CN113197842B - Cannabidiol injectable hydrogel, preparation method and application thereof - Google Patents

Abstract

The invention relates to cannabidiol injectable hydrogel which comprises cannabidiol, a medical degradable material, chitosan and beta-sodium glycerophosphate; wherein the solid content of the cannabidiol is 1.2-1.6 wt%, the solid content of the medical degradable material is 4.7-6.1 wt%, the solid content of the chitosan is 24.4-31.3 wt%, and the solid content of the beta-sodium glycerophosphate is 62.5-68.3 wt%; the cannabidiol injectable hydrogel has a water content of 93.0-94.5 wt%. The cannabidiol injectable hydrogel has temperature sensitivity, can be injected into joint cavities to fully fill the joint cavities, forms elastic gel with certain strength under the action of body temperature, has a slow release effect, and is used for treating symptoms such as fever, swelling and pain caused by arthritis.

Description

A kind of cannabidiol injectable hydrogel, preparation method and use thereof

technical field

The invention relates to the technical field of biomedicine, in particular to an injectable hydrogel containing cannabidiol CBD for treating gout arthritis and a preparation method.

Background technique

In recent years, with the improvement of living standards and the adjustment of dietary structure, the intake of high-sugar, high-protein, high-fat, and high-purine diets has increased, resulting in an increase in the incidence of gout year by year. Because gout is a chronic disease, it requires long-term Medication has seriously affected people's normal work.

The prior art mainly adopts diet therapy combined with oral drugs to prevent and treat gout. The prevention of gout is mainly to strictly control eating high-purine diets, such as soy products, high-protein diets, strictly abstain from alcohol, drink more water, promote urination, prevent uric acid deposition, and usually eat light, low-fat, low-sugar, and crude fiber. main. For acute onset arthritis, oral anti-inflammatory and hormonal drugs are the main treatment methods, while for long-term treatment of chronic gouty arthritis, hyperuricemia and tophi deposition should also be paid attention to. In the treatment of gouty arthritis, most patients are prone to intolerable systemic drug side effects when taking the drug for a long time, resulting in many patients discontinuing drug therapy because of intolerance. In addition, intra-articular injection is clinically proposed to get rid of the adverse reactions caused by systemic administration, but the rapid clearance of the drug from the joint shortens its local action time, and frequent intra-articular injection increases In view of the probability of joint cavity infection, in view of the above, it is urgent to construct a sustained-release preparation for local administration in the joint cavity to improve the therapeutic effect and the compliance of patients with medication, and to get rid of the limitations of traditional dosage forms.

Cannabidiol (CBD) is a non-addictive ingredient extracted from cannabis plants with antispasmodic, anti-anxiety, anti-inflammatory and other pharmacological effects. Value-added phenolics. At present, Israel, the United States, the United Kingdom and other developed countries have used it as raw materials and developed a variety of special drugs, beverages and cosmetics and other products. Cannabidiol is insoluble in water and is easily metabolized, destroyed or eliminated by the liver, and oral administration of cannabidiol will result in greatly reduced bioavailability.

In recent years, medical degradable materials have been widely used in clinical practice, these materials mainly include polylactic acid (PLA), polycaprolactone (PCL), polyglycolide (PGA), polylactic-co-glycolic acid (PLGA) ), PTMC (polytrimethylene carbonate), etc. Among them, poly(lactic-co-glycolic acid) (PLGA) is a biodegradable material approved by the US Food and Drug Administration (FDA) for use in the human body. It has good biocompatibility and can be slowly degraded in the body. The final products are carbon dioxide and water. Moreover, by adjusting the molecular weight of the polymer, the hydrophilicity and the ratio of lactic acid to glycolic acid, the degradation rate of PLGA can be controlled to achieve the purpose of controlled drug release. It is one of the widely used microsphere carrier materials.

Thermosensitive hydrogel is a new type of biomedical material that can change the state of sol/gel in response to changes in ambient temperature. When its temperature is lower than body temperature, it is liquid, which is easy to mix with drugs uniformly; it is injected into the human target in the form of liquid After being positioned, the disease cavity can be completely filled, and then cured in situ under the action of human body temperature to form a hydrogel with a specific shape of the disease cavity and a certain supporting effect, which is less traumatic, convenient for administration, accurate in dose and has a certain degree of efficacy. Controlled drug release effect and other characteristics. Thermosensitive hydrogels have been widely used in biomedical fields such as drug delivery and tissue engineering scaffolds in recent years.

