CN113679660A - Slow-release drug carrier and preparation method and application thereof - Google Patents
Slow-release drug carrier and preparation method and application thereof Download PDFInfo
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A61P35/00—Antineoplastic agents
Abstract
The invention provides a slow-release drug carrier, which is prepared from the following raw materials: graphene oxide, natural polysaccharide, genipin, glycolic acid, an organic solvent, polyvinyl alcohol and water. According to the slow-release drug carrier and the preparation method thereof provided by the invention, the used main raw materials are wide in source, the polysaccharide with good biocompatibility and biodegradability and the graphene oxide with a multifunctional group structure are crosslinked, and a solid microsphere structure is further formed under the reaction of glycolic acid and polyvinyl alcohol, so that the prepared slow-release drug carrier microsphere has good mechanical property, is suitable for being used as a drug-carrying gel, can enable drugs to be slowly released within a long time, achieves the effect of slow release of the drugs, and further enables the drugs to be fully utilized.
Description
Technical Field
The invention relates to the technical field of drug carriers, in particular to a slow-release drug carrier and a preparation method and application thereof.
Background
The drug sustained-release carrier has the function of providing sustained drug delivery to the administration site (such as tumor tissue), provides convenience for administration to patients through long-term (for example, days or weeks) drug sustained release, reduces the treatment frequency, lowers the nursing cost, and reduces the side effects of the rapidly released drug on other healthy tissues of the body. In drug delivery systems, drug carriers play a critical role.
The graphene is a carbon atom layer with single atom thickness, and is a two-dimensional carbon atom crystal in a hexagonal honeycomb crystal form. It is considered as the basic structural unit of fullerene, carbon nanotube and graphite, and is very important in the physical and material science field because of its special mechanical, quantum and electrical properties. The graphene oxide is a graphene derivative, has the same structure as graphene, is connected with a large number of hydrophilic functional groups such as carboxyl, hydroxyl, carbonyl and the like on a base surface which is formed by a layer of carbon atoms and extends infinitely in a two-dimensional space, has the characteristics of good dispersibility, extremely high drug loading capacity, certain slow release characteristic, obvious improvement of drug effect and the like in a biological environment, can overcome the problems of easy agglomeration, short drug effect time and the like when a drug is used alone, and is mainly applied to the aspects of drug loading systems, biological detection, biological imaging, tumor treatment and the like in the field of biological medicine.
Disclosure of Invention
The invention aims to provide a slow-release drug carrier and a preparation method and application thereof, which are characterized in that polysaccharide with good biocompatibility and biodegradability and graphene oxide with a multifunctional group structure are crosslinked, and a solid microsphere structure is further formed under the reaction of glycolic acid and polyvinyl alcohol.
The technical scheme of the invention is realized as follows:
the invention provides a slow-release drug carrier, which is prepared from the following raw materials: graphene oxide, natural polysaccharide, genipin, glycolic acid, an organic solvent, polyvinyl alcohol and water.
As a further improvement of the invention, the drug carrier is prepared from the following raw materials in parts by weight: 1-5 parts of graphene oxide, 2-7 parts of natural polysaccharide, 1-2 parts of genipin, 2-5 parts of glycolic acid, 10-20 parts of organic solvent, 10-15 parts of polyvinyl alcohol and 300 parts of water.
As a further improvement of the invention, the drug carrier is prepared from the following raw materials in parts by weight: 2-4 parts of graphene oxide, 3-6 parts of natural polysaccharide, 1.2-1.8 parts of genipin, 3-5 parts of glycolic acid, 12-18 parts of organic solvent, 11-14 parts of polyvinyl alcohol and 250 parts of water 150.
As a further improvement of the invention, the drug carrier is prepared from the following raw materials in parts by weight: 3 parts of graphene oxide, 5 parts of natural polysaccharide, 1.6 parts of genipin, 4 parts of glycolic acid, 16 parts of organic solvent, 13 parts of polyvinyl alcohol and 200 parts of water.
