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

Abstract

The present application provides a microneedle and a preparation method thereof, a microneedle patch and a preparation method thereof, and belongs to the field of microneedle technology. The microneedle has a tip and a root, and the microneedle includes an outer layer and an inner core. The outer layer extends from the tip to the root, and the outer layer is a quick-release layer, and the quick-release layer has a cavity inside; the inner core is arranged in the cavity, and the inner core includes a sustained-release layer. Under the same dissolution environment, the dissolution rate of the quick-release layer is greater than the dissolution rate of the sustained-release layer. The quick-release layer of the microneedle can be quickly dissolved and released to achieve a rapid and efficient drug effect, and the sustained-release layer can be slowly dissolved and released to achieve a long-term drug effect, thereby reducing the frequency of use of the microneedle and achieving a good therapeutic effect for stubborn diseases that are difficult to eradicate and prone to recurrence. At the same time, because the outer quick-release layer covers the inner core containing the sustained-release layer, the outer layer of the microneedle is a whole, which can make the mechanical strength of the entire microneedle higher.

Description

Technical Field

[0001] The present application relates to the field of microneedle technology, and in particular, to a microneedle and a method for preparing the same, a microneedle patch and a method for preparing the same. Background Art

[0002] Existing drug-loaded microneedles are generally composed of a needle tip and a substrate, in which the needle tip is mainly used for drug loading. After piercing the skin, the drug release time is adjusted by controlling the dissolution or biodegradation rate of the microneedle material, thereby achieving accurate drug release, and no sharp biological hazardous waste is left after piercing.

[0003] However, for some stubborn diseases that are difficult to eradicate and prone to recurrence, short-term administration cannot achieve good therapeutic effects. Slow-release drugs can not only reduce the number of administrations, improve compliance, and achieve the purpose of long-term treatment, but can also maintain stable blood drug concentrations to a certain extent, avoid peak and valley phenomena, and reduce toxic side effects. However, the slow-release method cannot achieve the desired therapeutic effect because the blood drug concentration of the drug is too low due to insufficient initial administration. Summary of the invention

[0004] The present 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 sustained-release layer, which can cooperate to achieve rapid and efficient drug effects and long-term drug effects; at the same time, by coating the inner core containing the sustained-release layer with the outer quick-release layer, the mechanical strength of the entire microneedle can be made higher.

[0005] In the first aspect, the present application provides a microneedle having a tip and a root, the microneedle comprising an outer layer and an inner core, the outer layer extending from the tip to the root, the outer layer being a quick-release layer, the quick-release layer having a cavity inside; the inner core being disposed in the cavity, the inner core comprising a sustained-release layer. Under the same dissolution environment, the dissolution rate of the quick-release layer is greater than the dissolution rate of the sustained-release layer.

[0006] In the above technical solution, the microneedle of the present application has a quick-release layer that can quickly dissolve and release the drug and a slow-release layer that can slowly dissolve and release the drug. The quick-release layer can quickly dissolve and release to achieve a quick and efficient drug effect, and the slow-release layer can slowly dissolve and release to achieve a long-term drug effect, thereby reducing the frequency of use of the microneedle and achieving a good therapeutic effect for stubborn diseases that are difficult to eradicate and prone to recurrence. At the same time, because the outer quick-release layer covers the inner core containing the slow-release layer, the outer layer of the microneedle is a whole, which can make the mechanical strength of the entire microneedle higher.

[0007] In combination with the first aspect, in a possible example, the outer layer at the root has an opening connected to the cavity, and the inner core and the root have a bubble layer at the opening.

[0008] The microneedle is usually fixed on the substrate layer through the root. When the outer layer at the root is fixed on the substrate layer, there is a bubble layer between the inner core and the substrate layer, which can reduce the contact area between the entire microneedle and the substrate layer, so that the microneedle can be quickly separated from the substrate layer.

[0009] In combination with the first aspect, in a possible example, the inner core includes at least one quick-release layer and at least one sustained-release layer. The inner core contains both the sustained-release layer and the quick-release layer, which can make the drug delivery more uniform.

[0010] In combination with the first aspect, in a possible example, the sustained-release layer and the quick-release layer are alternately arranged along the direction from the root to the tip, which can further improve the uniformity of drug administration and achieve a better drug administration effect.

[0011] In combination with the first aspect, in a possible example, at least the sustained-release layer carries the drug. In other embodiments, the sustained-release layer itself can be used as a drug.

[0012] In combination with the first aspect, in a possible example, both the quick-release layer and the sustained-release layer carry the drug. In other embodiments, the quick-release layer itself can also be used as a drug.

[0013] In combination with the first aspect, in a possible example, the drug carried in the fast-release layer and the sustained-release layer is the same drug, so that the same drug can be administered for a long time and the initial dosage is large.

[0014] In combination with the first aspect, in a possible example, the quick-release layer and the sustained-release layer are independently selected from any one or more of methacrylated gelatin, gelatin, sodium hyaluronate, sodium alginate, chitosan, polylactic acid-co-glycolic acid, silk fibroin, dextrin, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, chondroitin, dextran, sodium alginate, pullulan, maltose, poly-gamma-glutamic acid or polyvinyl pyrrolidone;

[0015] Optionally, the fast-release layer is sodium hyaluronate and the sustained-release layer is chitosan.

