CN110882209B - Graphene transdermal drug delivery microneedle - Google Patents
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- CN110882209B CN110882209B CN201911232938.5A CN201911232938A CN110882209B CN 110882209 B CN110882209 B CN 110882209B CN 201911232938 A CN201911232938 A CN 201911232938A CN 110882209 B CN110882209 B CN 110882209B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/32—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
Abstract
The invention provides a graphene transdermal drug delivery microneedle, wherein a base material of the microneedle is a pharmaceutically used biocompatible organic high molecular polymer, a graphene material is uniformly dispersed in the organic high molecular polymer, the organic high molecular polymer is one selected from polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid, polylactic acid-glycolic acid copolymer and carboxymethyl cellulose, and the graphene material is one selected from graphene or graphene treated by a chemical method and a physical method. The graphene transdermal drug delivery microneedle has good mechanical properties, so that the microneedle can easily penetrate through the stratum corneum; the graphene transdermal drug delivery microneedle has good capability of controlling drug release, and can control the drug release in an infrared light mode; the graphene transdermal drug delivery microneedle has excellent antibacterial performance, so that the microneedle is easy to store; the preparation method of the graphene transdermal drug delivery microneedle is simple and low in cost.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a medical instrument, and particularly relates to a graphene transdermal drug delivery microneedle.
Background
The microneedle transdermal drug delivery is a novel transdermal drug delivery mode, integrates the advantages of a subcutaneous injection drug delivery mode and a transdermal patch drug delivery mode, is painless and minimally invasive, has high drug absorption efficiency, and is rapidly developed in the research of the medical field, particularly in the research of treating epidermal lesions. However, the industrial development of polymer microneedles is still in the early stage.
In terms of mechanical properties, FDA-approved auxiliary materials such as polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), Hyaluronic Acid (HA), polylactic-co-glycolic acid (PLGA), carboxymethyl cellulose (CMC) and other polysaccharides can be manufactured to form polymer microneedle structures, but the mechanical properties that can be borne by conventional heating, drying and curing methods are low (most of all needles are less than <0.1N), and research HAs been conducted on forming a glassy state from PVA through repeated freeze thawing for 3-4 times and phase transformation, so that the high mechanical properties can be borne, but the time is long, the operation is complex, and the industrial production is not facilitated.
In terms of controlling drug release, the release rate of the drug can be adjusted by adjusting the proportion of the high molecular polymer, but a higher or lower proportion of the polymer may cause increased difficulty in manufacturing, and affect the problems of formability and mechanical properties of the microneedle, and the like.
In the aspect of the sterile performance of the microneedle, a special production workshop and strict operation specifications are required according to the manufacturing requirements of the injection preparation, and the cost is high.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a graphene transdermal drug delivery microneedle.
In order to achieve the purpose, the invention adopts the technical scheme that: a base material of the microneedle is a biocompatible organic high-molecular polymer used in pharmaceutics, graphene materials are uniformly dispersed in the organic high-molecular polymer, the organic high-molecular polymer is selected from one of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), Hyaluronic Acid (HA), polylactic-co-glycolic acid (PLGA) and carboxymethyl cellulose (CMC), and the graphene materials are graphene or one of graphene processed by chemical and physical methods.
The graphene material has excellent optical performance, stability and conductivity, good dispersibility in water and good biocompatibility, is easy for mass production, and can be uniformly dispersed into a pharmaceutically used organic high molecular polymer with biocompatibility to prepare the graphene transdermal drug delivery microneedle, the dispersibility of the graphene material in the organic high molecular polymer is good, and the obtained graphene transdermal drug delivery microneedle has good performance.
Preferably, the chemically and physically treated Graphene includes Graphene oxide (Graphene oxide), Reduced Graphene oxide (Reduced Graphene oxide), Hydrogenated Graphene, Nitrogenated Graphene, and Halogenated Graphene.
Preferably, the organic high molecular polymer is polyvinylpyrrolidone.
Preferably, the graphene material is graphene oxide.
The graphene oxide transdermal drug delivery microneedle prepared by matching the graphene oxide with the polyvinylpyrrolidone has good dispersibility in the polyvinylpyrrolidone, and the obtained graphene transdermal drug delivery microneedle has good performance.
Preferably, the usage ratio of the polyvinylpyrrolidone to the graphene oxide is as follows: 600-800 parts of polyvinylpyrrolidone and 0.01-1 part of graphene oxide.
