Drug-loaded microneedle, drug-loaded microneedle patch and electrically controlled drug release microneedle system

Abstract

The invention relates to the technical field of transdermal drug delivery, in particular to a drug-loaded microneedle, a drug-loaded microneedle patch and an electrically controlled drug release microneedle system.The drug-loaded microneedle comprises a needle body, a drug component and an electric sealing material, the needle body has biocompatibility and conductivity and is a hydrogel microneedle or a porous microneedle, and the drug component is attached to the drug-loaded microneedle patch. The medicine components are doped in the needle body or coated on the outer surface of the needle body. The electric sealing material is doped in the needle body and / or wraps the surface of the needle body, and the electric sealing material is connected with the needle body through at least one of covalent bonds, ionic bonds and coordinate bonds. When the drug-loaded microneedle is inserted into a target tissue, controlled release of drug components can be achieved through an electrical stimulation signal, and active components are guided into the target tissue through electric drive. According to the invention, the ion exchange behavior of the material is controlled through the electric field, so that the opening and closing of a drug release channel are realized, the purpose of electric switching chemical sealing is achieved, reversible control is realized by adjusting the intensity and direction of the electric field, and the accurate opening and closing of drug release are realized.

Description

Technical Field

[0001] The present invention relates to the technical field of transdermal drug delivery, and in particular to a drug-loaded microneedle, a drug-loaded microneedle patch, and an electrically regulated drug-releasing microneedle system. Background Art

[0002] Transdermal drug delivery is a common drug delivery method. Compared with oral drug delivery, it has higher bioavailability and improves patient compliance compared with injection. Microneedles are a new type of transdermal drug delivery system, which is formed by an array of several micron-sized needle tips. When administering drugs, microneedles can pierce the stratum corneum of the skin, thereby opening a microchannel from the stratum corneum to the epidermis or the superficial dermis for drug delivery, which is then absorbed by the capillaries. The active drug molecules circulate with the blood and reach the lesion site of the human body to play a therapeutic role. Compared with traditional transdermal drug delivery systems, due to the small needle tip and low height of the microneedle, the microneedle can only pass through the stratum corneum and will not reach the nerve endings of the dermis. Therefore, after piercing the skin, the damage to the skin structure is small, and the patient will not feel pain. The drug can be taken independently, with the advantages of accurate and fast administration, easy to carry and use, etc. Compared with traditional transdermal drug delivery systems, microneedle drug delivery combines the dual advantages of transdermal patches and subcutaneous injections, which can effectively improve skin permeability and increase the transdermal rate and utilization rate of drugs.

[0003] The existing transdermal drug delivery technology has the following problems:

[0004] (1) After the microneedles of the common microneedle drug delivery system are inserted into the skin tissue, the microneedles come into contact with the tissue fluid, and the active drug molecules contained in the microneedle body begin to diffuse passively under the action of the tissue fluid. The drug release cannot be autonomously controlled, and the precise controlled release of the drug cannot be achieved, which limits the development of this technology in sustained-release dosage form technology, especially in the application of cutting-edge fields such as the closed-loop system of intelligent controlled release of drugs based on on-site sensing and the digital automation of deep tissue drug delivery;

[0005] (2) In response to problem (1), some researchers have used water-insoluble polymer materials to form a uniform coating on the surface of microneedles. Due to the barrier of the coating, the drugs in the microneedles can only gradually penetrate to the outside through the pores in the coating, which slows down the release of the drugs, thereby achieving a sustained release effect of the drugs in the microneedles. However, this solution can only achieve a sustained release effect and still cannot achieve autonomous and controllable drug release. In addition, this solution is likely to cause drug residues in the microneedles, affecting the actual effective utilization rate of the drugs. Some researchers have also adopted the method of coating the surface of microneedles with biocompatible metal films, such as magnesium, tungsten, molybdenum, zinc or gold, to delay the biodegradation of microneedles. The biocompatible metal film serves as the gate of the drug reservoir. The electric trigger opens the metal gate through the cracks caused by anodic oxidation (usually for magnesium and molybdenum) or corrosion (usually for gold), which can effectively initiate the active release behavior. However, the decomposition or dissolution of the metal film in the tissue is an irreversible behavior, and the drug release is still uncontrollable. In addition, in this scheme, the metal film is easily peeled off from the surface of the microneedle due to cracks and cracks during the corrosion process, rather than the desired gradual dissolution, which further brings the risk of inflammation. Summary of the invention

[0006] In view of this, the purpose of the present invention is to provide drug-loaded microneedles, drug-loaded microneedle patches and electrically regulated drug release microneedle systems, so as to at least solve the problems existing in the prior art of being unable to achieve autonomous control of drug release and affecting the actual effective utilization rate of the drug.

[0007] The present invention solves the above technical problems by the following technical means:

[0008] In a first aspect, an embodiment of the present invention provides a drug-loaded microneedle, which is applied to an electrically regulated drug release microneedle system, and the drug-loaded microneedle comprises:

[0009] A needle body, wherein the conductive needle body is made of a biocompatible material and has conductivity, and the needle body is a hydrogel microneedle or a porous microneedle;

[0010] The drug component is mixed in the needle body or coated on the surface of the needle body;

[0011] An electric sealing material is doped inside the needle body and / or coated on the surface of the needle body, and the electric sealing material is connected to the needle body through at least one of a covalent bond, an ionic bond, and a coordination bond;

[0012] When the drug-loaded microneedle is inserted into the target tissue, the drug components can be controlled to be released through electrical signals, and the drug components can be introduced into the target tissue through electrical drive.

[0013] In some embodiments, the content of the electrical sealing material in the drug-loaded microneedle is 0.1wt% to 90wt%; the electrical sealing material is selected from one or more of ion exchange materials, ionic liquids, electroactive hydrogels, porous insulating polymer membranes, and nanocomposites.

[0014] In some embodiments, the ion exchange material is selected from at least one of a cation exchange functional group and an anion exchange functional group;

[0015] The ionic liquid includes choline chloride, choline dihydrogen phosphate, choline diphosphate, choline bicarbonate, 1-ethyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium chloride, 1-methylimidazolium acetate, choline glycine, choline lactate, choline arginine, tetrabutylphosphine methane sulfonate, choline methane sulfonate, choline iodide, ammonium acetate, choline acetate, ethylammonium nitrate, dihydroxyacetic acid choline, glycerophosphocholine, 1-butylpyridinium chloride, 1-ethylpyridinium acetate, 1-butylpiperidinium acetate, 1-ethylpiperidinium phosphate, proline-lactic acid, proline benzoate, ethylammonium lactate, triethylammonium phosphate, 1,3-dimethylimidazolium hydrogen sulfate, 1-methylimidazolium formate, 1-ethylimidazolium thiocyanate, 1- Butylimidazole acetate, choline succinate, choline phosphate, ammonium sucrose octaacetate, histidine chloride, histidine phosphate, histidine acetate, lysine acetate, lysine lactate, ethanolamine lactate, ethanolammonium phosphate, arginine acetate, proline lactate, methionine chloride, 1-methylpiperidinic acid, 1-butylpiperazine phosphate, poly(1-vinyl-3-ethylimidazole) bromide, polycholine phosphate, triethylammonium sulfate, choline-urea mixture, lactic acid-based DES, 1-ethyl-3-methylimidazole glycinate, 1-ethyl-3-methylimidazole glutamate, 1-ethyl-3-methylimidazole alanine, 1-ethyl-3-methylimidazole proline, 1-butyl-3-methylimidazole glycinate, 1-butyl- 3-Methylimidazole glutamate, 1-butyl-3-methylimidazole alanine, 1-butyl-3-methylimidazole proline, 1-ethyl-3-methylimidazole hexafluorophosphate, 1-ethyl-3-methylimidazole phosphate, 1-ethyl-3-methylimidazole dihydrogen phosphate, 1-butyl-3-methylimidazole hexafluorophosphate, 1-butyl-3-methylimidazole dihydrogen phosphate, deoxycholic acid quaternary ammonium salt, deoxycholic acid imidazolium salt, glycocholic acid quaternary ammonium salt, glycocholic acid imidazolium salt, cholic acid quaternary ammonium salt, cholic acid imidazolium salt, 1-phenethyl-3-methylimidazole salt, glycine methyl ester hydrochloride, acetate quaternary ammonium salt, phosphate quaternary ammonium salt, L-arginine acetate, L-histidine citrate, L-alanine ethyl ester bromide, guanidine chloride ionic liquid, guanidine carbonate Ionic liquids, guanidine phosphate, choline-aspartic acid, choline-glutamic acid, choline acetate, choline citrate, tetramethylammonium glycine, tetraethylammonium lysine, tetramethylammonium trifluoromethanesulfonate, dodecyltrimethylammonium bromide, choline methanesulfonate ion, ammonium p-toluenesulfonate ion, ethyl ammonium methanesulfonate, choline p-toluenesulfonate, triethylammonium phosphate, potassium dibutyl phosphate, triethyl ammonium phosphate, potassium dibutyl phosphate, betaine hydrochloride, dodecylbetaine ammonium bromide, betaine phosphate, N-methylpyrrolidone hydrogen sulfate, N-butylpyrrolidone bistrifluoromethanesulfonimide, N-methylpyrrolidone-lactate, N-butylpyrrolidine-acetate, morpholine hydrochloride, 4-methylmorpholine nitrate, N-methylmorpholine methanesulfonate,N-Ethylmorpholine p-toluenesulfonate, ethyl piperidine bromide, N-methylpiperidinium tetrafluoroborate, 1-methylpiperidinium nitrate, 1-butylpiperidinium acetate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-ethyl-3-methylimidazolium acetate, tributylmethylphosphonium bistrifluoromethanesulfonimide, tetrabutylphosphonium acetate, hydroxyapatite-imidazole ionic liquid, hydroxyapatite-pyridine ionic liquid, chitosan lactate, sodium calcium alginate, potassium gluconate, glucosamine hydrochloride, N-methylpyrrolidone hydrogen sulfate, N-ethylpyrrolidone tetrafluoroborate, triethylsulfonium tetrafluoroborate, dimethylphenylsulfonium hexafluorophosphorus at least one of 2-(4-(2-methyl-2-thiazole) tetrafluoroborate, 5-methyl-2-propyl-2-thiazole acetate, 2-methylfuran tetrafluoroborate, 3-furanammonium formate, indole-3-acetate, N-methylindole bromide, adenine acetate, guanine hydrochloride, 9-methylcarbazole nitrate, and N-ethylcarbazole tetrafluoroborate; or,

[0016] The electroactive hydrogel comprises at least one of polyvinyl alcohol-based hydrogel, polyacrylamide-based hydrogel, poly(3,4-ethylenedioxythiophene)-based hydrogel, polypyrrole-based hydrogel, polyaniline-based hydrogel, polyamide-based hydrogel, poly(urethane)-based hydrogel, polyvinylpyrrolidone-based hydrogel, polyurethane / poly(3,4-ethylenedioxythiophene) composite hydrogel, polylactic acid / polycaprolactone composite hydrogel, poly(2-methyl-2-ethyl acrylate)-based hydrogel, poly(acrylonitrile)-based hydrogel, polystyrene-based hydrogel, and electroactive polymer-based hydrogel; or,

[0017] The porous insulating polymer film includes at least one of polyimide, polyvinylidene fluoride, polytetrafluoroethylene, polyvinyl chloride, polyetheretherketone, and polyvinyl alcohol; or,

[0018] The nanocomposite material comprises at least one of polyvinyl alcohol / titanium oxide, polyvinyl pyrrolidone / titanium oxide, polyurethane / titanium oxide, polyamide / titanium oxide, polyvinyl alcohol / nano-silicon, polyvinyl pyrrolidone / nano-silicon, polyurethane / nano-silicon, polyamide / nano-silicon, polyvinyl alcohol / carbon quantum dots, polyvinyl pyrrolidone / carbon quantum dots, polyurethane / carbon quantum dots, polyamide / carbon quantum dots, polyvinyl alcohol / silver nanowires, polyvinyl pyrrolidone / silver nanowires, polyurethane / silver nanowires, polyamide / silver nanowires, polyvinyl alcohol / gold nanoparticles, polyvinyl pyrrolidone / gold nanoparticles, polyurethane / gold nanoparticles, polyamide / gold nanoparticles, polyvinyl alcohol / copper nanoparticles, polyvinyl pyrrolidone / copper nanoparticles, polyurethane / copper nanoparticles, and polyamide / copper nanoparticles.