As a further improvement of the invention, the natural polysaccharide is one or a mixture of several selected from chitosan, starch, cyclodextrin, maltodextrin, cellulose, lignin, hydroxymethyl cellulose and alginic acid.
As a further improvement of the invention, the organic solvent is one or a mixture of more of petroleum ether, dichloromethane, ethyl acetate, chloroform, toluene, methyl acetate and n-hexane.
The invention further provides a preparation method of the sustained-release drug carrier, which comprises the following steps:
s1, dissolving graphene oxide and natural polysaccharide in first part of water, uniformly mixing by ultrasonic waves, heating to 70-90 ℃, adding genipin, and stirring for reacting for 1-3 hours to obtain a feed liquid;
s2, dissolving the feed liquid obtained in the step S1 and glycolic acid in an organic solvent, fully dissolving and uniformly mixing to form an oil phase, and performing ultrasonic oscillation to disperse uniformly to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring at 0-10 ℃ to volatilize the organic solvent, after the organic solvent is volatilized completely, freeze-drying and solidifying the microspheres, repeatedly washing the obtained microspheres with a buffer solution, and centrifugally drying to obtain the slow-release drug carrier.
As a further improvement of the present invention, the volume ratio of the first portion of water to the second portion of water is 1: (2-5); the ultrasonic power is 1000-1500W, and the stirring speed is 500-700 r/min.
As a further improvement of the present invention, the freeze-drying conditions are: firstly, cooling to-10 ℃ for 10-20min, then continuously cooling to-25 ℃ for 10-15h, wherein the buffer solution is PBS buffer solution or HCl-Tris buffer solution, the pH value is 7.1-7.5, and the centrifugal drying condition is that after centrifugation is carried out for 10-20min at the rotating speed of 5000-7000r/min, the solid is dried to constant weight at the temperature of 50-70 ℃.
The invention further protects the application of the sustained-release drug carrier in preparing an anti-tumor drug delivery system.
The invention has the following beneficial effects: the emulsion crosslinking method has the advantages that various hydrophilic or hydrophobic medicines can be entrapped, the microsphere structure is compact, the sphere is regular, and the medicine carrying amount is ideal. The natural polysaccharide/graphene oxide microsphere prepolymer is prepared by selecting a natural cross-linking agent genipin, so that the natural polysaccharide/graphene oxide microsphere prepolymer has good biocompatibility and biodegradability, and the toxic and side effects are remarkably reduced;
according to the slow-release drug carrier and the preparation method thereof provided by the invention, the used main raw materials are wide in source, the polysaccharide with good biocompatibility and biodegradability and the graphene oxide with a multifunctional group structure are crosslinked, and a solid microsphere structure is further formed under the reaction of glycolic acid and polyvinyl alcohol, so that the prepared slow-release drug carrier microsphere has good mechanical property, is suitable for being used as a drug-carrying gel, can enable drugs to be slowly released within a long time, achieves the effect of slow release of the drugs, and further enables the drugs to be fully utilized.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a schematic diagram of sustained release drug carrier microspheres prepared in example 5 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The raw materials comprise the following components in parts by weight: 1 part of graphene oxide, 2 parts of hydroxymethyl cellulose, 1 part of genipin, 2 parts of glycolic acid, 10 parts of methyl acetate, 10 parts of polyvinyl alcohol and 100 parts of water.