The inventor finds that when the dosage ratio of the polyvinylpyrrolidone to the graphene oxide is as follows: 600 plus 800 parts by weight of polyvinylpyrrolidone and 0.01-1 part by weight of graphene oxide, the graphene transdermal drug delivery microneedle has good mechanical properties, drug release control capability and antibacterial property.
More preferably, the usage ratio of the polyvinylpyrrolidone to the graphene oxide is as follows: 800 parts by weight of polyvinylpyrrolidone and 0.1-1 part by weight of graphene oxide.
The inventor finds that when the dosage ratio of the polyvinylpyrrolidone to the graphene oxide is as follows: when 800 parts by weight of polyvinylpyrrolidone and 0.1-1 part by weight of graphene oxide are used, the graphene transdermal drug delivery microneedle has better mechanical property, drug release control capability and antibacterial property
Preferably, the usage ratio of the polyvinylpyrrolidone to the graphene oxide is as follows: 800 parts by weight of polyvinylpyrrolidone and 0.1-0.5 part by weight of graphene oxide.
The inventor finds that when the dosage ratio of the polyvinylpyrrolidone to the graphene oxide is as follows: when 800 parts by weight of polyvinylpyrrolidone and 0.1-0.5 part by weight of graphene oxide, the graphene transdermal drug delivery microneedle has better mechanical property, drug release control capability and antibacterial property.
Preferably, the polyvinylpyrrolidone has a molecular weight of 30000.
The invention also provides a graphene transdermal drug delivery microneedle system, and a drug is loaded on any one of the graphene transdermal drug delivery microneedles.
The invention also provides a preparation method of any one of the graphene transdermal drug delivery microneedles, which comprises the following steps:
(1) uniformly dispersing an organic high molecular polymer with biocompatibility used in pharmaceutics in a solvent to obtain a dispersion system A, wherein the organic high molecular polymer is selected from one of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), Hyaluronic Acid (HA), polylactic-co-glycolic acid (PLGA) and carboxymethyl cellulose (CMC);
(2) uniformly dispersing a graphene material in the dispersion system A, and removing bubbles to obtain a dispersion system B, wherein the graphene material is one of graphene or graphene treated by a chemical or physical method;
(3) and (3) molding and baking the dispersion system B, and then demolding to obtain the graphene transdermal drug delivery microneedle.
Preferably, the solvent is water.
The organic high molecular polymer and the graphene material have good dispersibility in water, and water is selected as a solvent, so that the graphene oxide can be uniformly dispersed in the polyvinylpyrrolidone, and the graphene oxide is safe and nontoxic.
Preferably, the dispersing method in the step (1) is ultrasonic treatment at room temperature for 10-20 min.
Preferably, the baking conditions in step (3) are: baking at 60-80 deg.C for 24-36 hr.
Preferably, the concentration of the graphene oxide in the dispersion system B is 0.01-1 mg/mL.
The invention has the beneficial effects that: the graphene transdermal drug delivery microneedle has good mechanical property, so that the microneedle can easily penetrate through a stratum corneum, has good drug release control capability, and can control drug release in an infrared light mode.
Drawings
Fig. 1 is an electron micrograph of Fluorescein Isothiocyanate (FITC) -loaded microneedles according to an embodiment of the present invention.
Fig. 2 is an electron microscope image of a cross section of a microneedle according to an embodiment of the present invention.
Fig. 3 is a raman spectroscopy analysis chart of the dispersibility of graphene oxide in the microneedle according to the embodiment of the present invention.
Fig. 4(a) is a graph showing the results of mechanical property tests of microneedles according to embodiments of the present invention; (b) a graph showing the results of the transdermal drug delivery efficiency of the microneedles according to the embodiments of the present invention; (c) is a graph of the results of the antimicrobial performance of the microneedles according to embodiments of the present invention.
Fig. 5 is a graph showing the results of mechanical property tests of microneedles according to embodiments of the present invention.
FIG. 6 is a sectional view of the depth of penetration of the microneedle into the rat skin according to the embodiment of the present invention.
Fig. 7 is a graph showing the results of a mold infection experiment of microneedles in which microneedles according to an embodiment of the present invention are exposed to air.