SUMMARY OF THE INVENTION

The invention provides a cannabidiol-containing injectable hydrogel for treating gout arthritis and a preparation method thereof.

Technical scheme of the present invention:

In order to solve the above problems, the present invention proposes a preparation method of a cannabidiol-containing injectable hydrogel for treating gout arthritis.

A cannabidiol injectable hydrogel comprising cannabidiol, a medically degradable material, chitosan and sodium beta-glycerophosphate; the solid content of cannabidiol in the cannabidiol injectable hydrogel is 1.2%- 1.6% wt, the solid content of medical degradable materials is 4.7%-6.1% wt, the solid content of chitosan is 24.4%-31.3% wt, and the solid content of sodium β-glycerophosphate is 62.5%-68.3% wt.

Preferably, the water content of the cannabidiol injectable hydrogel is 93.0%-94.5% wt.

Preferably, the medical degradable material is one of polylactic acid PLA, polycaprolactone PCL and polylactic acid-glycolic acid copolymer PLGA.

Preferably, the cannabidiol and the medical degradable material in the cannabidiol injectable hydrogel form dispersed microspheres, and the particle size of the microspheres ranges from 20 to 150 microns; the cannabidiol injectable water The gel is in a liquid sol state at 4-36 °C, and when the temperature exceeds 36 °C, it is in a gel state when it reaches 36-38 °C.

A preparation method of cannabidiol injectable hydrogel. After dissolving cannabidiol and medical degradable material respectively in the same organic solvent to form a solution, the two solutions are mixed and then added dropwise to an aqueous solution of chitosan , continue to stir until the organic solvent is completely volatilized, and finally add β-sodium glycerophosphate aqueous solution to disperse it uniformly.

Preferably, the organic solvent is an organic solvent immiscible with water, including dichloromethane or chloroform.

Preferably, the chitosan aqueous solution is the chitosan aqueous solution obtained by adding chitosan to a dilute acid aqueous solution, and its concentration is 2.0%wt, and the acid in the dilute acid aqueous solution is glacial acetic acid, hydrochloric acid or citric acid. A kind of, the concentration of described dilute acid aqueous solution is 0.1mol/L;

The concentration range of the β-sodium glycerophosphate aqueous solution is 28.6%-35.9% wt.

Preferably, in order to assist the dissolving of cannabidiol, the cannabidiol is dissolved in the organic solvent by ultrasound or heating, the power of the ultrasonic generator is 50W, the frequency is 40KHz, and the ultrasonic time is 1-5min; the temperature of the heating is ^30oC - ^50oC .

Preferably, under the condition of mechanical stirring at 300 rpm, the β-sodium glycerophosphate solution is added to the chitosan aqueous solution containing cannabidiol and medical degradable material, sheared at a high speed of 10,000 rpm for 20 seconds, and continued to be mechanically stirred at 300 rpm After 12-24 hours, the organic solvent is naturally volatilized, then filtered, sealed, and allowed to stand in a refrigerator at 4° C. for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.

Use of a cannabidiol injectable hydrogel for the treatment of fever, swelling and pain conditions associated with arthritis.

Beneficial effects of the present invention:

The main active ingredient in the cannabidiol injectable hydrogel of the present invention is cannabidiol, which has a sustained-release effect and is used for the treatment of symptoms such as fever, swelling, and pain caused by arthritis. The preparation method of the cannabidiol injectable hydrogel of the present invention is simple and feasible, the in vitro drug release burst is small, and the sustained release time reaches 10 days. The invention can maintain the relatively stable release of cannabidiol, increase the availability of the drug, and thus improve the medication compliance of patients.

After the cannabidiol injectable hydrogel of the present invention is injected into the joint cavity, the cannabidiol is diffused and released and the medical degradable material is degraded and released to achieve a sustained-release therapeutic effect, avoiding the sudden release of cannabidiol, prolonging the drug action time, and reducing drug injection. The number of times to reduce the pain of frequent injections.

The cannabidiol injectable hydrogel of the present invention has temperature sensitivity, can fill the joint cavity after being injected into the joint cavity, and forms an elastic gel with a certain strength under the action of body temperature, which can buffer joint stress, lubricate the joint surface, Reduce joint friction and vibration, improve joint function and other functions.

