CN113197852B - Cannabidiol nano micelle preparation and preparation method thereof - Google Patents
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Abstract
The invention discloses a cannabidiol nano micelle preparation and a preparation method thereof. The raw materials comprise the following main materials in percentage by weight: cannabidiol 5-33% and auxiliary materials: 20-60% of a block copolymer and 10-50% of an amphiphilic surfactant, wherein the weight ratio of the main material to the auxiliary material is 1. The preparation method comprises the following steps: dissolving the block copolymer and the amphiphilic surfactant by using an organic solvent, adding cannabidiol, uniformly mixing by ultrasonic waves, and standing; placing the obtained solution in a vacuum rotary evaporator to remove the solvent, and drying to obtain solid particles which are cannabidiol nano solid particles; dissolving the solid particles with distilled water to obtain cannabidiol nano micelle solution. The invention adopts micelle carrier technology to deliver the cannabidiol for the first time, increases the water solubility of the cannabidiol and improves the bioavailability of the cannabidiol.
Description
Technical Field
The invention relates to a nano micelle preparation capable of improving the water solubility of cannabidiol, in particular to a self-assembly nano micelle preparation entrapping cannabidiol under the combined action of a block copolymer and an amphiphilic surfactant and a preparation method thereof, belonging to the technical field of medical preparations.
Background
Cannabidiol (CBD) is a pure natural component extracted from cannabis sativa plant, is a main non-addictive component in cannabis sativa, and has pharmacological effects of treating epilepsy, resisting anxiety, treating pain, resisting inflammation, protecting nerves and the like, and skin caring, skin repairing, whitening and tendering and the like. The pharmacological mechanism of cannabidiol in producing analgesia is mainly related to cannabinoid CB1 receptors and CB2 receptors in organisms. CB1 receptors achieve analgesic effects by directly inhibiting the release of gamma-aminobutyric acid (GABA) in the grey matter around the mesolimbic aqueduct and in the RVM, as well as glutamate in the spinal cord. CB2 receptors inhibit allergic inflammation by attenuating nerve growth factor-induced mast cell degranulation and neutrophil accumulation, and thus mediate immunosuppression, and have anti-inflammatory and analgesic effects superior to those of aspirin, which is well known and widely used. GABA neurotransmitter in human brain has sedative effect and inhibits excitability of brain center. Cannabidiol can help control the consumption of GABA neurotransmitter, inhibit cerebral excitation, reduce epileptic seizure, and improve the curative effect of other antiepileptic drugs. Cannabidiol helps to maintain the level of endocannabinoids at a reasonable level, which is perceived as pleasant and pleasant by the patient without being as addictive as Tetrahydrocannabinol (THC). The cannabinaceae is divided into industrial cannabis and narcotic cannabis, the industrial cannabis refers to cannabis with the tetrahydrocannabinol content of less than 0.3%, and China refers to the industrial cannabis as hemp. At present, the widely applied hemp at home and abroad is industrial hemp which is considered to have no drug utilization value and is applied to the fields of textile, paper making, food, medicine, sanitation, daily chemicals and the like.
Cannabidiol has the molecular formula C 21 H 30 O 2 The character of the compound is white to light yellow resin or crystal, the melting point is 66 ℃ to 67 ℃, and the compound is almost insoluble in water and is dissolved in organic solvents such as ethanol, methanol, ether, benzene, chloroform and the like. CBD has been demonstrated to possess a variety of pharmacological activities and is a research drug with great potential. Currently only FDA approved oral solution of Epidiolex from GW company is on the market for the treatment of refractory childhood epilepsyAnd Sativex (CBD: THC = 1) oromucosal spray for the treatment of pain associated with multiple sclerosis. The oral utilization of the CBD is limited to a great extent by the inherent properties of the CBD, the problems of polymorphism, poor water solubility, large oral individual difference and stability exist, the oral bioavailability of the CBD in a human body is only 6%, and the CBD is easy to pass through first-pass metabolism, so that the CBD has low absorption rate. For example, patent nos. CN 110179862A and CN 111000827A disclose a cyclodextrin inclusion cannabidiol-based nano-preparation, and CN 110063937A and CN 110742861A disclose a cannabidiol self-emulsifying nano-emulsion preparation, which solves the problem of poor solubility of CBD, but β -cyclodextrin itself has low solubility in water, is easy to crack and unstable in strong acid, and has low inclusion amount, while the self-emulsifying nano-emulsion preparation has the problems of complex components, stability, economy and the like.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the cannabidiol nano-micelle preparation which is formed by self-assembly based on the combined action of rubusoside or stevioside or theasaponin and poloxamer, the preparation method thereof and the cannabidiol nano-micelle preparation with high stability, high drug loading capacity and high bioavailability are provided, and the nano-micelle preparation can be used as a solution preparation and a solid preparation, and further can be used for multi-way drug delivery such as oral absorption, transdermal/transmucosal absorption, spray inhalation injection and the like.