[0019] In some embodiments, the hydrogel microneedle is made of at least one raw material including methacrylated hyaluronic acid, poly(glycolic acid), poly-L-lactide, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, polylactic acid, polyglycolic acid, chitosan, polycaprolactone, polylactic acid-glycolic acid copolymer, polymethyl vinyl ether / maleic acid, poly(methyl vinyl ether maleic anhydride, silk protein, polyethylene glycol, methacryloyl gelatin, γ-polyglutamic acid, cross-linked copolymer of 2-hydroxyethyl methacrylate, N-dimethylformamide, glycine and 2-ethoxyethanol, poly(styrene-b-acrylic acid), polyethylene glycol diacrylate, sodium polystyrene sulfonate, poly-N-isopropylacrylamide, sodium alginate, polycarbonate, agarose, pectin and gelatin.

[0020] In some embodiments, the porous microneedle is made of at least one raw material including silicon, alumina, titanium, medical grade stainless steel, gelatin, sodium alginate, hyaluronic acid, chitosan, hydroxypropyl methylcellulose, polyamide, polyurethane, polycarbonate, polycaprolactone, polysuccinate, polyethylene glycol diacrylate, polyacrylamide, polyacrylic acid, γ-polyglutamic acid, gelatin-methacrylamide, poly(ethylene glycol-co-methacrylic acid), poly(glycidyl methacrylate), poly(lactic acid-co-glycolic acid), polydimethylsiloxane, polyvinyl pyrrolidone, cellulose acetate, silk fibroin, polylactic acid, carboxymethyl cellulose, hydroxyapatite composite, diatomaceous earth-polymer composite, silica nanoparticle doped polymer, starch-chitosan composite, collagen-gelatin composite, calcium sulfate dihydrate and calcium phosphate dihydrate.

[0021] In some embodiments, the drug-loaded microneedle further includes a conductive electrode, and the needle body is located above the conductive electrode and connected to the conductive electrode as a working electrode of the electrically regulated drug release microneedle system.

[0022] In some embodiments, the conductive electrode is made of silicon, silicon dioxide, silicon nitride, graphite, graphene, poly (3,4-ethylenedioxythiophene) polystyrene sulfonate, poly [3,6-bis (40-dodecyl [2,20] biphenylthio-5-yl) -2,5-bis (2-hexyldecyl) -2,5-dihydropyrrolo [3,4-c] pyrrole -1,4-dione], polymethyl methacrylate, polyethylene glycol, pentacene, tetracene, anthracene, naphthalene, α-6-thiophene, α-4-thiophene, perylene and its derivatives, rubrene and its derivatives, coronene and its derivatives, perylene tetracarboxylic acid diimide and its derivatives, perylene tetracarboxylic acid dianhydride and its derivatives, polythiophene and its derivatives, poly (p-phenylene vinylene) and its derivatives, poly (p-phenylene) and its derivatives, poly (fluorene) and its derivatives. The invention is prepared from at least one of the following raw materials: biomaterials, polythiophene 1,2-vinylidene and its derivatives, polythiophene-heterocyclic aromatic polymers and its derivatives, naphthalene oligophenylene and its derivatives, a-5-thiophene oligothiophene and its derivatives, metal-free phthalocyanine and its derivatives, benzene tetracarboxylic acid dianhydride and its derivatives, benzene tetracarboxylic acid diimide and its derivatives, naphthalene tetracarboxylic acid diimide and its derivatives, naphthalene tetracarboxylic acid dianhydride and its derivatives, nitrile rubber, styrene-ethylene-butylene-styrene, carbon nanotubes, Ag / AgCl, PR-PEGMA, IGZO, IGZTO, IGTO, IZO, ITO, InO, Cu, Ag, Al, Mo, Li, Mg, Ti, Ta, Au, Cr, W, Ni, Pt, Pd, and Ga.

[0023] In the second aspect, an embodiment of the present invention further discloses a drug-loaded microneedle patch, which includes a substrate and the drug-loaded microneedles described in the first aspect, as well as electrode leads and conductive electrodes, wherein the electrode leads are connected to the drug-loaded microneedles; the conductive electrodes and electrode leads are formed on the substrate, the drug-loaded microneedles are formed on the conductive electrodes, and the electrode leads are connected to the conductive electrodes; or, the substrate and the needle body are integrally formed, and the drug-loaded microneedle patch also includes a substrate, the substrate is located on the substrate, the electrode leads and the conductive electrodes are both formed on the substrate, and the position of the conductive electrodes corresponds to the position of the needle body.

[0024] In some embodiments, the drug-loaded microneedle patch further includes an insulating packaging layer, and the insulating packaging layer covers the electrode leads.

[0025] In a third aspect, an embodiment of the present invention further discloses an electrically regulated drug release microneedle system, comprising the drug-loaded microneedle patch described in the second aspect above.

[0026] The drug-loaded microneedles, drug-loaded microneedle patches, and electrically regulated drug-releasing microneedle systems of the present invention have the following advantages:

[0027] In terms of drug loading: hydrogel microneedles or porous microneedles are mesh skeletons with three-dimensional spatial structures. The introduced electro-switching chemical sealing materials are connected to the mesh skeleton carriers by at least one of covalent bonds, ionic bonds or coordination bonds; cationic or anionic drugs and / or neutral and macromolecular drugs encapsulated in charged nanocarriers are combined with electro-switching chemical sealing materials through electrostatic interactions, hydrogen bonds and other interactions, thereby achieving drug loading. At the same time, with the help of the high loading characteristics of ion exchange, the drug loading capacity of the microneedles is increased, and a very unique solution is provided for drugs with poor solubility. The amount of loaded drugs and the release rate can be controlled by adjusting factors such as the type and density of functional groups and the material properties of the microneedles. When the microneedles are inserted into the skin tissue, in the absence of an electric field, due to the interaction between the electro-switching chemical sealing material and the drug ions, the passive diffusion of the drug ions in the microneedles is constrained, and the drugs will not diffuse into the tissues, enhancing the environmental stability of the drug-loaded microneedles, effectively preventing the unplanned leakage of drugs under no electric field conditions, and achieving the effect of chemical sealing.

[0028] In terms of increasing conductivity: The conductivity of microneedles is mainly contributed by ion migration. Ion exchange functional groups, ionic liquids, etc. can increase the concentration of free ions in the solution, thereby improving conductivity. Ion exchange functional groups are usually hydrophilic. After these groups absorb water, they can form more hydrated ion environments in the hydrogel, which is conducive to the diffusion and migration of ions. The network formed by hydrated ions not only helps to enhance the migration of ions, but also reduces the energy loss during ion migration to a certain extent. Ion exchange functional groups (such as sulfonic acid groups (–SO 3 - ), carboxylic acid group (–COO - ), quaternary ammonium salt groups, etc.) release mobile ions through ionization in the microneedles. These mobile ions migrate under the action of the electric field, enhancing the ionic conductivity of the microneedles. Ionic liquids themselves are composed of ions. When introduced into microneedles, the ions of the ionic liquids can be distributed in the three-dimensional network structure of the microneedles, forming a continuous ion conduction channel inside the microneedles, increasing the concentration of mobile ions, and improving the ion migration environment. Ion exchange functional groups, ionic liquids, etc. can form a more uniform ion network in the hydrogel and improve the continuity of the ion migration path. Especially when microneedles are used in electrochemical devices, uniformly distributed ion exchange functional groups or ionic liquids can improve the stability and sensitivity of the current response.

[0029] In terms of electrical signal control: when the hydrogel microneedles and / or porous microneedles are inserted into the skin, they quickly absorb tissue fluid to form a transcutaneous ionic connection. Electrical signals will form an electric field inside the microneedles. The existence of the electric field will polarize the ion exchange functional groups and change the interaction force between them and the drug molecules. For positively charged drug molecules, under the action of the electric field, they will be attracted by the negative electrode and migrate to the negative electrode; negatively charged drug molecules will migrate to the positive electrode; and the transport of neutral molecules is dominated by the directional movement of the solvent caused by the electromigration of ions under the external electric field. Electrical signals will also drive the movement of ions in the environment surrounding the microneedles. For example, there are various electrolyte ions in the skin tissue, such as sodium ions (Na + ), chloride ion (Cl - ) etc. Under the action of the electric field, these ions will form a concentration gradient near the surface of the microneedle, thereby affecting the binding state of the electro-switchable chemical sealing material and the drug molecules.

[0030] In terms of drug release: when the electric field is turned on, the ion complex in the deposited layer at the interface between the drug-loaded microneedle and the tissue decomposes under the action of the electric field, restoring the ion selectivity of the interface. Due to the ion movement and polarization of the functional group caused by the electric signal, the binding force between the drug ion and the functional group is weakened, and the drug is released from the microneedle. The released drug ions accelerate migration under the action of the external electric field, achieving local release and therapeutic effects of the drug. The drug release rate can be precisely controlled by adjusting parameters such as the intensity, frequency and duration of the electric signal. Higher electric signal intensity or frequency may lead to faster ion movement and stronger functional group polarization, thereby accelerating drug release; while lower electric signal parameters will slow down the drug release rate. The ion exchange behavior of the material is controlled by the electric field, thereby realizing the opening and closing of the drug release channel, and achieving the purpose of electrically switching chemical sealing. Reversible control is achieved by adjusting the intensity and direction of the electric field, thereby achieving precise switching of drug release. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is a schematic diagram of the structure of the drug-loaded microneedle of Example 1;

[0032] Figure 2 is a schematic structural diagram of the drug-loaded microneedle patch of Example 1;

[0033] Figure 3 It is a schematic diagram of the structure of the electrically regulated drug release microneedle system;

[0034] Figure 4 is a schematic structural diagram of the drug-loaded microneedle of Example 2;

[0035] Figure 5 is a schematic structural diagram of the drug-loaded microneedle patch of Example 2;

[0036] Figure 6 is a schematic structural diagram of the drug-loaded microneedle of Example 3;

[0037] Figure 7 is a schematic structural diagram of the drug-loaded microneedle patch of Example 3;

[0038] Figure 8 is another schematic diagram of the structure of drug-loaded microneedles;

[0039] Among them, the drug-loaded microneedle 100, the needle body 110, the electrical sealing material 120, the conductive electrode 130, the drug-loaded microneedle patch 200, the substrate 210, the electrode lead 220, the insulating packaging layer 230, the substrate 240, the electrically regulated drug release microneedle system 300, the power supply 310, the control device 320, the counter electrode 330, and the skin tissue 0. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical solution and advantages of the embodiments of the present application clearer, the technical solution in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0041] In the embodiments of the present application, words such as "exemplary" or "for example" are used to indicate examples, illustrations or descriptions. Any embodiment or design described as "exemplary" or "for example" in the embodiments of the present application should not be interpreted as being more preferred or more advantageous than other embodiments or designs. Specifically, the use of words such as "exemplary" or "for example" is intended to present related concepts in a specific way.

[0042] The drug-loaded microneedle 100 of the present application is applied to an electrically controlled drug release microneedle system 300, which includes a needle body 110, a drug component and an electrical sealing material 120. The needle body 110 is made of a biocompatible material and has conductivity. The needle body 110 is a hydrogel microneedle or a porous microneedle, and the drug component is doped in the needle body 110 or coated on the surface of the needle body 110. The electrical sealing material 120 is doped in the interior of the needle body 110 and / or coated on the surface of the needle body 110, and the electrical sealing material 120 is connected to the needle body 110 by at least one of a covalent bond, an ionic bond, and a coordination bond. When the drug-loaded microneedle 100 is inserted into the target tissue, the controlled release of the drug component can be achieved through an electrical stimulation signal, and the active ingredient can be introduced into the target tissue by electrical drive.