The preparation method of the slow-release drug carrier comprises the following steps:
s1, dissolving graphene oxide and hydroxymethyl cellulose in first part of water, ultrasonically mixing uniformly, heating to 70 ℃, adding genipin, stirring and reacting for 1h at the stirring speed of 500r/min to obtain a feed liquid;
s2, dissolving the feed liquid obtained in the step S1 and glycolic acid in methyl acetate, fully dissolving and uniformly mixing to form an oil phase, and uniformly dispersing by ultrasonic oscillation with the ultrasonic power of 1000W to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring at 0 ℃ to volatilize methyl acetate, and freeze-drying and solidifying the microspheres after the organic solvent is volatilized completely, wherein the freeze-drying conditions are as follows: firstly, cooling to-10 ℃ for 10min, then continuously cooling to-25 ℃ for 10h, repeatedly washing the obtained microspheres with buffer solution, and centrifugally drying under the conditions that the microspheres are centrifuged at the rotating speed of 5000r/min for 10min, and then the solid is dried to constant weight at the temperature of 50 ℃ to obtain the sustained-release drug carrier.
The buffer solution is PBS buffer solution, and the pH value is 7.1;
the volume ratio of the first part of water to the second part of water is 1: 2.
example 2
The raw materials comprise the following components in parts by weight: 5 parts of graphene oxide, 7 parts of alginic acid, 2 parts of genipin, 5 parts of glycolic acid, 20 parts of n-hexane, 15 parts of polyvinyl alcohol and 300 parts of water.
The preparation method of the slow-release drug carrier comprises the following steps:
s1, dissolving graphene oxide and alginic acid in a first part of water, uniformly mixing by ultrasonic waves, heating to 90 ℃, adding genipin, stirring and reacting for 3 hours at the stirring speed of 700r/min to obtain a feed liquid;
s2, dissolving the material liquid obtained in the step S1 and glycolic acid in n-hexane, fully dissolving and uniformly mixing to form an oil phase, and uniformly dispersing by ultrasonic oscillation with the ultrasonic power of 1500W to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring and volatilizing n-hexane at 10 ℃, and freeze-drying and solidifying the microspheres after the organic solvent is volatilized completely, wherein the freeze-drying conditions are as follows: firstly, cooling to-10 ℃ for 20min, then continuously cooling to-25 ℃ for 15h, repeatedly washing the obtained microspheres with buffer solution, and centrifugally drying under the conditions that the microspheres are centrifuged at the rotating speed of 7000r/min for 20min, and then the solid is dried to constant weight at the temperature of 70 ℃ to obtain the sustained-release drug carrier.
The buffer solution is HCl-Tris buffer solution, and the pH value is 7.5;
the volume ratio of the first part of water to the second part of water is 1: 5.
example 3
The raw materials comprise the following components in parts by weight: 2 parts of graphene oxide, 3 parts of cellulose, 1.2 parts of genipin, 3 parts of glycolic acid, 12 parts of cellulose, 11 parts of polyvinyl alcohol and 150 parts of water.
The preparation method of the slow-release drug carrier comprises the following steps:
s1, dissolving graphene oxide and cellulose in first part of water, uniformly mixing by ultrasonic waves, heating to 75 ℃, adding genipin, stirring and reacting for 2 hours at the stirring speed of 550r/min to obtain a feed liquid;
s2, dissolving the feed liquid obtained in the step S1 and glycolic acid in cellulose, fully dissolving and uniformly mixing to form an oil phase, and uniformly dispersing by ultrasonic oscillation with the ultrasonic power of 1150W to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring and volatilizing cellulose at the temperature of 2 ℃, and freeze-drying and solidifying the microspheres after the organic solvent is volatilized completely, wherein the freeze-drying conditions are as follows: firstly, cooling to-10 ℃ for 12min, then continuously cooling to-25 ℃ for 11h, repeatedly washing the obtained microspheres with buffer solution, and centrifugally drying under the conditions that after centrifugation is carried out for 12min at the rotating speed of 5500r/min, the solid is dried to constant weight at the temperature of 55 ℃ to obtain the slow-release drug carrier.
The buffer solution is PBS buffer solution, and the pH value is 7.2;
the volume ratio of the first part of water to the second part of water is 1: 3.
example 4
The raw materials comprise the following components in parts by weight: 4 parts of graphene oxide, 6 parts of maltodextrin, 1.8 parts of genipin, 5 parts of glycolic acid, 18 parts of dichloromethane, 14 parts of polyvinyl alcohol and 250 parts of water.