[0016] The above material selection can achieve the effect of rapid dissolution of the quick-release layer and slow dissolution or biodegradation of the sustained-release layer.

[0017] In combination with the first aspect, in a possible example, the microneedles are used to prevent or treat hair loss, and the loaded drugs include small molecules that promote hair growth;

[0018] Optionally, the hair growth promoting small molecules include one or more of minoxidil and its derivatives, capsaicin, Platycladus orientalis leaves, finasteride, valproic acid, deoxycortisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17α-estradiol, adenosine, all-trans retinoic acid, fluoroidil, RU-58841, suberoxime acid, 2-cyano-3-(1-phenyl-1H-indol-3-yl)-2-propionic acid, (4-methoxycarbonyl)phenyl ester and ketoconazole.

[0019] In the above example, the microneedle of the present application can load the hair growth promoting ingredients into the microneedle body. When the microneedle is inserted into the scalp, the needle body stimulates the dermal papilla and hair follicle stem cells, increases the blood supply to the hair follicles and promotes the recovery of hair growth. After the microneedle is inserted, the needle body passes through the stratum corneum and enters the epidermis and dermis. The fast-release layer first dissolves and releases the hair growth ingredients to achieve fast-release drug delivery, and the sustained-release layer remains in the scalp to slowly and continuously release the hair growth ingredients to achieve long-term continuous drug delivery.

[0020] In a second aspect, the present application provides a method for preparing the above-mentioned microneedle, which comprises: S1, preparing a quick-release layer mixed solution: taking a solute for the quick-release layer and dissolving it in a polar solvent to prepare a quick-release layer mixed solution;

[0021] S2, preparing a sustained-release layer mixed solution: dissolving a solute for the sustained-release layer in an organic acid or inorganic acid solution to obtain a sustained-release layer mixed solution;

[0022] S3, placing the quick-release layer mixed solution prepared in step S1 in a microneedle mold, first centrifuging or vacuuming, and then drying to form a quick-release layer with a cavity;

[0023] S4, placing the sustained-release layer mixture prepared in step S2 into the cavity of the quick-release layer in step S3, first centrifuging or vacuuming, and then drying to form a sustained-release layer to prepare microneedles.

[0024] In the above technical scheme, the preparation method of the microneedle of the present application is simple, easier to control, and has a high microneedle forming rate. The prepared microneedle has a fast-release layer that quickly dissolves and releases the drug and a slow-release layer that slowly dissolves and releases the drug, achieving a good therapeutic effect for stubborn diseases that are difficult to eradicate and prone to recurrence. At the same time, the overall strength of the microneedle is relatively high.

[0025] In combination with the second aspect, in a possible example, the method further includes: S5, repeating steps S3 and S4 alternately to prepare microneedles with a layered structure in which a fast-release layer and a sustained-release layer are alternately distributed. The microneedles prepared by this method can achieve a better dispersion effect of drug delivery.

[0026] In combination with the second aspect, in a possible example, in the mixed solution of the rapid release layer, the mass fraction of the solute for the rapid release layer is 4.8% to 9.1%;

[0027] Optionally, in the mixed solution of the sustained-release layer, the mass fraction of the solute for the sustained-release layer is 4.8% to 6.25%;

[0028] 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;

[0029] Optionally, the solute for the sustained-release layer in S2 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 cyclohexane 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.

[0030] In combination with the second aspect, in a possible example, the sustained-release layer contains a drug, and the sustained-release layer mixed solution prepared in step S2 is also mixed with a drug solution.

[0031] In combination with the second aspect, in a possible example, the fast release layer contains a drug, and the fast release layer mixture prepared in step S1 is also mixed with a drug solution; optionally, the mass fraction of the solute for the fast release layer in the fast release layer mixture is 4.3% to 7.6%.

[0032] In combination with the second aspect, in a possible example, the centrifuge in S3 is centrifuged at a speed of 3000 r / min to 30000 r / min for 5 to 90 min or vacuumed at -95 Kpa to -30 Kpa for 5 to 60 min, and then placed in a dryer at 30° C. to 200° C. for 10 to 24 h. A quick-release layer with a cavity can be formed under the conditions of high-speed, long-term centrifugation or vacuuming.

[0033] In combination with the second aspect, in a possible example, the centrifuge in S4 is centrifuged at a speed of 3000r / min to 30000r / min for 1min to 60min or vacuumed at -95Kpa to -30Kpa for 1min to 50min, and then placed in a dryer at 30°C to 100°C for 30min to 24h. A sustained-release layer can be formed under the conditions of high-speed short-time centrifugation or vacuuming, and in combination with the drying conditions, a bubble layer can be formed at the root of the position.

[0034] In combination with the second aspect, in a possible example, the sustained-release layer mixture is replaced with a sustained-release layer powder in S4, and the preparation method of the sustained-release layer powder is: drying the sustained-release layer mixture prepared in step S2, and grinding the dried solid with a grinding instrument to prepare a sustained-release layer powder. The powdered sustained-release layer makes the drug carried by it more dispersed in the microneedle, and after being inserted into the human skin, the drug is more evenly dispersed and remains in the skin for slow release.