[0043] In some embodiments, the content of the electrical sealing material in the drug-loaded microneedle is 0.1 wt% to 90 wt%, and the electrical sealing material is selected from one or more of ion exchange materials, ionic liquids, electroactive hydrogels, porous insulating polymer membranes, and nanocomposites. Specifically, the ion exchange material is selected from a cation exchange functional group sulfonic acid group (-SO 3 - ), carboxylic acid group (-COO - ), phosphate group (-PO 4 2- ), phosphonic acid group (-PO 3 2- ), phenolic acid group (-ArO-), thiol group (-SH), pyridine carboxylate (-PyCOO - ), sulfate ester (-OSO 3 - ), sulfinic acid group (-SO 2 - ), aminocarboxylate (-CH(NH 3 + )COO - ), enolic acid group (-C=CO - ), hydroxamate (-C(=NOH)-OH - ), esterified carboxylic acid group (-COOR), phosphite group (-HPO 3 - ), acetylsulfonate (-CH 2 -SO 3 - ), thiocarboxylic acid group (-COS - ), dithiophosphate (-PS 2 - ), hydroxysulfonic acid group (-OH-SO 3 - ), nitrile acid group (-CN-COO - ), acrylic acid (-CH 2 =CHCOO - ), maleic anhydride group (-C 2 O 3 - ), fulvenoic acid hydroxyl (-C 6 H 3 (OH) 2 -SO 3 - ), hydroxycarboxylic acid group (-C(OH)COO - ), aminocarboxylic acid group (-NH 2 -COO - ), nitrocarboxylic acid group (-NO 2 COO - ), thiosulfonic acid group (-S-SO3 - ), selenoic acid (-SeO 3 - ), selenite (-SeO 2 - ), phosphosulfate (-PO 3 -SO 3 - ), silicate group (-SiO 4 - )、polymerizable ester group (-R(COO - ) n ), oxalate (-COO - -COO - ), cyano group (-C≡N-COO - ), fluorinated sulfonic acid (-SO 2 F), phosphodiester (-PO 2 OR), acetamido (-C(O)-NH 2 ), aminoamide (-NH 2 -C(O)-NH 2 ), aminosulfite group (-NH 2 -SO 3 - ), nitrate ester (-NO 2 -COO - ), pyrrolidinyl (-C 4 H 7 -NH 3 + ), boron trifluoride (-BF 3 - ), aromatic sulfonic acid group (-C 6 H 5 SO 3 - ), nitrogen heterocyclic group (-N + (CH 3 ) 2 ), trimethylsilyl (-Si(CH 3 ) 3 ), aromatic sulfate (-ArSO 3 - ), sulfonyl (-SO 2 - ), aluminate (-AlO 4 2- ), fluorosulfonic acid (-FSO 3 - ), phosphorus trichloride (-POCl 3 - ), phosphate group (-PO 4 2-), vinyl sulfonic acid (-CH 2 =CHSO 3 - ), aminosulfonic acid (-NH 2 SO 3 - ), allylsulfonic acid (-CH 2 =CH-CH 2 SO 3 - ), pentaerythritol (-C 5 H 10 (OH) 5 SO 3 - ), aminonitrite (-NH 2 NO 2 - ), olefin group (-C=C-COO - ), nitrile sulfate (-C≡N-SO 3 - ), nitroso group (-NO-COO - ), alkyd group (-C(OH) 2 COO - ), difluorophosphate (-PO 2 F 2 - ) or at least one selected from anion exchange functional groups quaternary ammonium groups (-NR 3 + ), primary amine (-NH 3 + ), secondary amine (-NH 2 + R), tertiary amine (-NR 2 + R'), guanidine (-C(=NH)NH 2 + ), imidazolyl (-C 3 H 3 N 2 + ), pyridyl (-C 5 H 5 N + ), phosphino (-PR 3 + ), anion exchange functional groups (providing positive charge), quaternary phosphine groups (-PR 4 + ), quaternary ammonium sulfide (-S + R 3 ), thiourea (-CSNH 2 + ), amidino (-C(=NH)NH +R), nitrogen heterocyclic cationic group (-N + (R) 3 ), guanidine (-NHC (NH 2 ) 2 + ), aminoamidino (-NH-C(=NH)-NH 2 + ), isothiourea (-C(=NH)-NH + -R), thiazolium cation group (-SC 3 N + ), benzimidazolium cation group (-C 6 H 4 -NH-N + ), imidazolium (-C 3 H 3 N 2 + -R), tetrazolium cation group (-C 2 N 4 H 3 + ), azasulfuryl cation (-S + -N(R) 2 ), piperidinium cation (-C 5 H 10 NH + ), piperazine cation group (-C 4 H 10 N 2 + ), aminophosphonic acid group (-NH-PO 3 H + ), sulfonamide cation group (-SO 2 -NH 3 + ), hydroxylamine cationic group (-NH 2 -OH + ), hydrazone cation group (-C=N-NH 2 + ), amidinophosphate (-C(=NH)-NH-PO 3 + ), amine sulfonate cation (-NH-S + -R 2 ), selenium cation (-Se + ), pyrrole cation group (-C 4 H 4 NH + ), thiophene cation group (-C 4 H 4 S + ), enamine cation group (-CH=NH +), acetal cation group (-C(O)-CH 2 + ), guanidine quaternary ammonium group (-C(=NH)-NH-R 3 + ), anion exchange functional groups (providing positive charge), quaternary amine groups (-NR 4 + ), ammonium (-NH 4 + ), nitrite (-NO 2 - ), fluorinated quaternary ammonium group (-N + (CF 3 ) 3 ), choline cationic group (-N + (CH 3 ) 3 ), sodium chloride cation group (-Na + ), diethylamino cationic group (-N(CH 2 CH 3 ) 2 + ), pyrrolyl cation (-C 4 H 4 NH 2 + ), pyridinium-sulfur cation (-C 6 H 5 N + -S), nitrogen compound cationic group (-NR 2 C(NH 2 ) 2 + ), metal organic group cation group (-MOR), nitride cation group (-N≡N + ), enamine cation group (-CH 2 =NH + ), acrylamino (-NH-CH 2 -CH=CH 2 + ), diethylamino (-N(C 2 H 5 ) 2 + ), tetrazolyl (-C 2 H 3 N 4 + ), pyridine-thiol nitrogen group (-C 6 H 5 N + -S), imidazolone cation group (-C 3 H 4 N 2 O+ ), guanidine cation (-C(=NH)-NH 2 + ), sodium acetate cation group (-Na + / COO - ), thioline cation group (-C 6 H 4 S + ), azide cation group (-N 3 + ), ammonium fluoride cation group (-NH 4 + ), amine sulfide anion group (-NHR-S - ), oxidized sulfur cation radical (-SO 4 2- ), amide cationic group (-C(O)-NH 2 + ), phosphide cation group (-PO 4 2- / NH 4 + ), nitride cation group (-N≡N + ), enamine cation group (-CH 2 =NH + ), acrylamino (-NH-CH 2 -CH=CH 2 + ), diethylamino (-N(C 2 H 5 ) 2 + ), tetrazolyl (-C 2 H 3 N 4 + ), pyridine-thiol nitrogen group (-C 6 H 5 N + -S), imidazolone cation group (-C 3 H 4 N 2 O + ), guanidine cation (-C(=NH)-NH 2 + ), sodium acetate cation group (-Na + / COO - ), thioline cation group (-C 6 H 4 S + ), azide cation group (-N 3 + ), ammonium fluoride cation group (-NH 4+ ), amine sulfide anion group (-NHR-S - ), oxidized sulfur cation radical (-SO 4 2- ), amide cationic group (-C(O)-NH 2 + ), phosphide cation group (-PO 4 2- / NH 4 + ) at least one of.

[0044] Among them, the ionic liquids include choline chloride, choline dihydrogen phosphate, choline diphosphate, choline bicarbonate, 1-ethyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium chloride, 1-methylimidazolium acetate, choline glycine, choline lactate, choline arginine, tetrabutylphosphine methanesulfonate, choline methanesulfonate, choline iodide, ammonium acetate, choline acetate, ethylammonium nitrate, dihydroxyacetic acid choline, glycerophosphocholine, 1-butylpyridinium chloride, 1-ethylpyridinium acetate, 1-butylpiperidinium acetate, 1-ethylpiperidinium phosphate, proline-lactic acid, proline benzoate, ethylammonium lactate, triethylammonium phosphate, 1,3-dimethylimidazolium hydrogen sulfate, 1-methylimidazolium formate, 1-ethylimidazolium thiocyanate, 1 -Butyl imidazole acetate, choline succinate, choline phosphate, ammonium sucrose octaacetate, histidine chloride, histidine phosphate, histidine acetate, lysine acetate, lysine lactate, ethanolamine lactate, ethanolammonium phosphate, arginine acetate, proline lactate, methionine chloride, 1-methylpiperidinic acid, 1-butylpiperazine phosphate, poly(1-vinyl-3-ethylimidazole) bromide, polycholine phosphate, triethylammonium sulfate, choline-urea mixture, lactic acid-based DES, 1-ethyl-3-methylimidazolium glycinate, 1-ethyl-3-methylimidazolium glutamate, 1-ethyl-3-methylimidazolium alanine, 1-ethyl-3-methylimidazolium proline, 1-butyl-3-methylimidazolium glycinate, 1-butyl- 3-Methylimidazole glutamate, 1-butyl-3-methylimidazole alanine, 1-butyl-3-methylimidazole proline, 1-ethyl-3-methylimidazole hexafluorophosphate, 1-ethyl-3-methylimidazole phosphate, 1-ethyl-3-methylimidazole dihydrogen phosphate, 1-butyl-3-methylimidazole hexafluorophosphate, 1-butyl-3-methylimidazole dihydrogen phosphate, deoxycholic acid quaternary ammonium salt, deoxycholic acid imidazolium salt, glycocholic acid quaternary ammonium salt, glycocholic acid imidazolium salt, cholic acid quaternary ammonium salt, cholic acid imidazolium salt, 1-phenethyl-3-methylimidazole salt, glycine methyl ester hydrochloride, acetate quaternary ammonium salt, phosphate quaternary ammonium salt, L-arginine acetate, L-histidine citrate, L-alanine ethyl ester bromide, guanidine chloride ionic liquid, guanidine carbonate Ionic liquids, guanidine phosphate, choline-aspartic acid, choline-glutamic acid, choline acetate, choline citrate, tetramethylammonium glycine, tetraethylammonium lysine, tetramethylammonium trifluoromethanesulfonate, dodecyltrimethylammonium bromide, choline methanesulfonate ion, ammonium p-toluenesulfonate ion, ethyl ammonium methanesulfonate, choline p-toluenesulfonate, triethylammonium phosphate, potassium dibutyl phosphate, triethyl ammonium phosphate, potassium dibutyl phosphate, betaine hydrochloride, dodecylbetaine ammonium bromide, betaine phosphate, N-methylpyrrolidone hydrogen sulfate, N-butylpyrrolidone bistrifluoromethanesulfonimide, N-methylpyrrolidone-lactate, N-butylpyrrolidine-acetate, morpholine hydrochloride, 4-methylmorpholine nitrate, N-methylmorpholine methanesulfonate,N-Ethylmorpholine p-toluenesulfonate, ethyl piperidine bromide, N-methylpiperidinium tetrafluoroborate, 1-methylpiperidinium nitrate, 1-butylpiperidinium acetate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-ethyl-3-methylimidazolium acetate, tributylmethylphosphonium bistrifluoromethanesulfonimide, tetrabutylphosphonium acetate, hydroxyapatite-imidazole ionic liquid, hydroxyapatite-pyridine ionic liquid, chitosan lactate, sodium calcium alginate, potassium gluconate, glucosamine hydrochloride, N-methylpyrrolidone hydrogen sulfate, N-ethylpyrrolidone tetrafluoroborate, triethylsulfonium tetrafluoroborate, dimethylphenylsulfonium hexafluoroborate At least one of fluorophosphate, hydroxyethyltrimethylammonium formate, dihydroxypropylammonium acetate, methylisopropylsulfone ammonium salt, dimethylsulfone choline salt, N-benzylethylenediamine bistrifluoromethanesulfonimide, N-allyl-1,3-propylenediamine acetate, 2-methylthiazole bromide, 4-methyl-5-hydroxyethylthiazole nitrate, 2-ethyloxazole tetrafluoroborate, 5-methyl-2-propyloxazole acetate, 2-methylfuran tetrafluoroborate, 3-furanammonium formate, indole-3-acetate, N-methylindole bromide, adenine acetate, guanine hydrochloride, 9-methylcarbazole nitrate, and N-ethylcarbazole tetrafluoroborate.

[0045] The electroactive hydrogel includes at least one of polyvinyl alcohol (PVA)-based hydrogel, polyacrylamide (PAM)-based hydrogel, poly(3,4-ethylenedioxythiophene) (PEDOT)-based hydrogel, polypyrrole (PPy)-based hydrogel, polyaniline (PANI)-based hydrogel, polyamide (PA)-based hydrogel, poly(urethane) (PU)-based hydrogel, polyvinylpyrrolidone (PVP)-based hydrogel, polyurethane (PU) / poly(3,4-ethylenedioxythiophene) (PEDOT) composite hydrogel, polylactic acid (PLA) / polycaprolactone (PCL) composite hydrogel, poly(2-methyl-2-ethyl acrylate) (PMMA)-based hydrogel, poly(acrylonitrile) (PAN)-based hydrogel, polystyrene (PS)-based hydrogel, and electroactive polymer (EAPs)-based hydrogel.

[0046] The porous insulating polymer film includes at least one of polyimide (PI), polyvinylidene fluoride (PVDF), polytetrafluoroethylene (PTFE), polyvinyl chloride (PVC), polyetheretherketone (PEEK), and polyvinyl alcohol (PVA).

