CN113197852B - Cannabidiol nano-micelle preparation and preparation method thereof - Google Patents

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

Cannabidiol nano-micelle preparation and preparation method thereof

technical field

The invention relates to a nano-micelle preparation capable of improving the water solubility of cannabidiol, in particular to a self-assembled nano-micelle preparation in which a block copolymer and an amphiphilic surfactant work together to load cannabidiol and a preparation method thereof , belongs to the technical field of pharmaceutical preparations.

Background technique

Cannabidiol (CBD) is a pure natural ingredient extracted from the hemp plant. It is the main non-addictive ingredient in hemp. Skin repair, whitening and skin rejuvenation. The analgesic pharmacological mechanism of cannabidiol is mainly related to the cannabinoid CB1 receptor and CB2 receptor in the organism. CB1 receptors achieve analgesic effects by directly inhibiting the release of γ-aminobutyric acid (GABA) in the periaqueductal gray matter of the midbrain and the RVM and glutamate in the spinal cord. CB2 receptor inhibits allergic inflammation by weakening nerve growth factor-induced mast cell degranulation and neutrophil aggregation, and thus mediates immunosuppressive effect to achieve anti-inflammatory and analgesic effects, and the effect is stronger than the well-known and Widely used aspirin. The GABA neurotransmitter in the human brain has a calming effect and inhibits the excitability of the brain center. Cannabidiol can help control the consumption of GABA neurotransmitters, suppress brain excitation, reduce seizures, and can also help improve the efficacy of other antiepileptic drugs. Cannabidiol can help maintain endogenous cannabinoids at a reasonable level, making patients feel good and happy, without being addictive like tetrahydrocannabinol (THC). Cannabis is divided into industrial hemp and drug hemp. Industrial hemp refers to hemp with a tetrahydrocannabinol content of less than 0.3%. In my country, industrial hemp is called hemp. The hemp that is widely used at home and abroad is industrial hemp. Industrial hemp is considered to have no drug use value. Its applications include at least textiles, papermaking, food, medicine, hygiene, daily chemicals and other fields.

The molecular formula of cannabidiol is C ₂₁ H ₃₀ O ₂ , and its properties are white to light yellow resin or crystal, with a melting point of 66°C-67°C, almost insoluble in water, and soluble in organic solvents such as ethanol, methanol, ether, benzene, and chloroform . CBD has been proven to have a variety of pharmacological activities and is a research drug with great potential. Currently on the market are only FDA-approved Epidiolex oral solution from GW for the treatment of refractory childhood epilepsy and Sativex (CBD:THC=1:1) oromucosal spray for the treatment of pain associated with multiple sclerosis. The inherent properties of CBD itself limit its oral utilization to a large extent, and there are polymorphism, poor water solubility, large individual differences in oral administration, and stability problems. Its oral bioavailability in humans is only 6%, and it is easy to lead to CBD low absorption rate. Several patents have been published on the issue of improving the solubility and bioavailability of CBD. For example, patent numbers CN 110179862 A, CN 111000827 A disclose nano-preparations based on cyclodextrin inclusion cannabidiol, CN 110063937 A, CN 110742861 A discloses a cannabidiol self-emulsifying nanoemulsion preparation, which solves the problem of poor solubility of CBD, but the solubility of β-cyclodextrin itself in water is low, and it is easily cracked and unstable under strong acid, and its loading capacity is not high. However, self-emulsifying nanoemulsion preparations have problems such as complex components, stability, and economy.

Contents of the invention

The technical problem to be solved by the present invention is to provide a self-assembled cannabidiol nano-micelle preparation based on rubusoside, stevioside or tea saponin and poloxamer, and its preparation method and a high stability, Cannabidiol nanomicelle preparations with high drug loading and high bioavailability can be used as both solution preparations and solid preparations, and can be further used for oral absorption, transdermal/transmucosal absorption, spray inhalation Multiple routes of administration such as injections.