The preparation method of the slow-release drug carrier comprises the following steps:
s1, dissolving graphene oxide and maltodextrin in first part of water, uniformly mixing by ultrasonic waves, heating to 85 ℃, adding genipin, stirring and reacting for 2 hours at the stirring speed of 650r/min to obtain a feed liquid;
s2, dissolving the feed liquid obtained in the step S1 and glycolic acid in dichloromethane, fully dissolving and uniformly mixing to form an oil phase, and uniformly dispersing by ultrasonic oscillation with the ultrasonic power of 1450W to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring at 8 ℃ to volatilize dichloromethane, and freeze-drying and solidifying the microspheres after the organic solvent is volatilized completely, wherein the freeze-drying conditions are as follows: firstly, cooling to-10 ℃ for 18min, then continuously cooling to-25 ℃ for 14h, repeatedly washing the obtained microspheres with a buffer solution, and centrifugally drying under the conditions that the microspheres are centrifuged at the rotating speed of 6500r/min for 18min, and then the solid is dried to constant weight at the temperature of 65 ℃ to obtain the slow-release drug carrier.
The buffer solution is PBS buffer solution or HCl-Tris buffer solution, and the pH value is 7.4;
the volume ratio of the first part of water to the second part of water is 1: 4.
example 5
The raw materials comprise the following components in parts by weight: 3 parts of graphene oxide, 5 parts of starch, 1.6 parts of genipin, 4 parts of glycolic acid, 16 parts of ethyl acetate, 13 parts of polyvinyl alcohol and 200 parts of water.
The preparation method of the slow-release drug carrier comprises the following steps:
s1, dissolving graphene oxide and starch in first part of water, uniformly mixing by ultrasonic waves, heating to 80 ℃, adding genipin, stirring and reacting for 2 hours at the stirring speed of 600r/min to obtain a feed liquid;
s2, dissolving the feed liquid obtained in the step S1 and glycolic acid in ethyl acetate, fully dissolving and uniformly mixing to form an oil phase, and uniformly dispersing by ultrasonic oscillation with the ultrasonic power of 1250W to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring at 5 ℃ to volatilize ethyl acetate, and freeze-drying and solidifying the microspheres after the organic solvent is volatilized completely, wherein the freeze-drying conditions are as follows: firstly, cooling to-10 ℃ for 15min, then continuously cooling to-25 ℃ for 13h, repeatedly washing the obtained microspheres with buffer solution, and centrifugally drying under the conditions that the microspheres are centrifuged at 6000r/min for 15min, and then the solid is dried to constant weight at 50-70 ℃ to obtain the slow-release drug carrier.
The buffer solution is HCl-Tris buffer solution, and the pH value is 7.3;
the volume ratio of the first part of water to the second part of water is 1: 3.
fig. 1 is a morphological diagram of the sustained-release drug carrier microsphere prepared in this example, which shows that after the processes of balling, drying, etc., the microsphere under the optical lens is uniformly and roundly dispersed, the sphericity is better, and the particle size range is narrower. The observation of an optical microscope shows that the diameter of the sustained-release drug carrier microsphere is 220-320 mu m, and the average particle diameter (265 +/-12) mu m.
Comparative example 1
Compared with example 5, no graphene oxide was added, and other conditions were not changed.
The raw materials comprise the following components in parts by weight: 8 parts of starch, 1.6 parts of genipin, 4 parts of glycolic acid, 16 parts of ethyl acetate, 13 parts of polyvinyl alcohol and 200 parts of water.