[0035] In a third aspect, the present application example provides a microneedle patch, comprising a substrate layer and the above-mentioned microneedles, wherein the roots are arranged on the substrate layer.

[0036] In the above technical solution, the outer layers of the microneedles in the microneedle patch are all quick-release layers, and the mechanical strength of the microneedles is relatively high; at the same time, the quick-release layer extends to the root connected to the substrate layer, and when the quick-release layer dissolves, the microneedles can be easily separated from the substrate layer.

[0037] In combination with the third aspect, in a possible example, roots of the plurality of microneedles are all disposed on the substrate layer, and the plurality of microneedles are distributed in an array.

[0038] In the above technical solution, the microneedles include multiple ones, and the multiple microneedles are distributed in an array, which can make the drug delivery of the microneedle patch more uniform and the treatment effect better. At the same time, under the action of the substrate layer, it is also convenient for the entire microneedle array to be evenly pressed and pushed into the skin.

[0039] In combination with the third aspect, in a possible example, the substrate layer composition includes any one or more of polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid or its salt, lactose, sorbitol, dextran, trehalose and sucrose;

[0040] Optionally, the component of the substrate layer is a mixture of sodium hyaluronate and polyvinyl alcohol.

[0041] In the above technical solution, sodium hyaluronate and polyvinyl alcohol are used to prepare the substrate layer. The hydrogen bonding between sodium hyaluronate and polyvinyl alcohol can improve the toughness and solubility of the substrate.

[0042] In conjunction with the third aspect, in a possible example, the microneedles are connected to the substrate layer through the outer layer. When the quick-release layer of the outer layer dissolves, the microneedles can be quickly separated from the substrate layer, resulting in a better separation effect.

[0043] In combination with the third aspect, in a possible example, the contact area between the microneedle and the substrate layer is smaller than the area of ​​the orthographic projection of the microneedle on the substrate layer.

[0044] In the above technical solution, the contact area between the microneedles and the substrate layer is relatively small. When dissolving, the area of ​​the quick-release layer that needs to be dissolved is also reduced, so that the substrate layer and the microneedles can be separated quickly.

[0045] In combination with the third aspect, in a possible example, a bubble layer is provided at the connection between the microneedle and the substrate layer.

[0046] In the above technical solution, the provision of the bubble layer can make the contact area between the microneedles and the substrate layer smaller, so that the microneedles and the substrate layer can be separated as quickly as possible.

[0047] In a fourth aspect, the present application example provides a method for preparing a microneedle patch, comprising:

[0048] P1, preparing a substrate layer mixed solution: dissolving a solute for the substrate layer in a polar solvent to prepare a substrate layer mixed solution;

[0049] P2, pouring the substrate layer mixed solution in step P1 into a mold with microneedles, first centrifuging or vacuuming, and then drying to obtain a microneedle patch.

[0050] In the above technical solution, the prepared microneedle patch has higher strength, and the microneedles and the substrate layer are easier to combine together.

[0051] In combination with the fourth aspect, in a 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 1:1 to 10:1;

[0052] Optionally, in the substrate layer mixed solution, the mass fraction of sodium hyaluronate and polyvinyl alcohol is 4.8% to 6.3%.

[0053] In the above technical solution, it is convenient to form a substrate layer of a mixture of sodium hyaluronate and polyvinyl alcohol.

[0054] In combination with the fourth aspect, in a possible example, in step P2, the centrifuge is centrifuged at a speed of 3000 r / min to 30000 r / min for 1 min to 60 min or vacuumed at -95 Kpa to -30 Kpa for 1 min to 50 min; then it is placed in a dryer or a vacuum oven, dried at room temperature for 5 h to 24 h, and then heated to 30°C to 200°C and dried for 0.5 h to 12 h. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0056] Figure 1This is a schematic structural diagram of the first microneedle patch of the embodiment of the present application;

[0057] Figure 2 This is a schematic diagram of the structure of the second microneedle patch of the embodiment of the present application;

[0058] Figure 3 This is a schematic structural diagram of a third microneedle patch according to an embodiment of the present application;

[0059] Figure 4 This is a schematic structural diagram of a fourth microneedle patch according to an embodiment of the present application;

[0060] Figure 5 This is a schematic diagram of a microneedle patch according to an embodiment of the present application in which the quick-release layer has not yet dissolved after being inserted into the skin;

[0061] Figure 6 This is a schematic diagram of the microneedle patch of the embodiment of the present application after the quick-release layer is dissolved and released after being inserted into the skin;

[0062] Figure 7 This is a flow chart of the preparation process of the microneedle patch of an embodiment of the present application.

[0063] Icon: 10-microneedle patch; 100-microneedle; 200-substrate layer; 110-tip; 120-root; 130-outer layer; 140-inner core; 150-fast release layer; 160-sustained release layer; 300-drug-loaded; 400-bubble layer. DETAILED DESCRIPTION

[0064] The following embodiments of the technical solution of the present application are described in detail in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solution of the present application, and are therefore only used as examples, and cannot be used to limit the scope of protection of the present application.

