CN113197842B - Cannabidiol injectable hydrogel, preparation method and application thereof - Google Patents
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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
Technical Field
The invention relates to the technical field of biological medicines, in particular to a cannabidiol CBD-containing medicine capable of being injected into hydrogel and used for treating gout and arthritis and a preparation method thereof.
Background
In recent years, with the improvement of living standard and the adjustment of dietary structure, the intake of high-sugar, high-protein, high-fat and high-purine diets is increased, so that the incidence rate of gout is increased year by year, and because gout is a chronic disease and needs to be taken for a long time, the normal work of people is seriously influenced.
In the prior art, gout is mainly prevented and treated by combining dietotherapy with oral medicines. The gout is prevented mainly by strictly controlling the eating of high-purine diets such as bean products and high-protein diets, strictly abstaining from alcohol, drinking more, promoting urination and preventing uric acid deposition, and the diet is mainly light, low-fat, low-sugar and crude fiber diet at ordinary times. Acute onset arthritis is treated primarily with oral anti-inflammatory, hormonal drug control, while chronic gouty arthritis is treated with attention to both hyperuricemia and tophus deposition. When the gouty arthritis is treated, intolerable side effects of the whole body medicine easily appear when most patients take the medicine for a long time, so that many patients stop the medicine treatment because of intolerability. In addition, the clinically proposed intra-articular injection administration is to get rid of adverse reactions caused by a systemic administration mode, but the rapid clearance of the drug from the articular cavity shortens the local action time of the drug, and frequent intra-articular injection increases the probability of intra-articular infection.
Cannabidiol (CBD) is a non-addictive component extracted from cannabis plant, has pharmacological effects of anti-spasm, anti-anxiety, anti-inflammatory, etc., and is a nontoxic phenol substance with high added value for use in medicine, cosmetics, and health food. Developed countries such as Israel, America, and UK have been developed to develop various products such as specific medicines, beverages, and cosmetics. Cannabidiol is insoluble in water and is easily metabolized, destroyed or eliminated by the liver, and oral administration of cannabidiol results in greatly reduced bioavailability.
In recent years, medical degradable materials have been widely used clinically, and these materials mainly include polylactic acid (PLA), Polycaprolactone (PCL), Polyglycolide (PGA), polylactic-co-glycolic acid (PLGA), PTMC (polytrimethylene carbonate), and the like. The polylactic-co-glycolic acid (PLGA) is a biodegradable material approved by the Food and Drug Administration (FDA) for human body, has good biocompatibility, can be slowly degraded in vivo, and the final product is carbon dioxide and water.
The temperature-sensitive hydrogel is a novel biomedical material which can change the sol/gel state in response to the change of environmental temperature, is in a liquid state when the temperature is lower than the body temperature, and is easy to be uniformly mixed with medicines; the hydrogel can be completely filled in a diseased cavity after being injected to a target position of a human body in a liquid form, and then is cured in situ under the action of the body temperature to form hydrogel which has a specific shape of the diseased cavity and a certain supporting effect, and has the characteristics of small wound, convenient administration, accurate dosage, certain controlled release effect of the drug and the like. Temperature-sensitive hydrogels have been widely used in biomedical fields such as drug delivery, tissue engineering scaffolds, etc.
Inner appearance of the invention
The invention provides a cannabidiol-containing injectable hydrogel for treating gout and arthritis and a preparation method thereof.
The technical scheme of the invention is as follows:
in order to solve the problems, the invention provides a preparation method of a cannabidiol-containing injectable hydrogel for treating gout and arthritis.
A cannabidiol injectable hydrogel comprises cannabidiol, medical degradable material, chitosan and beta-sodium glycerophosphate; the cannabidiol injectable hydrogel comprises 1.2-1.6 wt% of cannabidiol, 4.7-6.1 wt% of medical degradable material, 24.4-31.3 wt% of chitosan and 62.5-68.3 wt% of sodium beta-glycerophosphate.