The preparation method of the slow-release drug carrier comprises the following steps:
s1, dissolving starch in first part of water, uniformly mixing by ultrasonic waves, heating to 80 ℃, adding genipin, stirring and reacting for 2 hours at the stirring speed of 600r/min to obtain a feed liquid;
s2, dissolving the feed liquid obtained in the step S1 and glycolic acid in ethyl acetate, fully dissolving and uniformly mixing to form an oil phase, and uniformly dispersing by ultrasonic oscillation with the ultrasonic power of 1250W to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring at 5 ℃ to volatilize ethyl acetate, and freeze-drying and solidifying the microspheres after the organic solvent is volatilized completely, wherein the freeze-drying conditions are as follows: firstly, cooling to-10 ℃ for 15min, then continuously cooling to-25 ℃ for 13h, repeatedly washing the obtained microspheres with buffer solution, and centrifugally drying under the conditions that the microspheres are centrifuged at 6000r/min for 15min, and then the solid is dried to constant weight at 50-70 ℃ to obtain the slow-release drug carrier.
The buffer solution is HCl-Tris buffer solution, and the pH value is 7.3;
the volume ratio of the first part of water to the second part of water is 1: 3.
comparative example 2
Compared to example 5, no starch was added, and the other conditions were unchanged.
The raw materials comprise the following components in parts by weight: 8 parts of graphene oxide, 1.6 parts of genipin, 4 parts of glycolic acid, 16 parts of ethyl acetate, 13 parts of polyvinyl alcohol and 200 parts of water.
The preparation method of the slow-release drug carrier comprises the following steps:
s1, dissolving graphene oxide in a first part of water, uniformly mixing by ultrasonic waves, heating to 80 ℃, adding genipin, stirring and reacting for 2 hours at a stirring speed of 600r/min to obtain a feed liquid;
s2, dissolving the feed liquid obtained in the step S1 and glycolic acid in ethyl acetate, fully dissolving and uniformly mixing to form an oil phase, and uniformly dispersing by ultrasonic oscillation with the ultrasonic power of 1250W to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring at 5 ℃ to volatilize ethyl acetate, and freeze-drying and solidifying the microspheres after the organic solvent is volatilized completely, wherein the freeze-drying conditions are as follows: firstly, cooling to-10 ℃ for 15min, then continuously cooling to-25 ℃ for 13h, repeatedly washing the obtained microspheres with buffer solution, and centrifugally drying under the conditions that the microspheres are centrifuged at 6000r/min for 15min, and then the solid is dried to constant weight at 50-70 ℃ to obtain the slow-release drug carrier.
The buffer solution is HCl-Tris buffer solution, and the pH value is 7.3;
the volume ratio of the first part of water to the second part of water is 1: 3.
comparative example 3
Compared with example 5, genipin was replaced with pentanediol, and other conditions were not changed.
The raw materials comprise the following components in parts by weight: 3 parts of graphene oxide, 5 parts of starch, 1.6 parts of pentanediol, 4 parts of glycolic acid, 16 parts of ethyl acetate, 13 parts of polyvinyl alcohol and 200 parts of water.
The preparation method of the slow-release drug carrier comprises the following steps:
s1, dissolving graphene oxide and starch in first part of water, ultrasonically mixing uniformly, heating to 80 ℃, adding pentanediol, stirring and reacting for 2 hours at the stirring speed of 600r/min to obtain a feed liquid;
s2, dissolving the feed liquid obtained in the step S1 and glycolic acid in ethyl acetate, fully dissolving and uniformly mixing to form an oil phase, and uniformly dispersing by ultrasonic oscillation with the ultrasonic power of 1250W to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring at 5 ℃ to volatilize ethyl acetate, and freeze-drying and solidifying the microspheres after the organic solvent is volatilized completely, wherein the freeze-drying conditions are as follows: firstly, cooling to-10 ℃ for 15min, then continuously cooling to-25 ℃ for 13h, repeatedly washing the obtained microspheres with buffer solution, and centrifugally drying under the conditions that the microspheres are centrifuged at 6000r/min for 15min, and then the solid is dried to constant weight at 50-70 ℃ to obtain the slow-release drug carrier.
