CN115920222A

CN115920222A - Microneedle and preparation method thereof, microneedle patch and preparation method thereof

Info

Publication number: CN115920222A
Application number: CN202211515768.3A
Authority: CN
Inventors: 杨泽宇; 郭仪; 杨柏超; 赵红彩; 周顺; 余进波
Original assignee: Chengdu Rotex Technology Co ltd
Current assignee: Chengdu Rotex Technology Co ltd
Priority date: 2022-11-29
Filing date: 2022-11-29
Publication date: 2023-04-07

Abstract

The application provides a microneedle and a preparation method thereof, a microneedle patch and a preparation method thereof, and belongs to the technical field of microneedles. The microneedle comprises a tip and a root, and comprises an outer layer and an inner core, wherein the outer layer extends from the tip to the root, the outer layer is a quick release layer, and a cavity is arranged in the quick release layer; the inner core is arranged in the cavity and comprises a slow release layer. Under the same dissolving environment, the dissolution rate of the quick release layer is greater than that of the slow release layer. The quick release layer of the microneedle can be quickly dissolved and released to realize the quick and efficient function of the drug effect, and the slow release layer can be slowly dissolved and released to realize the long-time function of the drug effect, so that the use frequency of the microneedle is reduced, and a good treatment effect is achieved on intractable diseases which are difficult to eradicate and easy to relapse. Meanwhile, the rapid release layer on the outer layer covers the inner core containing the slow release layer, and the outer layer of the microneedle is a whole, so that the mechanical strength of the whole microneedle is higher.

Description

Microneedle and preparation method thereof, microneedle patch and preparation method thereof

Technical Field

The application relates to the technical field of microneedles, in particular to a microneedle and a preparation method thereof, a microneedle patch and a preparation method thereof.

Background

The existing drug-loaded micro-needle is generally composed of a needle point and a substrate, wherein the needle point is mainly used for carrying drugs, and the drug release time is adjusted by controlling the dissolution or biodegradation rate of a micro-needle material after the micro-needle penetrates into the skin, so that the accurate drug release is realized, and sharp biohazardous wastes cannot be left after the micro-needle penetrates.

However, for some intractable diseases which are difficult to eradicate and easy to relapse, short-term administration cannot achieve good treatment effect. The slow release drug can reduce the frequency of drug administration, improve the compliance and realize the purpose of long-term treatment, and can also maintain the stability of blood drug concentration to a certain degree, avoid the peak valley phenomenon and reduce the toxic and side effect. However, the slow release mode causes the blood concentration of the drug to be too low due to insufficient initial administration, and the due curative effect cannot be achieved.

Disclosure of Invention

The application provides a microneedle and a preparation method thereof, a microneedle patch and a preparation method thereof, wherein the outer layer is a quick release layer, and the inner core contains a slow release layer, so that the rapid and efficient play of the drug effect and the long-time action of the drug effect can be realized in a matching manner; meanwhile, the inner core containing the slow release layer is coated by the outer quick release layer, so that the mechanical strength of the whole microneedle is higher.

In a first aspect, the present application provides a microneedle, which has a tip and a root, and includes an outer layer and an inner core, wherein the outer layer extends from the tip to the root, the outer layer is a quick release layer, and a cavity is formed inside the quick release layer; the inner core is arranged in the cavity and comprises a slow release layer. Under the same dissolving environment, the dissolution rate of the quick release layer is greater than that of the slow release layer.

In the technical scheme, the microneedle has a quick release layer capable of quickly dissolving and releasing the drug and a slow release layer capable of slowly dissolving and releasing the drug, the quick release layer can quickly dissolve and release the drug to quickly and efficiently play a role in achieving a drug effect, and the slow release layer can slowly dissolve and release the drug to achieve a long-time effect of the drug effect, so that the use frequency of the microneedle is reduced, and a good treatment effect is achieved on intractable diseases which are difficult to eradicate and easy to relapse. Meanwhile, the rapid release layer of the outer layer covers the inner core containing the slow release layer, and the outer layer of the microneedle is a whole, so that the mechanical strength of the whole microneedle is higher.

With reference to the first aspect, in one possible example, the outer layer at the root has an opening communicating with the cavity, the inner core and the root have a bubble layer at the opening.

The microneedle is usually fixed on the substrate layer through the root, and when the outer layer at the root is fixed on the substrate layer, the bubble layer is arranged between the inner core and the substrate layer, so that the contact area of the whole microneedle and the substrate layer is smaller, and the microneedle can be quickly separated from the substrate layer.

In one possible example, in combination with the first aspect, the inner core comprises at least one fast-release layer and at least one slow-release layer. The inner core contains a slow release layer and a quick release layer, so that the drug delivery can be dispersed more uniformly.

In one possible example, in combination with the first aspect, the slow release layers and the fast release layers are alternately arranged in a root-to-tip direction. Can further improve the uniformity of administration and ensure better administration effect.

In one possible example, in combination with the first aspect, at least the slow release layer carries a drug-loaded substance. In other embodiments, the sustained release layer itself may be used as the drug.

In combination with the first aspect, in one possible example, the drug-loaded substance is loaded in both the fast-release layer and the slow-release layer. In other embodiments, the quick release layer itself may be used as a medicament.

In combination with the first aspect, in one possible example, the loaded drugs in the fast-release layer and the slow-release layer are the same drug. The same drug can be administered for a long period of time and the initial dose is large.

In one possible example, in combination with the first aspect, the fast-release layer and the slow-release layer are each independently selected from any one or more of methacrylic acid acylated gelatin, sodium hyaluronate, sodium alginate, chitosan, polylactic acid-glycolic acid copolymer, silk fibroin, dextrin, carboxymethyl cellulose, hydroxypropyl methyl cellulose, cartilaginous thioflavine, dextran, sodium alginate, pullulan, maltose, poly-gamma-glutamic acid, or polyvinylpyrrolidone;

optionally, the quick release layer is sodium hyaluronate and the slow release layer is chitosan.

The selection of the materials can achieve the effects of quick dissolution of the quick release layer, slow dissolution of the slow release layer or biodegradation.

In one possible example, in combination with the first aspect, the microneedle is for preventing or treating hair loss, and the drug-loaded substance includes a hair growth promoting small molecule;

alternatively, the hair growth promoting small molecule comprises one or more of minoxidil and its derivatives, capsaicin, cacumen Platycladi, finasteride, valproic acid, deoxycrtisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17 alpha-estradiol, adenosine, all-trans retinoic acid, florobil, RU-58841, cork hydroxamic acid, 2-cyano-3- (1-phenyl-1H-indol-3-yl) -2-propionic acid, (4-methoxycarbonyl) phenyl ester and ketoconazole.