In order to solve the above problems, the present invention provides the following technical solutions:
the cannabidiol nano micelle preparation comprises the following main materials in percentage by weight: cannabidiol 5% -33% and auxiliary materials: 20-60% of a block copolymer and 10-50% of an amphiphilic surfactant, wherein the weight ratio of the main material to the auxiliary material is (1).
Preferably, the block copolymer is a triblock copolymer: poloxamers, having an average molecular weight of from 0.98 to 1.46 ten thousand, have the properties of a hydrophilic and a hydrophobic part in their molecule.
More preferably, the poloxamer is any one or combination of poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407. Poloxamers are a class of PEO-PPO-PEO non-ionic triblock copolymers composed of polyethylene oxide (PEO), polypropylene oxide (PPO) and are sold under the trade names pluronic, lutrol F (BASF, germany) and poloxamer (ICI), the Chinese name being poloxamer or pluronic. The poloxamer series contains more than 30 polymers with different PPO and PEO block ratios, and all have surface activity. Poloxamer 407 has good water solubility, and a unique hydrophobic core-hydrophilic shell structure enables the poloxamer to have amphipathy, good surface activity and reverse gelation property, has low toxicity in vivo, and is an ideal administration carrier for hydrophobic drugs. The active components are mainly used as emulsifying agents and solubilizing agents in pharmaceutical preparations, the surface solubility of other functional components is increased due to the micelle formation of the surfactant, and the active components can also be used as absorption promoters, have good compatibility with skin and can promote the absorption of other active components by the skin.
Preferably, the amphiphilic surfactant is natural amphiphilic surfactant rubusoside or stevioside (also called stevioside). The rubusoside and stevioside are diterpene glycosides, are similar in chemical structure and are both composed of tetracyclic diterpene aglycones, and the differences between the rubusoside and the stevioside are only the amount of glucose connected on a side chain. Both the two are natural high-efficiency sweeteners, are safe to eat, have no toxic or side effect, have the effects of reducing blood fat, blood sugar and the like, and are ideal sweet substitutes. Because rubusoside and stevioside have hydrophilic groups and hydrophobic groups, the rubusoside and stevioside can be used as surfactants, can form micelle shapes with hollow shell structures by self-assembly in water, and can increase the solubility and the stability of insoluble micromolecules. Theasaponin is also used as a surfactant in the present invention because it has an amphiphilic structure.
Preferably, the raw materials of the cannabidiol nano-micelle preparation comprise 25% of cannabidiol, 25% of rubusoside and 50% of poloxamer in percentage by weight.
Preferably, the nanomicelle preparation also comprises a stabilizer, so that the stability of the preparation is further improved.
Preferably, the stabilizer is one or a mixture of several of hydroxypropyl methylcellulose, polyethylene glycol 4000, polyethylene glycol 6000, polyvinyl alcohol 17-88, beta-cyclodextrin, vitamin E polyethylene glycol succinate, povidone k30, povidone k90, povidone KVA64, carbomer, copovidone, xanthan gum, microcrystalline cellulose, PEG400, glycerol, glyceryl monostearate, tween 80, tween 20, tween 60, transcutol P, polyoxyethylene castor oil and polyglycerol ester.
