Electrically controlled release separable microneedle patch and drug delivery device

Abstract

The invention relates to the technical field of microneedle drug delivery, in particular to an electric controlled release separable microneedle patch and a drug delivery device.The microneedle patch comprises a substrate, a microneedle array and a sacrificial layer, the substrate comprises a first surface and a second surface which are oppositely arranged, the first surface is used for being attached to the surface of biological tissue, and the microneedle array is located on the first surface; the microneedle array comprises a plurality of needle bodies, the needle bodies contain effective substances to be conveyed, the sacrificial layer is located between the substrate and the needle bodies, the sacrificial layer is made of a conductive material, the sacrificial layer can be damaged by electrifying the sacrificial layer, and the needle bodies are promoted to be separated from the substrate. According to the electrically controlled-release separable microneedle patch, the sacrificial layer can be quickly damaged by applying the current to the sacrificial layer, so that the needle body and the substrate are quickly separated, the discomfort caused by the fact that the substrate is attached to the surface of biological tissue for a long time is avoided, and the dependency of a user is further improved.

Description

Technical Field

[0001] The present invention relates to the technical field of microneedle drug delivery, and particularly to an electrically controlled release separable microneedle patch and a drug delivery device. Background Art

[0002] Subcutaneous injection using a hypodermic needle has always been considered the most common drug delivery technique, which aims to overcome the skin barrier around the outermost layer of the human body. If this outermost barrier is overcome, almost all types of drugs - from small molecules to proteins or genes - can be delivered through blood vessels in the subcutaneous fat layer. However, traditional subcutaneous injection needles directly entering blood vessels through subcutaneous injection are invasive and cause great pain because the needles also stimulate the surrounding nerves.

[0003] Transdermal drug delivery is a way of drug delivery through the skin, which can avoid the interference of the gastrointestinal environment on the drug effect and the "first-pass effect" of the liver, maintain a constant optimal blood drug concentration or physiological effect, extend the effective action time, reduce the number of drug administrations, and patients can self-administer the drug with good compliance. In recent years, microneedle technology has received extensive attention because it can penetrate the stratum corneum of the skin or mucosa and directly deliver drugs to blood vessels, thus achieving rapid drug absorption. As a new painless transdermal drug delivery technology, soluble microneedles can painlessly create micron-level drug delivery channels on the skin, enhance the permeability of the skin to active drugs, especially macromolecular active ingredients, and its advantages of painlessness, safety, easy operation, etc. make it one of the research and development hotspots in the field of transdermal drug delivery. The microneedle drug patch containing soluble microneedles solves the problems of low drug conduction efficiency and obvious pain in the existing transdermal drug delivery technology, and brings a new painless, safe and efficient transdermal drug delivery method for consumers, which is widely used in the beauty field and the pharmaceutical field.

[0004] For traditional soluble microneedle patches, since what is often added is a soluble high molecular polymer, after the microneedles penetrate the skin, the dissolution rate of the microneedle body is relatively slow, and it takes several minutes or even longer to completely dissolve. It is necessary to wait until the soluble needle body dissolves before the base can be peeled off. This will cause the skin to be isolated from air and water for a long time, resulting in stuffiness and dampness on the skin surface, a strong foreign body sensation during application, bringing discomfort or inconvenience to patients, and may also, under the action of external force, change the position or characteristics of the microneedles in an undesirable manner, affecting the drug delivery effect. Patent CN105596287A discloses an actively separable soluble microneedle and its preparation method, which adds a soluble layer between the soluble needle body and the base. The soluble layer dissolves by absorbing the moisture on the skin surface and the tissue fluid exuded by the skin to complete the separation of the soluble needle body and the base sheet. However, under normal conditions, the moisture exhaled from the skin surface is limited. Depending only on the moisture on the skin surface, the dissolution rate of the soluble layer is not much different from that of the needle body, and the rapid separation of the base layer and the needle body still cannot be achieved. Summary of the Invention

[0005] In view of this, an object of the present invention is to provide an electrically controlled release separable microneedle patch and a drug delivery device, so as to at least solve the problem that the base and the needle body cannot be quickly separated after the microneedle is inserted into the skin tissue in the existing separable microneedle patch.

[0006] The present invention solves the above technical problems through the following technical means:

[0007] In a first aspect, an embodiment of the present invention discloses an electrically controlled release separable microneedle patch, including:

[0008] A base, including a first surface and a second surface arranged opposite to each other, the first surface is used for adhering to the surface of a biological tissue;

[0009] A microneedle array extending from the base, the microneedle array is located on the first surface, the microneedle array includes a plurality of needle bodies, and the needle bodies contain an active substance to be delivered;

[0010] A sacrificial layer, located between the base and the needle body, the sacrificial layer is made of a conductive material, and energizing the sacrificial layer can cause the sacrificial layer to be damaged and promote the separation of the needle body from the base.

[0011] In combination with the first aspect, in some embodiments, the sacrificial layer is connected with a power transmission wire, and the resistivity of any position of the sacrificial layer is greater than that of the power transmission wire.

[0012] In combination with the first aspect, in some embodiments, the resistivity of the sacrificial layer gradually increases from the edge to the center.

[0013] In combination with the first aspect, in some embodiments, the sacrificial layer is a thin film with a uniform thickness; or the sacrificial layer is a mesh or ring-shaped thin film; or the thickness of the sacrificial layer gradually thins from the edge to the center.

[0014] In combination with the first aspect, in some embodiments, the sacrificial layer is made of at least one material selected from gold, platinum, titanium, copper, aluminum, silver, magnesium, zinc, palladium, tin, bismuth, indium, antimony, Au / Si, Au / Ge, Pt / Ir, Ni / Ti, In / Sn, Bi / Sb, titanium alloy, magnesium alloy, zinc alloy, iron-based alloy, calcium-based alloy, platinum silicide.

[0015] Alternatively, the sacrificial layer is made of at least one material selected from polylactic acid / carbon black, polylactic acid / carbon nanotubes, polylactic acid / carbon nanofibers, polylactic acid / polyvinyl alcohol, polyvinyl alcohol / sodium chloride, polyvinyl alcohol / lithium chloride, polyethylene glycol / sodium chloride, polyethylene glycol / lithium chloride, polyethylene glycol / gold nanoparticles, polyacrylonitrile / carbon nanotubes, polycaprolactone / graphene, polycaprolactone / silver nanoparticles, polyglycolic acid / graphene, polyurethane / multi-walled carbon nanotubes, collagen / silver nanowires, fibrin / carbon nanotubes, gelatin / silver nanowires, gelatin / gold nanoparticle hydrogel, silk fibroin / zinc oxide, cellulose nanocrystals / silver nanoparticles, cellulose nanocrystals / carbon black hydrogel, polypyrrole hydrogel, chitosan / polypyrrole hydrogel, sodium alginate / graphene composite hydrogel, sodium alginate / polythiophene ionic hydrogel, polyacrylamide / polyaniline hydrogel, hydroxyapatite / silver nanoparticles, tricalcium phosphate / silver nanowires, octacalcium phosphate / carbon nanotubes, calcium silicate / graphene, calcium silicate / carbon black, zirconia / gold nanoparticles, bioactive glass / silver nanowires, barium titanate / polypyrrole, poly(3,4-ethylenedioxythiophene)-polystyrenesulfonate, polyaniline, polypyrrole.

[0016] In combination with the first aspect, in some embodiments, the power transmission wire is made of at least one selected from gold, platinum, titanium, copper, aluminum, silver, magnesium, zinc, molybdenum, tungsten, nickel, iron.

[0017] In combination with the first aspect, in some embodiments, the microneedle patch further includes an insulating layer that only covers all the power transmission wires; or, the insulating layer covers the sacrificial layer located outside the needle body and all the power transmission wires.