In the above example, the microneedles of the present application may be loaded with a hair growth promoting composition into the body of the microneedle, and after the microneedles penetrate into the scalp, the body stimulates the dermal papilla and the hair follicle stem cells, increasing the blood supply to the hair follicle and promoting the restoration of hair growth. After the micro-needle is penetrated, the needle body penetrates through the horny layer to enter the epidermis and the dermis, the quick-release layer is firstly dissolved to release the hair growth components to realize quick-release administration, and the slow-release layer is remained in the scalp to slowly and continuously release the hair growth components to realize long-term continuous administration.

In a second aspect, the present application provides a method for preparing the microneedle, which comprises: s1, preparing a mixed solution of a quick release layer: dissolving the fast-release layer in a polar solvent by using a solute to prepare a fast-release layer mixed solution;

s2, preparing a slow-release layer mixed solution: dissolving a solute for the sustained-release layer in an organic acid or inorganic acid solution to prepare a sustained-release layer mixed solution;

s3, placing the quick release layer mixed solution prepared in the step S1 in a microneedle mould, centrifuging or vacuumizing, and drying to form a quick release layer with a cavity;

and S4, placing the mixed solution of the sustained-release layer prepared in the step S2 into the cavity of the rapid-release layer in the step S3, performing centrifugation or vacuumizing treatment, and then performing drying treatment to form the sustained-release layer to prepare the microneedle.

In the technical scheme, the preparation method of the microneedle is simple and convenient, is easier to control, and has high microneedle forming rate. The prepared microneedle has a quick release layer for quickly dissolving and releasing the drug and a slow release layer for slowly dissolving and releasing the drug, and achieves good treatment effect on intractable diseases which are difficult to eradicate and easy to relapse. Meanwhile, the overall strength of the microneedle is high.

In combination with the second aspect, in a possible example, the method further includes: and S5, repeating and alternating the steps S3 and S4 to prepare the microneedle with the layered structure, wherein the rapid release layer and the slow release layer are alternately distributed. The microneedle prepared by the method can ensure better dispersion effect of administration.

With reference to the second aspect, in one possible example, in the mixed solution of the quick release layer, the mass fraction of the solute for the quick release layer is 4.8% to 9.1%;

optionally, in the mixed solution of the sustained-release layer, the mass fraction of the solute for the sustained-release layer is 4.8% -6.25%;

optionally, the solute for the fast-release layer in S1 is sodium hyaluronate, and the polar solvent is one of water, methanol, ethanol, isopropanol, n-butanol, acetone, chloroform, and tetrahydrofuran;

optionally, in S2, the solute for the sustained-release layer is chitosan, the organic acid solution is one of acetic acid, citric acid, formic acid, propionic acid, butyric acid, caprylic acid, adipic acid, oxalic acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzoic acid, phenylacetic acid, phthalic acid, terephthalic acid, valeric acid, caproic acid, capric acid, stearic acid, palmitic acid, acrylic acid and naphthenic acid, and the inorganic acid solution is one of diluted hydrochloric acid, hypochlorous acid, nitric acid, chlorous acid, boric acid, carbonic acid and silicic acid.

In combination with the second aspect, in one possible example, the drug-loaded substance is contained in the sustained release layer, and the drug-loaded substance solution is further mixed in the sustained release layer mixed solution obtained in step S2.

With reference to the second aspect, in one possible example, the drug-loaded substance is mixed in the quick release layer, and the drug-loaded substance solution is also mixed in the mixed solution of the quick release layer prepared in step S1; optionally, the mass fraction of the solute for the quick release layer in the mixed solution of the quick release layer is 4.3-7.6%.

In combination with the second aspect, in a possible example, the centrifuge in S3 is centrifuged at 3000 r/min-30000 r/min for 5 min-90 min or vacuumized at-95 KPa-30 KPa for 5 min-60 min, and then dried in a drier at 30-200 ℃ for 10 min-24 h. The quick release layer with the cavity can be formed under the conditions of high speed and long time centrifugation or vacuum pumping.

In combination with the second aspect, in a possible example, the centrifuge in S4 is centrifuged at 3000 r/min-30000 r/min for 1 min-60 min or vacuumized at-95 KPa-30 KPa for 1 min-50 min, and then placed in a drier to be dried at 30-100 ℃ for 30 min-24 h. The sustained-release layer can be formed under the conditions of high-speed short-time centrifugation or vacuum evacuation, and the bubble layer can be formed at the root of the site in accordance with the drying conditions.

In combination with the second aspect, in a possible example, the sustained-release layer mixed solution is prepared by replacing the sustained-release layer powder in S4, and the sustained-release layer powder is prepared by: and (3) drying the mixed solution of the sustained-release layer prepared in the step (S2), and grinding the dried solid by using a grinding instrument to prepare powder of the sustained-release layer. The powdery slow release layer enables the drug-loaded substance to be more dispersed in the microneedle, and after the microneedle is pricked into the skin of a human body, the drug is more uniformly dispersed and left in the skin for slow release.

In a third aspect, the present application provides a microneedle patch, including a substrate layer and the microneedle, where a root portion is disposed on the substrate layer.

In the technical scheme, the outer layer of the micro-needle in the micro-needle patch is a quick release layer, so that the mechanical strength of the micro-needle is high; meanwhile, the quick release layer extends to the root part connected with the substrate layer, so that the microneedle can be easily separated from the substrate layer when the quick release layer is dissolved.

With reference to the third aspect, in one possible example, the roots of the microneedles are disposed on the substrate layer, and the microneedles are distributed in an array.

In above-mentioned technical scheme, the micropin includes a plurality ofly, and a plurality of micropins are the array and distribute, can make the dosing of micropin paster more even, and therapeutic effect is better, simultaneously, also be convenient for the whole even pressurized of micropin array to push in the skin under the effect of substrate layer.

In one possible example, in combination with the third aspect, the backing layer component includes any one or more of polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid or a salt thereof, lactose, sorbitol, dextran, trehalose, and sucrose;

optionally, the composition of the backing layer is a mixture of sodium hyaluronate and polyvinyl alcohol.

In the technical scheme, the substrate layer is prepared by matching sodium hyaluronate and polyvinyl alcohol, and the toughness and the solubility of the substrate can be improved by the hydrogen bond effect between the sodium hyaluronate and the polyvinyl alcohol.

In one possible example, in combination with the third aspect, the microneedle is connected to the substrate layer through the outer layer. When the quick release layer of the outer layer is dissolved, the microneedle and the substrate layer can be quickly separated, and the separation effect is better.