In order to solve the above problems, the present invention provides the following technical solutions:

A cannabidiol nano-micelle preparation, the raw materials of which include main ingredients in weight percentage: cannabidiol 5%-33% and auxiliary materials: block copolymer 20%-60%, amphiphilic surfactant 10%- 50%, the weight ratio of the main material and the auxiliary material is 1:2-1:20.

Preferably, the block copolymer is a tri-block copolymer: poloxamer, its average molecular weight is 09,800 to 14,600, and its molecule has properties of hydrophilic and hydrophobic parts.

More preferably, the poloxamer is any one or a combination of poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407. Poloxamers are a class of PEO-PPO-PEO nonionic triblock copolymers composed of polyoxyethylene (PEO) and polyoxypropylene (PPO), with trade names of pluronic, lutrol F (BASF, Germany) and Poloxamer (ICI), the Chinese name is Poloxamer or Pronick. The Poloxamer series contains more than 30 polymers with different PPO and PEO block ratios, all of which have surface activity. Poloxamer 407 itself has good water solubility, and its unique hydrophobic core-hydrophilic shell structure makes it amphiphilic, and has good surface activity and reverse gelation properties. It has low toxicity in vivo and is an ideal choice for hydrophobic drugs. drug delivery vehicle. It is mainly used as an emulsifier and solubilizer in pharmaceutical preparations. Because the surfactant forms micelles to increase the surface solubility of other functional ingredients, it can also be used as an absorption accelerator. This ingredient has good compatibility with the skin and can promote the skin to be effective for other ingredient absorption.

Preferably, the amphiphilic surfactant is natural amphiphilic surfactant rubusoside or stevioside (also known as stevioside). Both rubusoside and stevioside are diterpene glycosides, which are similar in chemical structure and are composed of tetracyclic diterpene aglycones. The difference between the two is only the amount of glucose connected to the side chain. Both are natural high-efficiency sweeteners, safe to eat, non-toxic and side effects, and have the effect of lowering blood fat and blood sugar, and are ideal sweet substitutes. Since rubusoside and stevioside have hydrophilic groups and hydrophobic groups, they can be used as surfactants, which can self-assemble in water to form micellar shapes with empty shell structures, increasing the solubility and stability of insoluble small molecules. Tea saponin is also used as a surfactant in the present invention because of its amphiphilic structure.

Preferably, the raw materials of the cannabidiol nano-micelle preparation include 25% cannabidiol, 25% rubusoside and 50% poloxamer by weight percentage.

Preferably, the nanomicelle formulation further includes a stabilizer to further improve the stability of the formulation.

Preferably, the stabilizer is hydroxypropylmethylcellulose, methylcellulose, polyethylene glycol 4000, polyethylene glycol 6000, polyvinyl alcohol 17-88, β-cyclodextrin, vitamin E polyethylene Glycol succinate, povidone k30, povidone k90, povidone KVA64, carbomer, copovidone, xanthan gum, microcrystalline cellulose, PEG400, glycerin, glyceryl monostearate, spit Any one or a mixture of Wen 80, Tween 20, Tween 60, Transcutol P, polyoxyethylene castor oil and polyglycerol ester.

Preferably, the raw materials of the cannabidiol nanomicelle preparation include cannabidiol 25%-35%, rubusoside 10%-30%, poloxamer 20-50% and stabilizer 1- 10%.

More preferably, the raw materials of the cannabidiol nano-micelle preparation include 30% cannabidiol, 30% rubusoside, 35% poloxamer and 5% stabilizer by weight percentage.

Preferably, the encapsulation efficiency of cannabidiol in the cannabidiol nano-micelle preparation is 60%-90%.

Preferably, the drug loading of cannabidiol in the cannabidiol nano-micelle preparation is 5%-30%.

