4000 and PEG6000 according to a ratio of 1:1, melting 10g of Tween 80 into uniform liquid at 80 ℃, adding the cannabidiol ethanol solution into the molten liquid, uniformly mixing, evaporating ethanol in a water bath at 80 ℃, then placing the mixed solution in an ice water bath, and cooling and solidifying to obtain a solid dispersion 3.
Example 4:
20g of whole lineage oil (with a CBD content of 80%) is weighed, 140g of poloxamer 188 and 10g of Tween 80 are melted together under the condition of a water bath at 70 ℃ to form uniform liquid, and the uniform liquid is directly placed in a refrigerator at-8 ℃ for freezing for 24 hours to obtain a solid dispersion 4.
Comparative example 2
Same as example 2 except that tween 80 was not added.
Comparative example 3
Same as example 2 except that the carrier was replaced with zein.
Comparative example 4
20g of whole lineage oil (with 80% of CBD content) and 150g of poloxamer 188 are weighed, mixed and stirred together under the condition of a water bath at 70 ℃, and then directly placed in a refrigerator at-8 ℃ for freezing for 24 hours to obtain a solid dispersion.
The solid dispersions prepared in the above examples and comparative examples were tested for particle size and transmittance in aqueous solution according to the test methods described above, and the results are shown in table 1:
TABLE 1
| Sample (I) | Particle size nm | PDI value | Transmittance of light% |
| Example 1 | 155.1 | 0.080 | 92.09 |
| Example 2 | 123.5 | 0.115 | 89.78 |
| Example 3 | 134.9 | 0.189 | 86.43 |
| Example 4 | 156.8 | 0.050 | 90.37 |
| Comparative example 1a | 273.6 | 0.282 | 61.19 |
| Comparative example 1b | 179.9 | 0.269 | 65.58 |
| Comparative example 2 | 277.2 | 0.225 | 69.31 |
| Comparative example 3 | 721.9 | 0.484 | 49.20 |
| Comparative example 4 | 156.9 | 0.533 | 70.09 |
From the above data, it can be seen that the cannabidiol solid dispersion prepared by the method of the present application has a lower particle size when dispersed in water and has a smaller PDI value, the smaller PDI value indicates that the better the aqueous solution dispersion, the more uniform the particles are dispersed. The solution has better transmittance, and the state of the aqueous solution is clear and transparent. The solid dispersant prepared without adding the surfactant cannot reach a completely clear and transparent state, and is milky white after being dissolved in water.
In addition, the cannabidiol solid dispersion prepared by the method successfully disperses the cannabidiol in different water-soluble carriers through different processes, so that the solid dispersion with good water solubility is obtained.
The solid dispersion prepared by the method is used in the following specific application examples, so that the application direction of the cannabidiol is expanded.
Application example 1: the solid dispersion 4 prepared in example 1 was added to emollient water in an amount of 0.2% and mixed well to obtain clear and transparent cannabidiol emollient water.
Application example 2: 30g of the solid dispersion 1 obtained in example 1 was dissolved in 230g of purified water, heated to 60 ℃ and stirred, and then 70g of maltodextrin was added thereto, followed by shearing, emulsification and spray drying to obtain a water-soluble powder. The obtained powder is easy to store and has better heat resistance than solid dispersion.
Application example 3: 30g of the solid dispersion 2 prepared in example 2 is dissolved in 150g of purified water, the temperature is raised to 60 ℃, the mixture is stirred, 70g of sodium starch octenyl succinate is added, and the microcapsule product is prepared after shearing emulsification and spray granulation. The prepared microcapsule is convenient to store, has heat resistance superior to that of a solid dispersion, has good fluidity, has an angle of repose of 36 degrees detected by a powder comprehensive characteristic tester, meets the production requirements, and can be tableted and encapsulated.
During the application process, the cannabidiol powder prepared by the application examples 1-4 has good water solubility, good dissolution speed and wide application fields.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (20)
1. A preparation method of a solid dispersion, which is prepared from cannabidiol oil or Cannabidiol (CBD) crystals, an emulsifier and a biologically acceptable water-soluble carrier, comprises the following preparation processes:
the method comprises the following steps:
melting and mixing cannabidiol oil or Cannabidiol (CBD) crystals, an emulsifier and a water-soluble carrier to form a uniform molten mixed solution; then, directly placing the molten mixed solution at-40-4 ℃ for cooling to form a solid dispersion; or
The second method comprises the following steps:
dispersing cannabidiol oil or Cannabidiol (CBD) crystals, an emulsifier and a water-soluble carrier in ethanol, and fully mixing to form a uniform mixed solution; step (2), after the step (1), drying the mixed solution to remove the solvent to obtain a solid dispersion; or
The third method comprises the following steps:
dissolving cannabidiol oil or Cannabidiol (CBD) crystals in ethanol to form a uniform dispersion; step (2), melting and blending the emulsifier and the biologically acceptable carrier to form a uniform mixed solution; step (3), uniformly mixing the dispersion liquid obtained in the step (1) with the mixed liquid obtained in the step (2), and drying the mixed liquid to remove the solvent to obtain a solid dispersion;
in the first method, the water-soluble carrier is selected from one or more than two of polyethylene glycol and poloxamer; the water-soluble carrier in the second method or the third method is selected from one or more than two of polyvinylpyrrolidone, polyethylene glycol, poloxamer, hydroxypropyl cellulose, hydroxypropyl methylcellulose and phthalate;
the order of steps (1) and (2) in method three can be switched.