In combination with the third aspect, in one possible example, the area of contact of the microneedle with the substrate layer is smaller than the area of an orthographic projection of the microneedle on the substrate layer.

In the technical scheme, the contact area between the microneedle and the substrate layer is relatively small, and the area of the quick release layer needing to be dissolved is also reduced when the microneedle is dissolved, so that the substrate layer and the microneedle can be quickly separated.

In one possible example, in combination with the third aspect, the microneedle has a bubble layer at a junction with the substrate layer.

In the technical scheme, the arrangement of the bubble layer can enable the contact area between the micro-needle and the substrate layer to be smaller, so that the micro-needle and the substrate layer can be separated as soon as possible.

In a fourth aspect, the present application provides a method for preparing a microneedle patch, including:

p1, preparing a substrate layer mixed solution: dissolving a substrate layer in a polar solvent by using a solute to prepare a substrate layer mixed solution;

and P2, pouring the substrate layer mixed solution obtained in the step P1 into a mold with microneedles, centrifuging or vacuumizing, and drying to obtain the microneedle patch.

In the technical scheme, the prepared microneedle patch is high in strength, and microneedles are more easily combined with the substrate layer.

With reference to the fourth aspect, in one possible example, in step P1, the solute for the substrate layer is sodium hyaluronate and polyvinyl alcohol, and the mass ratio of sodium hyaluronate to polyvinyl alcohol is 1 to 10;

optionally, in the substrate layer mixed solution, the mass fraction of the sodium hyaluronate and the polyvinyl alcohol is 4.8% -6.3%.

In the technical scheme, the substrate layer mixed by the sodium hyaluronate and the polyvinyl alcohol is conveniently formed.

In combination with the fourth aspect, in a possible example, the centrifuge in the step P2 centrifuges at a rotation speed of 3000 r/min-30000 r/min for 1 min-60 min or vacuumizes at a vacuum condition of-95 Kpa-30 Kpa for 1 min-50 min; then placing the mixture into a dryer or a vacuum oven, drying the mixture for 5 to 24 hours at room temperature, and then heating the mixture to 30 to 200 ℃ for drying the mixture for 0.5 to 12 hours.

Drawings

To more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present application and therefore should not be considered as limiting the scope, and those skilled in the art can also obtain other related drawings based on the drawings without inventive efforts.

Fig. 1 is a schematic structural view of a first microneedle patch according to an embodiment of the present application;

fig. 2 is a schematic structural view of a second microneedle patch according to an embodiment of the present application;

fig. 3 is a schematic structural view of a third microneedle patch according to an embodiment of the present application;

fig. 4 is a schematic structural view of a fourth microneedle patch according to an embodiment of the present application;

fig. 5 is a schematic view of a microneedle patch according to an embodiment of the present application inserted into the skin with the quick release layer not yet dissolved;

fig. 6 is a schematic view of a microneedle patch according to an embodiment of the present application after dissolution and release of a quick release layer after insertion into the skin;

fig. 7 is a flow chart of a fabrication process for a microneedle patch in an embodiment of the present application.

An icon: 10-microneedle patches; 100-microneedles; 200-a substrate layer; 110-tip; 120-root; 130-an outer layer; 140-an inner core; 150-a quick release layer; 160-a slow release layer; 300-drug-loaded substance; 400-bubble layer.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to the accompanying drawings. The following examples are merely used to more clearly illustrate the technical solutions of the present application, and therefore are only examples, and the protection scope of the present application is not limited thereby.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs; the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application; the terms "including" and "having," and any variations thereof, in the description of the present application and in the description of the above figures, are intended to cover non-exclusive inclusions.

Reference herein to "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment can be included in at least one embodiment of the application. The appearances of the phrase in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments. It is explicitly and implicitly understood by one skilled in the art that the embodiments described herein can be combined with other embodiments.

In the description of the embodiments of the present application, the term "plurality" refers to two or more (including two). In the description of the embodiments of the present application, the terms "upper", "bottom", "inner", and the like refer to orientations or positional relationships based on orientations or positional relationships shown in the drawings, and are only used for convenience in describing the embodiments of the present application and for simplifying the description, but do not indicate or imply that the referred devices or elements must have a specific orientation, be constructed in a specific orientation, and operate, and thus, should not be construed as limiting the embodiments of the present application.

In the description of the embodiments of the present application, unless otherwise explicitly stated or limited, the terms "connected" and "fixed" are used in a broad sense, e.g., they may be fixedly connected, detachably connected, or integrated; mechanical connection or electrical connection is also possible; either directly or indirectly through intervening media, either internally or in any other relationship. The specific meanings of the above terms in the embodiments of the present application can be understood by those of ordinary skill in the art according to specific situations.

The inventor notices that for some intractable diseases which are difficult to eradicate and easy to relapse, short-term administration cannot achieve good treatment effect. The slow release of the medicine can reduce the frequency of administration, improve the compliance and realize the purpose of long-term treatment, and can also maintain the stable blood concentration to a certain extent, avoid the peak valley phenomenon and reduce the toxic and side effect. However, the slow release method has insufficient initial administration, which results in too low blood concentration of the drug and thus fails to achieve the desired therapeutic effect.

In order to relieve the technical problem that the refractory diseases which are difficult to eradicate and easy to relapse cannot achieve good treatment effect by short-term administration, the applicant finds that quick-release and slow-release medicaments can be used in a matched manner, so that the effect of the medicaments can be quickly and efficiently played by quick release, and the effect of the medicaments can be played for a long time by slow release.

In view of the above, the applicant has conducted intensive studies to design a microneedle patch 10, and referring to fig. 1 to 4, the microneedle patch 10 includes microneedles 100 and a substrate layer 200.

Microneedle 100 includes an outer layer 130 and an inner core 140, with inner core 140 and outer layer 130 collectively forming the needle body structure of microneedle 100. The microneedle 100 has a tip 110 and a root 120, the outer layer 130 extends from the tip 110 to the root 120, and the root 120 is disposed on the backing layer 200. Optionally, the needle structure is pyramidal or conical in shape. For example, the needle structure may be in the shape of a triangular pyramid, a rectangular pyramid or a conical cone.

In the present application, the outer layer 130 is a quick release layer 150, and a cavity is formed inside the quick release layer 150; an inner core 140 is disposed within the cavity, the inner core 140 including a sustained release layer 160. Under the same dissolution environment, the dissolution rate of the fast-release layer 150 is greater than that of the slow-release layer 160.