[0047] Nanocomposites include polyvinyl alcohol (PVA) / titanium oxide, polyvinyl pyrrolidone (PVP) / titanium oxide, polyurethane (PU) / titanium oxide, polyamide (PA) / titanium oxide, polyvinyl alcohol (PVA) / nanosilicon, polyvinyl pyrrolidone (PVP) / nanosilicon, polyurethane (PU) / nanosilicon, polyamide (PA) / nanosilicon, polyvinyl alcohol (PVA) / carbon quantum dots (CQDs), polyvinyl pyrrolidone (PVP) / carbon quantum dots (CQDs), polyurethane (PU) / carbon quantum dots (CQDs), polyamide (PA) / carbon quantum dots (CQDs), polyvinyl alcohol (PVA) / silver nanowires (AgNWs), polyvinyl pyrrolidone (PVP) / silver nanowires (AgNWs), At least one of rice nanowires (AgNWs), polyurethane (PU) / silver nanowires (AgNWs), polyamide (PA) / silver nanowires (AgNWs), polyvinyl alcohol (PVA) / gold nanoparticles (AuNPs), polyvinyl pyrrolidone (PVP) / gold nanoparticles (AuNPs), polyurethane (PU) / gold nanoparticles (AuNPs), polyamide (PA) / gold nanoparticles (AuNPs), polyvinyl alcohol (PVA) / copper nanoparticles (CuNPs), polyvinyl pyrrolidone (PVP) / copper nanoparticles (CuNPs), polyurethane (PU) / copper nanoparticles (CuNPs), and polyamide (PA) / copper nanoparticles (CuNPs).

[0048] The hydrogel microneedles are made of methacrylated hyaluronic acid (MeHA), poly(glycolic acid) (PGA), poly-L-lactide (PLLA), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyacrylic acid (PAA), polylactic acid (PLA), polyglycolic acid (PGA), chitosan (CS), polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), polymethyl vinyl ether / maleic acid (PMVE / MA), poly(methyl vinyl ether maleic anhydride) (PMVE / MAH), silk fibroin (S F), polyethylene glycol (PEG), methacryloyl gelatin (GelMA), γ-polyglutamic acid (γ-PGA), cross-linked copolymer of 2-hydroxyethyl methacrylate (pHEMA), N-dimethylformamide, glycine and 2-ethoxyethanol, poly (styrene-b-acrylic acid) (PS-b-PAA), polyethylene glycol diacrylate (PEGDA), sodium polystyrene sulfonate (PSS), poly N-isopropylacrylamide (PNIPAAm), sodium alginate, polycarbonate, agarose, pectin and gelatin.

[0049] The porous microneedles are made of silicon, alumina, titanium, medical grade stainless steel (316L), gelatin, sodium alginate, hyaluronic acid, chitosan, hydroxypropyl methylcellulose, polyamide (nylon), polyurethane (PU), polycarbonate (PC), polycaprolactone (PCL), polysuccinate, polyethylene glycol diacrylate (PEGDA), polyacrylamide (PAM), polyacrylic acid (PAA), γ-polyglutamic acid (γ-PGA), gelatin-methacrylamide (GelMA), poly(ethylene glycol-co-methacrylic acid), poly(methacrylic acid) The invention is prepared from at least one of poly(ethylene glycol) (PGMA), poly(lactic acid-co-glycolic acid) (PLGA), polydimethylsiloxane (PDMS), polyvinylpyrrolidone (PVP), cellulose acetate, silk fibroin (SF), poly(lactic acid) (PLA), carboxymethyl cellulose (CMC), hydroxyapatite (HA) composite, diatomaceous earth-polymer composite, polymer doped with silica nanoparticles, starch-chitosan composite, collagen-gelatin composite, calcium sulfate dihydrate (CaS) and calcium phosphate dihydrate (CaP).

[0050] In some embodiments, the drug-loaded microneedle further includes a conductive electrode, and the needle body is located above the conductive electrode and connected to the conductive electrode as a working electrode of the electrically regulated drug release microneedle system. The conductive electrode includes silicon, silicon dioxide, silicon nitride, graphite, graphene, poly (3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), poly [3,6-bis (40-dodecyl [2,20] biphenylthio-5-yl) -2,5-bis (2-hexyldecyl) -2,5-dihydropyrrolo [3,4-c] pyrrole-1,4-dione] (PDQT), polymethyl methacrylate (PMMA), polyethylene glycol (PEO), pentacene, tetracene, anthracene, naphthalene, a-6-thiophene, a-4-thiophene, perylene and its derivatives, rubrene and its derivatives, coronene and its derivatives, perylene tetracarboxylic acid diimide and its derivatives, perylene tetracarboxylic acid dianhydride and its derivatives, polythiophene and its derivatives, polyparaphenylene vinylene and its derivatives, polyparaphenylene and its derivatives, polyfluorene and its derivatives, polythiophene 1,2-vinylidene and its derivatives, polythiophene-heterocyclic aromatic polymers and their derivatives, naphthalene oligophenylene and its derivatives, a-5-thiophene oligothiophene and its derivatives, metal-free phthalocyanine and its derivatives, benzene tetracarboxylic acid dianhydride and its derivatives, benzene tetracarboxylic acid diimide and its derivatives, naphthalene tetracarboxylic acid diimide and its derivatives, and naphthalene tetracarboxylic acid dianhydride and its derivatives, nitrile rubber (NBR), styrene-ethylene-butylene-styrene (SEBS), carbon nanotubes, Ag / AgCl, PR-PEGMA, IGZO, IGZTO, IGTO, IZO, ITO, InO, Cu, Ag, Al, Mo, Li, Mg, Ti, Ta, Au, Cr, W, Ni, Pt, Pd, and Ga.

[0051] In some embodiments, the drug ingredient is selected from one or more of cationic drugs, anionic drugs, neutral or macromolecular drugs, and effective ingredients of skin care products. The drug-loaded microneedles can freely set the content of the loaded drug ingredient according to the number of needles arranged in the microneedle array, and the weight of the loaded drug ingredient is between 1 pg (pg) and 1000 g (g).

[0052] In some embodiments, the needle body can be tubular, truncated cone, cone or other shapes that can penetrate, for example, the dermis, mucosa, oral epithelium, deep dermis, bone, etc. The length of the drug-loaded microneedle can range from 100 μm to 2000 μm, or even longer. The microneedles of the present invention have a wide range of uses, so the length of the microneedle can be designed according to the expected delivery location of the drug in the subject. In order to allow the drug to penetrate deeper, the microneedle can have the above-mentioned longer length range; in order to penetrate thinner surfaces and tissue layers to avoid the microneedle from contacting nerves that may cause pain, the microneedle can have the above-mentioned shorter length range.

[0053] In some embodiments, the drug-loaded microneedle further comprises a conductive component, which is located between the needle body and the conductive electrode, and the conductive component comprises at least one of an ionic liquid, a conductive polymer, a conductive nanometal material, a carbon-based material, a nanocomposite reinforced material, and a metal oxide / salt. Specifically, the conductive polymer comprises at least one of poly(3,4-ethylenedioxythiophene)-polystyrene sulfonic acid (PEDOT:PSS), polypyrrole (PPy), polyaniline (PANI), polythiophene (PTh), poly(3-hexylthiophene) (P3HT), diketopyrrolopyrrole (DPP) and its derivatives. The conductive nanometal material comprises at least one of silver nanowires (AgNWs), copper nanowires (CuNWs), gold nanoparticles (AuNPs), and copper nanoparticles (CuNPs). The carbon-based material comprises at least one of graphene and its derivatives (graphene oxide, reduced graphene oxide), carbon nanotubes (CNTs), carbon fibers, and carbon quantum dots (CQDs). The nanocomposite reinforcement material includes at least one of two-dimensional transition metal carbides / nitrides (MXene), silicene and phosphorene. The metal oxide / salt includes at least one of oxides of In, Sn, Zn and Cd and their composite multi-element oxides, silver nitrate, silver acetate and silver halide.

[0054] The drug-loaded microneedle patch 200 of the present application includes the drug-loaded microneedle 100 and the substrate 210, as well as the electrode lead 220 and the conductive electrode 130, wherein the electrode lead 220 is connected to the drug-loaded microneedle 100. The conductive electrode 130 and the electrode lead 220 are formed on the substrate 210, the drug-loaded microneedle 100 is formed on the conductive electrode 130, and the electrode lead 220 is connected to the conductive electrode 130 (see Figure 1 and 4); or, the substrate 210 and the needle body 110 are integrally formed, the drug-loaded microneedle patch 200 further includes a substrate 240, the substrate 210 is located on the substrate 240, the electrode lead 220 and the conductive electrode 130 are both formed on the substrate 240, and the position of the conductive electrode 130 corresponds to the position of the needle body 110 (see Figure 6 and 8 ).

[0055] The material of the substrate can be the same as that of the needle body, or can be selected from at least one of glass, silicon wafer, polyvinyl alcohol (PVA), polyester (PET), polyethersulfone (PES), polyimide (PI), polyethylene naphthalate (PEN), polyurethane (PU), polydimethylsiloxane (PDMS), thermoplastic polyurethane (TPU), liquid crystal polymer (LCP), polytetrafluoroethylene (PTFE), polycarbonate (PC), poly(lactic acid-glycolic acid) (PLGA), poly(glycolic acid) (PGA), poly-L-lactide (PLA), polyvinylpyrrolidone (PVP), polystyrene-block-poly(ethylene-cyclobutene)-block-polystyrene, hydrogel, silica gel, paper, and fabric materials.

[0056] The electrode lead is made of at least one raw material including Cu, Ag, Al, Mo, Mg, Ti, Ta, Au, Cr, W, Ni, Pt, Pd, Ga, two-dimensional transition metal carbide / nitride (MXene), graphite, graphene, carbon nanotubes, carbon fiber, metal nanowires, metal nanosheets, metal grids, liquid metals, polypyrrole, polyaniline, polyacetylene, poly(p-phenylene sulfide), poly(p-phenylene), polythiophene, polypropylene, zinc oxide, polyvinylidene fluoride, PEDOT:PSS, PEG-PPG-PEG, and acrylate.

[0057] In order to prevent leakage, the drug-loaded microneedle patch also includes an insulating packaging layer, which covers the electrode leads and provides necessary insulating packaging for the electrode leads.

[0058] The insulating packaging layer is made of at least one raw material including aluminum oxide, silicon oxide, silicon nitride, boron nitride, polyvinyl alcohol (PVA), polyester (PET), polyether sulfone (PES), polyimide (PI), polyethylene naphthalate (PEN), polyurethane (PU), polydimethylsiloxane (PDMS), thermoplastic polyurethane (TPU), liquid crystal polymer (LCP), polytetrafluoroethylene (PTFE), polycarbonate (PC), pV3D3 polymer film, polystyrene-block-poly(ethylene-cyclobutene)-block-polystyrene, liquid metal, polypropylene, silica gel, paper, polyester non-woven fabric, aromatic polyamide paper, and vulcanized fiber.

[0059] See also Figure 3The electrically regulated drug release microneedle system 300 of the present application includes the above-mentioned drug-loaded microneedle patch 200, and also includes a power supply 310, a control device 320 and a counter electrode 330. The power supply 310 is used to provide power for the electrically regulated drug release microneedle system. The control device is used to provide an electrical signal to the circuit connected to the drug-loaded microneedle. The counter electrode 330 is used to form a closed loop with the power supply 310, the control device 320, the skin tissue and the electrically regulated drug release microneedle system and the circuit connected to the electrically regulated drug release microneedle system for the transmission of electrical signals. When the electrically regulated drug release microneedle system is used, the drug-loaded microneedle array is applied to the subject as a working electrode, the counter electrode is placed on the subject to form a loop, and the control device is operated to deliver the drug from the microneedle array. In this embodiment, the drug-loaded microneedle can be inserted into the surface of the subject's skin, mucosal layer, bone, etc., and the operation of the iontophoresis device can include transferring current between the anode and the cathode to establish a voltage, thereby delivering the drug component through the drug-loaded microneedle. The applied current and voltage can be controlled at a level that does not cause discomfort or even pain to the subject. Delivery of the drug agent from the drug loaded microneedle array can deliver the drug agent to and / or through the dermis of the subject, and / or the mucosa of the subject, and / or the deep dermis of the subject, and / or the bone of the subject.

[0060] See also Figure 1 , Figure 1 The electrical sealing material 120 of the drug-loaded microneedle is doped inside the needle body 110. The needle body 110 is attached to the conductive electrode 130 and connected to the conductive electrode 130 as the working electrode of the electrically controlled drug release microneedle system. The conductive electrode 130 and the electrode lead 220 are both formed on the substrate 210, and the insulating packaging layer 230 is formed on the substrate 210 and covers the electrode lead 220.