The present invention also provides a preparation method of the above-mentioned cannabidiol nano-micelle preparation, comprising the following steps:

Step 1): dissolving the block copolymer and the amphiphilic surfactant in an organic solvent to obtain a clear solution;

Step 2): Add cannabidiol to the clarified solution obtained in step 1), add a stabilizer as needed, mix evenly with ultrasound, and let stand;

Step 3): transfer the solution obtained in step 2) to a rotary evaporator, put it in a water bath at 35°C-60°C and vacuumize the rotary evaporation to remove the solvent, and the solid particles obtained after drying are cannabidiol nano solid particles;

Step 4): dissolving the solid particles obtained in step 3) with distilled water to obtain a cannabidiol nano-micelle solution.

Preferably, the organic solvent in the step 1) is at least one of methanol, absolute ethanol, propanol and the aforementioned alcohol aqueous solution; the volume concentration of the alcohol aqueous solution is 60%-90%.

Preferably, the ultrasonic temperature in step 2) is 25°C-50°C, and the time is 20-40min; the standing time is more than 30min.

Micelles refer to invisible ordered aggregates formed by the association of several solute molecules or ions in a solution. They have the structure of an inner "core" and an "outer" shell, and are amphiphilic composed of hydrophilic and hydrophobic chains. They can self-assemble in water above the critical micelle concentration (CMC). Nanomicelles have the ability to encapsulate hydrophobic drugs into their cores and deliver them to desired sites at concentrations exceeding the inherent solubility of the drug; moreover, not only can the encapsulated drug be protected from possible inducing degradation and Metabolized GI content, but also imparts sustained release and direct cellular uptake properties. rubusoside, stevioside or tea saponin has good surface activity, and is easy to self-assemble in aqueous solution to form a micelle structure. Encapsulation efficiency and drug loading, the obtained micellar solution is clear and transparent. Using block copolymers and natural surfactants to prepare nanomicelle solutions can not only increase the solubility of poorly soluble drugs to a large extent, but also protect the stability of poorly soluble drugs, which is better than single block copolymerization. The effect of nanomicelle solution prepared by compound or surfactant is better.

In order to improve the water solubility and first-pass metabolism of CBD, the present invention develops a self-assembled nanomicelle preparation that can not only improve the solubility of CBD but also reduce the first-pass metabolism of CBD. The present invention uses the micellar carrier technology to deliver cannabidiol for the first time, increases the water solubility of cannabidiol and improves the bioavailability of cannabidiol. Compared with the prior art, the present invention has the following beneficial effects:

(1) The present invention can significantly increase the water solubility of cannabidiol, and the micellar solution belongs to a thermodynamically and dynamically stable colloidal solution system, which can make CBD have good stability.

(2) The present invention belongs to nanoscale preparations, which are soluble in water and have a clear and transparent solution, small particle size and fast penetration, which can enhance passive targeting, avoid first-pass metabolism by the liver, and enhance absorption and utilization.

(3) The nano preparation component auxiliary materials of the present invention are safe and easy to obtain, the preparation method is simple, and it is applicable to industrial production.

(4) The nano-preparation of the present invention can be used as both a solid preparation and a liquid preparation. The solid preparation includes tablets, capsules, and granules; the liquid preparation includes oral solutions, injections, and drops; Injection and other usage directions are applied.

detailed description

In order to make the present invention more comprehensible, preferred embodiments are described in detail as follows.

Example 1

Weigh 2g rubusoside and 1g poloxamer, add an appropriate amount of absolute ethanol to dissolve; then weigh 100mg CBD and add it to the above solution, ultrasonically dissolve and mix well, and let stand for 30min; Rotate the solution to remove absolute ethanol, water bath Remove ethanol at a temperature of 37°C until a transparent solid film is formed; take out the solid and add 5 mL of distilled water to redissolve, and filter with a 0.45 μm filter membrane to remove unencapsulated insoluble matter to obtain a cannabidiol micellar solution.

The obtained cannabidiol micellar solution is a colorless, clear and transparent solution, and no drug precipitates solid out after being placed at room temperature for 24 hours. The measured cannabidiol encapsulation efficiency is 90.25%, and the drug loading is 3.01%.