Description of drawings

Figure 1 is an optical microscope photo of the cannabidiol injectable hydrogel of Example 1 (200 times);

Figure 2 is a graph showing the cumulative release curve of the cannabidiol injectable hydrogel of Example 1 after gelation at 37 ^° C.

Detailed ways

Example 1

1. Weigh 0.10g of cannabidiol powder and add it to a stoppered conical flask containing 10 mL of dichloromethane. When the water temperature in the ultrasonic cleaner is 30°C, place the conical flask and ultrasonically vibrate for 5 minutes, stirring continuously. Until the cannabidiol is completely dissolved; weigh 0.50g of PLGA, divide it into 3 equal parts and add it to 10mL of dichloromethane and keep stirring until dissolved. Under constant stirring, the above two solutions are uniformly mixed and then filtered to obtain a cannabidiol/PLGA solution (the mass ratio of cannabidiol and PLGA is 1:5), which is sealed for later use.

2. Weigh 2.0 g of chitosan, divide it into 3 parts and add it to 100 mL of 0.1 mol/L glacial acetic acid aqueous solution, stir mechanically for 2 hours at room temperature, and filter after the chitosan is completely dissolved to obtain an aqueous solution of chitosan for use; 5.6 g of β-glycerophosphate sodium, dissolved in 10 mL of deionized water for use.

3. Preparation of cannabidiol/PLGA microspheres. Under the condition of mechanical stirring at 300 rpm, the above-mentioned cannabidiol/PLGA solution was dropped into the chitosan aqueous solution, and the mixed solution was sheared at a high speed of 10,000 rpm for 20 seconds, and then mechanically stirred at 300 rpm for 12 hours to gradually volatilize the organic solvent.

4. Preparation of cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, the above-mentioned β-sodium glycerophosphate aqueous solution is slowly added to the above-mentioned mixed solution, and after continuous mechanical stirring for 2 hours, it is passed through a microporous filter membrane, sealed and placed in a 4 ^o C refrigerator for 2 hours to defoaming, namely Cannabidiol injectable hydrogels are available.

Example 2

1. Weigh 0.10g of cannabidiol powder and add it to a 10mL dichloromethane conical flask with a stopper. When the water temperature in the ultrasonic cleaner is 40°C, place the conical flask and ultrasonically vibrate for 3 minutes, and stir continuously until the cannabis The diphenol was completely dissolved; 0.5 g of PLA was weighed, divided into 3 equal parts, and added to 10 mL of dichloromethane with constant stirring until dissolved. Under constant stirring, the above two solutions were mixed uniformly and then filtered to obtain a cannabidiol/PLA solution (the mass ratio of cannabidiol and PLA was 1:5), which was sealed for later use.

2. Weigh 2.0 g of chitosan, divide it into 3 parts and add it to 100 mL of 0.1 mol/L glacial acetic acid aqueous solution, stir mechanically for 2 hours at room temperature, and filter after the chitosan is completely dissolved to obtain an aqueous solution of chitosan for use; 5.6 g of β-glycerophosphate sodium, dissolved in 10 mL of deionized water for use.

3. Preparation of cannabidiol/PLA microspheres. Under the condition of mechanical stirring at 300 rpm, the above-mentioned cannabidiol/PLA solution was dropped into the chitosan aqueous solution, and the mixed solution was sheared at a high speed at 10,000 rpm for 20 seconds, and then mechanical stirring was continued at 300 rpm for 12 hours to gradually volatilize the organic solvent.

4. Preparation of cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, the above-mentioned β-sodium glycerophosphate aqueous solution is slowly added to the above-mentioned mixed solution, and after continuous mechanical stirring for 2 hours, it is passed through a microporous filter membrane, sealed and placed in a 4 ^o C refrigerator for 2 hours to defoaming, namely Cannabidiol injectable hydrogels are available.

Example 3

1. Weigh 0.10g of cannabidiol powder and add it to a 10mL dichloromethane conical flask with stopper. When the water temperature in the ultrasonic cleaner is 50°C, place the conical flask and ultrasonically vibrate for 1min, stirring continuously until the cannabis The diphenol was completely dissolved; 0.50 g of PCL was weighed, divided into 3 equal parts, and added to 10 mL of dichloromethane with constant stirring until dissolved. Under constant stirring, the above two solutions are uniformly mixed and filtered to obtain a cannabidiol/PCL solution (the mass ratio of cannabidiol and PCL is 1:5), which is sealed for use.