The buffer solution is HCl-Tris buffer solution, and the pH value is 7.3;
the volume ratio of the first part of water to the second part of water is 1: 3.
test example 1 Performance test
The sustained-release drug carrier microspheres prepared in examples 1 to 5 of the present invention and comparative examples 1 to 3 were subjected to performance tests, and the results are shown in table 1.
Free swell capacity and time to reach 60% free swell capacity test method: 1 gram of absorbent disintegrant material can absorb grams of an aqueous solution containing 0.9% sodium chloride under a negligible load or restraining force, such as a load of about 0.01 psi, over a 10 hour period.
The sample cup consisted of a plastic cylinder with an inside diameter of 1 inch and an outside diameter of 1.25 inches. A 200 mesh metal screen with 75 micron openings was bonded to the end opening of the cylinder to form the bottom of the sample cup by heating the screen above the melting point of the plastic and pressing the plastic cylinder against the hot screen to melt the plastic and attach the screen to the plastic cylinder.
An improved gauge for determining the swelling of a sample upon absorption of saline is Mitutoyo digital Indicator, IDCSeries 543, Model 543-. The thickness gauge supplied by Mitutoyo Corporation has a spring connected to a probe within a chamber of the gauge. The spring was removed to provide a free-falling probe with a downward force of about 27 grams. In addition, the cap on top of the probe at the top of the caliper chamber was also removed to allow the probe to be connected to a suspended spring S (available from McMaster-Carr Supply Co., Chicago, IIinois, Item No.9640K41) that serves to offset or reduce the downward force of the probe to about 1 + -0.5 grams. A wire hook may be attached to the top of the probe to connect the probe to the suspended spring. An extended pointer (Mitutoyo Corporation, Part No.131279) is also provided at the bottom end of the probe so that the probe can be inserted into a sample cup.
For the measurement, 0.160 g of an absorbent disintegrant sample was placed in a sample cup. The sample was then covered with a plastic spacer disk weighing 4.4 grams and having a diameter of about 0.995 inches, which functions to prevent the sample from being disturbed during the test and to allow the load to be applied evenly to the sample. The sample cup and material sample and pad disk were then weighed to obtain their dry weights. The sample cup is placed in a petri dish on the platform and the laboratory lift is raised until the top edge of the plastic pad disk contacts the tip of the probe. The thickness gauge was zeroed. A sufficient amount of saline solution (50-100 ml) was added to the petri dish to initiate the test. The distance of the rise of the disc of the plastic pad caused by the swelling of the sample by the absorption of the saline solution was measured by a probe. This distance multiplied by the internal cross-sectional area of the sample cup is the volume of expansion of the sample caused by absorption. The amount of saline solution absorbed can be readily calculated by combining the density of the saline solution and the weight of the sample. The weight of saline solution absorbed after 10 hours, i.e. the free expansion capacity expressed in grams per gram of absorbent disintegrant. If desired, the readings from the modified gauge may be continuously input into a computer (Mitutoyo digital miniature processor DP-2DX) to make calculations and give free expansion capacity. As a cross check, the free swell capacity can also be determined by measuring the difference in weight of the sample cup before and after the test, which is the amount of solution absorbed by the sample.
The time to reach 60% free expansion capacity is readily determined by continuous monitoring of the free expansion capacity provided by the computer.
Method for determining the expansion capacity under load and the time to reach 60% expansion capacity under load: 1 gram of the absorbent disintegrant material absorbed grams of a 0.9% sodium chloride aqueous solution after 10 hours under an applied load or restraining force of about 0.3 psi. The method for determining the absorption under load value of the absorbent disintegrant was substantially the same as the method for determining the free swell capacity, except that a 100 gram weight was placed on top of the plastic pad disk, thereby applying a load of about 0.3 psi to the absorbent disintegrant which had absorbed the saline solution.