[0065] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by technicians in the technical field to which this application belongs; the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit this application; the terms "including" and "having" in the specification of this application and the above-mentioned drawings and any variations thereof are intended to cover non-exclusive inclusions.

[0066] Reference to "embodiments" herein means that a particular feature, structure, or characteristic described in conjunction with the embodiments may be included in at least one embodiment of the present application. The appearance of the phrase in various locations in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described herein may be combined with other embodiments.

[0067] In the description of the embodiments of the present application, the term "plurality" refers to more than two (including two). In the description of the embodiments of the present application, the orientation or positional relationship indicated by the technical terms "upper", "bottom", "inner", etc. is based on the orientation or positional relationship shown in the drawings, which is only for the convenience of describing the embodiments of the present application and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the embodiments of the present application.

[0068] In the description of the embodiments of the present application, unless otherwise clearly specified and limited, technical terms such as "connection" and "fixation" should be understood in a broad sense. For example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium, and it can be the internal connection of two elements or the interaction relationship between two elements. For ordinary technicians in this field, the specific meanings of the above terms in the embodiments of the present application can be understood according to specific circumstances.

[0069] The inventors have noticed that for some intractable diseases that are difficult to eradicate and prone to relapse, short-term administration cannot achieve good therapeutic effects. Slow-release drugs can not only reduce the number of administrations, improve compliance, and achieve the purpose of long-term treatment, but can also maintain stable blood drug concentrations to a certain extent, avoid peak and valley phenomena, and reduce toxic and side effects. However, the slow-release method does not achieve the desired therapeutic effect because the blood drug concentration of the drug is too low due to insufficient initial administration.

[0070] In order to alleviate the technical problem that short-term administration of drugs cannot achieve good therapeutic effects for stubborn diseases that are difficult to eradicate and prone to recurrence, the applicant has discovered that rapid-release and slow-release drugs can be used in combination, which can achieve both rapid and efficient drug effects through rapid release and long-term drug effects through slow release.

[0071] Based on the above considerations, the applicant has conducted in-depth research and designed a microneedle patch 10, see Figure 1 to Figure 4 The microneedle patch 10 includes microneedles 100 and a substrate layer 200 .

[0072] The microneedle 100 includes an outer layer 130 and an inner core 140, and the inner core 140 and the outer layer 130 together form a needle body structure of the microneedle 100. The microneedle 100 has a tip 110 and a root 120, and the outer layer 130 extends from the tip 110 to the root 120, and the root 120 is disposed on the substrate layer 200. Optionally, the shape of the needle body structure is a pyramid or a cone. For example, the shape of the needle body structure can be a triangular pyramid, a quadrangular pyramid or a cone.

[0073] In the present application, the outer layer 130 is a quick-release layer 150, which has a cavity inside; the inner core 140 is disposed in the cavity, and the inner core 140 includes a sustained-release layer 160. Under the same dissolution environment, the dissolution rate of the quick-release layer 150 is greater than the dissolution rate of the sustained-release layer 160.

[0074] In such a microneedle patch 10, the microneedle 100 has a quick-release layer 150 that can quickly dissolve and release the drug, and a sustained-release layer 160 that can slowly dissolve and release the drug. The quick-release layer 150 can quickly dissolve and release to achieve a rapid and efficient drug effect, and the sustained-release layer 160 can slowly dissolve and release to achieve a long-term drug effect, thereby reducing the frequency of use of the microneedle 100 and achieving a good therapeutic effect on stubborn diseases that are difficult to eradicate and prone to recurrence.

[0075] At the same time, since the quick-release layer 150 of the outer layer 130 covers the inner core 140 containing the sustained-release layer 160, the outer layer 130 of the microneedle 100 is a whole, which can make the mechanical strength of the entire microneedle 100 higher, so that the microneedle body is not easy to break, and the insertion controllability is better. At the same time, the quick-release layer 150 extends to the root 120 connected to the substrate layer 200, and when the quick-release layer 150 dissolves, the microneedle 100 can be easily separated from the substrate layer 200.

[0076] In some embodiments, the substrate layer 200 comprises any one or more of polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid or its salt, lactose, sorbitol, dextran, trehalose and sucrose.

[0077] Optionally, the substrate layer 200 is composed of a mixture of sodium hyaluronate and polyvinyl alcohol. The substrate layer 200 is prepared by combining sodium hyaluronate and polyvinyl alcohol. The hydrogen bonding between sodium hyaluronate and polyvinyl alcohol can improve the toughness and solubility of the substrate.

[0078] In the present application, the mass ratio of sodium hyaluronate to polyvinyl alcohol is 1:1 to 10:1. Optionally, the mass ratio of sodium hyaluronate to polyvinyl alcohol is 3:1. In other embodiments, the mass ratio of sodium hyaluronate to polyvinyl alcohol is 1:1, 2:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1.

[0079] In some embodiments, the quick-release layer 150 may carry the drug 300; in other embodiments, the quick-release layer 150 itself may also be used as a drug carrier. The sustained-release layer 160 may also carry the drug 300; in other embodiments, the sustained-release layer 160 itself may also be used as a drug carrier.