Preferably, the cannabidiol injectable hydrogel has a water content of 93.0% to 94.5% by weight.
Preferably, the medical degradable material is one of polylactic acid (PLA), Polycaprolactone (PCL) and polylactic-co-glycolic acid (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 microns to 150 microns; the cannabidiol injectable hydrogel is in a liquid sol state at 4-36 ℃, and is in a gel state when the temperature exceeds 36 ℃ and reaches 36-38 ℃.
A cannabidiol injectable hydrogel is prepared by dissolving cannabidiol and medical degradable material in the same organic solvent to form solution, mixing the two solutions, adding dropwise into chitosan water solution, stirring until the organic solvent is completely volatilized, and adding beta-sodium glycerophosphate water solution to disperse uniformly.
Preferably, the organic solvent is an organic solvent immiscible with water, including dichloromethane or trichloromethane.
Preferably, the chitosan aqueous solution is obtained by adding chitosan into a dilute acid aqueous solution, the concentration of the chitosan aqueous solution is 2.0 wt%, the acid in the dilute acid aqueous solution is one of glacial acetic acid, hydrochloric acid or citric acid, and the concentration of the dilute acid aqueous solution is 0.1 mol/L;
the concentration range of the beta-sodium glycerophosphate aqueous solution is 28.6-35.9 wt%.
Preferably, in order to assist the dissolution of the cannabidiol, the cannabidiol is dissolved in the organic solvent by ultrasonic treatment or heating, the power of an ultrasonic generator is 50W, the frequency is 40KHz, and the ultrasonic treatment time is 1-5 min; the heating temperature is 30 deg.C o C-50 o C。
Preferably, under the condition of mechanical stirring at 300rpm, adding a beta-sodium glycerophosphate solution into the chitosan aqueous solution containing the cannabidiol and the medical degradable material, shearing at 10000rpm for 20 seconds at a high speed, continuously mechanically stirring at 300rpm for 12-24 hours to naturally volatilize the organic solvent, filtering, sealing, standing in a refrigerator at 4 ℃ for 2 hours to defoam, and thus obtaining the cannabidiol injectable hydrogel.
Use of cannabidiol injectable hydrogel for the treatment of fever, swelling and pain due to arthritis.
The invention has the beneficial effects that:
the cannabidiol serving as a main active ingredient in the cannabidiol injectable hydrogel has a slow-release effect, and is used for treating symptoms such as fever, swelling and pain caused by arthritis. The preparation method of the cannabidiol injectable hydrogel is simple and easy to implement, 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 the cannabidiol and increase the utilization rate of the medicament, thereby improving the medication compliance of patients.
The cannabidiol injectable hydrogel disclosed by the invention achieves a sustained-release treatment effect due to diffusion release of cannabidiol and degradation release of medical degradable materials after being injected into a joint cavity, avoids sudden release of cannabidiol, prolongs the drug action time, reduces the drug injection frequency and reduces the pain of patients caused by frequent injection.
The cannabidiol injectable hydrogel disclosed by the invention has temperature sensitivity, can be used for filling joint cavities after being injected into the joint cavities, can form elastic gel with certain strength under the action of body temperature, and can play roles in buffering joint stress, lubricating joint surfaces, relieving joint friction and vibration, improving joint movement functions and the like.
Drawings
FIG. 1 is an optical microscopic photograph (200X) of an injectable hydrogel of cannabidiol of example 1;
FIG. 2 shows an injectable hydrogel of cannabidiol at 37 of example 1 o C, cumulative release curve chart after gelling.