Example 2

Weigh 250mg rubusoside and 150mg poloxamer, add an appropriate amount of 90% ethanol to dissolve; then weigh 100mg CBD and add it to the above solution, ultrasonically dissolve and mix evenly, and let stand for 30min; the solution is rotatively evaporated to remove the solvent, and the temperature of the water bath is 50 Remove the solvent at ℃ until a transparent solid film is formed; take out the solid and add 5 mL of distilled water to redissolve, and filter with a 0.45 μm filter membrane to remove unencapsulated insoluble matter to obtain the cannabidiol micellar solution.

The obtained cannabidiol micelle solution was a colorless, clear and transparent solution, and no precipitated solids were precipitated after being placed at room temperature for 24 hours. The measured cannabidiol encapsulation efficiency was 85.65%, and the drug loading was 18.42%.

Example 3

Weigh 100mg stevioside and 280mg poloxamer, add an appropriate amount of 80% ethanol to dissolve; then weigh 100mg CBD and add it to the above solution, ultrasonically dissolve and mix well, and let stand for 30min; Rotate the solution to remove absolute ethanol, water bath Remove ethanol at a temperature of 37°C until a transparent solid film is formed; take out the solid and add 5 mL of distilled water to redissolve, and filter with a 0.45 μm filter membrane to remove unencapsulated insoluble matter to obtain a cannabidiol micellar solution.

The obtained cannabidiol micellar solution was a colorless transparent clear solution, and no precipitated solids were precipitated after being placed at room temperature for 24 hours. The measured cannabidiol encapsulation efficiency was 65.15%, and the drug loading was 13.45%.

Example 4

Weigh 100mg rubusoside and 200mg poloxamer, add an appropriate amount of 90% propanol to dissolve; then weigh 100mg CBD and add to the above solution, then add 5mg hydroxypropylmethylcellulose as a stabilizer, ultrasonically dissolve and mix evenly, static Let it sit for 30 minutes; remove the solvent by rotary evaporation, and remove the solvent at a water bath temperature of 37°C until a transparent solid film is formed; take out the solid and add 5 mL of distilled water to redissolve, and filter with a 0.45 μm filter membrane to remove unencapsulated insoluble matter to obtain cannabidiol gum Beam solution.

The obtained cannabidiol micellar solution was a colorless transparent clear solution, and no precipitated solids were precipitated after being placed at room temperature for 24 hours. The measured cannabidiol encapsulation efficiency was 85.65%, and the drug loading was 18.68%.

Example 5

Weigh 150mg of stevioside and 100mg of poloxamer, add an appropriate amount of 90% methanol to dissolve; then weigh 100mg of CBD and add to the above solution, then add 10mg of carbomer as a stabilizer, ultrasonically dissolve and mix well, and let stand for 30min; The solution was subjected to rotary evaporation to remove the solvent, and the water bath temperature was 37°C to remove the solvent until a transparent solid film was formed; the solid was taken out and redissolved in 5 mL of distilled water, and filtered with a 0.45 μm filter membrane to remove unencapsulated insoluble matter to obtain the cannabidiol micellar solution.

The obtained cannabidiol micellar solution was a colorless transparent clear solution, and no precipitated solids were precipitated after being placed at room temperature for 24 hours. The measured cannabidiol encapsulation efficiency was 71.89%, and the drug loading was 20.24%.

Example 6

Weigh 80mg rubusoside and 100mg poloxamer, add an appropriate amount of 75% ethanol to dissolve; then weigh 100mg CBD and add to the above solution, then add 20mg polyethylene glycol 6000 as a stabilizer, ultrasonically dissolve and mix well, and let stand for 30min Carry out rotary evaporation to remove the solvent from the solution, and remove the solvent at a water bath temperature of 37°C until a transparent solid film is formed; take out the solid and add 5 mL of distilled water to redissolve, and filter with a 0.45 μm filter membrane to remove unencapsulated insoluble matter to obtain the cannabidiol micellar solution .

The obtained cannabidiol micellar solution was a colorless transparent clear solution, and no precipitated solids were precipitated after being placed at room temperature for 24 hours. The measured cannabidiol encapsulation efficiency was 90.05%, and the drug loading was 30.01%.

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.