[0080] Optionally, the drug 300 carried in the fast-release layer 150 and the sustained-release layer 160 is the same drug, so that the same drug can be administered for a long time and the initial dosage is large.

[0081] For example, the quick-release layer 150 and the sustained-release layer 160 are independently selected from any one or more of methacrylated gelatin, gelatin, sodium hyaluronate, sodium alginate, chitosan, polylactic acid-co-glycolic acid, silk fibroin, dextrin, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, chondroitin, dextran, sodium alginate, pullulan, maltose, poly-gamma-glutamic acid or polyvinyl pyrrolidone. Optionally, the quick-release layer 150 is sodium hyaluronate and the sustained-release layer 160 is chitosan.

[0082] When used as a microneedle for preventing or treating hair loss, the drug 300 carried in this application includes a small molecule that promotes hair growth; optionally, the small molecule that promotes hair growth includes minoxidil and its derivatives, capsaicin, Platycladus orientalis, finasteride, valproic acid, deoxycortisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17α-estradiol, adenosine, all-trans retinoic acid, fluoroidil, RU-58841, suberoxime acid, 2-cyano-3-(1-phenyl-1H-indol-3-yl)-2-propionic acid, (4-methoxycarbonyl) phenyl ester and ketoconazole. Based on this, if used as a medicinal microneedle for other diseases, the drug 300 carried can be directly replaced by the corresponding drug component, such as a medical microneedle for diabetes, and the drug 300 carried is a hypoglycemic drug such as insulin.

[0083] It should be noted that the carried drugs in this application are not general drugs in the pharmaceutical field for treating diseases. They refer to materials that can play a certain function as drugs. For example, capsaicin, Platycladus orientalis leaves, etc. are non-drug ingredients, but they can prevent or treat hair loss, and they are still carried drugs in this application.

[0084] The microneedle patch 10 of the present application can load the hair growth promoting component into the needle body of the microneedle 100. When the microneedle 100 of the microneedle patch 10 penetrates the scalp, the needle body stimulates the dermal papilla and hair follicle stem cells, increases the blood supply to the hair follicles and promotes the recovery and growth of hair. After the microneedle 100 penetrates, the needle body passes through the stratum corneum and enters the epidermis and dermis. The quick-release layer 150 first dissolves and releases the hair growth component, and the slow-release layer 160 remains in the scalp to slowly and continuously release the hair growth component.

[0085] In the present application, the microneedle patch 10 may include a plurality of microneedles 100, the roots 120 of the plurality of microneedles 100 are all disposed on the substrate layer 200, and the plurality of microneedles 100 are distributed in an array, which can make the drug delivery of the microneedle patch 10 more uniform and achieve better therapeutic effects.

[0086] Please continue reading Figure 1 and Figure 2 , the inner core 140 in the microneedle 100 can be all sustained-release layers 160. After the microneedle 100 pierces the skin under the action of external pressure, the outer layer 130 and the quick-release layer 150 first dissolve and quickly release the drug, and then the inner layer and the sustained-release layer 160 slowly dissolve and release the drug, so as to achieve a long-term effect of the drug, thereby reducing the frequency of use of the microneedle 100 and achieving a good therapeutic effect for stubborn diseases that are difficult to eradicate and prone to recurrence.

[0087] Please continue reading Figure 3 and Figure 4 The inner core 140 includes at least one quick-release layer 150 and at least one sustained-release layer 160. The inner core 140 contains both the sustained-release layer 160 and the quick-release layer 150, which can make the drug delivery more uniform.

[0088] Optionally, the sustained-release layer 160 and the quick-release layer 150 are alternately arranged along the direction from the root 120 to the tip 110. This can further improve the uniformity of drug administration and achieve a better drug administration effect.

[0089] In some embodiments, the microneedle 100 may be connected to the substrate layer 200 through the outer layer 130 and the inner core 140. When the inner core 140 is connected to the substrate layer 200, it may be connected to the substrate layer 200 through the quick-release layer 150 of the inner core 140. When the microneedle 100 penetrates 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 achieve separation of the microneedle 100 and the substrate layer 200.

[0090] In some embodiments, the microneedle 100 can also be connected to the substrate layer 200 through the outer layer 130. The outer layer 130 is a quick-release layer 150. When the quick-release layer 150 of the outer layer 130 dissolves, the microneedle 100 can be quickly separated from the substrate layer 200, and the separation effect is better.

[0091] The inventors have also noticed that the current needle body mainly penetrates the skin under the action of external pressure, and the base can be withdrawn after it dissolves or before it dissolves. However, due to the recovery effect of the skin itself, the microneedle 100 often cannot completely detach from the base or fully dissolve in the skin, thereby failing to completely and evenly introduce the drug into the deep layer of the skin, resulting in poor functional effects of the microneedle 100.