Detailed Description
Example 1
1. Weighing 0.10g of cannabidiol powder, adding into a conical flask with a plug containing 10mL of dichloromethane, placing the conical flask into an ultrasonic cleaner at the temperature of 30 ℃, ultrasonically vibrating for 5min, and continuously stirring until the cannabidiol is completely dissolved; 0.50g PLGA was weighed out and added in 3 portions on average to 10mL dichloromethane with constant stirring until dissolved. Mixing the two solutions uniformly under continuous stirring, filtering to obtain cannabidiol/PLGA solution (the weight ratio of cannabidiol to PLGA is 1: 5), and sealing for later use.
2. Weighing 2.0g of chitosan, averagely dividing into 3 parts, adding the 3 parts into 100mL of 0.1mol/L glacial acetic acid aqueous solution, mechanically stirring for 2 hours at room temperature, and filtering after the chitosan is completely dissolved to obtain chitosan aqueous solution for later use; 5.6g of beta-sodium glycerophosphate is weighed and dissolved in 10mL of deionized water for later use.
3. And preparing the cannabidiol/PLGA microspheres. Dropping the cannabidiol/PLGA solution into the chitosan aqueous solution under the condition of mechanical stirring at 300rpm, shearing the mixed solution at 10000rpm for 20 seconds at high speed, and continuing to mechanically stir at 300rpm for 12 hours to gradually volatilize the organic solvent.
4. Preparing cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, slowly adding the beta-sodium glycerophosphate aqueous solution into the mixed solution, continuously mechanically stirring for 2 hours, filtering through a microporous filter membrane, sealing and placing 4 o And standing in a refrigerator for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.
Example 2
1. Weighing 0.10g of cannabidiol powder, adding into a conical flask with a plug and 10mL of dichloromethane, placing the conical flask into an ultrasonic cleaner at 40 ℃ and ultrasonically vibrating for 3min, and continuously stirring until the cannabidiol is completely dissolved; 0.5g of PLA was weighed out and added in 3 portions on average to 10mL of methylene chloride with stirring until dissolved. Mixing the above two solutions under stirring, filtering to obtain cannabidiol/PLA solution (weight ratio of cannabidiol to PLA is 1: 5), and sealing for use.
2. Weighing 2.0g of chitosan, averagely dividing into 3 parts, adding the 3 parts into 100mL of 0.1mol/L glacial acetic acid aqueous solution, mechanically stirring for 2 hours at room temperature, and filtering after the chitosan is completely dissolved to obtain chitosan aqueous solution for later use; 5.6g of beta-sodium glycerophosphate is weighed and dissolved in 10mL of deionized water for later use.
3. Preparing cannabidiol/PLA microspheres. Under the condition of mechanical stirring at 300rpm, the cannabidiol/PLA solution is dripped into the chitosan aqueous solution, the mixed solution is sheared at 10000rpm for 20 seconds at high speed, and then the mechanical stirring is continued at 300rpm for 12 hours, so that the organic solvent is gradually volatilized.
4. Preparing cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, slowly adding the beta-sodium glycerophosphate aqueous solution into the mixed solution, continuously mechanically stirring for 2 hours, and passing through microporesFilter membrane, seal-in 4 o And C, standing in a refrigerator for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.
Example 3
1. Weighing 0.10g of cannabidiol powder, adding into a conical flask with a plug and 10mL of dichloromethane, placing the conical flask into an ultrasonic cleaner at 50 ℃, ultrasonically vibrating for 1min, and continuously stirring until the cannabidiol is completely dissolved; 0.50g of PCL is weighed out and added in 3 portions on average to 10mL of dichloromethane with continuous stirring until dissolved. Mixing the above two solutions under stirring, filtering to obtain cannabidiol/PCL solution (weight ratio of cannabidiol to PCL is 1: 5), and sealing.
2. Weighing 2.0g of chitosan, averagely dividing into 3 parts, adding the 3 parts into 100mL of 0.1mol/L glacial acetic acid aqueous solution, mechanically stirring for 2 hours at room temperature, and filtering after the chitosan is completely dissolved to obtain chitosan aqueous solution for later use; 5.6g of beta-sodium glycerophosphate is weighed and dissolved in 10mL of deionized water for later use.