2. A preparation method of a solid dispersion comprises the following steps:
melting and mixing cannabidiol oil or Cannabidiol (CBD) crystal, poloxamer 188 and one or two of PEG4000 and PEG6000 to form uniform melt mixed solution; and then directly placing the molten mixed solution at-40-4 ℃ for cooling to form a solid dispersion, wherein the total amount of poloxamer 188 and one or two of PEG4000 and PEG6000 is added in an amount enough to disperse the cannabidiol oil or Cannabidiol (CBD) crystals to form the solid dispersion, and the mass ratio of poloxamer 188 to one or two of PEG4000 and PEG6000 is 1:1-1: 5.
3. The method for preparing a solid dispersion according to claim 1, wherein the step of drying to remove the solvent to obtain the solid dispersion according to the second or third method is carried out by one or a combination of the following methods: drying under reduced pressure, heating to evaporate solvent, and cooling to solidify.
4. The process for preparing a solid dispersion according to claim 3, wherein the second process comprises removing the solvent by drying under reduced pressure to obtain a solid dispersion; removing the solvent by heating to evaporate the solvent and then cooling and solidifying to obtain a solid dispersion; the cooling temperature is-40 ℃ to 10 ℃, preferably-30 ℃ to 4 ℃, and most preferably-20 ℃ to 0 ℃.
5. The method for preparing a solid dispersion according to claim 1 or 2, wherein the cannabidiol oil is derived from a full spectrum cannabis oil, wherein the Cannabidiol (CBD) content is 50 wt% or more and the Cannabidivarin (CBDV) content is 40 wt% or less; or the purity of the Cannabidiol (CBD) crystal is more than 98 wt%.
6. The method for preparing a solid dispersion according to any one of claims 1 and 3 to 5, wherein the emulsifier comprises: one or more of sucrose ester, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, mono-diglycerol fatty acid ester and phospholipid; preferably, the emulsifier is selected from one or more of polyvinyl alcohol and polyoxyethylene sorbitan fatty acid ester.
7. The method for preparing the solid dispersion according to any one of claims 1 and 3 to 6, wherein the polyethylene glycol is selected from one or a combination of two of PEG4000 and PEG 6000; the poloxamer is selected from poloxamer 188.
8. The method for preparing a solid dispersion according to any one of claims 1 and 3 to 7, wherein the amount of water-soluble carrier added is 35 wt% to 94 wt%, preferably 40 wt% to 90 wt%, more preferably 50 wt% to 85 wt%, most preferably 60 wt% to 80 wt%, based on the total mass of the cannabidiol oil or Cannabidiol (CBD) crystals, the emulsifier and the water-soluble carrier.
9. The method of any one of claims 1 and 3 to 8, wherein the emulsifier is added in an amount of 1 wt% to 50 wt%, preferably 2 wt% to 30 wt%, more preferably 3 wt% to 15 wt%, and most preferably 5 wt% to 10 wt%, based on the total mass of the cannabidiol oil or Cannabidiol (CBD) crystals, the emulsifier, and the water-soluble carrier.
10. A method of preparing a solid dispersion according to any one of claims 1 to 9 wherein the solid dispersion obtained is 3% to 30%, preferably 4 to 20%, more preferably 5 to 15%, most preferably 6 to 12% Cannabidiol (CBD).
11. The method for producing a solid dispersion according to any one of claims 1 to 10, further comprising a step of pulverizing the obtained solid dispersion; optionally, a step of sieving the crushed dispersion is included.
12. A solid dispersion produced by the method for producing a solid dispersion according to any one of claims 1 to 11.
13. The composition comprising the solid dispersion of claim 12, further comprising one or more of proteins, carbohydrates, hydrocolloids, and pharmaceutical excipients.
14. The composition according to claim 13, wherein the protein is selected from one or more of soy protein isolate, gelatin, zein, casein and salts thereof, preferably gelatin;
the carbohydrate is selected from one or more of corn starch, sodium starch octenylsuccinate, maltodextrin, sucrose and cyclodextrin, and is preferably one or more of sodium starch octenylsuccinate and maltodextrin;
the hydrophilic colloid substance is one or more than two of acacia, carrageenan and xanthan gum, preferably acacia;
the pharmaceutic adjuvant is selected from one or more of sorbitol, mannitol, magnesium stearate and microcrystalline cellulose.
15. A product prepared from the solid dispersion of claim 12 and the composition of any one of claims 13-14, by a process comprising:
dissolving cannabidiol solid dispersion in water, optionally adding the above proteins, carbohydrates, hydrophilic colloids or medicinal adjuvants, shearing, emulsifying, and spray drying to obtain powder.
16. The product of claim 15, wherein the product is a powder, microcapsule, tablet or capsule.
17. The product of claim 16, wherein said microcapsules are used to prepare capsules.
18. Use of the solid dispersion according to claim 12 and the composition according to any one of claims 13 to 14 in food products, beverages, skin care products, cleaning products, daily use chemical products and pharmaceutical products.
19. The use of claim 18, wherein Cannabidiol (CBD) is added to the use in an amount of 5 to 5000ppm of the solid dispersion of cannabidiol; alternatively, 0.01 to 50 wt% of a solid dispersant is added based on the total mass of the obtained product.
20. Food, beverage, skin care product, cleaning product, daily chemical product or pharmaceutical product comprising the solid dispersion according to claim 12 and the composition according to any one of claims 13 to 14.
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