Preferably, the cannabidiol nano-micelle preparation comprises, by weight, 25% -35% of cannabidiol, 10% -30% of rubusoside, 20% -50% of poloxamer and 1% -10% of a stabilizer.
More preferably, the raw materials of the cannabidiol nano-micelle preparation comprise 30% of cannabidiol, 30% of rubusoside, 35% of poloxamer and 5% of stabilizer in percentage by weight.
Preferably, the encapsulation efficiency of the cannabidiol in the cannabidiol nano-micelle preparation is 60% -90%.
Preferably, the drug loading rate of the cannabidiol in the cannabidiol nano micelle preparation is 5% -30%.
The invention also provides a preparation method of the cannabidiol nano micelle preparation, which comprises the following steps:
step 1): dissolving the block copolymer and the amphiphilic surfactant by using an organic solvent to obtain a clear solution;
step 2): adding cannabidiol into the clear solution obtained in the step 1), adding a stabilizer according to the requirement, performing ultrasonic mixing uniformly, and standing;
step 3): transferring the solution obtained in the step 2) into a rotary evaporator, carrying out water bath at 35-60 ℃, vacuumizing, carrying out rotary evaporation to remove the solvent, and drying to obtain solid particles, namely cannabidiol nano solid particles;
step 4): dissolving the solid particles obtained in the step 3) with distilled water to obtain the cannabidiol nano micelle solution.
Preferably, the organic solvent in step 1) is at least one of methanol, absolute ethanol, propanol and an aqueous solution of the aforementioned alcohol; the volume concentration of the alcohol aqueous solution is 60-90%.
Preferably, the temperature of the ultrasound in the step 2) is 25-50 ℃, and the time is 20-40min; standing for more than 30 min.
Micelles refer to macroscopic, ordered aggregates formed by the association of several solute molecules or ions in solution, having a structure of an inner "core" and an "outer" shell, formed by amphiphilic substances consisting of hydrophilic and hydrophobic chains, which can self-assemble in water above the Critical Micelle Concentration (CMC). Nanomicelles have the ability to encapsulate hydrophobic drugs into their cores and are capable of delivering drugs to a desired site at concentrations that exceed the intrinsic solubility of the drug; furthermore, not only can the encapsulated drug be protected from contact with GI contents that may induce degradation and metabolism, but it is also given sustained release and direct cellular uptake characteristics. The rubusoside, the stevioside or the theasaponin have good surface activity, are easy to self-assemble in aqueous solution to form a micelle structure, have better effect than single action when being used for encapsulating cannabidiol together with poloxamer, show high encapsulation rate and drug loading rate, and the obtained micelle solution is clear and transparent. The nano-micelle solution is prepared by the combined action of the block copolymer and the natural surfactant, so that the solubility of the insoluble drug is improved to a great extent, the stability of the insoluble drug is protected, and the nano-micelle solution has better effect than the nano-micelle solution prepared by the single block copolymer or the surfactant.
In order to improve the problems of water solubility and easiness in first-pass metabolism of CBD, the invention develops a self-assembled nano micelle preparation which can improve the solubility of CBD and reduce the first-pass metabolism of CBD. The invention adopts micelle carrier technology to deliver the cannabidiol for the first time, increases the water solubility of the cannabidiol and improves the bioavailability of the cannabidiol. Compared with the prior art, the invention has the following beneficial effects:
(1) The invention can obviously increase the water solubility of cannabidiol, and the micellar solution belongs to a colloidal solution system with stable heat and dynamics, so that the CBD has good stability.
(2) The invention belongs to a nano-scale preparation, is dissolved in water, has clear and transparent solution, small particle size and quick penetration, can enhance passive targeting, avoids first-pass metabolism by liver and enhances absorption and utilization.
(3) The nanometer preparation has safe and easily obtained auxiliary materials, simple preparation method and is suitable for industrial production.