3. Preparing cannabidiol/PCL microspheres. Under the condition of mechanical stirring at 300rpm, the cannabidiol/PCL solution is dripped into a chitosan water solution, the mixed solution is sheared at 10000rpm for 20 seconds at high speed, and then the mechanical stirring is continued at 300rpm for 12 hours, so that the organic solvent is gradually volatilized.
4. Preparing cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, slowly adding the beta-sodium glycerophosphate aqueous solution into the mixed solution, continuously mechanically stirring for 2 hours, filtering through a microporous filter membrane, sealing and placing 4 o And standing in a refrigerator for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.
Example 4
1. Weighing 0.10g of cannabidiol powder, adding into a conical flask with a plug containing 10mL of dichloromethane, placing the conical flask into an ultrasonic cleaner at 40 ℃ and ultrasonically vibrating for 3min, and continuously stirring until the cannabidiol is completely dissolved; 0.40g PLGA was weighed out and added in 3 portions on average to 10mL dichloromethane with constant stirring until dissolved. Mixing the two solutions uniformly under continuous stirring, filtering to obtain cannabidiol/PLGA solution (the weight ratio of cannabidiol to PLGA is 1: 4), and sealing for later use.
2. Weighing 2.0g of chitosan, averagely dividing into 3 parts, adding the 3 parts into 100mL of 0.1mol/L hydrochloric acid aqueous solution, mechanically stirring for 2 hours at room temperature, and filtering after the chitosan is completely dissolved to obtain chitosan aqueous solution for later use; weighing 4.8g of beta-sodium glycerophosphate and dissolving in 10mL of deionized water for later use.
3. Preparing cannabidiol/PLGA microspheres. Dropping the cannabidiol/PLGA solution into the chitosan aqueous solution under the condition of mechanical stirring at 300rpm, shearing the mixed solution at 10000rpm for 20 seconds at high speed, and continuing to mechanically stir at 300rpm for 24 hours to gradually volatilize the organic solvent.
4. Preparing cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, slowly adding the beta-sodium glycerophosphate aqueous solution into the mixed solution, continuously mechanically stirring for 2 hours, filtering through a microporous filter membrane, sealing and placing 4 o And standing in a refrigerator for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.
Example 5
1. Weighing 0.10g of cannabidiol powder, adding into a conical flask with a plug containing 10mL of dichloromethane, placing the conical flask into an ultrasonic cleaner at 40 ℃ and ultrasonically vibrating for 3min, and continuously stirring until the cannabidiol is completely dissolved; 0.4g of PLA was weighed out and added in 3 portions on average to 10mL of methylene chloride with stirring until dissolved. Mixing the two solutions uniformly under continuous stirring, filtering to obtain cannabidiol/PLA solution (weight ratio of cannabidiol to PLGA is 1: 5), and sealing for use.
2. Weighing 2.0g of chitosan, averagely dividing into 3 parts, adding the 3 parts into 100mL of 0.1mol/L hydrochloric acid aqueous solution, mechanically stirring for 2 hours at room temperature, and filtering after the chitosan is completely dissolved to obtain chitosan aqueous solution for later use; 4.8g of sodium beta-glycerophosphate is weighed and dissolved in 10mL of deionized water for later use.
3. Preparing cannabidiol/PLA microspheres. Under the condition of mechanical stirring at 300rpm, the cannabidiol/PLA solution is dripped into the chitosan aqueous solution, the mixed solution is sheared at 10000rpm for 20 seconds at high speed, and then the mechanical stirring is continued at 300rpm for 24 hours, so that the organic solvent is gradually volatilized.
4. Preparing cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, slowly adding the beta-sodium glycerophosphate aqueous solution into the mixed solution, continuously mechanically stirring for 2 hours, filtering through a microporous filter membrane, sealing and placing 4 o And standing in a refrigerator for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.