In such a microneedle patch 10, the microneedles 100 have a fast-release layer 150 capable of rapidly dissolving and releasing the drugs and a slow-release layer 160 capable of slowly dissolving and releasing the drugs, the fast-release layer 150 can be rapidly dissolved and released to achieve a rapid and efficient action of the drug effect, and the slow-release layer 160 can be slowly dissolved and released to achieve a long-term action of the drug effect, so that the use frequency of the microneedles 100 is reduced, and a good treatment effect is achieved for intractable diseases which are difficult to eradicate and are easy to recur.

Meanwhile, since the inner core 140 containing the sustained release layer 160 is coated by the fast release layer 150 of the outer layer 130, the outer layer 130 of the microneedle 100 is a whole, so that the mechanical strength of the whole microneedle 100 is higher, and thus, the microneedle body is not easy to break, and the penetration controllability is better. Meanwhile, the quick release layer 150 extends to the root portion 120 connected to the substrate layer 200, so that the microneedle 100 can be easily separated from the substrate layer 200 when the quick release layer 150 is dissolved.

In some embodiments, the substrate layer 200 composition includes any one or more of polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid or a salt thereof, lactose, sorbitol, dextran, trehalose, and sucrose.

Optionally, the composition of the substrate layer 200 is a mixture of sodium hyaluronate and polyvinyl alcohol. The substrate layer 200 is prepared by matching sodium hyaluronate and polyvinyl alcohol, and the toughness and the solubility of the substrate can be improved by the hydrogen bond effect between the sodium hyaluronate and the polyvinyl alcohol.

In the present application, the mass ratio of sodium hyaluronate to polyvinyl alcohol is 1 to 10. Alternatively, the mass ratio of sodium hyaluronate to polyvinyl alcohol is 3. In other embodiments, the mass ratio of sodium hyaluronate and polyvinyl alcohol is 1, 2.

In some embodiments, the fast release layer 150 may carry a drug-loaded substance 300; in other embodiments, the fast release layer 150 itself may also be used as a drug carrier. The slow release layer 160 may also carry a drug 300; in other embodiments, the sustained release layer 160 itself may also be used as a carrier for the drug.

Optionally, the drug 300 in the fast release layer 150 and the slow release layer 160 are the same drug. The same drug can be administered for a long period of time and the initial dose is large.

For example: the quick release layer 150 and the slow release layer 160 are independently selected from one or more of methacrylic acidylated gelatin, sodium hyaluronate, sodium alginate, chitosan, polylactic acid-glycolic acid copolymer, silk fibroin, dextrin, carboxymethyl cellulose, hydroxypropyl methyl cellulose, cartilaginous thioflavine, dextran, sodium alginate, pullulan, maltose, poly gamma-glutamic acid or polyvinylpyrrolidone. Optionally, the fast-release layer 150 is sodium hyaluronate and the slow-release layer 160 is chitosan.

As a microneedle for preventing or treating alopecia, the drug-loaded 300 in the present application includes a hair growth promoting small molecule; alternatively, the hair growth promoting small molecule comprises one or more of minoxidil and its derivatives, capsaicin, cacumen Platycladi, finasteride, valproic acid, deoxycrtisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17 alpha-estradiol, adenosine, all-trans retinoic acid, florobil, RU-58841, cork hydroxamic acid, 2-cyano-3- (1-phenyl-1H-indol-3-yl) -2-propionic acid, (4-methoxycarbonyl) phenyl ester and ketoconazole. Based on this, if the microneedle is used for medical treatment of other diseases, the drug 300 can be directly replaced by corresponding drug components, and if the microneedle is used for diabetes, the drug 300 is a hypoglycemic drug such as insulin.

It should be noted that: the drug-loaded substance in the present application is not a general drug in the pharmaceutical field of disease treatment, and it means that all materials capable of playing a certain function are drugs, for example: capsaicin, cacumen biotae and the like belong to non-medicinal components, but the capsaicin, the cacumen biotae and the like can play a role in preventing or treating alopecia and still belong to the medicine-carried substances in the application.

The microneedle patch 10 of the present application can load the hair growth promoting component into the needle body of the microneedle 100, and after the microneedle 100 of the microneedle patch 10 pierces the scalp, the needle body stimulates the dermal papilla and the hair follicle stem cells, increases the blood supply of the hair follicle, and promotes the hair to recover and grow. After the microneedles 100 are penetrated, the needles penetrate through the stratum corneum into the epidermis and dermis layers, the quick release layer 150 dissolves to release the hair growth components first, and the slow release layer 160 remains in the scalp to release the hair growth components slowly and continuously.

In this application, the microneedle patch 10 may include a plurality of microneedles 100, the roots 120 of the microneedles 100 are all disposed on the substrate layer 200, and the microneedles 100 are distributed in an array manner, so that the administration of the microneedle patch 10 is more uniform, and the therapeutic effect is better.

With continued reference to fig. 1 and 2, the inner core 140 of the microneedle 100 may be entirely a sustained release layer 160. After the microneedle 100 is penetrated into the skin under the action of external pressure, the outer layer 130 quick release layer 150 dissolves and quickly releases the drug, and then the inner layer slow release layer 160 slowly dissolves and releases the drug, so that the long-time effect of the drug effect is realized, the use frequency of the microneedle 100 is reduced, and a good treatment effect is achieved on intractable diseases which are difficult to eradicate and easy to relapse.

With continued reference to fig. 3 and 4, the inner core 140 includes at least one fast-releasing layer 150 and at least one slow-releasing layer 160. The inner core 140 contains both the sustained release layer 160 and the fast release layer 150, so that the administration can be dispersed more uniformly.

Alternatively, the slow release layers 160 and the fast release layers 150 are alternately disposed in a direction from the root 120 to the tip 110. Can further improve the uniformity of administration and ensure better administration effect.

In some embodiments, microneedle 100 can be coupled to substrate layer 200 via outer layer 130 and inner core 140, and when inner core 140 is coupled to substrate layer 200, can be coupled to substrate layer 200 via quick release layer 150 of inner core 140. Upon penetration of the microneedles 100 into the skin, the quick release layer 150 of the outer layer 130 and the quick release layer 150 of the inner core 140 may be dissolved together to effect separation of the microneedles 100 and the substrate layer 200.

In some embodiments, the microneedle 100 may further be connected to the substrate layer 200 through the outer layer 130, and the outer layer 130 is the quick release layer 150, so that when the quick release layer 150 of the outer layer 130 is dissolved, the microneedle 100 can be quickly separated from the substrate layer 200, and the separation effect is better.

The inventor also noticed that the current needle body mainly pierces the skin under the action of external pressure, and only needs to withdraw the substrate after dissolving or before dissolving, but because the skin itself has a recovery effect, the microneedle 100 often fails to completely separate from the substrate or fully dissolve in the skin, so that the microneedle 100 cannot completely and uniformly introduce the drug into the deep layer of the skin, and the function and effect of the microneedle 100 are not good.