(4) The nanometer preparation can be used as a solid preparation and a liquid preparation, wherein the solid preparation comprises tablets, capsules and granules; liquid preparations include oral solutions, injections, drops; can be applied to the application directions of oral administration, transdermal administration, injection and the like.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments are described in detail below.
Example 1
Weighing 2g of rubusoside and 1g of poloxamer, and adding a proper amount of absolute ethyl alcohol for dissolving; then 100mg of CBD is weighed and added into the solution, dissolved and mixed evenly by ultrasonic, and kept stand for 30min; carrying out rotary evaporation on the solution to remove absolute ethyl alcohol, and removing the ethyl alcohol at the water bath temperature of 37 ℃ until a transparent solid film is formed; taking out the solid, adding 5mL of distilled water for redissolving, and filtering by using a 0.45 mu m filter membrane to remove the non-encapsulated insoluble substances to obtain the cannabidiol micelle solution.
The obtained cannabidiol micelle solution is colorless clear transparent solution, no drug precipitation solid is separated out after the cannabidiol micelle solution is placed for 24 hours at room temperature, the encapsulation rate of the cannabidiol is 90.25 percent, and the drug-loading rate is 3.01 percent.
Example 2
Weighing 250mg of rubusoside and 150mg of poloxamer, and adding a proper amount of 90% ethanol for dissolving; then 100mg of CBD is weighed and added into the solution, dissolved and mixed evenly by ultrasonic, and kept stand for 30min; performing rotary evaporation on the solution to remove the solvent, and removing the solvent at the water bath temperature of 50 ℃ until a transparent solid film is formed; taking out the solid, adding 5mL of distilled water for redissolving, and filtering by using a 0.45 mu m filter membrane to remove the non-encapsulated insoluble substances to obtain the cannabidiol micelle solution.
The obtained cannabidiol micellar solution is colorless clear transparent solution, no precipitate solid is separated out after the cannabidiol micellar solution is placed for 24 hours at room temperature, the encapsulation rate of the cannabidiol is 85.65 percent, and the drug loading is 18.42 percent.
Example 3
Weighing 100mg stevioside and 280mg poloxamer, and adding a proper amount of 80% ethanol for dissolving; then 100mg of CBD is weighed and added into the solution, dissolved and mixed evenly by ultrasonic, and kept stand for 30min; carrying out rotary evaporation on the solution to remove absolute ethyl alcohol, and removing the ethyl alcohol at the water bath temperature of 37 ℃ until a transparent solid film is formed; taking out the solid, adding 5mL of distilled water for redissolving, and filtering by using a 0.45 mu m filter membrane to remove the non-encapsulated insoluble substances to obtain the cannabidiol micelle solution.
The obtained cannabidiol micellar solution is colorless transparent clear solution, no precipitate solid is separated out after the cannabidiol micellar solution is placed for 24 hours at room temperature, the encapsulation rate of the cannabidiol is 65.15 percent, and the drug loading is 13.45 percent.
Example 4
Weighing 100mg rubusoside and 200mg poloxamer, and adding appropriate amount of 90% propanol for dissolving; then 100mg of CBD is weighed and added into the solution, 5mg of hydroxypropyl methylcellulose is added to be used as a stabilizing agent, ultrasonic dissolution and mixing are carried out uniformly, and standing is carried out for 30min; performing rotary evaporation on the solution to remove the solvent, and removing the solvent at the water bath temperature of 37 ℃ until a transparent solid film is formed; taking out the solid, adding 5mL of distilled water for redissolving, and filtering by using a 0.45 mu m filter membrane to remove the non-encapsulated insoluble substances to obtain the cannabidiol micelle solution.
The obtained cannabidiol micellar solution is colorless transparent clear solution, no precipitate solid is separated out after the cannabidiol micellar solution is placed for 24 hours at room temperature, the encapsulation rate of the cannabidiol is 85.65 percent, and the drug loading is 18.68 percent.