2. Weigh 2.0 g of chitosan, divide it into 3 parts and add it to 100 mL of 0.1 mol/L glacial acetic acid aqueous solution, stir mechanically for 2 hours at room temperature, and filter after the chitosan is completely dissolved to obtain an aqueous solution of chitosan for use; 5.6 g of β-glycerophosphate sodium, dissolved in 10 mL of deionized water for use.

3. Preparation of cannabidiol/PCL microspheres. Under the condition of mechanical stirring at 300 rpm, the above-mentioned cannabidiol/PCL solution was dropped into the chitosan aqueous solution, and the mixed solution was sheared at a high speed at 10,000 rpm for 20 seconds, and then mechanical stirring was continued at 300 rpm for 12 hours to gradually volatilize the organic solvent.

4. Preparation of cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, the above-mentioned β-sodium glycerophosphate aqueous solution is slowly added to the above-mentioned mixed solution, and after continuous mechanical stirring for 2 hours, it is passed through a microporous filter membrane, sealed and placed in a 4 ^o C refrigerator for 2 hours to defoaming, namely Cannabidiol injectable hydrogels are available.

Example 4

1. Weigh 0.10g of cannabidiol powder and add it to a stoppered conical flask containing 10 mL of dichloromethane. When the water temperature in the ultrasonic cleaner is 40°C, place the conical flask and ultrasonically vibrate for 3 minutes, stirring continuously. Until the cannabidiol is completely dissolved; weigh 0.40 g of PLGA, divide it into 3 equal parts and add it to 10 mL of dichloromethane and keep stirring until dissolved. Under constant stirring, the above two solutions are uniformly mixed and then filtered to obtain a cannabidiol/PLGA solution (the mass ratio of cannabidiol and PLGA is 1:4), which is sealed for later use.

2. Weigh 2.0 g of chitosan, divide it into 3 parts and add it to 100 mL of 0.1 mol/L hydrochloric acid aqueous solution, stir mechanically for 2 hours at room temperature, and filter after the chitosan is completely dissolved to obtain an aqueous solution of chitosan for use; -4.8 g of sodium glycerophosphate, dissolved in 10 mL of deionized water for later use.

3. Preparation of cannabidiol/PLGA microspheres. Under the condition of 300rpm mechanical stirring, the above-mentioned cannabidiol/PLGA solution was dropped into the chitosan aqueous solution, and the mixed solution was sheared at a high speed of 10000rpm for 20 seconds, and then mechanically stirred at 300rpm for 24 hours, so that the organic solvent was gradually volatilized.

4. Preparation of cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, the above-mentioned β-sodium glycerophosphate aqueous solution is slowly added to the above-mentioned mixed solution, and after continuous mechanical stirring for 2 hours, it is passed through a microporous filter membrane, sealed and placed in a 4 ^o C refrigerator for 2 hours to defoaming, namely Cannabidiol injectable hydrogels are available.

Example 5

1. Weigh 0.10g of cannabidiol powder and add it to a stoppered conical flask containing 10 mL of dichloromethane. When the water temperature in the ultrasonic cleaner is 40°C, place the conical flask and ultrasonically vibrate for 3 minutes, stirring continuously. Until the cannabidiol is completely dissolved; weigh 0.4 g of PLA, divide it into 3 equal parts, and add it to 10 mL of dichloromethane with constant stirring until dissolved. Under constant stirring, the above two solutions are mixed uniformly and then filtered to obtain a cannabidiol/PLA solution (the mass ratio of cannabidiol and PLGA is 1:5), which is sealed for later use.

2. Weigh 2.0 g of chitosan, divide it into 3 parts and add it to 100 mL of 0.1 mol/L hydrochloric acid aqueous solution, stir mechanically for 2 hours at room temperature, and filter after the chitosan is completely dissolved to obtain an aqueous solution of chitosan for use; -4.8 g of sodium glycerophosphate, dissolved in 10 mL of deionized water for later use.

3. Preparation of cannabidiol/PLA microspheres. Under the condition of mechanical stirring at 300 rpm, the above-mentioned cannabidiol/PLA solution was dropped into the chitosan aqueous solution, and the mixed solution was sheared at a high speed at 10,000 rpm for 20 seconds, and then mechanical stirring was continued at 300 rpm for 24 hours, so that the organic solvent was gradually volatilized.