Example 6
1. Weighing 0.10g of cannabidiol powder, adding into a conical flask with a plug containing 10mL of dichloromethane, placing the conical flask into an ultrasonic cleaner at 40 ℃ and ultrasonically vibrating for 3min, and continuously stirring until the cannabidiol is completely dissolved; 0.40g of PCL was weighed out and added to 10mL of dichloromethane in 3 portions on average with stirring until dissolved. Mixing the above two solutions under stirring, filtering to obtain cannabidiol/PCL solution (weight ratio of cannabidiol to PCL is 1: 4), and sealing.
2. Weighing 2.0g of chitosan, averagely dividing into 3 parts, adding the 3 parts into 100mL of 0.1mol/L glacial acetic acid aqueous solution, mechanically stirring for 2 hours at room temperature, and filtering after the chitosan is completely dissolved to obtain chitosan aqueous solution for later use; weighing 4.8g of beta-sodium glycerophosphate and dissolving in 10mL of deionized water for later use.
3. Preparing cannabidiol/PCL microspheres. Under the condition of mechanical stirring at 300rpm, the cannabidiol/PCL solution is dripped into the chitosan water solution, the mixed solution is sheared at 10000rpm for 20 seconds at high speed, and then the mechanical stirring is continued at 300rpm for 24 hours, so that the organic solvent is gradually volatilized.
4. Preparing cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, slowly adding the beta-sodium glycero-phosphate aqueous solution into the mixed solution, continuously mechanically stirring for 2 hours, filtering by a microporous filter membrane, sealing and placing 4 o And C, standing in a refrigerator for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.
Example 7
1. Weighing 0.10g cannabidiol powder, adding into a conical flask with a plug containing 10mL chloroform, placing the conical flask in an ultrasonic cleaner at 50 deg.C, and ultrasonically vibrating for 1min while stirring until cannabidiol is completely dissolved; 0.3g PLGA was weighed out and added to 10mL chloroform in 3 portions on average with constant stirring until dissolved. Mixing the two solutions uniformly under continuous stirring, filtering to obtain cannabidiol/PLGA solution (the weight ratio of cannabidiol to PLGA is 1: 3), and sealing for later use.
2. Weighing 2.0g of chitosan, averagely dividing into 3 parts, adding the 3 parts into 100mL of 0.1mol/L citric acid aqueous solution, mechanically stirring for 2 hours at room temperature, and filtering after the chitosan is completely dissolved to obtain chitosan aqueous solution for later use; weighing 4.0g of beta-sodium glycerophosphate and dissolving in 10mL of deionized water for later use.
3. And preparing the cannabidiol/PLGA microspheres. Dropping the cannabidiol/PLGA solution into the chitosan aqueous solution under the mechanical stirring condition of 300rpm, shearing the mixed solution at the high speed of 10000rpm for 20 seconds, and continuing to mechanically stir at 300rpm for 24 hours to gradually volatilize the organic solvent.
4. Preparing cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, slowly adding the beta-sodium glycerophosphate aqueous solution into the mixed solution, continuously mechanically stirring for 2 hours, filtering through a microporous filter membrane, sealing and placing 4 o And standing in a refrigerator for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.
Example 8
1. Weighing 0.10g cannabidiol powder, adding into a conical flask with a plug containing 10mL chloroform, placing the conical flask in an ultrasonic cleaner at 50 deg.C, and ultrasonically vibrating for 1min while stirring until cannabidiol is completely dissolved; 0.3g of PLA was weighed out and added to 10mL of chloroform in 3 portions on average with stirring until dissolved. Mixing the above two solutions under stirring, filtering to obtain cannabidiol/PLA solution (weight ratio of cannabidiol to PLA is 1: 3), and sealing for use.