[0061] See also Figure 4 , Figure 4 The electrical sealing material 120 of the drug-loaded microneedle is coated on the surface of the needle body 110 to form an electrically switchable sealing layer. The needle body 110 is attached to the conductive electrode 130 and connected to the conductive electrode 130 as a working electrode of the electrically controlled drug release microneedle system. The conductive electrode 130 and the electrode lead 220 are both formed on the substrate 210, and the insulating packaging layer 230 is formed on the substrate 210 and covers the electrode lead 220.

[0062] See also Figure 6 , Figure 6 The electrical sealing material 120 of the drug-loaded microneedle is doped inside the needle body 110. The needle body 110 and the substrate 210 are integrally formed with the same material, the conductive electrode 130 and the electrode lead 220 are both formed on the substrate 240, the substrate 210 covers the substrate 240, and the position of the needle body 110 corresponds to the position of the conductive electrode 130.

[0063] See also Figure 8 , Figure 8 The electrical sealing material 120 of the drug-loaded microneedle is coated on the surface of the needle body 110. The needle body 110 and the substrate 210 are integrally formed with the same material, the conductive electrode 130 and the electrode lead 220 are both formed on the substrate 240, the insulating packaging layer is also formed on the substrate 240 and covers the electrode lead 220, the substrate 210 covers the insulating packaging layer on the substrate 240, and the position of the needle body 110 corresponds to the position of the conductive electrode 130.

[0064] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with the accompanying drawings and specific implementation methods.

[0065] Example 1

[0066] Please refer to Figure 1 In this embodiment, a drug-loaded microneedle 100 includes a needle body 110, a drug component, an electrical sealing material 120 and a conductive electrode 130, wherein the electrical sealing material 120 is doped inside the needle body. The needle body 110 is attached to the conductive electrode 130 and connected to the conductive electrode 130 as a working electrode of the electrically regulated drug release microneedle system. The needle body is a hydrogel microneedle made of a biocompatible material, the drug component loaded in the hydrogel microneedle is lidocaine hydrochloride, the electrical sealing material is polyacrylic acid (PAA), and the conductive electrode is Ag / AgCl. Part of the preparation method of the drug-loaded microneedle is as follows:

[0067] Take 8g PVA and add 60ml buffer solution (phosphate buffer with pH = 7.4), stir in a 90℃ oil bath for 2.5 hours until completely dissolved. Add polyacrylic acid (PAA) according to PVA:PAA = 8:1 (mass ratio), stir for 1.5 hours to obtain a mixed solution. Weigh an appropriate amount of lidocaine hydrochloride (according to the expected drug loading, for example, weigh 10%-15% of the mass of the hydrogel), dissolve it in the mixed solution and add it, stir evenly, and heat crosslink at 120℃ for 35 minutes to complete the functional group binding and drug loading to obtain a functionalized hydrogel solution. Prepared using micro-electromechanical system (MEMS) micromachining technology, the mold material is selected as PDMS, which has good biocompatibility and flexibility, and is easy to demold. The prepared functionalized hydrogel solution was injected into the microneedle mold cavity (the microneedle mold cavity was conical in shape), centrifuged at 3000rpm for 5 minutes, and vacuum assisted (vacuum degree -0.08MPa, maintained for 3 minutes) to ensure that the solution evenly filled the cavity and removed bubbles. The corresponding conditions were strictly controlled to complete cross-linking and curing, so that the hydrogel was formed into a microneedle structure, and demolding was performed to obtain the initial hydrogel microneedle with drug loading and cation exchange function.

[0068] Please refer to Figure 2The drug-loaded microneedle patch 200 in this embodiment includes the above-mentioned hydrogel microneedle primary product, a substrate 210, an electrode lead 220 formed on the substrate 210, and an insulating packaging layer 230. The electrode lead 220 is connected to the drug-loaded microneedle 100, and the needle body 110 is attached to the conductive electrode 130, and the conductive electrode 130 is formed on the substrate 210. The insulating packaging layer 230 is formed on the substrate 210 and covers the electrode lead 220, but the insulating packaging layer 230 does not cover the drug-loaded microneedle 100. The material of the substrate 210 is PET, the material of the electrode lead 220 is silver, the material of the insulating packaging layer is polyimide (PI), and the conductive electrode 130 is connected to the positive pole of the power supply. The Ag electrode lead pattern adapted to the layout of the drug-loaded microneedle array is designed, and the Ag slurry containing 2% (mass fraction) nanocellulose (NFC) as an additive is selected by screen printing technology. NFC can improve the printing performance of the slurry, and has biocompatibility, and can enhance adhesion after curing. The Ag slurry was printed on a polyethylene terephthalate (PET) film treated with oxygen plasma for 10 minutes (oxygen plasma treatment can improve the hydrophilicity and biocompatibility of PET). The screen size was 300 mesh, the scraper angle was 60°, and the scraper speed was 50 mm / s. It was then dried in a 90°C oven for 30 minutes and sintered at 120°C for 10 minutes (heating rate 5°C / min) to allow the Ag particles to be well sintered and bonded to form a stable conductive path to form an Ag electrode lead array. A PI film was coated on the Ag electrode lead array as an insulating layer, and electrode sites connected to the drug-loaded microneedles were reserved at the corresponding positions. AgCl was generated at the microneedle sites corresponding to the Ag electrode lead array by electrochemical oxidation. Saturated potassium chloride (KCl) solution was used as the electrolyte, the pH was maintained at 6-7, and a three-electrode system was used. The working electrode was the corresponding site of the Ag electrode lead array, the reference electrode was a saturated calomel electrode (SCE), and the counter electrode was a platinum sheet electrode. Under the control of a constant potential instrument, a potential of 0.2 V (relative to SCE) was applied for an oxidation time of 30-40 minutes to generate a uniform and dense AgCl layer on the Ag surface, forming an Ag / AgCl microneedle base, i.e., a conductive electrode.

[0069] The method of surface modification combined with physical nesting is used to increase adhesion: the bottom of the hydrogel microneedle product (opposite to the skin contact) is plasma treated with argon plasma at a power of 100W for 5 minutes to produce a micro-nano rough structure on the surface, increase the contact area, and introduce active groups at the same time. Chemical etching of the surface of the Ag / AgCl microneedle base, such as briefly soaking in dilute nitric acid (concentration 0.5mol / L) for 30 seconds and rinsing, can also produce a microscopic rough surface to increase the mechanical interlocking with the microneedle. The treated hydrogel microneedle product is precisely aligned with the Ag / AgCl microneedle base, and a certain pressure (pressure 0.8N, maintained for 10 seconds) is applied using a special mold to partially embed the hydrogel microneedle product into the surface of the base. With the help of physical nesting and chemical bonding, the two are firmly connected to ensure smooth conductive paths and meet the requirements of ion electrophoresis.

[0070] Connect the electrode lead array to the necessary wires to access the electrically controlled drug release microneedle system 300, please refer to Figure 3 , the electrically regulated drug release microneedle system 300 also includes a power supply 310, a control device 320 and a counter electrode 330. Among them, the power supply 310 is used to provide power for the electrically regulated drug release microneedle system 300; the control device 320 is used to provide an electrical signal to the circuit connected to the drug-loaded microneedle. The power supply 310 is connected to the control device 320, the conductive electrode 130 in the drug-loaded microneedle 100 is electrically connected to the control device 320 through a wire, and the counter electrode 330 is connected to the control device 320 through a wire, and the counter electrode 330 and the drug-loaded microneedle patch 200 are both attached to the skin tissue 0. The counter electrode can only contain an electrolyte salt solution hydrogel, and the counter electrode 330 is used to form a closed loop with the power supply 310, the control device 320, the skin tissue 0 and the drug-loaded microneedle 100 and the circuit connected to the drug-loaded microneedle 100 for the transmission of electrical signals.

[0071] The drug-loaded microneedle patch 200 in this embodiment is used to deliver the local anesthetic lidocaine hydrochloride to sensory nerves, for example but not limited to oral and maxillofacial surgery. Lidocaine hydrochloride is a strong acid organic weak base salt, which is easily dissociated into cations in solution. Lidocaine is an amide medium-acting local anesthetic, which is widely used clinically. The blood concentration is >5μg / ml, which means poisoning may occur. There have been many reports of poisoning caused by overdose or accidental injection into blood vessels. Therefore, the controllable, stable and rapid release of lidocaine during treatment is particularly important. The drug-loaded microneedle in this embodiment includes a needle body matrix of a biocompatible cross-linked polymer, in which the weakly acidic group carboxyl-COO of the electrical sealing material is combined. -. The electrical sealing material is covalently linked to the mesh skeleton carrier of the needle body and electrostatically bonds with the dissociated lidocaine cations to achieve drug loading. At the same time, the high loading characteristics of ion exchange are used to increase the drug loading capacity of the microneedle. The amount of loaded drug and the release rate can be controlled by adjusting factors such as the density of functional groups and the material properties of the microneedle. Because of the interaction between the electrically switched chemical sealing materials, when the microneedle is inserted into the skin tissue, the passive diffusion of drug ions is constrained in the absence of an electric field, thereby enhancing the environmental stability of the drug-loaded microneedle. Applying a mild external current (0.5mA / cm 2 ), the drug-loaded microneedle patch with electrically regulated drug release can achieve precise controlled release of drugs and enhance the penetration of drugs into and / or through the layers of the skin, mucous membranes and / or cortical bone, such as reaching nerves, thereby quickly producing a sustained and controlled anesthetic effect. The dose of electrically regulated drug delivery is proportional to the amount of charge passed, and the delivered drug dose can be controlled by current density, current type and application time.

[0072] The end of the drug-loaded microneedle 100 in this embodiment can be inserted into the surface of the subject's skin, mucosal layer, bone, etc. A control device is used to transfer current between the anode and the cathode to establish a voltage, thereby delivering lidocaine hydrochloride from the drug-loaded microneedle array. The applied current and voltage can be controlled at a level that does not cause discomfort or even pain to the subject. Delivery of lidocaine hydrochloride from the drug-loaded microneedle array can include delivering lidocaine hydrochloride to and / or through the dermis of the subject, and / or the mucosa of the subject, and / or the deep dermis of the subject, and / or the bone of the subject.

[0073] Example 2

[0074] Please refer to Figure 4 In this embodiment, a drug-loaded microneedle 100 includes a needle body 110, a drug component, an electrical sealing material 120 and a conductive electrode 130, wherein the electrical sealing material 120 is coated on the surface of the needle body 110 to form an electrically switchable sealing layer. The needle body 110 is located on the conductive electrode 130 and is connected to the conductive electrode 130 as a working electrode of the electrically regulated drug release microneedle system. The needle body is a porous microneedle made of poly(lactic-co-glycolic acid) (PLGA), the drug component loaded in the porous microneedle is methotrexate, the electrical sealing material is an anion exchange material quaternary ammonium cellulose (QAC), and the conductive electrode is Ag / AgCl. Part of the preparation method of the drug-loaded microneedle is as follows:

[0075] Poly(lactic-co-glycolic acid) (PLGA) was dissolved in a suitable organic solvent, which was a mixture of dichloromethane (DCM) and N-methylpyrrolidone (NMP) in a ratio of 3:1 (volume ratio), to prepare a 18% (mass volume ratio) PLGA solution. A mold with a specific microneedle shape was prepared using micromachining technology. The mold material can be selected from medical silicone, which is convenient for demolding and has good biocompatibility. The prepared PLGA solution was injected into the mold microneedle cavity (the mold microneedle cavity is a cone), centrifuged at 2500rpm for 8 minutes, combined with vacuum assistance (vacuum degree -0.06MPa, maintained for 5 minutes), to ensure that the solution completely filled the cavity and removed bubbles. The mold filled with the solution was placed in a fume hood to allow the organic solvent to evaporate slowly, so that the PLGA was solidified and formed, and the PLGA microneedle was obtained after demolding. The formed PLGA microneedles are placed in a porogen solution, such as a polyvinyl alcohol (PVA) aqueous solution, and soaked for a certain period of time (such as 1-2 hours) to allow the porogen to fully penetrate into the microneedles. Subsequently, the microneedles are transferred to pure water, and a porous structure is formed inside the microneedles by dissolving the porogen. The pure water is continuously replaced to ensure that the porogen is completely removed, and then the microneedles are freeze-dried to obtain porous PLGA microneedles. Weigh methotrexate (according to the expected drug loading, for example, 5%-10% of the mass of PLGA), dissolve methotrexate in a suitable solvent, such as a phosphate buffer solution (PBS) with a pH of 7.4, and prepare a drug solution of a certain concentration, the concentration of which is determined according to the required drug loading, generally 5-20 mg / mL. The prepared porous PLGA microneedles are immersed in the methotrexate solution, and slowly stirred at a low temperature (such as 4°C) to allow the drug to enter the porous structure of the microneedles by diffusion. The immersion time is adjusted according to the porosity and drug concentration of the microneedle, usually 12-24 hours. After loading, remove the microneedle and gently absorb the excess drug solution on the surface with filter paper. Dissolve quaternary ammonium cellulose in water to prepare a QAC aqueous solution with a concentration of 2-5% (w / v). Ultrasonic treatment can be used to accelerate the dissolution and ensure that the solution is uniform. The porous PLGA microneedle loaded with drugs is vertically immersed in the QAC solution and stays for a certain time (such as 30-60 seconds) to fully wet the surface of the microneedle. Then slowly and evenly remove the microneedle from the solution, and use the solvent to evaporate to form a uniform QAC coating on the surface of the microneedle. Repeat the dip coating 2-3 times to increase the thickness and uniformity of the coating. After each dip coating, dry the microneedle at room temperature or dry it in a low-temperature oven (such as 30°C) to ensure that the solvent is completely evaporated. To enhance the stability of the QAC coating, a cross-linking treatment can be performed. The dip-coated microneedles are immersed in a solution containing a crosslinking agent, such as a glutaraldehyde solution (concentration of 0.1-0.5%), for 30-60 minutes. After the crosslinking reaction is completed, the microneedles are fully rinsed with deionized water to remove the unreacted crosslinking agent.