4. Preparation of cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, the above-mentioned β-sodium glycerophosphate aqueous solution is slowly added to the above-mentioned mixed solution, and after mechanical stirring is continued for 2 hours, it is passed through a microporous filter membrane, sealed and placed in a 4 ^o C refrigerator for 2 hours to defoaming, namely Cannabidiol injectable hydrogels are available.

Example 6

1. Weigh 0.10g of cannabidiol powder and add it to a stoppered conical flask containing 10 mL of dichloromethane. When the water temperature in the ultrasonic cleaner is 40°C, place the conical flask and ultrasonically vibrate for 3 minutes, stirring continuously. Until the cannabidiol is completely dissolved; weigh 0.40g PCL, divide it into 3 equal parts and add it to 10mL dichloromethane and stir continuously until dissolved. Under constant stirring, the above two solutions are uniformly mixed and then filtered to obtain a cannabidiol/PCL solution (the mass ratio of cannabidiol and PCL is 1:4), which is sealed for later use.

2. Weigh 2.0 g of chitosan, divide it into 3 parts and add it to 100 mL of 0.1 mol/L glacial acetic acid aqueous solution, stir mechanically for 2 hours at room temperature, and filter after the chitosan is completely dissolved to obtain an aqueous solution of chitosan for use; 4.8 g of sodium β-glycerophosphate, dissolved in 10 mL of deionized water for later use.

3. Preparation of cannabidiol/PCL microspheres. Under the condition of mechanical stirring at 300 rpm, the above-mentioned cannabidiol/PCL solution was dropped into the chitosan aqueous solution, and the mixed solution was sheared at a high speed at 10,000 rpm for 20 seconds, and then mechanical stirring was continued at 300 rpm for 24 hours, so that the organic solvent was gradually volatilized.

4. Preparation of cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, the above-mentioned β-sodium glycerophosphate aqueous solution is slowly added to the above-mentioned mixed solution, and after continuous mechanical stirring for 2 hours, it is passed through a microporous filter membrane, sealed and placed in a 4 ^o C refrigerator for 2 hours to defoaming, namely Cannabidiol injectable hydrogels are available.

Example 7

1. Weigh 0.10g of cannabidiol powder and add it to a stoppered conical flask containing 10 mL of chloroform. When the water temperature in the ultrasonic cleaner is 50°C, place the conical flask and ultrasonically vibrate for 1min, stirring continuously. Until the cannabidiol is completely dissolved; weigh 0.3 g of PLGA, divide it into 3 equal parts and add it to 10 mL of chloroform, stirring continuously until dissolved. Under constant stirring, the above two solutions are uniformly mixed and then filtered to obtain a cannabidiol/PLGA solution (the mass ratio of cannabidiol and PLGA is 1:3), which is sealed for later use.

2. Weigh 2.0 g of chitosan, divide it into 3 parts and add it to 100 mL of 0.1 mol/L citric acid aqueous solution, stir mechanically for 2 hours at room temperature, and filter after the chitosan is completely dissolved to obtain an aqueous chitosan solution for later use; 4.0 g of sodium β-glycerophosphate, dissolved in 10 mL of deionized water for later use.

3. Preparation of cannabidiol/PLGA microspheres. Under the condition of 300rpm mechanical stirring, the above-mentioned cannabidiol/PLGA solution was dropped into the chitosan aqueous solution, and the mixed solution was sheared at a high speed of 10000rpm for 20 seconds, and then mechanically stirred at 300rpm for 24 hours, so that the organic solvent was gradually volatilized.

4. Preparation of cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, the above-mentioned β-sodium glycerophosphate aqueous solution is slowly added to the above-mentioned mixed solution, and after continuous mechanical stirring for 2 hours, it is passed through a microporous filter membrane, sealed and placed in a 4 ^o C refrigerator for 2 hours to defoaming, namely Cannabidiol injectable hydrogels are available.

Example 8

1. Weigh 0.10g of cannabidiol powder and add it to a stoppered conical flask containing 10 mL of chloroform. When the water temperature in the ultrasonic cleaner is 50°C, place the conical flask and ultrasonically vibrate for 1min, stirring continuously. Until the cannabidiol is completely dissolved; weigh 0.3 g of PLA, divide it into 3 equal parts, and add it to 10 mL of chloroform with constant stirring until dissolved. Under constant stirring, the above two solutions are uniformly mixed and filtered to obtain a cannabidiol/PLA solution (the mass ratio of cannabidiol and PLA is 1:3), which is sealed for later use.