[0092] See also Figure 2 and Figure 4In order to alleviate the technical problem that the microneedle 100 cannot be completely separated from the substrate or fully dissolved in the skin, the applicant has found that the inner core 140 can be made not to fully extend to the root 120, and the outer layer 130 at the root 120 has an opening connected to the cavity, and the inner core 140 and the root 120 have a bubble layer 400 at the opening. The microneedle 100 is usually fixed on the substrate layer 200 at the root 120. When the outer layer 130 at the root 120 is fixed on the substrate layer 200, there is a bubble layer 400 between the inner core 140 and the substrate layer 200, which can make the contact area between the microneedle 100 and the substrate layer 200 smaller than the area of ​​the positive projection of the microneedle 100 on the substrate layer 200, so that the microneedle 100 can be quickly separated from the substrate layer 200.

[0093] See also Figure 5 and Figure 6 When the sustained-release layer 160 does not directly contact the substrate layer 200, after the microneedle 100 penetrates the skin, the quick-release layer 150 can be quickly dissolved and released to achieve a rapid and efficient drug effect, thereby ensuring good separation from the substrate, while the sustained-release layer 160 does not directly contact the substrate layer 200 and can be separated from the substrate layer 200, so that both the sustained-release layer 160 and the quick-release layer 150 can completely enter the human skin and fully release the drug effect they carry.

[0094] After introducing the structure of the microneedle patch 10 above, the preparation method of the microneedle patch 10 will be specifically introduced below. Figure 7 For a flow chart of the preparation process of the microneedle patch 10 of the present application embodiment, please refer to Figure 7 , the preparation method comprises the following steps:

[0095] S1, preparing a quick-release layer mixed solution: dissolving a quick-release layer solute in a polar solvent to prepare a quick-release layer mixed solution.

[0096] Wherein, the solute for the quick-release layer can be any one or more of methacrylated gelatin, gelatin, sodium hyaluronate, sodium alginate, chitosan, polylactic acid-co-glycolic acid, silk fibroin, dextrin, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, chondroitin, dextran, sodium alginate, pullulan, maltose, poly-gamma-glutamic acid or polyvinyl pyrrolidone. Optionally, the solute for the quick-release layer can be sodium hyaluronate. The polar solvent is one of water, methanol, ethanol, isopropanol, n-butanol, acetone, chloroform and tetrahydrofuran.

[0097] In the present application, the drug 300 can also be added to the quick-release layer mixture. When used as a microneedle for preventing or treating hair loss, the drug 300 includes a small molecule that promotes hair growth; optionally, the small molecule that promotes hair growth includes one or more of minoxidil and its derivatives, capsaicin, Platycladus orientalis leaves, finasteride, valproic acid, deoxycortisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17α-estradiol, adenosine, all-trans retinoic acid, fluoroidil, RU-58841, suberoxime acid, 2-cyano-3-(1-phenyl-1H-indol-3-yl)-2-propionic acid, (4-methoxycarbonyl)phenyl ester and ketoconazole.

[0098] Optionally, if the mixed solution of the fast-release layer does not contain the loaded drug, the mass fraction of the solute for the fast-release layer is 4.8% to 9.1%; if the mixed solution of the fast-release layer contains the loaded drug, the mass fraction of the solute for the fast-release layer is 4.3% to 7.6%, and the mass fraction of the loaded drug is 4.8% to 5.2%.

[0099] S2, preparing a sustained-release layer mixed solution: dissolving a solute for the sustained-release layer in an organic acid or inorganic acid solution to obtain a sustained-release layer mixed solution.

[0100] The solute for the sustained-release layer can be any one or more of methacrylated gelatin, gelatin, sodium hyaluronate, sodium alginate, chitosan, polylactic acid-co-glycolic acid, silk fibroin, dextrin, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, chondroitin, dextran, sodium alginate, pullulan, maltose, poly-gamma-glutamic acid or polyvinyl pyrrolidone. Under the same dissolution conditions, the dissolution rate of the solute for the quick-release layer is greater than the dissolution rate of the solute for the sustained-release layer.

[0101] Optionally, the solute for the sustained-release layer can 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 cyclohexane 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.

[0102] Optionally, in the mixed solution of the sustained-release layer, the mass fraction of the solute for the sustained-release layer is 4.8% to 6.25%.

[0103] In the present application, the sustained-release layer mixture can also be added with a loaded drug 300, and the loaded drug 300 includes a small molecule that promotes hair growth; optionally, the small molecule that promotes hair growth includes one or more of minoxidil and its derivatives, capsaicin, Platycladus orientalis leaves, finasteride, valproic acid, deoxycortisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17α-estradiol, adenosine, all-trans retinoic acid, fluoroidil, RU-58841, suberoxime acid, 2-cyano-3-(1-phenyl-1H-indol-3-yl)-2-propionic acid, (4-methoxycarbonyl)phenyl ester and ketoconazole.

[0104] S3, placing the quick-release layer mixed solution prepared in step S1 in the microneedle mold, firstly centrifuging or vacuuming, and then drying to form a quick-release layer 150 with a cavity.

[0105] Optionally, the mixture is centrifuged at 3000 r / min to 30000 r / min for 5 to 90 min or vacuumed at -95 KPa to -30 KPa for 5 to 60 min, and then placed in a dryer for drying at 30° C. to 200° C. for 10 to 24 h. The quick-release layer 150 with a cavity can be formed by adjusting the content of the quick-release layer solute under high-speed, long-term centrifugation or vacuuming.