Referring to fig. 2 and 4, in order to alleviate the technical problem that the microneedles 100 cannot be completely separated from the substrate or sufficiently dissolved in the skin, the applicant has found that the inner core 140 may not extend completely to the root portion 120, the outer layer 130 at the root portion 120 has an opening communicating with the cavity, and the inner core 140 and the root portion 120 have a bubble layer 400 at the opening. The microneedles 100 are generally fixed on the substrate layer 200 through the root parts 120, when the outer layer 130 at the root parts 120 is fixed on the substrate layer 200, the bubble layer 400 is arranged between the inner core 140 and the substrate layer 200, so that the contact area of the microneedles 100 and the substrate layer 200 is smaller than the orthographic projection area of the microneedles 100 on the substrate layer 200, and the microneedles 100 can be quickly separated from the substrate layer 200.

Referring to fig. 5 and 6, the quick release layer 150 can be quickly dissolved and released to realize quick and efficient drug effect after the microneedle 100 penetrates into the skin without the slow release layer 160 directly contacting the substrate layer 200, so as to ensure good separation from the substrate, while the slow release layer 160 does not directly contact the substrate layer 200 and can be separated from the substrate layer 200, so that both the slow release layer 160 and the quick release layer 150 can completely enter the skin of the human body and fully release the loaded drug effect.

After the structure of the microneedle patch 10 is described above, a method for manufacturing the microneedle patch 10 will be described in detail below. Fig. 7 is a flowchart of a process for manufacturing the microneedle patch 10 according to the embodiment of the present application, and referring to fig. 7, the manufacturing method includes the steps of:

s1, preparing a mixed solution of a quick release layer: dissolving the fast-release layer in a polar solvent by using a solute to prepare a fast-release layer mixed solution.

Wherein the solute for the quick release layer can be any one or more of methacrylic acid acylated gelatin, sodium hyaluronate, sodium alginate, chitosan, polylactic acid-glycolic acid copolymer, silk fibroin, dextrin, carboxymethyl cellulose, hydroxypropyl methyl cellulose, cartilaginous sulfur, dextran, sodium alginate, amylopectin, maltose, poly gamma-glutamic acid or polyvinylpyrrolidone. Alternatively, the solute for the quick release layer may be sodium hyaluronate. The polar solvent is one of water, methanol, ethanol, isopropanol, n-butanol, acetone, chloroform, and tetrahydrofuran.

In the application, the drug-loaded substance 300 can be further added into the quick-release layer mixed solution, and when the micro-needle is used as a micro-needle for preventing or treating alopecia, the drug-loaded substance 300 comprises hair growth promoting small molecules; alternatively, the hair growth promoting small molecule comprises one or more of minoxidil and its derivatives, capsaicin, cacumen Platycladi, finasteride, valproic acid, deoxycrtisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17 alpha-estradiol, adenosine, all-trans retinoic acid, florobil, RU-58841, cork hydroxamic acid, 2-cyano-3- (1-phenyl-1H-indol-3-yl) -2-propionic acid, (4-methoxycarbonyl) phenyl ester and ketoconazole.

Optionally, if the mixed solution of the quick release layer does not contain the drug-loaded substance, the mass fraction of the solute for the quick release layer is 4.8-9.1%; if the mixed solution of the quick release layer contains the drug-loaded substance, the mass fraction of the solute for the quick release layer is 4.3-7.6%, and the mass fraction of the drug-loaded substance is 4.8-5.2%.

S2, preparing a slow-release layer mixed solution: dissolving the sustained-release layer in organic acid or inorganic acid solution with solute to obtain a sustained-release layer mixed solution.

Wherein the solute for the slow release layer can be any one or more of methacrylic acid acylated gelatin, sodium hyaluronate, sodium alginate, chitosan, polylactic acid-glycolic acid copolymer, silk fibroin, dextrin, carboxymethyl cellulose, hydroxypropyl methyl cellulose, cartilaginous sulfur, dextran, sodium alginate, amylopectin, maltose, poly gamma-glutamic acid or polyvinylpyrrolidone. And under the same dissolving condition, the dissolving rate of the solute for the quick release layer is greater than that of the solute for the slow release layer.

Alternatively, the solute for the sustained-release layer may be chitosan, the organic acid solution is one of acetic acid, citric acid, formic acid, propionic acid, butyric acid, caprylic acid, adipic acid, oxalic acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzoic acid, phenylacetic acid, phthalic acid, terephthalic acid, valeric acid, caproic acid, capric acid, stearic acid, palmitic acid, acrylic acid and naphthenic acid, and the inorganic acid solution is one of diluted hydrochloric acid, hypochlorous acid, nitric acid, chlorous acid, boric acid, carbonic acid and silicic acid.

Optionally, in the mixed solution of the sustained-release layer, the mass fraction of the solute for the sustained-release layer is 4.8% -6.25%.

In the application, the mixed solution of the slow release layer can also be added with a drug-loaded substance 300, wherein the drug-loaded substance 300 comprises hair growth promoting micromolecules; optionally, the hair growth promoting small molecule comprises one or more of minoxidil and its derivatives, capsaicin, thujab, finasteride, valproic acid, deoxycortisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17 α -estradiol, adenosine, all-trans retinoic acid, flurodil, RU-58841, cork hydroxamic acid, 2-cyano-3- (1-phenyl-1H-indol-3-yl) -2-propionic acid, (4-methoxycarbonyl) phenyl ester and ketoconazole.

And S3, placing the quick release layer mixed solution prepared in the step S1 in a microneedle mould, centrifuging or vacuumizing, and drying to form the quick release layer 150 with a cavity.

Optionally, centrifuging for 5min to 90min at a rotating speed of 3000r/min to 30000r/min in a centrifuge or vacuumizing for 5min to 60min under the condition of-95 KPa to-30 KPa, and then drying for 10min to 24h at the temperature of 30 ℃ to 200 ℃ in a dryer. The fast release layer 150 with the cavity can be formed by matching with the content of the solute of the fast release layer under the conditions of high-speed long-time centrifugation or vacuum pumping.

And S4, placing the mixed solution of the sustained-release layer prepared in the step S2 into the cavity of the rapid-release layer 150 in the step S3, performing centrifugation or vacuum pumping, and then performing drying treatment to form the sustained-release layer 160, so as to prepare the microneedle 100.