2. Weigh 2.0 g of chitosan, divide it into 3 parts and add it to 100 mL of 0.1 mol/L citric acid aqueous solution, stir mechanically for 2 hours at room temperature, and filter after the chitosan is completely dissolved to obtain an aqueous chitosan solution for later use; 4.0 g of sodium β-glycerophosphate, dissolved in 10 mL of deionized water for later use.

3. Preparation of cannabidiol/PLA microspheres. Under the condition of mechanical stirring at 300 rpm, the above-mentioned cannabidiol/PLA solution was dropped into the chitosan aqueous solution, and the mixed solution was sheared at a high speed at 10,000 rpm for 20 seconds, and then mechanical stirring was continued at 300 rpm for 24 hours, so that the organic solvent was gradually volatilized.

4. Preparation of cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, the above-mentioned β-sodium glycerophosphate aqueous solution is slowly added to the above-mentioned mixed solution, and after mechanical stirring is continued for 2 hours, it is passed through a microporous filter membrane, sealed and placed in a 4 ^o C refrigerator for 2 hours to defoaming, namely Cannabidiol injectable hydrogels are available.

Example 9

1. Weigh 0.10g of cannabidiol powder and add it to a stoppered conical flask containing 10 mL of chloroform. When the water temperature in the ultrasonic cleaner is 50°C, place the conical flask and ultrasonically vibrate for 1min, stirring continuously. Until the cannabidiol is completely dissolved; weigh 0.3 g of PCL, divide it into 3 equal parts, and add it to 10 mL of chloroform with constant stirring until dissolved. Under constant stirring, the above two solutions are uniformly mixed and then filtered to obtain a cannabidiol/PCL solution (the mass ratio of cannabidiol and PCL is 1:3), which is sealed for later use.

2. Weigh 2.0 g of chitosan, divide it into 3 parts and add it to 100 mL of 0.1 mol/L citric acid aqueous solution, stir mechanically for 2 hours at room temperature, and filter after the chitosan is completely dissolved to obtain an aqueous chitosan solution for later use; 4.0 g of sodium β-glycerophosphate, dissolved in 10 mL of deionized water for later use.

3. Preparation of cannabidiol/PCL microspheres. Under the condition of mechanical stirring at 300 rpm, the above cannabidiol/PCL solution was dropped into the chitosan aqueous solution, and the mixed solution was sheared at a high speed of 10,000 rpm for 20 seconds, and then mechanical stirring was continued at 300 rpm for 24 hours, so that the organic solvent was gradually volatilized.

4. Preparation of cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, the above-mentioned β-sodium glycerophosphate aqueous solution is slowly added to the above-mentioned mixed solution, and after continuous mechanical stirring for 2 hours, it is passed through a microporous filter membrane, sealed and placed in a 4 ^o C refrigerator for 2 hours to defoaming, namely Cannabidiol injectable hydrogels are available.

Experimental results of Example 1

1. Microstructure of cannabidiol injectable hydrogels

The microscopic morphology of the cannabidiol injectable hydrogel was preliminarily observed with an optical microscope. Pipette a small amount of hydrogel onto a glass slide with a plastic tip dropper, cover it with a cover glass, adjust the microscope to observe and take pictures, as shown in Figure 1, with a magnification of 200 times. It can be seen from the photos that there are spherical particle structures with uneven particle size distribution in the gel within the visual field.

2. Determination of gelation time

The sol-gel phase transition gelation time of cannabidiol injectable hydrogels was determined using the test tube inversion method. Take out ^2mL of cannabidiol injectable hydrogel from the refrigerator at 4oC and place it in a 10mL test tube, put it in a constant temperature water bath at ^20oC for 5 minutes, and place the test tube in a constant temperature water bath at ^37oC to start timing, Tilt the test tube by 45 ^° every 10s, observe whether the hydrogel in the test tube is inclined with the test tube, record the time when the liquid level stops tilting as the gelation time, and obtain the cannabis by measuring the above-mentioned sample 5 times in parallel and calculating the average value. The gelation time of the diphenol injectable hydrogel was 10 minutes.