The time to reach the 60% absorbency under load value is readily determined by continuous monitoring of the absorbency under load value provided by the computer.
The free swell capacity and the time to reach 60% free swell capacity and the swell capacity under load and the time to reach 60% swell capacity of the absorbent disintegrators were measured according to the above methods.
The results are shown in Table 1.
TABLE 1
Test example 2 determination of drug Release Rate
The test samples were:
1g of the sustained-release drug carrier microspheres obtained in examples 1 to 5 and comparative examples 1 to 3 was dissolved in 10g of deionized water, 2mL of a 1.5 wt% doxorubicin solution was added thereto, the mixture was heated to 45 ℃ and sufficiently stirred to react for 1 hour, and then the mixture was filtered, and the solid was washed and dried to be used as a test sample.
And a sample of a commercially available doxorubicin slow-release drug carrier (prepared by the laboratory of Wenzhou university of medical science according to the technology of patent: 201610100355.7).
The detection method comprises the following steps:
for each test sample, 6 test tubes each having a length of 17mm and containing 10ml of a compound sodium chloride injection (ringer's solution) (second part of the chinese pharmacopoeia 2005) were prepared. The test tube was placed in a 37 ℃ thermostatic bath and was kept still all the time. Wrapping the test sample with gauze, soaking in compound sodium chloride injection solution in test tube 1, taking out the test sample at regular intervals, and sequentially soaking in the compound sodium chloride injection solution in the next test tube. The release of drug into solution is determined spectrophotometrically or by HPLC or other suitable methods.
The results are shown in Table 2.
Table 2 drug vehicle in vitro (cumulative) release test results
| Group of | 1(％/hour) | 2(％/hour) | 3(％/hour) | 4(％/hour) | 5(％/hour) |
| Example 1 | 12 | 35 | 52 | 89 | 99 |
| Example 2 | 13 | 34 | 59 | 86 | 99 |
| Example 3 | 14 | 34 | 60 | 85 | 101 |
| Example 4 | 11 | 37 | 55 | 87 | 99 |
| Example 5 | 14 | 31 | 50 | 85 | 100 |
| Comparative example 1 | 40 | 65 | 92 | 100 | 100 |
| Comparative example 2 | 36 | 52 | 87 | 101 | 101 |
| Comparative example 3 | 21 | 25 | 25 | 25 | 25 |
| Is commercially available | 45 | 72 | 99 | 100 | 100 |
As can be seen from the above table, when the sustained-release drug carrier microspheres prepared in embodiments 1 to 5 of the present invention are used for preparing an doxorubicin sustained-release drug, the drug release rate is average, and the release of all drugs can be completed within 5 hours.
The comparative examples 1 and 2 are not added with graphene oxide or natural polysaccharide respectively, the drug release rate is remarkably accelerated, and the addition of the graphene oxide or the natural polysaccharide has a synergistic effect on the slow release effect of the microsphere drug.
In comparative example 3, the release amount of adriamycin is not increased any more after reaching 25% after 2 hours by replacing the genipin with the pentanediol, because glutaraldehyde can react with the drug with amino groups to inactivate the drug, and meanwhile, the unreacted cross-linking agent is difficult to completely remove and has certain toxic and side effects on the human body, thereby limiting the application of the emulsion cross-linking method, and therefore, the genipin has better biocompatibility and drug universality by replacing the pentanediol with the genipin.