[0018] In combination with the first aspect, in some embodiments, the needle body is made of at least one material selected from hyaluronic acid, polyvinyl alcohol, polylactic acid, polyglycolic acid, chitosan, polycaprolactone polyester, polyhydroxyalkanoate, poly-α-hydroxy acid, poly-β-hydroxy acid, poly(3-hydroxybutyrate-co-valerate), poly(3-hydroxypropionate), poly(3-hydroxyhexanoate), poly(4-hydroxy acid), poly(4-hydroxybutyrate), poly(4-hydroxypentanoate), poly(4-hydroxyhexanoate), poly(ester amide), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poly(dioxanone), poly(orthoester), poly(anhydride), poly(glycolic acid-co-trimethylenecarbonate), poly(phosphate ester), poly(phosphate ester urethane), poly(amino acid), poly(cyanoacrylate), poly(trimetylenecarbonate), poly(iminocarbonate), poly(tyrosine carbonate), polycarbonate, poly(alkylene oxalate), polyvinylpyrrolidone, polybutadiene, polyhydroxybutyric acid, polymethyl methacrylate, polypropylene, polystyrene, poly(vinyl acetal diethylaminoacetate), poly(vinyl acetate), poly(vinyl butyral), poly(vinyl formal), vinyl chloride-propylene-vinyl acetate copolymer, vinyl chloride-vinyl acetate copolymer, benzofuran indene polymer, dibutylamino hydroxypropyl ether, ethylene-vinyl acetate copolymer, glycerol distearate, 2-methyl-5-vinylpyridine methacrylate-methyl methacrylate copolymer, myristic acid, palmitic acid, stearic acid, behenic acid, cellulose or its derivatives, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, glycogen, chitin, chondroitin, dextrin, keratin sulfate, tallow, cetyl wax, beeswax, paraffin wax, castor wax, methacrylated hyaluronic acid, polyglycolic acid, poly-L-lactide, polyvinylpyrrolidone, polyacrylic acid, polyglycolic acid, poly(lactic acid-glycolic acid) copolymer, poly(methyl vinyl ether / maleic acid), poly(methyl vinyl ether maleic anhydride), silk fibroin, polyethylene glycol, methacrylated gelatin, γ-polyglutamic acid, copolymer of crosslinked 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.

[0019] In combination with the first aspect, in some embodiments, the substrate is made of the same material as the microneedle body or at least one material selected from glass, silicon wafer, polyvinyl alcohol, polyester, polyethersulfone, polypropylene, polyimide, polyethylene naphthalate, polyurethane, polydimethylsiloxane, thermoplastic polyurethane, liquid crystal polymer, polytetrafluoroethylene, polycarbonate, poly(lactic acid-glycolic acid), polyglycolic acid, poly-L-lactide, polyvinylpyrrolidone, polystyrene-block-poly(ethylene-cyclobutene)-block-polystyrene, hydrogel, silica gel, paper, medical non-woven fabric.

[0020] In a second aspect, an embodiment of the present invention further discloses a drug delivery device, which includes the electro-controlled release separable microneedle patch described in the first aspect above, and further includes a power source and a control device. The power source is connected to a transmission wire, and the control device controls the current input of the transmission wire.

[0021] In the electro-controlled release separable microneedle patch of the present invention, a conductive sacrificial layer is introduced between the needle body and the substrate. This sacrificial layer is similar to an electrical fuse. On the one hand, this sacrificial layer can conduct electricity; on the other hand, the sacrificial layer is sandwiched between the needle body and the substrate, and its thermal conductivity is lower than the environment where the transmission wire is located; on the third hand, the resistance value at any position of this sacrificial layer is greater than the resistance value of the transmission wire connected to it. For the above reasons, once a current is applied that flows through the sacrificial layer via the transmission wire, the temperature increase of the sacrificial layer caused by the applied current is much greater than the temperature increase of the transmission wire, and the sacrificial layer will be quickly ablated and damaged by electrothermal effect, thereby promoting the separation of the needle body in the microneedle array from the substrate. The electro-controlled release separable microneedle patch of the present invention can quickly destroy the sacrificial layer by applying a current to the sacrificial layer, realizing the rapid separation of the needle body and the substrate, avoiding the discomfort caused by the long-term attachment of the substrate to the biological tissue surface, and further improving the user's compliance. Description of the Drawings

[0022] Figure 1 is a schematic structural diagram of the electro-controlled release separable microneedle patch of Example 1;

[0023] Figure 2 is a schematic structural diagram of the electro-controlled release separable microneedle patch of Example 2;

[0024] Figure 3 is a schematic plan view of the electro-controlled release separable microneedle patch of Example 3;

[0025] Figure 4 is a partial cross-sectional view along the center line of the needle body in Example 3;

[0026] Figure 5 is a cross-sectional view of the electro-controlled release separable microneedle patch of Example 4;

[0027] Figure 6 is a time response diagram of the dynamic activation current curve after the electro-controlled release separable microneedle patch of Example 3 is powered on;

[0028] Among them, the substrate 100, the first surface 110, the second surface 120, the needle body 200, the sacrificial layer 300, the transmission wire 400, the input wire 410, the output wire 420, the insulating layer 500, the support layer 600. Detailed Embodiments

[0029] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the following will clearly and completely describe the technical solutions in the embodiments of this application with reference to the accompanying drawings in the embodiments of this application. Apparently, the described embodiments are some, but not all, of the embodiments of this application. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in this application without creative efforts shall fall within the scope of protection of this application.

[0030] The terms "first" and "second" in the description and claims of this article are used to distinguish different objects, rather than to describe a specific order of objects. In the description of the embodiments of this application, unless otherwise stated, the meaning of "a plurality" refers to two or more. For example, a plurality of processing units refers to two or more processing units, and a plurality of elements refers to two or more elements.

[0031] In the embodiments of this application, words such as "exemplary" or "for example" are used to indicate examples, illustrations, or explanations. Any embodiment or design solution described as "exemplary" or "for example" in the embodiments of this application should not be construed as being more preferred or having more advantages than other embodiments or design solutions. Rather, the use of words such as "exemplary" or "for example" is intended to present relevant concepts in a specific manner.

[0032] Please refer to Figures 1 - 5 , the electro-controlled release and separable microneedle patch of this application includes a substrate 100, a microneedle array, and a sacrificial layer 300. The substrate 100 includes a first surface 110 and a second surface 120 that are oppositely arranged, and the first surface 110 is used to adhere to the surface of a biological tissue. The microneedle array is located on the first surface 110, and the microneedle array includes a plurality of needle bodies 200. The needle bodies 200 contain an active substance to be delivered. The sacrificial layer 300 is located between the substrate 100 and the needle bodies 200. The sacrificial layer 300 is made of a conductive material. Applying an electric current to the sacrificial layer 300 can cause the sacrificial layer 300 to be damaged and promote the detachment of the needle bodies 200 from the substrate.

[0033] The active substance to be delivered can be a drug, protein, cell, or functional skin care ingredient, such as bovine serum albumin, minoxidil, paclitaxel, niacinamide, hyaluronic acid, azelaic acid, etc.

[0034] In some embodiments, the sacrificial layer 300 is connected to a power transmission wire 400. The resistivity of any position on the sacrificial layer 300 is greater than the resistivity of the power transmission wire 400. Further, the minimum resistance value on the sacrificial layer 300 is twice the resistance value of the power transmission wire 400.