[0076] Please refer to Figure 5The drug-loaded microneedle patch 200 in this embodiment includes the above-mentioned PLGA porous microneedle primary product, a substrate 210, an electrode lead 220 formed on the substrate 210, and an insulating packaging layer 230. The electrode lead 220 is connected to the drug-loaded microneedle 100, and the needle body 110 is attached to the conductive electrode 130, and the conductive electrode 130 is formed on the substrate 210. The insulating packaging layer 230 is formed on the substrate 210 and covers the conductive electrode 130 and the electrode lead 220, but the insulating packaging layer 230 does not cover the drug-loaded microneedle 100. The material of the substrate 210 is PI, the material of the electrode lead 220 is copper (Cu), the material of the insulating packaging layer 230 is thermoplastic polyurethane (TPU), and the conductive electrode 130 is connected to the negative pole of the power supply. A Cu electrode lead pattern matching the layout of the drug-loaded microneedle 100 was designed, and a copper (Cu) electrode lead array was made on a polyimide (PI) film by photolithography, etching, drilling, copper plating and other steps using a mature flexible circuit board (FPC) process. Thermoplastic polyurethane (TPU) was dissolved in tetrahydrofuran (THF) solvent to prepare a 10%-15% (mass volume ratio) solution. The TPU solution was evenly covered on the PI substrate and the Cu electrode lead using a spraying or spin coating process to form an insulating layer. During spraying, the spray gun pressure was controlled at 0.3-0.5MPa and the spraying distance was 15-20cm; for spin coating, the spray gun was rotated at a speed of 2000-3000rpm for 30-40 seconds. In the insulating layer corresponding to the Ag / AgCl electrode production site, a window of precise size was reserved using photolithography or laser drilling technology to ensure that the subsequent Ag / AgCl electrode production was not affected. The Cu electrode at the reserved window of the TPU insulating layer is surface treated, and a thin silver layer (silver layer thickness is about 0.5-1μm) is deposited on the Cu surface by chemical silver plating process to enhance conductivity and improve biocompatibility. The silver plating solution can use a mild formula containing silver ammonia complex as the main component to avoid the introduction of harmful impurities. Then, Ag / AgCl electrode is made on the Cu electrode by electrochemical deposition. Silver nitrate (AgNO 3 ) solution was used as the electrolyte with a concentration of 0.1 mol / L and a pH maintained at 5-6. A three-electrode system was used, with the working electrode being the Cu electrode window, the reference electrode being a saturated calomel electrode (SCE), and the counter electrode being a platinum electrode. First, under the control of a constant potential instrument, a -0.5 V potential (relative to SCE) was applied for a deposition time of 15-20 minutes to uniformly deposit a layer of Ag on the Cu surface; then the potential was switched to 0.2 V for an oxidation time of 20-30 minutes to convert part of the Ag into AgCl to form an Ag / AgCl microneedle base.

[0077] Conductive chitosan-dopamine composite coating was prepared on the Ag / AgCl microneedle base as a conductive electrode. Chitosan was dissolved in a weakly acidic solution (such as 1% acetic acid), and dopamine was added to the chitosan solution and stirred evenly. The pH value of the solution was controlled to be 8-8.5, triggering the oxidation of dopamine and generating polydopamine. To increase the conductivity, low concentration (<1% w / v) of carbon nanotubes or graphene oxide was added and ultrasonically dispersed evenly. A conductive chitosan-dopamine composite coating was formed on the Ag / AgCl electrode using a printing process, and the coating thickness was controlled to be 10-50 μm, which not only ensured conductivity and adhesion, but also avoided material waste. The bottom of the PLGA porous microneedle (opposite to the skin contact) was plasma treated with argon plasma at a power of 100 W for 5 minutes to produce a micro-nano rough structure on the surface, increase the contact area, and introduce active groups at the same time. The treated PLGA porous microneedles are precisely aligned with the Ag / AgCl microneedle base coated with the conductive chitosan-dopamine composite coating, and a certain pressure (pressure 0.8N) is applied using a special mold to maintain fixation, so that the conductive chitosan-dopamine composite coating is dried at room temperature or vacuum freeze-dried to avoid high-temperature curing affecting the stability of the material. Chitosan forms hydrogen bonds and coordination bonds with the metal surface through amino groups, and the polyphenol groups of polydopamine have good adhesion to both metal electrodes and microneedle materials. With the help of physical nesting and chemical bonding, the two are firmly connected; the chitosan-dopamine composite coating itself has a certain conductivity, and a small amount of conductive nanomaterials are added to further enhance it, ensuring that the conductive path is unobstructed and meeting the requirements of ion electroosmosis function.

[0078] Connect the electrode lead array to the necessary wires to access the electrically controlled drug release microneedle system 300, please refer to Figure 3 The electrically regulated drug release microneedle system 300 further includes a power source 310, a control device 320 and a counter electrode 330. The power source 310 is used to provide power to the electrically regulated drug release microneedle system 300; the control device 320 is used to provide an electrical signal to the circuit connected to the drug-loaded microneedle 100. The counter electrode 330 is used to form a closed loop with the power source 310, the control device 320, the skin tissue 0 and the drug-loaded microneedle 100 and the circuit connected to the drug-loaded microneedle 100 for the transmission of the electrical signal.

[0079] The drug-loaded microneedle patch 200 in this embodiment is used for topical transdermal administration of methotrexate. Methotrexate (4-amino-N10-methylpteroyl-L-glutamic acid; MTX) is a folic acid antagonist with antitumor activity, used to treat psoriasis and rheumatoid arthritis. It is known that systemic use of MTX can cause hepatotoxicity, inhibit bone marrow function and cause other adverse reactions, such as nausea, vomiting, anemia, fatigue, etc. Liver damage is a serious long-term effect observed in methotrexate treatment. Local administration of MTX at the site of psoriasis is likely to reduce systemic side effects associated with the drug and avoid first-pass elimination. MTX is a small molecule drug with a logP of -1.8 and a negative charge at physiological pH, so it can be delivered by a microneedle array that electrically regulates drug release through the negative electrode of the power supply. In this embodiment, a needle body matrix with a biocompatible cross-linked polymer is combined with an electrically switched chemical sealing material quaternized cellulose (QAC), which is positively charged and can undergo ion exchange with anionic drugs, and is derived from natural cellulose modification, and has better biocompatibility. PLGA porous microneedles are made by sequential operations of micromolding, freeze drying, hydrophilization and mechanical reinforcement. The quaternary ammonium salt group is covalently linked to the PLGA porous microneedle skeleton carrier, and then electrostatically binds to the dissociated MTX anion to achieve drug loading. At the same time, the high loading characteristics of ion exchange are used to increase the drug loading capacity of the microneedle. The amount of loaded drug and the release rate can be controlled by adjusting factors such as the density of functional groups and the material properties of the microneedle. Because of the interaction of the electrically switched chemical sealing material, the passive diffusion of drug ions is constrained when the microneedle is inserted into the skin tissue, which enhances the environmental stability of the drug-loaded microneedle. The microneedle patch with electrically regulated drug release can achieve precise controlled release of drugs, enhance drug penetration through the skin, and better control the amount of drug delivered. It has the advantages of local delivery of MTX without systemic side effects, and improves the clinical efficacy of MTX in the treatment of psoriasis and other skin diseases. Chitosan is a cheap and widely available natural polymer from marine organisms (crustaceans) with good biocompatibility, antibacterial and biodegradability; dopamine simulates the natural dopa structure (such as the role of dopamine in muscle), has excellent adhesion and biocompatibility, and is also a low-cost small molecule compound that is easy to purchase. The composite coating of the two is simple to prepare, does not require complex equipment, and the process can be scaled up. Chitosan can significantly improve its conductivity through chemical modification (such as covalent bonding with dopamine or composite with carbon nanomaterials). Conductive nanoparticles (such as graphene or carbon nanotubes) can be combined to further enhance conductivity while controlling costs. All materials are biodegradable and biocompatible materials, non-toxic and suitable for medical use. The use of chitosan-dopamine composite coating can enhance the adhesion between microneedles and metal electrodes while maintaining good conductivity and biocompatibility.

[0080] Example 3

[0081] Please refer to Figure 6 In this embodiment, a drug-loaded microneedle 100 includes a needle body 110, a drug component, an electric sealing material 120 and a conductive electrode 130, wherein the electric sealing material 120 is doped inside the needle body 110. The preparation material of the needle body 110 in this embodiment is the same as the preparation material of the substrate 210, and the needle body 110 and the substrate 210 are integrally formed. The needle body is a hydrogel microneedle made of polyethylene glycol diacrylate (PEGDA) and gelatin, the drug component loaded in the hydrogel microneedle is glucosamine or chondroitin sulfate, the electric sealing material is an ionic liquid choline dihydrogen phosphate (choline-DHP) or 1-ethyl-3-methylimidazole hydrochloride ([EMIM][Cl]), and the conductive electrode is Ag / AgCl.

[0082] The preparation method of the drug-loaded microneedles loaded with glucosamine is as follows: PEGDA and gelatin solutions are prepared separately, PEGDA is dissolved in an appropriate amount of phosphate buffer (PBS, pH 7.4) to prepare a solution with a PEGDA mass concentration of 22%; gelatin is slowly dissolved in deionized water at 40-50°C to prepare a gelatin mass concentration of 12%. The two are mixed in a ratio of PEGDA: gelatin = 3:1 (volume ratio), and magnetic stirring is performed for 2-3 hours to make it fully uniform. Ionic liquid choline dihydrogen phosphate (choline-DHP) is added in a ratio of PEGDA-gelatin mixed solution: choline-DHP = 10:1 (mass ratio), and stirring is continued for 1-2 hours to ensure that the ionic liquid is evenly dispersed. Glucosamine is weighed (according to the expected drug loading, for example, 8%-12% of the mass of the PEGDA-gelatin mixed solution), dissolved in a small amount of PBS, and then slowly dripped into the above mixed solution, stirred for 30-60 minutes, to ensure that the drug is evenly distributed in the system. Microelectromechanical system (MEMS) technology was used to prepare a microneedle mold with a specific shape. The mold material was PDMS, which has good biocompatibility, strong flexibility, and is easy to demold. The prepared PEGDA-gelatin mixture containing drugs and ionic liquids was injected into the mold microneedle cavity, centrifuged at 3000rpm for 6 minutes, combined with vacuum assistance (vacuum degree -0.07MPa, maintained for 4 minutes) to ensure that the solution completely filled the cavity and removed bubbles. The ultraviolet light cross-linking method was used, using an ultraviolet lamp with a wavelength of 365nm and a light intensity of 6mW / cm 2 The irradiation time is 12-18 minutes, so that the PEGDA is cross-linked and solidified, and the gelatin also stabilizes the structure to a certain extent. After demolding, the first product of PEGDA-gelatin hydrogel microneedle loaded with glucosamine and containing ionic liquid function is obtained.