In the figure, the concentration of Graphene Oxide (GO) represents the concentration of graphene oxide in the dispersion system B in the preparation method process in the example, Control represents the microneedle of comparative example 1, 10 μ g/ml GO represents the microneedle of example 1, 100 μ g/ml GO represents the microneedle of example 2, 500 μ g/ml GO represents the microneedle of example 3, and 1000 μ g/ml GO represents the microneedle of example 4.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
The graphene transdermal drug delivery microneedle provided by the embodiment of the invention is characterized in that a base material of the microneedle is polyvinylpyrrolidone (PVP), and Graphene Oxide (GO) is uniformly dispersed in the PVP;
wherein, the dosage proportion of the polyvinylpyrrolidone and the graphene oxide is as follows: 800 parts by weight of polyvinylpyrrolidone and 0.01 part by weight of graphene oxide;
polyvinylpyrrolidone has a molecular weight of 30000, i.e. PVP K30.
The preparation method of the graphene transdermal drug delivery microneedle of the embodiment comprises the following steps:
(1) adding 800mg of polyvinylpyrrolidone (PVP K30) into 1mL of water, and dissolving by ultrasonic treatment for 15min at room temperature to obtain a dispersion system A;
(2) adding 10 mu g of graphene oxide into the dispersion system A, uniformly stirring and dispersing, and removing bubbles to obtain a dispersion system B;
(3) and adding the dispersion system B into a microneedle mould made of PDMS, baking for 24-36h at 80 ℃, and demolding the microneedle to obtain the graphene transdermal delivery microneedle.
Example 2
The graphene transdermal drug delivery microneedle provided by the embodiment of the invention is characterized in that a substrate of the microneedle is polyvinylpyrrolidone, and graphene oxide is uniformly dispersed in the polyvinylpyrrolidone;
wherein, the dosage proportion of the polyvinylpyrrolidone and the graphene oxide is as follows: 800 parts by weight of polyvinylpyrrolidone and 0.1 part by weight of graphene oxide;
polyvinylpyrrolidone has a molecular weight of 30000, i.e. PVP K30.
The preparation method of the graphene transdermal drug delivery microneedle of the embodiment comprises the following steps:
(1) adding 800mg of polyvinylpyrrolidone into 1mL of water, and dissolving at room temperature for 15min by ultrasonic treatment to obtain a dispersion system A;
(2) adding 100 mu g of graphene oxide into the dispersion system A, uniformly stirring and dispersing, and removing bubbles to obtain a dispersion system B;
(3) and adding the dispersion system B into a microneedle mould made of PDMS, baking for 24-36h at 80 ℃, and demolding the microneedle to obtain the graphene transdermal delivery microneedle.
Example 3
The graphene transdermal drug delivery microneedle provided by the embodiment of the invention is characterized in that a substrate of the microneedle is polyvinylpyrrolidone, and graphene oxide is uniformly dispersed in the polyvinylpyrrolidone;
wherein, the dosage proportion of the polyvinylpyrrolidone and the graphene oxide is as follows: 800 parts by weight of polyvinylpyrrolidone and 0.5 part by weight of graphene oxide;
polyvinylpyrrolidone has a molecular weight of 30000, i.e. PVP K30.
The preparation method of the graphene transdermal drug delivery microneedle of the embodiment comprises the following steps:
(1) adding 800mg of polyvinylpyrrolidone into 1mL of water, and dissolving at room temperature for 15min by ultrasonic treatment to obtain a dispersion system A;
(2) adding 500 mu g of graphene oxide into the dispersion system A, uniformly stirring and dispersing, and removing bubbles to obtain a dispersion system B;
(3) and adding the dispersion system B into a microneedle mould made of PDMS, baking for 24-36h at 80 ℃, and demolding the microneedle to obtain the graphene transdermal delivery microneedle.
Example 4
The graphene transdermal drug delivery microneedle provided by the embodiment of the invention is characterized in that a substrate of the microneedle is polyvinylpyrrolidone, and graphene oxide is uniformly dispersed in the polyvinylpyrrolidone;
wherein, the dosage proportion of the polyvinylpyrrolidone and the graphene oxide is as follows: 800 parts by weight of polyvinylpyrrolidone and 1 part by weight of graphene oxide;
polyvinylpyrrolidone has a molecular weight of 30000, i.e. PVP K30.