[0035] In some embodiments, the resistivity of the sacrificial layer 300 gradually increases from the edge to the center. Specifically, in one implementation, an independent sacrificial layer is provided at the bottom of each needle body, that is, the sacrificial layers at the bottoms of adjacent needle bodies are disconnected and not connected, and the power transmission wire is connected to the sacrificial layer at the bottom of each needle body; in another implementation, the sacrificial layer is provided in a sheet on the substrate, that is, the sacrificial layers at the bottoms of each needle body are connected into a sheet, and the power transmission wires are distributed outside the sacrificial layer and connected to the sacrificial layer. However, in either of the above cases, the resistivity at the edge of the sacrificial layer gradually increases towards the center of the sacrificial layer. In some embodiments, the sacrificial layer 300 is a thin film with a uniform thickness; or the sacrificial layer 300 is a mesh or ring-shaped thin film; or the thickness of the sacrificial layer 300 gradually thins from the edge to the center. The thickness of the sacrificial layer 300 gradually thins from the edge to the center. Specifically, it can also be divided into two implementation methods. In one implementation method, an independent sacrificial layer is provided at the bottom of each needle body, that is, the sacrificial layers at the bottoms of adjacent needle bodies are disconnected and not connected, and the power transmission wire is connected to the sacrificial layer at the bottom of each needle body; in another implementation method, the sacrificial layer is provided in a sheet on the substrate, that is, the sacrificial layers at the bottoms of each needle body are connected into a sheet, and the power transmission wires are distributed outside the sacrificial layer and connected to the sacrificial layer. However, in either of the above cases, the thickness at the edge of the sacrificial layer gradually thins towards the center of the sacrificial layer.

[0036] In some embodiments, the sacrificial layer 300 is made of at least one material selected from gold, platinum, titanium, copper, aluminum, silver, magnesium, zinc, palladium, tin, bismuth, indium, antimony, Au / Si, Au / Ge, Pt / Ir, Ni / Ti, In / Sn, Bi / Sb, titanium alloy, magnesium alloy, zinc alloy, iron-based alloy, calcium-based alloy, platinum silicide.

[0037] In other embodiments, the sacrificial layer 300 is made of at least one material selected from polylactic acid / carbon black, polylactic acid / carbon nanotube, polylactic acid / carbon nanofiber, polylactic acid / polyvinyl alcohol, polyvinyl alcohol / sodium chloride, polyvinyl alcohol / lithium chloride, polyethylene glycol / sodium chloride, polyethylene glycol / lithium chloride, polyethylene glycol / gold nanoparticles, polyacrylonitrile / carbon nanotube, polycaprolactone / graphene, polycaprolactone / silver nanoparticles, polyglycolic acid / graphene, polyurethane / multi-walled carbon nanotube, collagen / silver nanowire, fibrin / carbon nanotube, gelatin / silver nanowire, gelatin / gold nanoparticle hydrogel, silk fibroin / zinc oxide, cellulose nanocrystal / silver nanoparticles, cellulose nanocrystal / carbon black hydrogel, polypyrrole hydrogel, chitosan / polypyrrole hydrogel, sodium alginate / graphene composite hydrogel, sodium alginate / polythiophene ionic hydrogel, polyacrylamide / polyaniline hydrogel, hydroxyapatite / silver nanoparticles, tricalcium phosphate / silver nanowire, octacalcium phosphate / carbon nanotube, calcium silicate / graphene, calcium silicate / carbon black, zirconia / gold nanoparticles, bioactive glass / silver nanowire, barium titanate / polypyrrole, poly(3,4-ethylenedioxythiophene)-polystyrenesulfonate, polyaniline, polypyrrole.

[0038] In some embodiments, the power transmission wire 400 is made of at least one selected from gold, platinum, titanium, copper, aluminum, silver, magnesium, zinc, molybdenum, tungsten, nickel, and iron.

[0039] The sacrificial layer 300 is used to isolate the bottom of the needle body 200 from the substrate 100. When an electric current is applied to the sacrificial layer 300, the sacrificial layer 300 is ablated and damaged, promoting the rapid detachment of the needle body 200 from the substrate 100. A sacrificial layer 300 is provided between each needle body 200 and the substrate 100. In order to enable the needle body 200 to completely detach from the substrate 100, the edge of the sacrificial layer 300 at the bottom of each needle body 200 is located outside the edge of the needle body 200.

[0040] In the electro-controlled release separable microneedle patch of the present application, by introducing a conductive electro-sacrificial layer 300 between the needle body 200 and the substrate 100, the resistance value of the sacrificial layer 300 is much greater than the resistance value of the connected power transmission wire 400. Once an electric current flowing through the sacrificial layer 300 via the power transmission wire 400 is applied, the temperature increase amplitude of the sacrificial layer 300 caused by the applied current is much greater than the temperature increase amplitude of the power transmission wire 400. The sacrificial layer 300 is ablated and damaged by electrothermal, resulting in the separation of the drug-loaded microneedle body 200 from the substrate 100. The sacrificial layer 300 is a conductive thin film. The sacrificial layer 300 can be a complete thin film, or a thin film in a mesh, ring or any other desired form. The sacrificial layer 300 can also be designed into a porous structure, such as honeycomb-shaped, sieve-shaped, etc. These shapes can evenly disperse the current, avoid local current concentration, increase the path resistance of the current passing through, and according to Joule's law Q = I 2 Rt (Q represents heat, I represents current, R represents resistance, t represents time), more heat is generated under the same current and time, which can accelerate ablation. Moreover, the porous structure increases the contact area with the surrounding medium, and the debris generated by ablation is more likely to diffuse, which is beneficial to the overall ablation.

[0041] In addition, in order to ensure that the entire sacrificial layer 300 is ablated, it is necessary to enhance the uniformity of the current on the sacrificial layer 300 thin film, improve the ablation effect, and achieve the overall ablation of the sacrificial layer 300. From the edge to the center of the sacrificial layer 300, its resistivity gradually increases. In this way, when the current passes through, the sacrificial layer 300 corresponding to the central part can generate more heat due to the high resistivity, realizing effective ablation of the central part. For example, the sacrificial layer 300 corresponding to the edge uses a material with a low resistivity, and a substance with a high resistivity is gradually doped towards the center. It can also be that the thickness of the sacrificial layer 300 gradually thins from the edge to the center, forming a sacrificial layer 300 structure with a thin middle and thick edges. According to the resistance formula:

[0042]

[0043] Under the same other conditions, the smaller the thickness, the larger the resistance. Therefore, when the sacrificial layer 300 is designed to have a thin middle and thick edges, the resistance in the middle is large. According to Joule's law Q = I 2 Rt (where Q represents heat, I represents current, R represents resistance, and t represents time), when the current and time are the same, the larger the resistance, the more heat is generated. Therefore, this structure will cause the sacrificial layer 300 corresponding to the central position to generate more heat when the current passes through, which is more conducive to the ablation of the middle part of the sacrificial layer 300, thereby promoting the effect of the overall ablation and destruction of the sacrificial layer 300.