3. In vitro drug release from cannabidiol injectable hydrogels

In vitro drug release experiments of cannabidiol injectable hydrogels were determined in a degradation dissolution tester. Take five 2mL cannabidiol injectable hydrogels and place them in a dialysis bag, tie the ends tightly, and place them in a constant temperature incubator at 37 ^° C for 15 min to form stable hydrogels. Add quantitative phosphate buffer (pH 7.4)/methanol (volume ratio of ^22/78 ) as the release medium in the dissolution vessel, turn on the degradation dissolution tester, set the rotation speed to 50rpm, and set the temperature to 37oC. When the temperature is stable, put the 5 dialysis bags into the dissolution vessel respectively, take samples regularly every day, and supplement the same release medium. The content of cannabidiol in the release solution was determined by high performance liquid chromatography (HPLC) and the average value was calculated. The released mass was calculated according to the standard curve and the cumulative release curve was drawn.

The cumulative release curve of the cannabidiol injectable hydrogel after gelation at 37 ^o C is shown in Figure 2. It can be seen from Figure 2 that the drug release in the initial stage gradually increases, and the drug release detected at this stage is mainly Due to the diffusion and dissolution of unencapsulated cannabidiol on the surface or in the gel of PLGA microspheres. With the continuous degradation of PLGA, the three-dimensional network structure of the polymer molecular chain is destroyed, and the release of the drug at this stage mainly comes from the cannabidiol encapsulated inside the PLGA microspheres. It can be seen from subsequent experiments that cannabidiol can be released continuously for 10 days, and the cumulative release quality reaches 79.3%. The results of in vitro drug release experiments of cannabidiol injectable hydrogel show that the cannabidiol injectable hydrogel system does not cause sudden release of cannabidiol, and achieves a good sustained release effect.

Claims (2)

1. a cannabidiol injectable hydrogel is characterized in that, comprising cannabidiol, medical degradable material, chitosan, beta-sodium glycerophosphate and water; cannabidiol in the cannabidiol injectable hydrogel The solid content of phenol was 1.2%-1.6% wt, the solid content of medical degradable materials was 4.7%-6.1% wt, the solid content of chitosan was 24.4%-31.3% wt, and the solid content of β-glycerophosphate was 62.5%-68.3% wt; The water content of the cannabidiol injectable hydrogel is 93.0%-94.5% wt; The medical degradable material is one of polylactic acid PLA, polycaprolactone PCL and polylactic acid-glycolic acid copolymer PLGA; cannabidiol and medical degradable material in the cannabidiol injectable hydrogel form Dispersed microspheres, the particle size of the microspheres is 20-150 microns; the cannabidiol injectable hydrogel is in a liquid sol state at 4-36°C, and reaches 36-38°C when the temperature exceeds 36°C gel state after The cannabidiol injectable hydrogel is prepared by the following method: after dissolving cannabidiol and medical degradable material respectively in the same organic solvent to form a solution, mixing the two solutions, under the condition of mechanical stirring at 300rpm , drop the above cannabidiol/medical degradable material mixed solution into the chitosan aqueous solution, shear at 10000rpm for 20 seconds, continue to mechanically stir at 300rpm for 12-24 hours, slowly add the β-glycerophosphate sodium aqueous solution, continue to mechanically Stir for 2 hours until the organic solvent is completely volatilized, pass through a microporous filter membrane, seal and place it in a 4 ^o C refrigerator for 2 hours to defoam, to obtain cannabidiol injectable hydrogel; The organic solvent is selected from dichloromethane or chloroform; The chitosan aqueous solution is the chitosan aqueous solution obtained by adding chitosan to the dilute acid aqueous solution, and its concentration is 2.0%wt, and the acid in the dilute acid aqueous solution is one of glacial acetic acid, hydrochloric acid or citric acid , the concentration of the dilute acid aqueous solution is 0.1mol/L; the concentration range of the β-sodium glycerophosphate aqueous solution is 28.6%-35.9% wt; In order to assist the dissolving of cannabidiol, the cannabidiol is dissolved in the organic solvent by ultrasound or heating, the power of the ultrasonic generator is 50W, the frequency is 40KHz, and the ultrasonic time is 1-5min; the temperature of the heating is 30 ^o C ^-50oC . 2. A cannabidiol injectable hydrogel as claimed in claim 1 is used in the preparation of a medicine for treating fever, swelling and pain caused by arthritis.

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