Optionally, centrifuging for 1min to 60min at a rotating speed of 3000 to 30000r/min in a centrifuge or vacuumizing for 1min to 50min under the condition of-95 Kpa to-30 Kpa, and then drying for 30min to 24h at the temperature of 30 to 100 ℃ in a dryer (vacuum oven). In the prior art, generally, drying is carried out at normal temperature, and if drying is directly carried out at high temperature, bubbles are easily generated, so that the mechanical strength of the microneedle is influenced; in the application, the content of the solute for the sustained-release layer in the sustained-release layer mixed solution is controlled, so that the drying can be carried out at high temperature, the drying time can be as short as 0.5h at least, bubbles cannot be formed in the sustained-release layer, and the mechanical strength of the microneedle is higher. Meanwhile, the sustained-release layer 160 may be formed under centrifugation or vacuum conditions at a high speed for a short time (a little shorter than the time of S3), the surface of the sustained-release layer 160 (the position of the inner core 140 near the root 120 of the microneedle 100) may be made flat, and the bubble layer 400 may be formed at the root 120 of the position in cooperation with the dry condition.

Alternatively, the steps S3 and S4 may be repeated to obtain the microneedle 100 having a layered structure in which the rapid-release layer 150 and the sustained-release layer 160 are alternately disposed. The microneedle 100 prepared by this method can provide a better dispersion effect for drug delivery.

In the application, the mixed solution of the sustained-release layer in S4 can be prepared by replacing the sustained-release layer powder with the sustained-release layer powder, and the preparation method of the sustained-release layer powder comprises the following steps: and (3) drying the mixed solution of the sustained-release layer prepared in the step (S2), and grinding the dried solid by using a grinding instrument to prepare powder of the sustained-release layer. The powdery slow release layer 160 enables the drug-loaded substance to be more dispersed in the micro-needle, and after the micro-needle is pricked into the skin of a human body, the drug is more uniformly dispersed and left in the skin for slow release.

S5, preparing a substrate layer mixed solution: and dissolving the substrate layer solute in a polar solvent to prepare a substrate layer mixed solution.

Wherein the solute for the backing layer may be any one or more of polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid or a salt thereof, lactose, sorbitol, dextran, trehalose, and sucrose.

Optionally, the solute for the substrate layer is sodium hyaluronate and polyvinyl alcohol, and the mass ratio of the sodium hyaluronate to the polyvinyl alcohol is 1. In the mixed solution of the substrate layer, the mass fraction of the sodium hyaluronate and the polyvinyl alcohol is 4.8-6.3%.

Illustratively, the mass fraction of the sodium hyaluronate and the polyvinyl alcohol in the substrate layer mixture is 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0%, or 6.3%.

And S6, pouring the substrate layer mixed solution obtained in the step S5 into a mold with the S4-formed microneedle 100, performing centrifugation or vacuum pumping treatment, and drying to obtain the microneedle patch 10.

Optionally, centrifuging for 1min to 60min in a centrifuge at a rotating speed of 3000r/min to 30000r/min or vacuumizing for 1min to 50min under the condition of-95 KPa to-30 KPa; then placing the mixture into a dryer or a vacuum oven, drying the mixture for 5 to 24 hours at room temperature, and then heating the mixture to 30 to 200 ℃ for drying the mixture for 0.5 to 12 hours. Drying at room temperature can volatilize the solvent for a period of time, then drying at high temperature, matching with the amount of solute of the substrate layer in the substrate mixed solution, drying at high temperature, wherein the drying time can be as short as 0.5h, and avoiding the generation of bubbles. The solutes for the underlayer are sodium hyaluronate and polyvinyl alcohol, and the underlayer 200 can be formed under the conditions of high speed and short time (slightly shorter time than S3) centrifugation or vacuum pumping, and the bubble layer 400 can be included on the surface of the underlayer 200.

In the present application, the order of steps S1, S2 and S5 is not limited, and S1, S2 and S5 may be performed first, or a corresponding solution may be prepared first, and then the solution may be poured, for example: step S1 is firstly carried out, and then step S3 is carried out; then step S2 is carried out, and then step S4 is carried out; step S5 is performed, and then step S6 is performed. The present application is not limited as long as the preparation of the corresponding solution is performed before the solution casting.

Wherein, in the substrate layer mixed solution, the higher the concentration of the sodium hyaluronate, the thinner the thickness of the bubble layer 400 in the formed microneedle patch 10; the concentration of sodium hyaluronate is low, and the thickness of the bubble layer 400 in the formed microneedle patch 10 is thick.

The microneedle patch 10 of the present application has a simple preparation method, and the prepared microneedle 100 has a rapid release layer 150 for rapidly dissolving and releasing the drug and a slow release layer 160 for slowly dissolving and releasing the drug, and achieves a good therapeutic effect for intractable diseases which are difficult to eradicate and easy to recur. Meanwhile, the microneedle 100 has high overall strength and good bonding effect with the substrate layer 200, and the microneedle 100 and the substrate layer 200 are easily separated after penetrating into the skin.

A microneedle patch 10 and a method for manufacturing the same according to the present application will be described in further detail with reference to examples below.

Example 1

The embodiment of the application provides a preparation method of a microneedle patch for preventing alopecia, which comprises the following steps:

(1) Pouring to form an outer quick-release layer

Preparing a mixed solution of a quick release layer:

dissolving 0.5g of sodium hyaluronate in 6.8mL of deionized water to prepare a sodium hyaluronate solution with the mass fraction of 6.8wt%, and mixing the sodium hyaluronate solution with 1.1mL of 5wt% minoxidil solution to prepare a quick-release layer mixed solution.

Pouring for the first time:

pouring the prepared mixed solution of the quick-release layer into a microneedle mould, placing the microneedle mould in a centrifuge, centrifuging for 15min at the rotating speed of 4000r/min, then placing in a dryer, drying for 30min at 40 ℃ to form an outer quick-release layer, and forming a cavity in the outer layer.

(2) Pouring to form a slow release layer

Preparing a slow-release layer mixed solution:

dissolving 0.5g of chitosan into 7.5mL of acetic acid aqueous solution with the mass fraction of 48.8wt% to prepare chitosan acetic acid aqueous solution, and mixing the chitosan acetic acid aqueous solution with 1.1mL of 5wt% minoxidil solution to prepare slow release layer mixed solution.

And (3) secondary pouring:

pouring the prepared mixed solution of the slow release layer into a cavity of the outer layer, placing the microneedle mould in a centrifuge, centrifuging for 3min at the rotating speed of 4000r/min, and then placing in a dryer, and drying for 30min at 40 ℃ to form the inner core slow release layer.

(3) And casting to form the substrate layer

Preparing a substrate layer mixed solution:

dissolving sodium hyaluronate and polyvinyl alcohol in deionized water according to the mass ratio of 3.