[0044] In this application, the destruction process of the sacrificial layer 300 is similar to the principle of an electrical fuse. The current passes through the sacrificial layer 300 and the connected power transmission wire 400, quickly heating the sacrificial layer 300 to the failure point. Due to the structural design of the sacrificial layer 300 and the surrounding environment, the heating preferentially occurs in the sacrificial layer 300. The sacrificial layer 300 will quickly fail within a few seconds after the activation current is applied, and the magnitude of the instantaneous current depends on the applied voltage and the material and size of the sacrificial layer 300. The relationship between voltage, current, and the resistance of the sacrificial layer 300 is as follows:

[0045]

[0046] where I is the current, V is the power supply voltage, R M is the resistance of the sacrificial layer 300, R T is the resistance of the power transmission wire 400, R Eis the resistance of the peripheral circuit. By reducing the resistance of the power transmission wire 400, thereby increasing the current under a given voltage, the heat generated in the sacrificial layer 300 can be increased. By increasing the resistance of the sacrificial layer 300, the heat of the sacrificial layer 300 can also be increased. When the resistance of the sacrificial layer 300 is equal to the sum of the resistances of other resistors in the circuit, the power efficiency is maximized. The possibility of the drug loaded in the tissue or the microneedle body 200 being thermally exposed during the activation of the sacrificial layer 300 is evaluated by calculating the dissipated energy and the temperature rise. Since the resistivity of the power transmission wire 400 is much lower than that of the sacrificial layer 300, the amount of heat generated around the power transmission wire 400 is much less than that around the sacrificial layer 300. Therefore, the energy dissipated at the sacrificial layer 300 is evaluated, rather than the energy dissipated at the power transmission wire 400. The amount of material that can be heated by the energy dissipated during the activation of the sacrificial layer 300 is related to the potential thermal exposure of the tissue and the drug formulation. Due to the short activation time (in milliseconds) and the small affected volume, the possibility of the drug loaded in the tissue or the microneedle body 200 being subjected to harmful thermal exposure during the activation of the sacrificial layer 300 is very low. The electrically conductive sacrificial layer 300 is removed by local resistive heating by applying an electric current. The advantage of this method is that it is not affected by the chemical properties of the environment around the device and is many times faster than the electrochemical method. The threshold current will cause electrothermal ablation of the sacrificial layer 300 within a time range of milliseconds through the sacrificial layer 300, resulting in the rapid separation of the microneedle body 200 from the substrate 100, further improving patient compliance.

[0047] In some embodiments, to improve the safety and effectiveness of the use of the microneedle patch, the microneedle patch further includes an insulating layer 500, and the insulating layer 500 only covers all the power transmission wires 400; alternatively, the insulating layer 500 covers the sacrificial layer 300 located outside the needle body 200 and all the power transmission wires 400.

[0048] In some embodiments, the needle body 200 is made of at least one material selected from hyaluronic acid, polyvinyl alcohol, polylactic acid, polyglycolic acid, chitosan, polycaprolactone polyester, polyhydroxyalkanoate, poly-α-hydroxy acid, poly-β-hydroxy acid, poly(3-hydroxybutyrate-co-valerate), poly(3-hydroxypropionate), poly(3-hydroxyhexanoate), poly(4-hydroxy acid), poly(4-hydroxybutyrate), poly(4-hydroxypentanoate), poly(4-hydroxyhexanoate), poly(ester amide), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poly(dioxanone), poly(orthoester), poly(anhydride), poly(glycolic acid-co-trimethylenecarbonate), poly(phosphate ester), poly(phosphate ester urethane), poly(amino acid), poly(cyanoacrylate), poly(trimethylenecarbonate), poly(iminocarbonate), poly(tyrosine carbonate), polycarbonate, poly(alkylene oxalate), polyvinylpyrrolidone, polybutadiene, polyhydroxybutyrate, polymethyl methacrylate, polypropylene, polystyrene, poly(vinyl acetal diethylaminoacetate), poly(vinyl acetate), poly(vinyl butyral), poly(vinyl formal), vinyl chloride-propylene-vinyl acetate copolymer, vinyl chloride-vinyl acetate copolymer, benzofuran indene polymer, dibutylamino hydroxypropyl ether, ethylene-vinyl acetate copolymer, glycerol distearate, 2-methyl-5-vinylpyridine methacrylate-methyl methacrylate copolymer, myristic acid, palmitic acid, stearic acid, behenic acid, cellulose or its derivatives, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, glycogen, chitin, chondroitin, dextrin, keratin sulfate, beef tallow, cetyl wax, beeswax, paraffin wax, castor wax, methacrylated hyaluronic acid, polyglycolic acid, poly-L-lactide, polyvinylpyrrolidone, polyacrylic acid, polyglycolic acid, poly(lactic acid-glycolic acid) copolymer, poly(methyl vinyl ether / maleic acid), poly(methyl vinyl ether maleic anhydride), silk fibroin, polyethylene glycol, methacrylated gelatin, γ-polyglutamic acid, copolymer of crosslinked 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.

[0049] In some embodiments, the substrate 100 is made of the same material as the microneedle body or at least one material selected from glass, silicon wafer, polyvinyl alcohol, polyester, polyethersulfone, polypropylene, polyimide, polyethylene naphthalate, polyurethane, polydimethylsiloxane, thermoplastic polyurethane, liquid crystal polymer, polytetrafluoroethylene, polycarbonate, poly(lactic acid-glycolic acid), polyglycolic acid, poly-L-lactide, polyvinylpyrrolidone, polystyrene-block-poly(ethylene-cyclobutene)-block-polystyrene, hydrogel, silica gel, paper, medical non-woven fabric.

[0050] To better understand the above technical solution, the above technical solution will be described in detail below in conjunction with the accompanying drawings of the specification and specific embodiments.

[0051] Example 1

[0052] Please refer to Figure 1 , the electro-controlled release and separable microneedle patch of this embodiment includes a substrate 100, a microneedle array, a sacrificial layer 300, a power transmission wire 400, and an insulating layer 500. The substrate 100 includes a first surface 110 and a second surface arranged opposite to each other. The first surface 110 is used to adhere to the surface of biological tissue, such as the skin. Both the microneedle array and the power transmission wire 400 are located on the first surface 110 of the substrate 100. The microneedle array includes a plurality of needle bodies 200, and the needle bodies 200 contain the active substance to be delivered. The sacrificial layer 300 is located between the substrate 100 and the needle bodies 200. Applying an electric current to the sacrificial layer 300 can cause the sacrificial layer 300 to be damaged, promoting the detachment of the needle bodies 200 from the substrate 100. The insulating layer 500 covers the sacrificial layer 300 outside the needle bodies 200 and all the power transmission wires 400 on the substrate 100. There is a gap between the insulating layer 500 and the outer wall of the needle bodies 200, so that when the needle bodies 200 are detached from the substrate 100, the needle bodies 200 can be smoothly separated from the substrate 100.

[0053] In this embodiment, the substrate 100 is made of medical non-woven fabric, the sacrificial layer 300 is a magnesium alloy gradient thin film, the material of the power transmission wire 400 is copper, the ratio of the resistance of the sacrificial layer 300 to the resistance of the power transmission wire 400 is about 100:1, the material of the needle bodies 200 is chitosan, and the active substance loaded in the needle bodies 200 is bovine serum albumin. The preparation method of the electro-controlled release and separable microneedle patch of this embodiment is as follows:

[0054] (1) Prepare the wire

[0055] Use a plasma processing device to modify the surface of the non-woven fabric. Specifically, at normal pressure, use air plasma, set the processing power to 100W, and the processing time to 60s, and perform plasma processing on the non-woven fabric to increase the surface roughness and active groups and improve the bonding force with the copper wire.

[0056] Copper wires are prepared by screen printing process. Silane coupling agent KH550 is added to the copper conductive ink, and the addition amount is 3% of the mass of the copper conductive ink. The silane coupling agent can form chemical bonds between the copper powder and the non-woven fabric, improving the adhesion of the copper wire. An appropriate amount of film-forming aids, such as ethylene glycol monobutyl ether, propylene glycol monomethyl ether acetate, etc., is added to the copper conductive ink, which can reduce the glass transition temperature of the resin, enable the copper conductive ink to form a continuous film at a lower temperature, and further improve the adhesion of the copper wire. The addition amount of the film-forming aid is 8% of the mass of the copper conductive ink. A 200-mesh screen is selected, and the printing speed is controlled at 150 mm / s for screen printing. Low-temperature plasma drying technology is adopted. Through the interaction between the plasma and the surface of the copper conductive ink, the volatilization of the solvent in the ink and the curing of the resin are promoted, and rapid drying can be achieved at a relatively low temperature (60 °C), effectively avoiding the influence of high temperature on the non-woven fabric. After drying, the thickness of the copper wire is about 50 μm, and the width is 300 μm.