The preparation method of the graphene transdermal drug delivery microneedle of the embodiment comprises the following steps:
(1) adding 800mg of polyvinylpyrrolidone into 1mL of water, and dissolving at room temperature for 15min by ultrasonic treatment to obtain a dispersion system A;
(2) adding 1000 mu g of graphene oxide into the dispersion system A, uniformly stirring and dispersing, and removing bubbles to obtain a dispersion system B;
(3) and adding the dispersion system B into a microneedle mould made of PDMS, baking for 24-36h at 80 ℃, and demolding the microneedle to obtain the graphene transdermal delivery microneedle.
Comparative example 1
The base material of the transdermal drug delivery microneedle is polyvinylpyrrolidone;
polyvinylpyrrolidone has a molecular weight of 30000, i.e. PVP K30.
The method for preparing the transdermal drug delivery microneedle of the present comparative example includes the steps of:
(1) adding 800mg of polyvinylpyrrolidone into 1mL of water, and dissolving at room temperature for 15min by ultrasonic treatment to obtain a dispersion system A;
(2) and adding the dispersion system A into a microneedle mould made of PDMS, baking for 24-36h at 80 ℃, and demolding the microneedle to obtain the polymer microneedle.
Experimental example 1
The surface topography of the microneedle cross section of example 4 and comparative example 1 is observed by an electron microscope, and as a result, as shown in fig. 2, the smoothness of the surface of the microneedle cross section of example (right GO-PVP in fig. 2) is obviously better than that of comparative example 1 (left PVP in fig. 2), in the surface topography of the microneedle cross section of the right example in fig. 2, the part indicated by an arrow is Graphene Oxide (GO) in the microneedle, and the smoothness of the surface of example 4 is better than that of comparative example 1, which indicates that the larger the amount of graphene oxide added to polyvinylpyrrolidone (PVP) in the microneedle is, the higher the smoothness of the microneedle surface is, and the mechanical friction of the microneedle against the skin is favorably reduced.
Raman spectroscopy analysis was performed on the microneedle of example 3, and the result is shown in fig. 3, which shows that graphene oxide has high dispersibility in polyvinylpyrrolidone.
Experimental example 2
Mechanical property test of microneedle
1. The mechanical properties that every micropin can bear are detected to application universal tester: the mechanical properties which the microneedles of examples 1 to 4 and comparative example 1 can bear are tested by using a universal testing machine, the detection method is a compression test, and the results are shown in fig. 4(a) and fig. 5, which shows that the mechanical properties of the microneedles of examples 1 to 4 in which graphene oxide is dispersed in polyvinylpyrrolidone are obviously better than those of the microneedles of comparative example 1; and the mechanical properties of example 3 were strongest, each needle able to withstand about 0.98N, whereas the polyvinylpyrrolidone microneedles of comparative example 1 were able to withstand only 0.12N, the mechanical properties of example 3 being improved by more than 8 times with respect to those of comparative example 1.
2. Depth of penetration of the microneedle into the skin: the skin of Kunming mice was peeled off, and the fat layer was removed. Fixing on a glass slide, vertically pricking the microneedles of examples 1-4 and comparative example 1 on the skin respectively, pressing with a 200g weight for 5min, removing the weight, allowing the microneedles to stay on the skin for 10min, removing the microneedles, performing OCT embedding and cryosectioning on the tissue, performing H & E staining, and performing microscopic imaging. As shown in FIG. 6, the addition of graphene oxide increased the penetration depth of the polymer microneedles into the skin, with example 3 penetrating the deepest skin depth of 650 μm, whereas the polyvinylpyrrolidone microneedles of the comparative example penetrated the skin depth of only 190 μm, and the penetration depth of the microneedles of example 3 into the skin of mice was increased by 3.4 times as compared to the microneedles of comparative example 1
Experimental example 3
Microneedle ability to control drug release.
1. Verifying the photothermal effect of the microneedle: the microneedles containing example 3 were dissolved in water and subjected to infrared irradiation (850nm,1W) to compare the change in irradiation time and solution temperature.
Experimental results show that the graphene oxide aqueous solution can reach 45 ℃ after being subjected to infrared illumination for 10min, and the microneedle solution of the embodiment 3 with the same concentration can reach 43 ℃, so that the microneedle system consisting of GO and PVP has an application prospect of photo-thermal controlled release.
2. Transdermal drug release experimental method
(1) Fluorescein Isothiocyanate (FITC) is added into the microneedles of examples 1-3 and comparative example 1 to serve as a model drug, and the fluorescence performance of the microneedles is detected by a microplate reader, so that the transdermal quantity is calculated.