Compared with the prior art, the emulsion crosslinking method has the advantages that various hydrophilic or hydrophobic medicines can be entrapped, the microsphere structure is compact, the sphere is regular, and the medicine carrying capacity is ideal. The natural polysaccharide/graphene oxide microsphere prepolymer is prepared by selecting a natural cross-linking agent genipin, so that the natural polysaccharide/graphene oxide microsphere prepolymer has good biocompatibility and biodegradability, and the toxic and side effects are remarkably reduced;
according to the slow-release drug carrier and the preparation method thereof provided by the invention, the used main raw materials are wide in source, the polysaccharide with good biocompatibility and biodegradability and the graphene oxide with a multifunctional group structure are crosslinked, and a solid microsphere structure is further formed under the reaction of glycolic acid and polyvinyl alcohol.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The slow-release drug carrier is characterized by being prepared from the following raw materials: graphene oxide, natural polysaccharide, genipin, glycolic acid, an organic solvent, polyvinyl alcohol and water.
2. The slow-release drug carrier according to claim 1, which is prepared from the following raw materials in parts by weight: 1-5 parts of graphene oxide, 2-7 parts of natural polysaccharide, 1-2 parts of genipin, 2-5 parts of glycolic acid, 10-20 parts of organic solvent, 10-15 parts of polyvinyl alcohol and 300 parts of water.
3. The slow-release drug carrier according to claim 2, which is prepared from the following raw materials in parts by weight: 2-4 parts of graphene oxide, 3-6 parts of natural polysaccharide, 1.2-1.8 parts of genipin, 3-5 parts of glycolic acid, 12-18 parts of organic solvent, 11-14 parts of polyvinyl alcohol and 250 parts of water 150.
4. The slow-release drug carrier according to claim 3, which is prepared from the following raw materials in parts by weight: 3 parts of graphene oxide, 5 parts of natural polysaccharide, 1.6 parts of genipin, 4 parts of glycolic acid, 16 parts of organic solvent, 13 parts of polyvinyl alcohol and 200 parts of water.
5. The sustained-release drug carrier according to claim 1, wherein the natural polysaccharide is one or more selected from chitosan, starch, cyclodextrin, maltodextrin, cellulose, lignin, hydroxymethyl cellulose, and alginic acid.
6. The sustained-release drug carrier according to claim 1, wherein the organic solvent is selected from one or more of petroleum ether, dichloromethane, ethyl acetate, chloroform, toluene, methyl acetate, and n-hexane.
7. A process for the preparation of a sustained release pharmaceutical carrier according to any one of claims 1 to 6, comprising the steps of:
s1, dissolving graphene oxide and natural polysaccharide in first part of water, uniformly mixing by ultrasonic waves, heating to 70-90 ℃, adding genipin, and stirring for reacting for 1-3 hours to obtain a feed liquid;
s2, dissolving the feed liquid obtained in the step S1 and glycolic acid in an organic solvent, fully dissolving and uniformly mixing to form an oil phase, and performing ultrasonic oscillation to disperse uniformly to obtain an emulsion;
s3, dissolving polyvinyl alcohol in the second part of water, and fully dissolving to obtain a solution;
s4, injecting the emulsion obtained in the step S2 into the solution obtained in the step S3, continuously stirring at 0-10 ℃ to volatilize the organic solvent, after the organic solvent is volatilized completely, freeze-drying and solidifying the microspheres, repeatedly washing the obtained microspheres with a buffer solution, and centrifugally drying to obtain the slow-release drug carrier.
8. The method of claim 7, wherein the volume ratio of the first portion of water to the second portion of water is 1: (2-5); the ultrasonic power is 1000-1500W, and the stirring speed is 500-700 r/min.
9. The method of claim 7, wherein the freeze-drying conditions are: firstly, cooling to-10 ℃ for 10-20min, then continuously cooling to-25 ℃ for 10-15h, wherein the buffer solution is PBS buffer solution or HCl-Tris buffer solution, the pH value is 7.1-7.5, and the centrifugal drying condition is that after centrifugation is carried out for 10-20min at the rotating speed of 5000-7000r/min, the solid is dried to constant weight at the temperature of 50-70 ℃.
10. Use of a sustained release pharmaceutical carrier according to any one of claims 1 to 6 in the manufacture of a delivery system for an anti-neoplastic drug.
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