[0057] (2) Preparation of the sacrificial layer

[0058] In this embodiment, the sacrificial layer 300 is a gradient resistor spiral structure. The resistivity of the sacrificial layer 300 corresponding to the position of the needle body 200 gradually increases from the edge of the needle body 200 to the center position of the bottom of the needle body 200. The center of the bottom of the needle body 200 is a high-resistance region (Mg + titanium nitride nanoparticles), and the edge of the bottom of the needle body 200 is a magnesium thin film. At normal pressure, air plasma is used, the treatment power is set to 100 W, and the treatment time is 60 s. A plasma treatment device is used to treat the surface of the medical non-woven fabric, so that more active groups are generated on the surface of the non-woven fabric, and the binding sites between the sacrificial layer 300 and the metal thin film are increased. Magnetron sputtering deposits titanium nitride (TiN) nanoparticles (diameter 20 - 50 nm) in the region of the substrate 100 corresponding to the center of the needle body 200. The magnesium thin film is prepared by screen printing, and the deposition area is controlled by a mask to form a resistivity gradient. Silane coupling agent KH570 is added to the magnesium conductive ink, and the addition amount is 4% of the mass of the magnesium conductive ink. KH570 can form chemical bonds between the magnesium powder and the non-woven fabric, effectively improving the adhesion of the magnesium thin film. An appropriate amount of low-boiling solvent isopropyl alcohol is added to the magnesium conductive ink to partially replace conventional solvents such as terpineol, reducing the boiling point of the overall solvent and facilitating volatilization at a lower temperature. The addition amount of isopropyl alcohol is 50% of the total amount of the solvent. Thermoplastic polyurethane (TPU) is introduced as an auxiliary binder, which can exhibit good viscosity and curing properties at a relatively low temperature, and the addition amount is 20% of the total amount of the binder. A 400-mesh screen is selected, and the printing speed is controlled at 50 mm / s for screen printing. Low-temperature plasma drying technology is adopted. Through the interaction between the plasma and the surface of the magnesium conductive ink, the volatilization of the solvent in the magnesium conductive ink and the curing of the resin are promoted, and rapid drying can be achieved at a relatively low temperature (60 °C), effectively avoiding the influence of high temperature on the non-woven fabric. After drying, the thickness of the magnesium thin film is 10 μm, and the magnesium thin film is connected to the copper wire.

[0059] (3) Preparation of the insulating layer

[0060] An insulating layer 500 is coated on the copper wire and the area of the sacrificial layer 300 exposed outside the needle body 200. The insulating material silicone rubber is coated by screen printing, the drying temperature is set to 150 °C, the drying time is 60 min, and the thickness of the silicone rubber insulating layer 500 after drying is about 5 μm.

[0061] (4) Preparation of the microneedle array

[0062] Chitosan was dissolved in 1% acetic acid solution and dialyzed in water for about 48 hours to remove excess acetic acid molecules, obtaining a chitosan solution with a pH of about 6. It was heated and concentrated to obtain a chitosan concentrate with a mass concentration of 8%. Bovine serum albumin was added to the chitosan concentrate and mixed evenly. The chitosan concentrate embedding bovine serum albumin (the mass fraction of bovine serum albumin was 50%) was added to the PDMS microneedle mold, and the solution was filled into the mold under vacuum assistance. Subsequently, it was centrifuged for several minutes to completely fill the microneedle mold with the polymer solution embedding bovine serum albumin. The PDMS mold carrying the polymer solution was placed in a dryer for pre-drying to obtain the initial microneedle product.

[0063] (5) Assembly

[0064] The sacrificial layer 300 prepared on the substrate 100 was precisely aligned with the initial microneedle product, and a certain pressure (pressure 0.8 N) was applied using a special mold to maintain fixation. Then, it was placed back in the dryer for further drying. After the polymer microneedles were completely dried, the microneedles were separated from the template, and an electrically controlled release separable microneedle patch loaded with bovine serum albumin was obtained.

[0065] Example 2

[0066] Please refer to Figure 2 , the electrically controlled release separable microneedle patch of this example includes a substrate 100, a microneedle array, a sacrificial layer 300, a power transmission wire 400, and an insulating layer 500. The substrate 100 includes a first surface 110 and a second surface arranged opposite to each other. The first surface 110 is used to fit on the surface of biological tissue, such as the skin. The microneedle array and the power transmission wire 400 are both located on the first surface 110. The microneedle array includes several needle bodies 200, and the needle bodies 200 contain the active substance to be delivered. The sacrificial layer 300 is located between the substrate 100 and the needle bodies 200. Applying electricity to the sacrificial layer 300 can cause the sacrificial layer 300 to be damaged and promote the separation of the needle bodies 200 from the substrate 100. There is a gap between the insulating layer 500 and the outer wall of the needle bodies 200, so that when the needle bodies 200 are separated from the substrate 100, the needle bodies 200 can be smoothly separated from the substrate 100.

[0067] In order to increase the resistance of the sacrificial layer 300, in this example, the thickness of the formed sacrificial layer 300 is lower than the thickness of the power transmission wire 400. If the sacrificial layer 300 is directly formed on the substrate 100, there will be a height difference between the sacrificial layer 300 and the power transmission wire 400, which is not conducive to the effective fitting of the substrate 100 with the surface of biological tissue. For this reason, a support layer 600 is also formed between the sacrificial layer 300 and the substrate 100. The total thickness of the support layer 600 and the sacrificial layer 300 is equal to the thickness of the power transmission wire 400, making the upper surface of the sacrificial layer 300 as flush as possible with the upper surface of the power transmission wire 400, which is more conducive to pushing the needle bodies 200 into the skin tissue.

[0068] In this embodiment, the substrate 100 is made of polyimide, the sacrificial layer 300 is a platinum / titanium / platinum thin film, the power transmission wire 400 is made of copper, the ratio of the resistance of the sacrificial layer 300 to the resistance of the power transmission wire 400 is about 50:1, the materials of the support layer 600 and the needle body 200 are both PLGA copolymers, and the drug loaded on the needle body 200 is minoxidil for promoting hair growth. The preparation method of the electro-controlled release separable microneedle patch in this embodiment is as follows:

[0069] (1) Preparation of the wire

[0070] Thermocompression bond a 20-μm-thick copper foil onto a 50-μm-thick polyimide film. Set the thermocompression temperature to 120 °C, the pressure to 1.2 MPa, and the thermocompression time to 5 minutes to ensure tight adhesion between the copper foil and the polyimide film. Select an ultraviolet pulsed laser with a wavelength of 355 nm to etch the pattern of the power transmission wire 400. Set the pulse width to 20 ns, the frequency to 120 kHz, and the energy density to 12 J / cm 2 , and the scanning speed to 10 mm / s. After etching, use a special copper etching cleaning solution to ultrasonically clean for 10 minutes, and then rinse thoroughly with deionized water to remove the copper chips and impurities generated during the etching process. Immerse in an antioxidant solution containing an organic corrosion inhibitor for 5 minutes to form a protective film on the surface of the copper wire to prevent oxidation, and then dry in an oven at 60 °C for 20 minutes.