[0106] S4, placing the sustained-release layer mixture prepared in step S2 into the cavity of the quick-release layer 150 in step S3, first centrifuging or vacuuming, and then drying to form a sustained-release layer 160, thereby preparing the microneedle 100.

[0107] Optionally, centrifuge at a speed of 3000 to 30000 r / min for 1 to 60 minutes or vacuum at -95Kpa to -30Kpa for 1 to 50 minutes, and then place it in a dryer (vacuum oven) and dry it at 30°C to 100°C for 30 minutes to 24 hours. The prior art generally dries at room temperature. If it is directly dried under high temperature conditions, bubbles are easily generated, which affects the mechanical strength of the microneedle. In this application, by controlling the content of the solute for the sustained-release layer in the sustained-release layer mixture, it can be dried under high temperature conditions, the drying time can be as short as 0.5 hours, and no bubbles will be formed in the sustained-release layer, so that the mechanical strength of the microneedle is also high. At the same time, the sustained-release layer 160 can be formed under high-speed and short-time (slightly shorter than the time of S3) centrifugation or vacuum conditions, so that the surface of the sustained-release layer 160 (the position of the inner core 140 close to the root 120 of the microneedle 100) can be made relatively flat, and in combination with the drying conditions, a bubble layer 400 can be formed at the root 120 of the position.

[0108] Optionally, the alternating steps S3 and S4 may be repeated to obtain a microneedle 100 having a layered structure in which the fast-release layer 150 and the sustained-release layer 160 are alternately distributed. The microneedle 100 prepared by this method can achieve a better dispersion effect of drug administration.

[0109] In the present application, the sustained-release layer mixture in S4 can also be replaced by a sustained-release layer powder, and the preparation method of the sustained-release layer powder is: drying the sustained-release layer mixture prepared in step S2, and grinding the dried solid with a grinding instrument to prepare a sustained-release layer powder. The powdered sustained-release layer 160 allows the drug to be more dispersed in the microneedle, and after being inserted into the human skin, the drug is more evenly dispersed and remains in the skin for slow release.

[0110] S5, preparing a substrate layer mixed solution: dissolving a solute for the substrate layer in a polar solvent to prepare a substrate layer mixed solution.

[0111] The solute for the substrate layer may be any one or more of polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid or its salt, lactose, sorbitol, dextran, trehalose and sucrose.

[0112] Optionally, the solutes for the substrate layer are sodium hyaluronate and polyvinyl alcohol, and the mass ratio of sodium hyaluronate to polyvinyl alcohol is 1:1 to 10:1. In the substrate layer mixed solution, the mass fraction of sodium hyaluronate and polyvinyl alcohol is 4.8% to 6.3%.

[0113] As an example, in the mixed solution of the substrate layer, the mass fractions of sodium hyaluronate and polyvinyl alcohol are 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0% or 6.3%.

[0114] S6, pouring the substrate layer mixed solution in step S5 into the mold having the microneedles 100 formed in S4, firstly performing centrifugation or vacuum treatment, and then performing drying treatment to obtain the microneedle patch 10.

[0115] Optionally, centrifuge at a speed of 3000r / min to 30000r / min in a centrifuge for 1min to 60min or vacuumize at -95Kpa to -30Kpa for 1min to 50min; then place it in a dryer or vacuum oven, dry it at room temperature for 5h to 24h, and then heat it to 30℃ to 200℃ and dry it for 0.5h to 12h. First dry it at room temperature, let the solvent evaporate for a period of time, and then dry it at a high temperature. According to the amount of substrate layer solute in the substrate mixture, it can be dried at a high temperature, and the drying time can be as short as 0.5h, and avoid the generation of bubbles. The solutes for the substrate layer are sodium hyaluronate and polyvinyl alcohol. The substrate layer 200 can be formed under the conditions of high-speed and short-time (slightly shorter than the time of S3) centrifugation or vacuuming, so that the surface of the substrate layer 200 contains a bubble layer 400.

[0116] In the present application, the order of steps S1, S2 and S5 is not limited, and S1, S2 and S5 can be performed first, or the corresponding solution can be prepared first and then the solution is poured, for example: first perform step S1, then perform step S3; then perform step S2, then perform step S4; then perform step S5, then perform step S6. The present application does not make any limitation, as long as the corresponding solution is prepared before the solution is poured.

[0117] Among them, in the substrate layer mixed liquid, the higher the concentration of sodium hyaluronate, the thinner the thickness of the bubble layer 400 in the formed microneedle patch 10; the lower the concentration of sodium hyaluronate, the thicker the bubble layer 400 in the formed microneedle patch 10.

[0118] The preparation method of the microneedle patch 10 of the present application is simple, and the prepared microneedle 100 has a fast-release layer 150 for rapidly dissolving and releasing the drug and a slow-release layer 160 for slowly dissolving and releasing the drug, achieving a good therapeutic effect for intractable diseases that are difficult to eradicate and prone to recurrence. At the same time, the overall strength of the microneedle 100 is high, and the bonding effect with the substrate layer 200 is good. After piercing the skin, the microneedle 100 and the substrate layer 200 are also easy to separate.