(2) The skin of Kunming mice was peeled off, and the fat layer was removed. Fixing on a glass slide, vertically pricking the microneedles of examples 1-4 and comparative example 1 on the skin respectively, pressing with 200g weight for 5min, removing the weight, standing the microneedles on the skin for 10min, removing the microneedles, fixing the skin on a Franz diffusion cell, and collecting the lower layer of 0.9% NaCl solution. Transdermal experiments were carried out at 37 ℃ and 350 rpm. And taking 200 mu L of fluorescence detection values at 0, 3, 6, 12, 21 and 26 hours respectively, immediately performing infrared illumination for 10min (850nm,1W), standing for 30min, then sampling 200 mu L of fluorescence detection values respectively, and finally calculating the transdermal efficiency of FITC by drawing a standard curve.
As shown in fig. 4(b), the higher the content of graphene oxide in the microneedle, the better the photothermal control drug release performance, and the drug release after light irradiation is significantly increased, and the photothermal control drug release performance of the microneedle of example 3 is the best.
Experimental example 4
The microneedles of example 1, example 2, example 3, example 4, and comparative example 1 were tested for antibacterial performance.
Dripping a solution of gram-positive bacteria representing staphylococcus aureus and gram-negative bacteria representing escherichia coli on the surface of the microneedle, culturing at 37 ℃ for 24 hours, and diluting and plating the solution.
As a result, as shown in fig. 4(c), as the content of graphene oxide in the microneedle increases, the antimicrobial property of the microneedle increases. The addition of the graphene into the microneedle is proved to enable the microneedle to have certain antibacterial performance.
The microneedles were exposed to air for three days, and then dissolved in PBS, plated, and cultured for 5 days.
As shown in fig. 7, which is a graph showing the results of the mold infection experiment of the microneedles of the inventive and comparative examples, many molds were observed on the petri dish for the microneedle of comparative example 1, while no mold was observed for the microneedles of examples 3 and 4, indicating that the microneedle of the present invention has the property of resisting mold and is convenient to store.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. The utility model provides a graphite alkene transdermal microneedle of dosing which characterized in that, the substrate of micropin is the organic high molecular polymer that has the biocompatibility that pharmacy used, evenly dispersed has the graphite alkene material in the organic high molecular polymer, organic high molecular polymer selects polyvinylpyrrolidone, the graphite alkene material is graphite oxide, polyvinylpyrrolidone and graphite oxide's quantity ratio is: 600-800 parts of polyvinylpyrrolidone and 0.01-1 part of graphene oxide.
2. The graphene transdermal drug delivery microneedle according to claim 1, wherein the dosage ratio of polyvinylpyrrolidone to graphene oxide is: 600-800 parts by weight of polyvinylpyrrolidone and 0.1-1 part by weight of graphene oxide.
3. The graphene transdermal drug delivery microneedle according to claim 1, wherein the dosage ratio of polyvinylpyrrolidone to graphene oxide is: 800 parts by weight of polyvinylpyrrolidone and 0.1-0.5 part by weight of graphene oxide.
4. The graphene transdermal drug delivery microneedle according to claim 3, wherein the polyvinylpyrrolidone has a molecular weight of 30000.
5. A graphene transdermal drug delivery microneedle system, wherein the graphene transdermal drug delivery microneedle according to any one of claims 1 to 4 is loaded with a drug.
6. A method for preparing a graphene transdermal drug delivery microneedle according to any one of claims 1 to 4, wherein the method comprises the following steps:
(1) uniformly dispersing an organic high molecular polymer with biocompatibility used in pharmaceutics in a solvent to obtain a dispersion system A, wherein the organic high molecular polymer is polyvinylpyrrolidone;
(2) uniformly dispersing a graphene material in the dispersion system A, and removing bubbles to obtain a dispersion system B, wherein the graphene material is graphene oxide;
(3) and (3) molding and baking the dispersion system B, and then demolding to obtain the graphene transdermal drug delivery microneedle.
7. The method of claim 6, wherein the solvent is water.
8. The method according to claim 6, wherein the dispersing method in the step (1) is ultrasonic at room temperature for 10-20 min; the baking conditions in the step (3) are as follows: baking at 60-80 deg.C for 24-36 hr.
9. The method according to claim 6, wherein the concentration of graphene oxide in dispersion B is 0.01-1 mg/mL.
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