[0071] (2) Preparation of the support layer

[0072] The PLGA support layer 600 is prepared by screen printing process. The PLGA substrate 100 is successively placed in acetone, ethanol, and deionized water, and ultrasonically cleaned for 10 minutes each to remove oil stains, dust, and impurities on the surface. The substrate 100 is treated with an oxygen plasma treatment device, with the power set at 100 W and the treatment time at 3 minutes, to make the surface of the substrate 100 have good hydrophilicity, which is beneficial to the adhesion of the PLGA ink. The PLGA particles are dissolved in dichloromethane or chloroform organic solvents, and the PLGA concentration is controlled at 12% (mass volume ratio), and stirred until completely dissolved to form a homogeneous solution. To improve the printing performance of the ink, an appropriate amount of silicone leveling agent (the addition amount is 1% of the mass of PLGA) and thickening agent hydroxyethyl cellulose (the addition amount is 2% of the mass of PLGA) are added. After stirring evenly, it is filtered through a 0.45 μm filter membrane to remove undissolved impurities. A flat screen printing machine is selected, the blade material is polyurethane, the hardness is 80 Shore hardness, and the blade angle is adjusted to 70°. The printing pressure is 0.2 MPa, and the printing speed is 30 mm / s to ensure that the ink is evenly transferred onto the substrate 100. The printed substrate 100 is naturally dried in a well-ventilated environment for 1 hour to volatilize most of the organic solvents. Then it is placed in an oven at 50 °C and dried for 3 hours to further remove the residual solvents. By means of thermal curing, the dried substrate 100 is placed in an oven, heated to 70 °C, and maintained for 2 hours to cause cross-linking reaction of the PLGA molecular chains, improving the stability and strength of the pattern. The thickness of the cured support layer 600 is 18 ± 1 μm.

[0073] (3) Preparation of the sacrificial layer

[0074] The sacrificial layer 300 platinum / titanium / platinum thin film is prepared by vacuum deposition process. Using a magnetron sputtering coating equipment, the air pressure in the vacuum chamber is pumped to below 5×10 -4 Pa to ensure the purity of the coating environment. The sputtering power is set at 150 W, and the argon gas flow rate is controlled at 15 sccm (standard cubic centimeters per minute). Argon is used as the sputtering gas, and its flow rate affects the formation of plasma and the sputtering effect. Platinum, titanium, and platinum are sputtered in sequence. First, according to the target thickness and deposition rate of the first platinum layer, the deposition time is about 15 minutes to obtain a first platinum layer with a thickness of about 0.2 microns; then, the middle titanium layer mainly plays a role in enhancing the adhesion between platinum and PLGA. The titanium layer is deposited for about 30 minutes to deposit a titanium layer with a thickness of about 0.9 microns, providing a good foundation for the upper second platinum layer in the follow-up; finally, platinum is deposited again for about 30 minutes to form a second platinum layer with a thickness of about 0.9 microns, making the total thickness of the platinum / titanium / platinum thin film reach about 2 microns, and the platinum / titanium / platinum thin film is connected to the copper wire.

[0075] (4) Preparation of the insulating layer

[0076] An insulating layer 500 is coated on the areas of the copper wire and the sacrificial layer 300 that are exposed outside the microneedle body 200. The insulating material silicone rubber is coated using a screen printing process. The drying temperature is 150 °C, and the drying time is 60 min. After drying, the thickness of the formed silicone rubber insulating layer 500 is approximately 5 μm.

[0077] (5) Preparation of the microneedle array

[0078] 1000 mg of diglyme is added to 80 mg of PLGA and 50 mg of minoxidil powder, and the mixture is stirred at 300 rpm at room temperature of 25 °C for 2 h. Then, pure water is added and stirring is continued for 1 h. A stainless steel wire mesh with a designed hole pattern is placed and aligned on the washed and dried PDMS mold, and is fixed using a special fixture. 100 μL of the solution is added to the stainless steel wire mesh PDMS mold, and then the stainless steel wire mesh PDMS mold is placed in a vacuum chamber. The air pressure in the vacuum chamber is pumped down to below 5×10 -4 Pa, and a negative pressure is applied to the stainless steel wire mesh PDMS mold through the vacuum chamber to completely fill the PDMS mold with the solution. The excess solution on the surface of the stainless steel wire mesh is scraped off and recovered using a spatula. Warm water vapor (80 °C) is gently blown over the screen printing mold at a flow rate of 1 l / min to further remove the residual solution. The stainless steel wire mesh PDMS mold is placed in a vacuum drying oven. The vacuum pressure is 0.08 MPa, and it is dried at 45 °C for 10 hours to remove approximately 90% of the solvent, obtaining 100 microneedle bodies 200 without a substrate with a height of 800 mm.

[0079] (6) Assembly

[0080] The sacrificial layer 300 prepared on the substrate 100 is precisely aligned with the PDMS mold after removing the stainless steel wire mesh, and a certain pressure (pressure 0.8 N) is applied using a special mold to maintain fixation. Then, it is placed back in the dryer for further drying. After the polymer microneedles are completely dried, the microneedles are detached from the template, obtaining the electro-controlled release separable microneedles loaded with minoxidil.

[0081] Example 3

[0082] Please refer to Figure 3 and Figure 4, the electro - controlled release and separable microneedle patch of this embodiment includes a substrate 100, a microneedle array, a sacrificial layer 300, a power - transmission wire 400, and an insulating layer 500. The substrate 100 includes a first surface 110 and a second surface which are oppositely arranged. The first surface 110 is used to adhere to the surface of a biological tissue, such as the skin. Both the microneedle array and the power - transmission wire 400 are located on the first surface 110. The microneedle array includes a number of needle bodies 200, and the needle bodies 200 contain the active substance to be delivered. The sacrificial layer 300 is located between the substrate 100 and the needle bodies 200. Applying electricity to the sacrificial layer 300 can cause the sacrificial layer 300 to be damaged, promoting the detachment of the needle bodies 200 from the substrate 100. There is a gap between the insulating layer 500 and the outer wall of the needle bodies 200, so that when the needle bodies 200 are detached from the substrate 100, the needle bodies 200 can be smoothly separated from the substrate 100.

[0083] Please refer to Figure 4 , in this embodiment, to achieve the electro - controlled release and separable of a single needle body 200 with independent addressing, the microneedle array is arranged in a square matrix. The power - transmission wire 400 includes an input wire 410 and an output wire 420. All the input wires 410 are arranged in parallel along the first direction (row), and all the output wires 420 are arranged in parallel along the second direction (column). The first direction and the second direction are perpendicular. At the position where the input wire 410 and the output wire 420 intersect perpendicularly, in order to avoid the direct connection between the input wire 410 and the output wire 420, an insulating layer 500 is provided between the input wire 410 and the output wire 420 for isolation. A sacrificial layer 300 is provided at the position where the input wire 410 and the output wire 420 intersect perpendicularly, that is, a sacrificial layer 300 is provided at the bottom of each needle body 200. The sacrificial layer 300 is provided at the position where the input wire 410 and the output wire 420 intersect perpendicularly, and both the input wire 410 and the output wire 420 are connected to the sacrificial layer 300. An insulating layer 500 is provided between the sacrificial layer 300 and the power - transmission wire 400, and the material of the insulating layer 500 is epoxy resin. The insulating layer 500 between the sacrificial layer 300 and the power - transmission wire 400 does not completely cover the power - transmission wire. Instead, on one side of the needle body 200, part of the power - transmission wire is exposed outside the insulating layer and is directly connected to the sacrificial layer. On the opposite side of the needle body, the insulating layer completely covers the power - transmission wire, that is, on the other side of the needle body, the sacrificial layer and the power - transmission wire are completely isolated by the insulating layer.