[0083] The preparation method of the drug-loaded microneedles containing chondroitin sulfate is as follows: PEGDA is dissolved in a phosphate buffer solution (PBS, pH 7.4) sterilized at high temperature and high pressure to prepare a solution with a PEGDA mass concentration of 22%-27%; gelatin is placed in sterile deionized water at 45-55°C and slowly stirred to dissolve to prepare a gelatin mass concentration of 12%-17% (mass volume ratio). The two are mixed in a ratio of PEGDA: gelatin = 4:1 (volume ratio), and a magnetic stirrer is used to continuously stir for 2.5-3.5 hours until the mixture is uniform and there is no stratification. The ionic liquid 1-ethyl-3-methylimidazole hydrochloride ([EMIM][Cl]) is added according to the ratio of PEGDA-gelatin mixed solution: [EMIM][Cl] = 8:1 (mass ratio), and stirring is continued for 1.5-2.5 hours to ensure that the ionic liquid is evenly dispersed in the system. Accurately weigh chondroitin sulfate (refer to the expected drug loading, for example, weigh 6%-10% of the mass of the PEGDA-gelatin mixture), dissolve it with a small amount of PBS preheated to 37°C, and slowly add the above mixture drop by drop, stirring while adding, and continue stirring for 40-70 minutes to ensure that the drug is evenly distributed and avoid agglomeration. With the help of microelectromechanical system (MEMS) precision manufacturing technology, a microneedle mold with a specific shape is created. The mold is made of medical-grade silicone material, which has excellent biocompatibility and good flexibility, and can greatly facilitate the demolding process. The prepared drug-containing and ionic liquid-containing PEGDA-gelatin mixture is injected into the microneedle cavity of the mold, first centrifuged at 3200rpm for 7 minutes, and then assisted by vacuum assistance (the vacuum degree is maintained at -0.075MPa for 5 minutes) to ensure that the solution fills the cavity in all directions and without dead ends, and at the same time completely eliminates bubbles. Turn on the ultraviolet light with a wavelength of 365nm for cross-linking and curing, and the light intensity is adjusted at 7mW / cm 2 The irradiation time is set to 14-20 minutes to promote the full cross-linking of PEGDA and the simultaneous stabilization of the gelatin structure. After demolding, the second product of PEGDA-gelatin hydrogel microneedle loaded with chondroitin sulfate and integrated with ionic liquid function can be obtained.

[0084] Please refer to Figure 7 The drug-loaded microneedle patch 200 in this embodiment includes the above-mentioned PEGDA-gelatin hydrogel microneedle primary product 1 or PEGDA-gelatin hydrogel microneedle primary product 1, a substrate 240 and an electrode lead 220 formed on the substrate 240, and an insulating packaging layer 230. The conductive electrode 130 is connected to the electrode lead 220, and the conductive electrode 130 is formed on the substrate 240. The base 210 is covered on the substrate 240, and the positions of the drug-loaded microneedle 110 and the conductive electrode 130 correspond. The insulating packaging layer 230 covers the electrode lead, and the material of the insulating packaging layer is thermoplastic polyurethane (TPU), and the conductive electrode is connected to the positive pole of the power supply.

[0085] A Cu electrode lead pattern matching the layout of the drug-loaded microneedle 100 was designed, and a copper (Cu) electrode lead array was made on a polyimide (PI) film by photolithography, etching, drilling, copper plating and other steps using a mature flexible circuit board (FPC) process. Thermoplastic polyurethane (TPU) was dissolved in tetrahydrofuran (THF) solvent to prepare a solution with a mass concentration of 10%-15% of thermoplastic polyurethane. The TPU solution was evenly covered on the PI substrate and the Cu electrode lead using a spraying or spin coating process to form an insulating encapsulation layer. During spraying, the spray gun pressure was controlled at 0.3-0.5MPa and the spraying distance was 15-20cm; for spin coating, the spray gun was rotated at a speed of 2000-3000rpm for 30-40 seconds. In the insulating encapsulation layer corresponding to the Ag / AgCl electrode production site, a window of precise size was reserved using photolithography or laser drilling technology to ensure that the subsequent Ag / AgCl electrode production was not affected. The Cu electrode at the reserved window of the TPU insulating layer is surface treated, and a thin silver layer (silver layer thickness is about 0.5-1μm) is deposited on the Cu surface by chemical silver plating process to enhance conductivity and improve biocompatibility. The silver plating solution can use a mild formula containing silver ammonia complex as the main component to avoid the introduction of harmful impurities. Then, Ag / AgCl electrode is made on the Cu electrode by electrochemical deposition. Silver nitrate (AgNO 3 ) solution was used as the electrolyte with a concentration of 0.1 mol / L and a pH maintained at 5-6. A three-electrode system was used, with the working electrode being the Cu electrode window, the reference electrode being a saturated calomel electrode (SCE), and the counter electrode being a platinum electrode. First, under the control of a constant potential instrument, a -0.5 V potential (relative to SCE) was applied for a deposition time of 15-20 minutes to uniformly deposit a layer of Ag on the Cu surface; then the potential was switched to 0.2 V for an oxidation time of 20-30 minutes to convert part of the Ag into AgCl to form an Ag / AgCl microneedle base.

[0086] Through mechanical grinding, sandblasting, acid etching and other methods, a microscopic rough structure is formed on the surface of the Ag / AgCl metal electrode to improve the mechanical interlocking force with the microneedle material. Then, a silane coupling agent containing a conductive group (mercaptopropyltrimethoxysilane (MPTMS) or aminopropyltriethoxysilane (APTES)) is used to modify the surface of the Ag / AgCl metal electrode. The siloxane group at one end of the silane coupling agent reacts with the metal oxide layer, and the functional group (such as amino or epoxy) at the other end chemically bonds with the polymer material. Select a silane coupling agent containing a conductive group, such as mercaptopropyltrimethoxysilane (MPTMS) or aminopropyltriethoxysilane (APTES). Prepare a 0.15% (v / v) silane solution, the solvent is anhydrous ethanol, and deionized water is added to regulate the hydrolysis reaction. Stir for 30 minutes until transparent and uniform. The coupling agent is patterned and coated on the Ag / AgCl metal electrode using printing, spraying, photolithography and other techniques to ensure that the coupling agent coating is extremely thin (<10nm) and will not significantly hinder the passage of current even if its conductivity is low. Let it stand at room temperature for 10 to 15 minutes to allow the silane coupling agent to fully react and deposit on the surface of the conductive electrode. The silane-coated conductive electrode is placed in an oven at 80 to 100°C and heated for 30 minutes to promote the covalent bonding of the silane coupling agent to the metal surface. To enhance the adhesion of the hydrogel microneedle surface, the hydrogel surface can be modified to functional groups that react with the silane coupling agent. Use a low concentration of mercaptosilane (such as MPTMS) or aminosilane (such as APTES) solution to gently coat the hydrogel surface and then dry it at room temperature. The treated drug-loaded microneedles are precisely aligned with the Ag / AgCl microneedle base coated with a silane coupling agent containing a conductive group, and a certain pressure (pressure 0.8N) is applied using a special mold to maintain fixation. The metal electrode and the hydrogel microneedle are kept in contact for 1 hour at room temperature, or the bonding can be accelerated at 50-60°C to ensure that the silane coupling agent forms a strong adhesion with the surface of the hydrogel microneedle. At this time, the covalent bond formed by the coupling agent and the electrode surface reacts with the hydrogel surface to ensure long-term and stable bonding.

[0087] Connect the electrode lead array to the necessary wires to access the electrically controlled drug release microneedle system 300, please refer to Figure 3 The electrically regulated drug release microneedle system 300 further includes a power source 310, a control device 320 and a counter electrode 330. The power source 310 is used to provide power to the electrically regulated drug release microneedle system 300; the control device 320 is used to provide an electrical signal to the circuit connected to the drug-loaded microneedle 100. The counter electrode 330 is used to form a closed loop with the power source 310, the control device 320, the skin tissue 0 and the drug-loaded microneedle 100 and the circuit connected to the drug-loaded microneedle 100 for the transmission of the electrical signal.

[0088] Osteoarthritis (OA) is the most common form of arthritis, and there is evidence that OA is an inevitable part of aging and is often associated with diabetes. Obesity, work-related injuries, and sports injuries are also partly responsible for OA. Elite athletes have a higher incidence of arthritis compared to non-athletes. The main goals of OA treatment include relieving pain and improving functional ability, and the main drugs of choice are nonsteroidal anti-inflammatory drugs (NSAIDs), but oral and injectable preparations are not without potential harm. Adverse reactions include gastrointestinal disorders and decreased immunity, especially in the elderly. Glucosamine is considered a possible way to relieve pain caused by arthritis. The human body relies on glucosamine to synthesize connective tissue and cartilage. Glucosamine is used as a starting material for tendons and ligaments, mucosal lining of the digestive and respiratory tracts, and synovial fluid in joints. It also supports healthy mucus secretion in the digestive, respiratory, and urinary tracts. There is evidence that glucosamine also helps improve joint structure. For people who experience frequent knee pain due to cartilage damage or osteoarthritis, supplementing with glucosamine can relieve pain and improve function to some extent. Some clinical trials have shown that glucosamine can prevent or slow the loss of cartilage rather than regrow it. Most athletes take glucosamine supplements through their diet to fight inflammation, repair cartilage and promote joint health. The adverse reactions of oral glucosamine supplements are mainly gastrointestinal symptoms such as nausea, constipation, bloating and diarrhea. Many topical compositions such as glucosamine sulfate creams have been developed to bypass the gastrointestinal tract and thus reduce the side effects associated with oral administration. Such topical compositions also have the additional advantage of acting faster in reducing pain and inflammation. If used near the joints, transdermal administration of glucosamine is more effective than oral administration. However, there are still challenges in optimizing and enhancing the therapeutic effects of these topical compositions.

[0089] This embodiment uses a hydrogel matrix formed by cross-linking polyethylene glycol diacrylate (PEGDA) and gelatin. The microneedles loaded with glucosamine are added with ionic liquid choline dihydrogen phosphate (choline-DHP), and the microneedles loaded with chondroitin sulfate are added with ionic liquid 1-ethyl-3-methylimidazole hydrochloride ([EMIM][Cl]), which can both achieve electrical switching chemical sealing and ionic conductivity at the same time. The ionic liquid in the microneedle provides a conductive channel to enhance the electroosmotic effect driven by the electric field; the drug molecules are released from the microneedle to the target tissue under the dual effects of electrostatic force and electroosmotic effect. Polyethylene glycol diacrylate (PEGDA) has good biocompatibility and hydrophilicity, and forms a stable network structure after cross-linking, which provides mechanical strength for the microneedle and can effectively carry drugs and functional components. Gelatin, derived from the hydrolysis of animal collagen, has excellent biocompatibility, can give the hydrogel microneedle a certain biological activity and cell adhesion, and cooperates with PEGDA to construct a suitable drug sustained release environment. Choline dihydrogen phosphate has good biocompatibility and moderate electrical conductivity. It forms ion channels in hydrogels, giving them good electrical conductivity and enhancing the electrical response characteristics of hydrogel microneedles. The phosphate anions of choline dihydrogen phosphate can bind to positively charged glucosamine through electrostatic interaction. This combination remains stable in the absence of an electric field, forming a dynamic ionic bond to prevent the drug from diffusing into the external environment. When an electric field is applied, the electroosmotic effect causes glucosamine to be released from the phosphate bond, achieving precise drug delivery in an electrically controlled manner. 1-Ethyl-3-methylimidazole hydrochloride has good biocompatibility and is compatible with hydrogel systems. Its ionic conductivity significantly improves the electrical conductivity of the hydrogel, which supports the drug controlled release function induced by an electric field; the positively charged imidazolium cation in 1-ethyl-3-methylimidazole hydrochloride forms an electrostatic interaction with the negative charge of chondroitin sulfate, so that the drug molecules are fixed in the hydrogel network in the absence of external stimulation. Under the condition of an external electric field, the drug molecules are driven out of electrostatic bondage and released to the target site on demand.

[0090] Ag / AgCl electrodes are used as anode and cathode respectively. Ag / AgCl electrodes provide stable electrochemical reactions to prevent other byproducts from interfering with drug release. Anode (positive electrode) area: Loading positively charged glucosamine-loaded microneedles. Cathode (negative electrode) area: Loading negatively charged chondroitin sulfate-loaded microneedles. Through an external electric field, the glucosamine at the anode is released to the target site under the repulsion of the positive charge, and the chondroitin sulfate at the cathode is released to the target site under the repulsion of the negative charge.

[0091] (1) Anode (Ag / AgCl anode) reaction

[0092] Chloride ions are oxidized at the anode to generate AgCl deposited on the electrode surface, while releasing electrons. The relevant reaction equations involved are as follows:

[0093] AgCl(s)+e- →Ag(s)+Cl -

[0094] (2) Cathode (Ag / AgCl cathode) reaction

[0095] Silver chloride is reduced at the cathode to generate chloride ions and deposit silver at the same time. The relevant reaction equations involved are as follows:

[0096] Ag(s)+Cl - →AgCl(s)+e -

[0097] This embodiment uses the reversible electrochemical reaction of Ag / AgCl electrodes and the electroosmotic effect enhanced by ionic liquids to successfully achieve the function of electrically controlled release of glucosamine and chondroitin sulfate, and combines glucosamine and chondroitin sulfate delivery for articular cartilage repair and anti-inflammation. The electric field strength is adjusted according to the patient's condition to achieve dynamic drug dosage control, provide precise drug release, and reduce systemic side effects. It is an efficient transdermal drug delivery strategy.