2. Weighing 2.0g of chitosan, averagely dividing into 3 parts, adding the 3 parts into 100mL of 0.1mol/L citric acid aqueous solution, mechanically stirring for 2 hours at room temperature, and filtering after the chitosan is completely dissolved to obtain chitosan aqueous solution for later use; 4.0g of sodium beta-glycerophosphate is weighed and dissolved in 10mL of deionized water for later use.
3. Preparing cannabidiol/PLA microspheres. Under the condition of mechanical stirring at 300rpm, the cannabidiol/PLA solution is dripped into the chitosan aqueous solution, the mixed solution is sheared at 10000rpm for 20 seconds at high speed, and then the mechanical stirring is continued at 300rpm for 24 hours, so that the organic solvent is gradually volatilized.
4. Preparing cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, slowly adding the beta-sodium glycerophosphate aqueous solution into the mixed solution, continuously mechanically stirring for 2 hours, filtering through a microporous filter membrane, sealing and placing 4 o And C, standing in a refrigerator for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.
Example 9
1. Weighing 0.10g of cannabidiol powder, adding into a conical flask with a plug containing 10mL of chloroform, placing the conical flask in an ultrasonic cleaner at 50 ℃, ultrasonically vibrating for 1min, and continuously stirring until the cannabidiol is completely dissolved; 0.3g of PCL is weighed out and added into 10mL of chloroform in 3 portions on average with continuous stirring until dissolved. Mixing the two solutions under stirring, filtering to obtain cannabidiol/PCL solution (weight ratio of cannabidiol to PCL is 1: 3), and sealing.
2. Weighing 2.0g of chitosan, averagely dividing into 3 parts, adding the 3 parts into 100mL of 0.1mol/L citric acid aqueous solution, mechanically stirring for 2 hours at room temperature, and filtering after the chitosan is completely dissolved to obtain chitosan aqueous solution for later use; weighing 4.0g of beta-sodium glycerophosphate and dissolving in 10mL of deionized water for later use.
3. Preparing cannabidiol/PCL microspheres. Under the condition of mechanical stirring at 300rpm, the cannabidiol/PCL solution is dripped into a chitosan water solution, the mixed solution is sheared at 10000rpm for 20 seconds at high speed, and then the mechanical stirring is continued at 300rpm for 24 hours, so that the organic solvent is gradually volatilized.
4. Preparing cannabidiol injectable hydrogel. After the organic solvent is completely volatilized, slowly adding the beta-sodium glycerophosphate aqueous solution into the mixed solution, continuously mechanically stirring for 2 hours, filtering through a microporous filter membrane, sealing and placing 4 o And standing in a refrigerator for 2 hours for defoaming to obtain the cannabidiol injectable hydrogel.
Experimental results of example 1
1. Microstructure of cannabidiol injectable hydrogel
The microscopic appearance of the cannabidiol injectable hydrogel is preliminarily observed by adopting an optical microscope. A small amount of hydrogel is sucked by a rubber head dropper and smeared on a glass slide, a cover glass is covered, a microscope is adjusted to observe and take a picture, the picture is shown in figure 1, and the magnification is 200 times. As can be seen from the photographs, the gel in the field of view has a spherical microparticle structure with a non-uniform particle size distribution.
2. Measurement of gelation time
The sol-gel phase transition gelation time of cannabidiol injectable hydrogel is determined by tube inversion method. From 4 o C refrigerator 2mL cannabidiol injectable hydrogel was removed and placed in 10mL test tube and 20 mL test tube o C after stabilizing in thermostatic waterbath for 5min, placing the test tube in 37% o C starting timing in the constant temperature water bath, and inclining the test tube 45 every 10s o The gelation time of the cannabidiol injectable hydrogel was 10 minutes, which was obtained by observing whether the hydrogel in the test tube was tilted with the test tube, taking the time when the liquid surface stopped tilting as the gelation time, measuring the above samples in parallel 5 times, and calculating the average value.