[0084] In this embodiment, the substrate 100 is made of glass, the sacrificial layer 300 is a PEDOT:PSS film, the materials of both the input wire 410 and the output wire 420 are silver, and the ratio of the resistance of the sacrificial layer 300 to the resistance of the power - transmission wire 400 is about 1000:1. The material of the needle body 200 is polycaprolactone, and the active substance loaded in the needle body 200 is paclitaxel. The preparation method of the electro - controlled release and separable microneedle patch of this embodiment is as follows:

[0085] (1) Prepare the wires

[0086] The power transmission wire 400 matrix is prepared on a glass substrate by using a screen printing silver paste wire process. The silver wire is 150 μm wide and 20 μm thick, and the insulating material at the junction of the first direction (row) and the second direction (column) is 10-μm-thick epoxy resin.

[0087] (2) Preparation of the sacrificial layer 300

[0088] The PEDOT:PSS film is prepared by using an inkjet printing process. After printing, it is heated in a stepped manner: 60 °C (10 min) → 120 °C (15 min) → 150 °C (5 min) to remove the residual solvent and improve the conductivity. The thickness of the dried PEDOT:PS film at the edge is 10 μm, and the thickness at the central region is 2 μm. The PEDOT:PS film is electrically connected to the input wire 410 and the output wire 420 respectively.

[0089] (3) Preparation of the insulating layer

[0090] The insulating layer 500 is coated on the regions of the silver wire and the sacrificial layer 300 that are exposed outside the micro-needle body 200. The insulating material epoxy resin is coated by using a screen printing process. After printing, the substrate 100 is placed in an oven at 120 °C and dried for 30 minutes to remove the solvent. The thickness of the cured epoxy resin insulating layer 500 is 10 μm.

[0091] (4) Preparation of the micro-needle array

[0092] Paclitaxel and polycaprolactone are mixed and melted at 70 °C to obtain a polycaprolactone melt containing paclitaxel (the mass fraction of paclitaxel is 0.1%, and the mass fraction of polycaprolactone is 99.9%). A stainless steel wire mesh with a designed hole pattern is placed and aligned on the washed and dried PDMS mold, and is fixed by using a special fixture. 50 μL of the solution is added to the stainless steel wire mesh PDMS mold, and then the stainless steel wire mesh PDMS mold is placed in a vacuum chamber. The air pressure in the vacuum chamber is pumped down to below 5×10 -4 Pa, and a negative pressure is applied to the stainless steel wire mesh PDMS mold through the vacuum chamber to make the solution completely fill the PDMS mold. The excess solution on the surface of the stainless steel wire mesh is scraped off and recovered. Warm water vapor (80 °C) is gently blown over the screen printing mold at a flow rate of 1 l / min to further remove the residual solution. The stainless steel wire mesh PDMS mold is placed in a vacuum drying oven. The vacuum air pressure is 0.08 MPa, and it is dried at 40 °C for 12 hours to remove about 90% of the solvent, obtaining a substrate-free 100 micro-needle body 200 with a height of 600 mm and a bottom diameter of 145 μm.

[0093] (5) Assembly

[0094] The sacrificial layer 300 prepared on the substrate 100 is precisely aligned with the PDMS mold after removing the stainless steel wire mesh, and a certain pressure (pressure 0.8 N) is applied using a special mold to maintain fixation. Then, it is placed back into the desiccator for further drying. After the polymer microneedles are completely dry, the microneedles are detached from the template, and the electro-controlled release separable microneedles loaded with encapsulated paclitaxel are obtained.

[0095] Figure 6 It is the time response diagram of the dynamic activation current curve flowing through the input wire 410, the sacrificial layer 300, and the output wire 420 after the electro-controlled release separable microneedle patch of this embodiment is powered on. Figure 6 The data shows that the sacrificial layer 300 fails within 50 ms after applying the activation current.

[0096] Example 4

[0097] Please refer to Figure 5 , the electro-controlled release separable microneedle patch of this embodiment includes a substrate 100, a microneedle array, a sacrificial layer 300, a power transmission wire 400, and an insulating layer 500. The substrate 100 includes a first surface 110 and a second surface arranged oppositely. The first surface 110 is used to adhere to the surface of biological tissue, such as the skin. The microneedle array and the power transmission wire 400 are both located on the first surface 110. The microneedle array includes a plurality of needle bodies 200, and the needle bodies 200 contain the active substance to be delivered. The sacrificial layer 300 is located between the substrate 100 and the needle bodies 200. Applying an electric current to the sacrificial layer 300 can cause the sacrificial layer 300 to be damaged, promoting the detachment of the needle bodies 200 from the substrate 100. There is a gap between the insulating layer 500 and the outer wall of the needle bodies 200, so that when the needle bodies 200 are detached from the substrate 100, the needle bodies 200 can be smoothly separated from the substrate 100.

[0098] In this embodiment, the thickness of the sacrificial layer 300 gradually thins from the edge of the needle body 200 towards the center of the needle body 200. The substrate 100 is made of polyethylene terephthalate, the material of the sacrificial layer 300 is cellulose nanocrystal / carbon black hydrogel, the material of the power transmission wire 400 is copper, the ratio of the resistance of the sacrificial layer 300 to the resistance of the power transmission wire 400 is about 300:1, the material of the needle body 200 is chitosan, and the active substance loaded in the needle body 200 is nicotinamide. The preparation method of the electro-controlled release separable microneedle patch of this embodiment is as follows:

[0099] (1) Prepare the wire

[0100] This step is basically the same as that in Example 1, except that the substrate 100 is replaced with polyethylene terephthalate, and the polyethylene terephthalate needs to be subjected to plasma treatment first, and the others are the same.

[0101] (2) Prepare the sacrificial layer

[0102] In this embodiment, the sacrificial layer 300 is a thin film structure, and the thickness of the sacrificial layer 300 gradually thins from the edge of the needle body 200 towards the center of the needle body 200. Under normal pressure, air plasma is used, the treatment power is set to 100 W, and the treatment time is 60 s. A plasma treatment device is used to treat the surface of polyethylene terephthalate, so that more active groups are generated on the surface of polyethylene terephthalate, increasing the binding sites between the sacrificial layer 300 and the metal thin film. The cellulose nanocrystal / carbon black hydrogel film is prepared by an inkjet printing process. The thickness of the cellulose nanocrystal / carbon black hydrogel film gradually decreases from the edge to the central region. The edge region is printed and superimposed multiple times, with a high droplet coverage rate and an increased deposition amount; the central region is sparsely printed, with a reduced deposition amount. After printing, the temperature is increased step by step at 50 °C (10 min) → 100 °C (20 min) to remove the residual solvent and improve the conductivity. The thickness of the thickest part of the dried cellulose nanocrystal / carbon black hydrogel film is 10 μm, and the position corresponding to the center of the bottom of the needle body 200 is the thinnest region, with a thickness of 2 μm.

[0103] (3) Preparation of the insulating layer

[0104] This step is exactly the same as that in Embodiment 1.

[0105] (4) Preparation of the microneedle array

[0106] Chitosan is dissolved in a 1% acetic acid solution, and excess acetic acid molecules are removed by dialysis in water for about 48 hours to obtain a chitosan solution with a pH of about 6. The solution is heated and concentrated to obtain a chitosan concentrate with a mass concentration of 8%. Niacinamide is added to the chitosan concentrate and mixed evenly. The chitosan concentrate embedding niacinamide (the mass fraction of niacinamide is 50%) is added to the PDMS microneedle mold, and the solution is filled into the mold under vacuum assistance. Subsequently, it is centrifuged for several minutes to completely fill the microneedle mold with the polymer solution embedding niacinamide. The PDMS mold carrying the polymer solution is placed in a dryer for pre-drying to obtain the initial microneedle product.