[0098] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. 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 the technical solutions of the present invention may be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, which should be included in the scope of the claims of the present invention. The techniques, shapes, and structural parts not described in detail in the present invention are all known technologies.

Claims

1. A drug-loaded microneedle, characterized in that: The drug-loaded microneedle is applied to an electrically regulated drug release microneedle system, and the drug-loaded microneedle comprises: A needle body, wherein the conductive needle body is made of a biocompatible material and has conductivity, and the needle body is a hydrogel microneedle or a porous microneedle; The drug component is mixed in the needle body or coated on the surface of the needle body; An electric sealing material is doped inside the needle body and / or coated on the surface of the needle body, and the electric sealing material is connected to the needle body through at least one of a covalent bond, an ionic bond, and a coordination bond; When the drug-loaded microneedle is inserted into the target tissue, the drug components can be controlled to be released through electrical signals, and the drug components can be introduced into the target tissue through electrical drive.

2. The drug-loaded microneedle according to claim 1, characterized in that: The content of the electric sealing material in the drug-loaded microneedle is 0.1wt% to 90wt%; the electric sealing material is selected from one or more of ion exchange materials, ionic liquids, electroactive hydrogels, porous insulating polymer membranes, and nanocomposite materials.

3. The drug-loaded microneedle according to claim 2, characterized in that: The ion exchange material is selected from at least one of a cation exchange functional group and an anion exchange functional group; The ionic liquid includes choline chloride, choline dihydrogen phosphate, choline diphosphate, choline bicarbonate, 1-ethyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium chloride, 1-methylimidazolium acetate, choline glycine, choline lactate, choline arginine, tetrabutylphosphine methane sulfonate, choline methane sulfonate, choline iodide, ammonium acetate, choline acetate, ethylammonium nitrate, dihydroxyacetic acid choline, glycerophosphocholine, 1-butylpyridinium chloride, 1-ethylpyridinium acetate, 1-butylpiperidinium acetate, 1-ethylpiperidinium phosphate, proline-lactic acid, proline benzoate, ethylammonium lactate, triethylammonium phosphate, 1,3-dimethylimidazolium hydrogen sulfate, 1-methylimidazolium formate, 1-ethylimidazolium thiocyanate, 1- Butylimidazole acetate, choline succinate, choline phosphate, ammonium sucrose octaacetate, histidine chloride, histidine phosphate, histidine acetate, lysine acetate, lysine lactate, ethanolamine lactate, ethanolammonium phosphate, arginine acetate, proline lactate, methionine chloride, 1-methylpiperidinic acid, 1-butylpiperazine phosphate, poly(1-vinyl-3-ethylimidazole) bromide, polycholine phosphate, triethylammonium sulfate, choline-urea mixture, lactic acid-based DES, 1-ethyl-3-methylimidazole glycinate, 1-ethyl-3-methylimidazole glutamate, 1-ethyl-3-methylimidazole alanine, 1-ethyl-3-methylimidazole proline, 1-butyl-3-methylimidazole glycinate, 1-butyl- 3-Methylimidazole glutamate, 1-butyl-3-methylimidazole alanine, 1-butyl-3-methylimidazole proline, 1-ethyl-3-methylimidazole hexafluorophosphate, 1-ethyl-3-methylimidazole phosphate, 1-ethyl-3-methylimidazole dihydrogen phosphate, 1-butyl-3-methylimidazole hexafluorophosphate, 1-butyl-3-methylimidazole dihydrogen phosphate, deoxycholic acid quaternary ammonium salt, deoxycholic acid imidazolium salt, glycocholic acid quaternary ammonium salt, glycocholic acid imidazolium salt, cholic acid quaternary ammonium salt, cholic acid imidazolium salt, 1-phenethyl-3-methylimidazole salt, glycine methyl ester hydrochloride, acetate quaternary ammonium salt, phosphate quaternary ammonium salt, L-arginine acetate, L-histidine citrate, L-alanine ethyl ester bromide, guanidine chloride ionic liquid, guanidine carbonate Ionic liquids, guanidine phosphate, choline-aspartic acid, choline-glutamic acid, choline acetate, choline citrate, tetramethylammonium glycine, tetraethylammonium lysine, tetramethylammonium trifluoromethanesulfonate, dodecyltrimethylammonium bromide, choline methanesulfonate ion, ammonium p-toluenesulfonate ion, ethyl ammonium methanesulfonate, choline p-toluenesulfonate, triethylammonium phosphate, potassium dibutyl phosphate, triethyl ammonium phosphate, potassium dibutyl phosphate, betaine hydrochloride, dodecylbetaine ammonium bromide, betaine phosphate, N-methylpyrrolidone hydrogen sulfate, N-butylpyrrolidone bistrifluoromethanesulfonimide, N-methylpyrrolidone-lactate, N-butylpyrrolidine-acetate, morpholine hydrochloride, 4-methylmorpholine nitrate, N-methylmorpholine methanesulfonate,N-Ethylmorpholine p-toluenesulfonate, ethyl piperidine bromide, N-methylpiperidinium tetrafluoroborate, 1-methylpiperidinium nitrate, 1-butylpiperidinium acetate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-ethyl-3-methylimidazolium acetate, tributylmethylphosphonium bistrifluoromethanesulfonimide, tetrabutylphosphonium acetate, hydroxyapatite-imidazole ionic liquid, hydroxyapatite-pyridine ionic liquid, chitosan lactate, sodium calcium alginate, potassium gluconate, glucosamine hydrochloride, N-methylpyrrolidone hydrogen sulfate, N-ethylpyrrolidone tetrafluoroborate, triethylsulfonium tetrafluoroborate, dimethylphenylsulfonium hexafluorophosphorus at least one of 2-(4-(2-methyl-2-thiazole) tetrafluoroborate, 5-methyl-2-propyl-2-thiazole acetate, 2-methylfuran tetrafluoroborate, 3-furanammonium formate, indole-3-acetate, N-methylindole bromide, adenine acetate, guanine hydrochloride, 9-methylcarbazole nitrate, and N-ethylcarbazole tetrafluoroborate; or, The electroactive hydrogel comprises at least one of polyvinyl alcohol-based hydrogel, polyacrylamide-based hydrogel, poly(3,4-ethylenedioxythiophene)-based hydrogel, polypyrrole-based hydrogel, polyaniline-based hydrogel, polyamide-based hydrogel, poly(urethane)-based hydrogel, polyvinylpyrrolidone-based hydrogel, polyurethane / poly(3,4-ethylenedioxythiophene) composite hydrogel, polylactic acid / polycaprolactone composite hydrogel, poly(2-methyl-2-ethyl acrylate)-based hydrogel, poly(acrylonitrile)-based hydrogel, polystyrene-based hydrogel, and electroactive polymer-based hydrogel; or, The porous insulating polymer film includes at least one of polyimide, polyvinylidene fluoride, polytetrafluoroethylene, polyvinyl chloride, polyetheretherketone, and polyvinyl alcohol; or, The nanocomposite material comprises at least one of polyvinyl alcohol / titanium oxide, polyvinyl pyrrolidone / titanium oxide, polyurethane / titanium oxide, polyamide / titanium oxide, polyvinyl alcohol / nano-silicon, polyvinyl pyrrolidone / nano-silicon, polyurethane / nano-silicon, polyamide / nano-silicon, polyvinyl alcohol / carbon quantum dots, polyvinyl pyrrolidone / carbon quantum dots, polyurethane / carbon quantum dots, polyamide / carbon quantum dots, polyvinyl alcohol / silver nanowires, polyvinyl pyrrolidone / silver nanowires, polyurethane / silver nanowires, polyamide / silver nanowires, polyvinyl alcohol / gold nanoparticles, polyvinyl pyrrolidone / gold nanoparticles, polyurethane / gold nanoparticles, polyamide / gold nanoparticles, polyvinyl alcohol / copper nanoparticles, polyvinyl pyrrolidone / copper nanoparticles, polyurethane / copper nanoparticles, and polyamide / copper nanoparticles.

4. The drug-loaded microneedle according to claim 1, characterized in that: The hydrogel microneedle is made of at least one raw material including methacrylated hyaluronic acid, poly(glycolic acid), poly-L-lactide, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, polylactic acid, polyglycolic acid, chitosan, polycaprolactone, polylactic acid-glycolic acid copolymer, polymethyl vinyl ether / maleic acid, poly(methyl vinyl ether maleic anhydride, silk protein, polyethylene glycol, methacryloyl gelatin, γ-polyglutamic acid, cross-linked copolymer of 2-hydroxyethyl methacrylate, N-dimethylformamide, glycine and 2-ethoxyethanol, poly(styrene-b-acrylic acid), polyethylene glycol diacrylate, sodium polystyrene sulfonate, poly-N-isopropylacrylamide, sodium alginate, polycarbonate, agarose, pectin and gelatin.

5. The drug-loaded microneedle according to claim 1, characterized in that: The porous microneedle is made of at least one raw material including silicon, aluminum oxide, titanium, medical grade stainless steel, gelatin, sodium alginate, hyaluronic acid, chitosan, hydroxypropyl methylcellulose, polyamide, polyurethane, polycarbonate, polycaprolactone, polysuccinate, polyethylene glycol diacrylate, polyacrylamide, polyacrylic acid, γ-polyglutamic acid, gelatin-methacrylamide, poly(ethylene glycol-co-methacrylic acid), poly(glycidyl methacrylate), poly(lactic acid-glycolic acid copolymer), polydimethylsiloxane, polyvinyl pyrrolidone, cellulose acetate, silk fibroin, polylactic acid, carboxymethyl cellulose, hydroxyapatite composite, diatomaceous earth-polymer composite, polymer doped with silica nanoparticles, starch-chitosan composite, collagen-gelatin composite, calcium sulfate dihydrate and calcium phosphate dihydrate.

6. The drug-loaded microneedle according to claim 1, characterized in that: The drug-loaded microneedle also includes a conductive electrode. The needle body is located above the conductive electrode and is connected to the conductive electrode as a working electrode of the electrically regulated drug release microneedle system.

7. The drug-loaded microneedle according to claim 6, characterized in that: The conductive electrode comprises silicon, silicon dioxide, silicon nitride, graphite, graphene, poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, poly[3,6-bis(40-dodecyl[2,20]biphenylthio-5-yl)-2,5-bis(2-hexyldecyl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione], polymethyl methacrylate, polyethylene glycol, pentacene, tetracene, anthracene, naphthalene, a-6-thiophene, a-4-thiophene, perylene and its derivatives, rubrene and its derivatives, coronene and its derivatives, perylenetetracarboxylic acid diimide and its derivatives, perylenetetracarboxylic acid dianhydride and its derivatives, polythiophene and its derivatives, polyparaphenyleneethylene and its derivatives, polyparaphenylene and its derivatives, polyfluorene and its derivatives, polythiophene and its derivatives The invention is prepared from at least one of 1,2-vinylidene and its derivatives, polythiophene-heterocyclic aromatic polymers and its derivatives, naphthalene oligoacene and its derivatives, a-5-thiophene oligothiophene and its derivatives, metal-free phthalocyanine and its derivatives, benzene tetracarboxylic acid dianhydride and its derivatives, benzene tetracarboxylic acid diimide and its derivatives, naphthalene tetracarboxylic acid diimide and its derivatives, naphthalene tetracarboxylic acid dianhydride and its derivatives, nitrile rubber, styrene-ethylene-butylene-styrene, carbon nanotubes, Ag / AgCl, PR-PEGMA, IGZO, IGZTO, IGTO, IZO, ITO, InO, Cu, Ag, Al, Mo, Li, Mg, Ti, Ta, Au, Cr, W, Ni, Pt, Pd and Ga.

8. A drug-loaded microneedle patch, characterized in that: The drug-loaded microneedle patch comprises a substrate and the drug-loaded microneedle according to any one of claims 1 to 7, as well as an electrode lead and a conductive electrode, wherein the electrode lead is connected to the drug-loaded microneedle; The conductive electrode and the electrode lead are formed on the substrate, the drug-loaded microneedle is formed on the conductive electrode, and the electrode lead is connected to the conductive electrode; or, The base and the needle body are integrally formed, and the drug-loaded microneedle patch also includes a substrate, the base is located on the substrate, the electrode lead and the conductive electrode are both formed on the substrate, and the position of the conductive electrode corresponds to the position of the needle body.

9. The drug-loaded microneedle according to claim 8, characterized in that: The drug-loaded microneedle patch also includes an insulating packaging layer, and the insulating packaging layer covers the electrode leads.

10. An electrically controlled drug release microneedle system, characterized in that: Comprising the drug-loaded microneedle patch as described in claim 8 or 9.

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