3. In vitro drug delivery of cannabidiol injectable hydrogels
The cannabidiol injectable hydrogel in-vitro drug release experiment is measured in a degradation dissolution tester. Placing 5 parts of cannabidiol injectable hydrogel 2mL each in a dialysis bag, fastening two ends of the hydrogel, and placing the hydrogel into a bag 37 o And C, standing in a constant temperature incubator for 15min to form stable hydrogel. Adding a quantitative phosphate buffer solution (pH 7.4)/methanol (volume ratio of 22/78) as release medium into the dissolution cup, starting a degradation dissolution tester, setting the rotation speed at 50rpm and the temperature at 37 o C. When the temperature is stable, 5 dialysis bags are respectively placed into the dissolution cups, the samples are taken at regular time every day, and the same release medium is supplemented. Determining cannabidiol content in the released solution by High Performance Liquid Chromatography (HPLC) and calculating average value. The release mass was calculated from the standard curve and a cumulative release curve was plotted.
The cannabidiol injectable hydrogel is 37 o The cumulative release curve after C gelling is shown in FIG. 2. it can be seen from FIG. 2 that the drug release amount gradually increases in the initial stage, and the drug release detected in this stage is mainly due to the diffusion dissolution of unencapsulated cannabidiol on the surface of PLGA microspheres or in the gel. With the continuous degradation of PLGA in the test, the three-dimensional network structure of the polymer molecular chain is destroyed, and the release of the drug at this stage mainly comes from cannabidiol encapsulated in the PLGA microspheres. Subsequent experiments show that the cannabidiol can be continuously released for 10 days, and the accumulated release mass reaches 79.3%. The results of in vitro drug release experiments of the cannabidiol injectable hydrogel show that the cannabidiol injectable hydrogel system does not cause the burst release of cannabidiol and achieves better sustained release effect.
Claims (2)
1. The cannabidiol injectable hydrogel is characterized by comprising cannabidiol, a medical degradable material, chitosan, beta-sodium glycerophosphate and water; 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 beta-sodium glycerophosphate is 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-glycolic acid copolymer (PLGA); the cannabidiol and the medical degradable material in the cannabidiol injectable hydrogel form dispersed microspheres, and the particle size range of the microspheres is 20-150 micrometers; the cannabidiol injectable hydrogel is in a liquid sol state at 4-36 ℃, and is in a gel state when the temperature exceeds 36 ℃ and reaches 36-38 ℃;
the cannabidiol injectable hydrogel is prepared by the following method: dissolving cannabidiol and medical degradable material in the same organic solvent to form solution, mixing the two solutions, dropping the mixture solution into chitosan aqueous solution under the condition of mechanical stirring at 300rpm, shearing at 10000rpm for 20 s, and continuing to mechanically stir at 300rpmStirring for 12-24 hr, slowly adding water solution of beta-sodium glycerophosphate, mechanically stirring for 2 hr until the organic solvent is completely volatilized, filtering with microporous filter membrane, sealing, and adding 4 o Standing in a refrigerator for 2 hours for defoaming to obtain cannabidiol injectable hydrogel;
the organic solvent is selected from dichloromethane or trichloromethane;
the chitosan aqueous solution is obtained by adding chitosan into a dilute acid aqueous solution, the concentration of the chitosan aqueous solution is 2.0% wt, the acid in the dilute acid aqueous solution is one of glacial acetic acid, hydrochloric acid or citric acid, and the concentration of the dilute acid aqueous solution is 0.1 mol/L; the concentration range of the beta-sodium glycerophosphate aqueous solution is 28.6-35.9 wt%;
dissolving cannabidiol in organic solvent by ultrasonic wave or heating, wherein the power of ultrasonic generator is 50W, frequency is 40KHz, and ultrasonic time is 1-5 min; the heating temperature is 30 deg.C o C-50 o C。
2. A cannabidiol injectable hydrogel as claimed in claim 1 for use in the manufacture of a medicament for the treatment of fever, swelling and pain conditions associated with arthritis.
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