And (3) third pouring:

pouring the prepared substrate layer mixed liquid into a microneedle mould, placing the microneedle mould in a centrifuge, centrifuging for 3min at the rotating speed of 4000r/min, and then placing in a dryer, and drying for 6h at 40 ℃ to form the substrate layer, thereby preparing the microneedle patch.

Comparative example 1

Comparative example 1 provides a method for preparing a microneedle patch for alopecia prevention, which includes the steps of:

(1) And casting to form needle body structure

Preparing a mixed solution of a quick-release layer:

1g of sodium hyaluronate is dissolved in 13.6mL of deionized water to prepare a sodium hyaluronate solution with the mass fraction of 5.8wt%, and then the sodium hyaluronate solution and 2.2mL of 5wt% minoxidil solution are mixed to prepare a fast-release layer mixed solution.

First pouring:

pouring the prepared mixed solution of the quick-release layer into a microneedle mould, placing the microneedle mould into a centrifuge, centrifuging for 3min at the rotating speed of 4000r/min, and then placing the microneedle mould into a dryer to dry for 30min at the temperature of 40 ℃ to form a needle body structure.

(2) And casting to form the substrate layer

Preparing a substrate layer mixed solution:

dissolving sodium hyaluronate and polyvinyl alcohol in deionized water according to the mass ratio of 0.5.

And (3) secondary pouring:

and placing the prepared substrate layer mixed solution in a centrifuge, pouring the substrate layer mixed solution in a microneedle mould, placing the microneedle mould in the centrifuge, centrifuging the microneedle mould for 3min at the rotating speed of 4000r/min, and then placing the microneedle mould in a dryer to dry the microneedle mould for 6h at the temperature of 40 ℃ to form a substrate layer, thereby preparing the microneedle patch.

Comparative example 2

Comparative example 2 provides a method for preparing a microneedle patch for alopecia prevention, which includes the steps of:

(1) And casting to form needle body structure

Preparing a slow-release layer mixed solution:

dissolving 1g of chitosan into 15mL of acetic acid aqueous solution with the mass fraction of 48.8wt% to prepare chitosan acetic acid aqueous solution, and mixing the chitosan acetic acid aqueous solution with 2.2mL of 5wt% minoxidil solution to prepare slow release layer mixed solution.

First pouring:

pouring the prepared slow release layer mixed solution into a microneedle mould, placing the microneedle mould in a centrifuge, centrifuging for 3min at the rotating speed of 4000r/min, and then placing in a dryer, and drying for 30min at 40 ℃ to form a needle body structure.

(2) And casting to form the substrate layer

Preparing a substrate layer mixed solution:

And (3) secondary pouring:

Test examples

Drug release experiments:

the microneedle patch provided by the embodiment is placed in blood, the half-life period of sodium hyaluronate is 2-5 min, and the catabolism of the sodium hyaluronate is a continuous rapid process. The chitosan-encapsulated drug is released through the swelling and degradation mechanism of the chitosan matrix, resulting in sustained release of the loaded drug for up to 28 days.

Example 1 experiment of microneedle patch (using rhodamine staining):

experiment one: the microneedle patch provided in example 1 was inserted into a hydrogel prepared in advance, and an electronic magnifier was used to record experimental phenomena, and it was found that the microneedle and the substrate layer can be separated by 100% within two minutes, and it was observed that only the fast-release layer and the rhodamine in the fast-release layer were dissolved in water and continuously diffused all around, and the rhodamine in the slow-release layer and the slow-release layer was not dissolved immediately and did not diffuse.

Experiment two: a certain number of male C57BL/6 mice were sacrificed, a 2cm by 2cm area was shaved on the back with a pet shaver, the depilatory cream was evenly applied, and after a while the depilatory cream together with the back fluff was washed off with water. The microneedle patch provided in example 1 was sequentially attached to the skin of the back of a mouse, the patch was stopped on the skin for 5min, and then the skin penetrated by the microneedle was removed and observed by sectioning, and it was found that there were many small holes labeled with rhodamine in the skin of the mouse, and a sustained release layer which was not dissolved in the small holes.

Comparative example 1 experiment of microneedle patch (quick release microneedles) (staining with rhodamine):

experiment one: the microneedle patch provided in comparative example 1 was inserted into the hydrogel prepared in advance and the experimental phenomenon was recorded with an electronic magnifier, and it was found that the microneedle tip and the substrate could be separated by 100% within two minutes, and that the polymer and rhodamine were rapidly dissolved and continuously diffused all around.

Experiment two: a certain number of male C57BL/6 mice were sacrificed, a 2cm by 2cm area was shaved on the back with a pet shaver, the depilatory cream was evenly applied, and after a while the depilatory cream together with the back fluff was washed off with water. The microneedle patch provided in comparative example 1 was sequentially attached to the skin of the back of the mouse, the patch was left on the skin for 5min, and then the skin punctured with the microneedle was removed and observed in section, and many small holes labeled with rhodamine were found in the skin of the mouse.

Comparative example 2 experiment of microneedle patch (sustained release microneedle) (using rhodamine staining):

experiment one: the microneedle patch provided in comparative example 2 was inserted into the hydrogel prepared in advance and the experimental phenomenon was recorded with an electronic magnifier, and it was found that the microneedle tip and the substrate were almost completely unable to be separated within two minutes, and it was observed that the polymer did not dissolve rhodamine and had a small amount of diffusion.

Experiment two: a certain number of male C57BL/6 mice were sacrificed, a 2cm X2cm area was shaved on the back with a pet shaver, and the depilatory cream was evenly applied and washed off with water together with the back fluff after a while. The microneedle patch provided in comparative example 2 was attached to the skin of the back of the mouse, and the patch was left on the skin for 5 minutes, and then the skin punctured by the microneedle was removed and observed in section, and it was found that there were many small holes in the skin of the mouse, but no rhodamine remained, indicating that the tip of the needle was not left in the skin of the mouse.

As can be seen from comparison between example 1 and comparative examples 1 (fast-release microneedles) and 2 (slow-release microneedles), the microneedle patch provided by the present application can realize rapid separation of microneedles from a substrate layer, and has a fast-release layer 150 for rapidly dissolving and releasing a drug and a slow-release layer 160 for slowly dissolving and releasing a drug, so as to achieve a good therapeutic effect on intractable diseases which are difficult to eradicate and easy to relapse.

The foregoing is illustrative of the present application and is not to be construed as limiting thereof, as numerous modifications and variations will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A microneedle, characterized in that the microneedle has a tip and a root, the microneedle comprises an outer layer and an inner core, the outer layer extends from the tip to the root, the outer layer is a quick release layer, and a cavity is arranged in the quick release layer; the inner core is arranged in the cavity and comprises a slow release layer;

under the same dissolving environment, the dissolving rate of the quick release layer is greater than that of the slow release layer.