[0107] (5) Assembly

[0108] The sacrificial layer 300 prepared on the substrate 100 is accurately aligned with the initial microneedle product, and a certain pressure (pressure 0.8 N) is applied using a special mold to maintain fixation. Then, it is placed back in the dryer for further drying. After the polymer microneedles are completely dried, the microneedles are separated from the template, and the electrically controlled release separable microneedle patch loaded with bovine serum albumin is obtained.

[0109] This application also discloses a drug delivery device including the electrically controlled release separable microneedle patch. The drug delivery device further includes a power source and a control device. The control device is electrically connected to the power source, the power source provides electrical energy for the control device, and the control device controls the current input of the transmission wire 400.

[0110] The above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered by the scope of the claims of the present invention. The technologies, shapes, and structures not described in detail in the present invention are all well-known technologies.

Claims

1. An electrically controlled release detachable microneedle patch, characterized in that: include: A substrate, comprising a first surface and a second surface arranged opposite to each other, wherein the first surface is used to be attached to a surface of a biological tissue; A microneedle array extending from the substrate, the microneedle array being located on the first surface, the microneedle array comprising a plurality of needle bodies, each of which contains an effective substance to be delivered; The sacrificial layer is located between the substrate and the needle body. The sacrificial layer is made of a conductive material. When electricity is supplied to the sacrificial layer, the sacrificial layer can be destroyed, thereby facilitating the needle body to separate from the substrate.

2. The electrically controlled release detachable microneedle patch according to claim 1, characterized in that: The sacrificial layer is connected to a transmission wire, and the resistivity of any position of the sacrificial layer is greater than the resistivity of the transmission wire.

3. The electrically controlled release detachable microneedle patch according to claim 2, characterized in that: The resistivity of the sacrificial layer gradually increases from the edge to the center.

4. The electrically controlled release detachable microneedle patch according to claim 2, characterized in that: The sacrificial layer is a film with uniform thickness; or the sacrificial layer is a mesh or ring-shaped film; or the thickness of the sacrificial layer gradually becomes thinner from the edge to the center.

5. The electrically controlled release detachable microneedle patch according to any one of claims 1 to 4, characterized in that: The sacrificial layer is made of at least one material selected from the group consisting of gold, platinum, titanium, copper, aluminum, silver, magnesium, zinc, palladium, tin, bismuth, indium, antimony, gold / silicon, gold / germanium, platinum / iridium, nickel / titanium, indium / tin, bismuth / antimony, titanium alloy, magnesium alloy, zinc alloy, iron-based alloy, calcium-based alloy, and platinum silicide; Alternatively, the sacrificial layer is selected from polylactic acid / carbon black, polylactic acid / carbon nanotubes, polylactic acid / carbon nanofibers, polylactic acid / polyvinyl alcohol, polyvinyl alcohol / sodium chloride, polyvinyl alcohol / lithium chloride, polyethylene glycol / sodium chloride, polyethylene glycol / lithium chloride, polyethylene glycol / gold nanoparticles, polyacrylonitrile / carbon nanotubes, polycaprolactone / graphene, polycaprolactone / silver nanoparticles, polyglycolic acid / graphene, polyurethane / multi-walled carbon nanotubes, collagen / silver nanowires, fibrin / carbon nanotubes, gelatin / silver nanowires, gelatin / gold nanoparticles hydrogels, silk fibroin / zinc oxide, cellulose nanowires, The hydrogel is made of at least one of rice crystals / silver nanoparticles, cellulose nanocrystals / carbon black hydrogel, polypyrrole hydrogel, chitosan / polypyrrole hydrogel, sodium alginate / graphene composite hydrogel, sodium alginate / polythiophene ion hydrogel, polyacrylamide / polyaniline hydrogel, hydroxyapatite / silver nanoparticles, tricalcium phosphate / silver nanowires, octacalcium phosphate / carbon nanotubes, calcium silicate / graphene, calcium silicate / carbon black, zirconium oxide / gold nanoparticles, bioactive glass / silver nanowires, barium titanate / polypyrrole, poly(3,4-styrenedioxythiophene)-polybenzenesulfonate), polyaniline, and polypyrrole.

6. The electrically controlled release detachable microneedle patch according to claim 2, characterized in that: The transmission wire is made of at least one of gold, platinum, titanium, copper, aluminum, silver, magnesium, zinc, molybdenum, tungsten, nickel and iron.

7. The electrically controlled release detachable microneedle patch according to claim 2, characterized in that: The microneedle patch further comprises an insulating layer, and the insulating layer only covers all the power transmission wires; or the insulating layer covers the sacrificial layer located outside the needle body and all the power transmission wires.

8. The electrically controlled release detachable microneedle patch according to claim 1, characterized in that: The needle body is selected from hyaluronic acid, polyvinyl alcohol, polylactic acid, polyglycolic acid, chitosan, polycaprolactone polyester, polyhydroxyalkanoate, poly α-hydroxy acid, poly β-hydroxy acid, poly 3-hydroxybutyrate-co-valerate, poly 3-hydroxypropionate, poly 3-hydroxyhexanoate, poly 4-hydroxy acid, poly 4-hydroxybutyrate, poly 4-hydroxyvalerate, poly 4-hydroxyhexanoate, polyester amide, polylactide, polyglycolide, polylactide-co-glycolide, polydioxanone, polyorthoester, polyanhydride, polyglycolic acid-co-trimethylene carbonate , polyphosphate, polyphosphate urethane, polyamino acid, polycyanoacrylate, polytrimethylene carbonate, polyimino carbonate, polytyrosine carbonate, polycarbonate, polyalkylene oxalate, polyvinyl pyrrolidone, polybutadiene, polyhydroxybutyric acid, polymethyl methacrylate, polypropylene, polystyrene, polyvinyl acetal diethylamino acetate, polyvinyl acetate, polyvinyl butyral, polyvinyl formal, vinyl chloride-propylene-vinyl acetate copolymer, vinyl chloride-vinyl acetate copolymer, benzofuran indene polymer, dibutylamine hydroxypropyl ether, ethylene-vinyl acetate copolymer, glyceryl distearate, 2-methyl-5-vinylpyridine methacrylate-methacrylic acid copolymer, myristic acid, palmitic acid, stearic acid, behenic acid, cellulose or its derivatives, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, glycogen, chitin, chondroitin, dextrin, keratan sulfate, tallow, spermaceti, beeswax, paraffin, castor wax, methacrylated hyaluronic acid, polyglycolic acid, poly-L-lactide, polyvinyl pyrrolidone , polyacrylic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polymethyl vinyl ether / maleic acid, poly(methyl vinyl ether maleic anhydride), silk protein, polyethylene glycol, methacrylated 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.

9. The electrically controlled release detachable microneedle patch according to claim 1, characterized in that: The substrate is made of the same material as the microneedle body or is made of at least one material selected from glass, silicon wafer, polyvinyl alcohol, polyester, polyethersulfone, polypropylene, polyimide, polyethylene naphthalate, polyurethane, polydimethylsiloxane, thermoplastic polyurethane, liquid crystal polymer, polytetrafluoroethylene, polycarbonate, poly(lactic acid-glycolic acid), polyglycolic acid, poly-L-lactide, polyvinyl pyrrolidone, polystyrene-block-poly(ethylene-cyclobutene)-block-polystyrene, hydrogel, silica gel, paper, and medical non-woven fabrics.

10. A drug delivery device, characterized in that: It comprises the electrically controlled release detachable microneedle patch as described in any one of claims 1 to 9, and also comprises a power source and a control device, wherein the power source is connected to a power transmission wire, and the control device controls the current input of the power transmission wire.

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