Example 5
Weighing 150mg of stevioside and 100mg of poloxamer, and adding a proper amount of 90% methanol for dissolving; weighing 100mg of CBD, adding into the solution, adding 10mg of carbomer as a stabilizer, dissolving and mixing uniformly by ultrasonic, and standing for 30min; performing rotary evaporation on the solution to remove the solvent, and removing the solvent at the water bath temperature of 37 ℃ until a transparent solid film is formed; taking out the solid, adding 5mL of distilled water for redissolving, and filtering by using a 0.45 mu m filter membrane to remove the non-encapsulated insoluble substances to obtain the cannabidiol micelle solution.
The obtained cannabidiol micellar solution is colorless transparent clear solution, no precipitate solid is separated out after the cannabidiol micellar solution is placed for 24 hours at room temperature, the encapsulation rate of the cannabidiol is 71.89 percent, and the drug loading rate is 20.24 percent.
Example 6
Weighing 80mg rubusoside and 100mg poloxamer, and adding appropriate amount of 75% ethanol for dissolving; weighing 100mg of CBD, adding into the solution, adding 20mg of polyethylene glycol 6000 as a stabilizer, dissolving and mixing uniformly by ultrasonic waves, and standing for 30min; performing rotary evaporation on the solution to remove the solvent, and removing the solvent at the water bath temperature of 37 ℃ until a transparent solid film is formed; taking out the solid, adding 5mL of distilled water for redissolving, and filtering by using a 0.45 mu m filter membrane to remove the non-encapsulated insoluble substances to obtain the cannabidiol micelle solution.
The obtained cannabidiol micelle solution is colorless transparent clear solution, no precipitate solid is separated out after the cannabidiol micelle solution is placed for 24 hours at room temperature, the encapsulation rate of the cannabidiol is 90.05 percent, and the drug-loading rate is 30.01 percent.
Claims (7)
1. The cannabidiol nano micelle preparation is characterized by comprising the following main materials in percentage by weight: cannabidiol 5% -33% and auxiliary materials: 20-60% of a block copolymer and 10-50% of an amphiphilic surfactant, wherein the weight ratio of the main material to the auxiliary material is (1); the block copolymer is a triblock copolymer: a poloxamer; the amphiphilic surfactant is natural amphiphilic surfactant rubusoside or stevioside; the cannabidiol nanomicelle formulation further comprises a stabilizer; the stabilizer is any one or a mixture of several of hydroxypropyl methylcellulose, polyethylene glycol 6000 and carbomer.
2. A cannabidiol nanomicelle formulation according to claim 1, wherein the block copolymer is a triblock copolymer having an average molecular weight of from 0.98 to 1.46 million.
3. A cannabidiol nanomicelle formulation according to any of claims 1-2, wherein cannabidiol has an encapsulation efficiency of cannabidiol in the cannabidiol nanomicelle formulation of between 60% and 90%.
4. A cannabidiol nanomicelle formulation according to any of claims 1 to 2, wherein the cannabidiol is loaded at a level of from 5% to 30% of the cannabidiol.
5. A method of preparing cannabidiol nanomicelle formulations according to any one of claims 1 to 4, comprising the steps of:
step 1): dissolving the block copolymer and the amphiphilic surfactant by using an organic solvent to obtain a clear solution;
step 2): adding cannabidiol into the clear solution obtained in the step 1), adding a stabilizer, uniformly mixing by ultrasonic waves, and standing;
step 3): transferring the solution obtained in the step 2) into a rotary evaporator, carrying out water bath at 35-60 ℃, vacuumizing, and carrying out rotary evaporation to remove the solvent, wherein the solid particles obtained after drying are cannabidiol nano solid particles;
and step 4): dissolving the solid particles obtained in the step 3) by using distilled water to obtain the cannabidiol nano micelle solution.
6. The method for preparing cannabidiol nanomicelle formulation according to claim 5, wherein the organic solvent of step 1) is at least one of methanol, absolute ethanol, propanol and aqueous solution of the aforementioned alcohols; the volume concentration of the alcohol aqueous solution is 60-90%.
7. The method for preparing cannabidiol nanomicelle formulation according to claim 5, wherein the ultrasound in step 2) is performed at 25-50 ℃ for 20-40min; standing for more than 30 min.
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