2. A microneedle according to claim 1, wherein the outer layer at the root has an opening communicating with the cavity, the inner core and the root having a bubble layer at the opening.

3. A microneedle according to claim 1, wherein said inner core comprises at least one fast release layer and at least one said slow release layer.

4. A microneedle according to claim 3, wherein the slow release layers and the fast release layers are alternately arranged in a direction from the root to the tip.

5. A microneedle according to any one of claims 1 to 4, wherein at least the release layer carries a drug-loaded substance.

6. A microneedle according to claim 5, wherein the fast release layer and the slow release layer each carry a drug-loaded substance.

7. A microneedle according to claim 6, wherein the drug-loaded substance in the rapid-release layer and the sustained-release layer is the same drug.

8. A microneedle according to claim 1, wherein the rapid release layer and the sustained release layer are each independently selected from any one or more of methacrylic acid acylated gelatin, sodium hyaluronate, sodium alginate, chitosan, polylactic acid-glycolic acid copolymer, silk fibroin, dextrin, carboxymethyl cellulose, hydroxypropyl methyl cellulose, cartilaginous thioflavine, dextran, sodium alginate, pullulan, maltose, poly-gamma-glutamic acid or polyvinylpyrrolidone;

optionally, the quick release layer is sodium hyaluronate, and the slow release layer is chitosan.

9. A microneedle according to claim 5, for use in preventing or treating hair loss, said drug-loaded substance comprising a hair-growth promoting small molecule;

optionally, the hair growth promoting small molecule comprises one or more of minoxidil and its derivatives, capsaicin, cacumen Platycladi, finasteride, valproic acid, deoxycrtisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17 alpha-estradiol, adenosine, all-trans retinoic acid, florobil, RU-58841, cork hydroxamic acid, 2-cyano-3- (1-phenyl-1H-indol-3-yl) -2-propionic acid, (4-methoxycarbonyl) phenyl ester and ketoconazole.

10. A method for producing a microneedle according to any one of claims 1 to 9, comprising:

s1, preparing a mixed solution of a quick release layer: dissolving the quick release layer in a polar solvent by using a solute to prepare a quick release layer mixed solution;

s2, preparing a slow-release layer mixed solution: dissolving the sustained-release layer in an organic acid or inorganic acid solution by using a solute to prepare a sustained-release layer mixed solution;

s3, placing the mixed solution of the quick release layer prepared in the step S1 in a microneedle mould, centrifuging or vacuumizing, and then drying to form the quick release layer with a cavity;

and S4, placing the mixed solution of the slow release layer prepared in the step S2 into the cavity of the quick release layer in the step S3, performing centrifugation or vacuumizing treatment, and then performing drying treatment to form the slow release layer to prepare the microneedle.

11. A method of preparing a microneedle according to claim 10, further comprising: and S5, repeating and alternating the steps S3 and S4 to prepare the microneedle with the layered structure, wherein the rapid release layer and the slow release layer are alternately distributed.

12. A method for preparing a microneedle according to claim 10, wherein the mass fraction of the solute for the rapid release layer in the rapid release layer mixture is 4.8% to 9.1%;

optionally, the solute for the quick release layer in S1 is sodium hyaluronate, and the polar solvent is one of water, methanol, ethanol, isopropanol, n-butanol, acetone, chloroform, and tetrahydrofuran;

13. A method of manufacturing a microneedle according to claim 10, wherein a drug to be carried is contained in the sustained release layer, and a drug to be carried solution is further mixed in the sustained release layer mixed solution prepared in step S2;

optionally, a drug to be carried is mixed in the quick release layer, and a drug to be carried solution is also mixed in the quick release layer mixed solution prepared in the step S1; optionally, the mass fraction of the solute for the quick release layer in the mixed solution of the quick release layer is 4.3% -7.6%.

14. The method for preparing a microneedle according to claim 10, wherein a centrifuge is centrifuged at 3000r/min to 30000r/min for 5min to 90min in S3 or vacuumed at-95 Kpa to-30 Kpa for 5min to 60min, and then placed in a drier to be dried at 30 ℃ to 200 ℃ for 10min to 24h.

15. The method for preparing microneedles in claim 10, wherein the centrifuge is centrifuged at 3000 r/min-30000 r/min for 1 min-60 min or vacuumized at-95 Kpa-30 Kpa for 1 min-50 min in S4, and then dried at 30-100 ℃ for 30 min-24 h in a dryer.

16. A method of manufacturing a microneedle according to claim 10, wherein the sustained-release layer mixed solution is prepared by replacing sustained-release layer powder in S4, and the method of preparing the sustained-release layer powder comprises: and (3) drying the mixed solution of the sustained-release layer prepared in the step (S2), and grinding the dried solid by using a grinding instrument to prepare the powder of the sustained-release layer.

17. A microneedle patch comprising a substrate layer and the microneedle according to any one of claims 1 to 9, wherein the base portion is provided on the substrate layer;

optionally, the roots of the microneedles are disposed on the substrate layer, and the microneedles are distributed in an array.

18. A microneedle patch according to claim 17, wherein said backing layer component comprises any one or more of polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid or a salt thereof, lactose, sorbitol, dextran, trehalose and sucrose;

optionally, the composition of the substrate layer is a mixture of sodium hyaluronate and polyvinyl alcohol.

19. A microneedle patch according to claim 17, wherein said microneedles are connected to said substrate layer through said outer layer.

20. A microneedle patch according to claim 19, wherein an area of contact of said microneedles with said substrate layer is smaller than an area of an orthographic projection of said microneedles on said substrate layer.

21. A microneedle patch according to claim 19, wherein the connection of the microneedles with the substrate layer has a bubble layer.

22. A method of manufacturing a microneedle patch according to any one of claims 17 to 21, comprising:

and P2, pouring the substrate layer mixed solution in the step P1 into a mold with microneedles, centrifuging or vacuumizing, and drying to obtain the microneedle patch.

23. The method for manufacturing a microneedle patch according to claim 22, wherein in step P1, the solutes for the substrate layer are sodium hyaluronate and polyvinyl alcohol, and the mass ratio of sodium hyaluronate to polyvinyl alcohol is 1;

24. A method for preparing a microneedle patch according to claim 22, wherein the centrifuge of step P2 is centrifuged at 3000r/min to 30000r/min for 1min to 60min or vacuumed at-95 Kpa to-30 Kpa for 1min to 50min; then placing the mixture into a dryer or a vacuum oven, drying the mixture for 5 to 24 hours at room temperature, and then heating the mixture to 30 to 200 ℃ for drying the mixture for 0.5 to 12 hours.