[0119] The following is a further detailed description of a microneedle patch 10 and a preparation method thereof of the present application in conjunction with embodiments.

[0120] Example 1

[0121] The present application embodiment provides a method for preparing a microneedle patch for preventing hair loss, comprising the following steps:

[0122] (1) Casting to form an outer quick-release layer

[0123] Prepare the rapid release layer mixture:

[0124] 0.5 g of sodium hyaluronate was dissolved in 6.8 mL of deionized water to prepare a sodium hyaluronate solution with a mass fraction of 6.8 wt %, and then the sodium hyaluronate solution and 1.1 mL of a 5 wt % minoxidil solution were mixed to prepare a quick-release layer mixture.

[0125] First pour:

[0126] The prepared quick-release layer mixture was poured into a microneedle mold, the microneedle mold was placed in a centrifuge and centrifuged at 4000 r / min for 15 min, and then placed in a dryer and dried at 40° C. for 30 min to form an outer quick-release layer, and a cavity was formed in the outer layer.

[0127] (2) Casting to form a sustained-release layer

[0128] Preparation of sustained-release layer mixture:

[0129] 0.5 g of chitosan was dissolved in 7.5 mL of 48.8 wt % acetic acid aqueous solution to prepare chitosan acetic acid aqueous solution, and then the chitosan acetic acid aqueous solution and 1.1 mL of 5 wt % minoxidil solution were mixed to prepare a sustained-release layer mixed solution.

[0130] Second pouring:

[0131] The prepared sustained-release layer mixture was poured into the cavity of the outer layer, the microneedle mold was placed in a centrifuge and centrifuged at a speed of 4000 r / min for 3 minutes, and then placed in a dryer and dried at 40° C. for 30 minutes to form an inner core sustained-release layer.

[0132] (3) Casting to form a substrate layer

[0133] Prepare the substrate mixture:

[0134] Sodium hyaluronate and polyvinyl alcohol were dissolved in deionized water at a mass ratio of 3:1 to prepare a substrate layer mixed solution with a mass fraction of 5.5 wt%.

[0135] Third pouring:

[0136] The prepared substrate layer mixture was poured into a microneedle mold, the microneedle mold was placed in a centrifuge and centrifuged at 4000 r / min for 3 minutes, and then placed in a dryer and dried at 40° C. for 6 hours to form a substrate layer, thereby preparing a microneedle patch.

[0137] Comparative Example 1

[0138] Comparative Example 1 provides a method for preparing a microneedle patch for preventing hair loss, which comprises the following steps:

[0139] (1) Casting to form the needle body structure

[0140] Prepare the rapid release layer mixture:

[0141] 1 g of sodium hyaluronate was dissolved in 13.6 mL of deionized water to prepare a sodium hyaluronate solution with a mass fraction of 5.8 wt %, and then the sodium hyaluronate solution and 2.2 mL of 5 wt % minoxidil solution were mixed to prepare a quick-release layer mixture.

[0142] First pour:

[0143] The prepared quick-release layer mixture was poured into a microneedle mold, the microneedle mold was placed in a centrifuge and centrifuged at a speed of 4000 r / min for 3 minutes, and then placed in a dryer and dried at 40° C. for 30 minutes to form a needle body structure.

[0144] (2) Casting to form a substrate layer

[0145] Prepare the substrate mixture:

[0146] Sodium hyaluronate and polyvinyl alcohol were dissolved in deionized water at a mass ratio of 0.5:1 to prepare a substrate layer mixed solution with a mass fraction of 5.5 wt%.

[0147] Second pouring:

[0148] The prepared substrate layer mixture was placed in a centrifuge and poured into a microneedle mold. The microneedle mold was placed in a centrifuge and centrifuged at 4000 r / min for 3 minutes. Then, it was placed in a dryer and dried at 40°C for 6 hours to form a substrate layer, thereby preparing a microneedle patch.

[0149] Comparative Example 2

[0150] Comparative Example 2 provides a method for preparing a microneedle patch for preventing hair loss, which comprises the following steps:

[0151] (1) Casting to form the needle body structure

[0152] Preparation of sustained-release layer mixture:

[0153] 1 g of chitosan was dissolved in 15 mL of 48.8 wt % acetic acid aqueous solution to prepare chitosan acetic acid aqueous solution, and then the chitosan acetic acid aqueous solution and 2.2 mL of 5 wt % minoxidil solution were mixed to prepare a sustained-release layer mixed solution.

[0154] First pour:

[0155] The prepared sustained-release layer mixture was poured into a microneedle mold, the microneedle mold was placed in a centrifuge and centrifuged at a speed of 4000 r / min for 3 minutes, and then placed in a dryer and dried at 40° C. for 30 minutes to form a needle body structure.

[0156] (2) Casting to form a substrate layer

[0157] Prepare the substrate mixture:

[0158] Sodium hyaluronate and polyvinyl alcohol were dissolved in deionized water at a mass ratio of 0.5:1 to prepare a second mixed solution with a mass fraction of 5.5 wt %.

[0159] Second pouring:

[0160] The prepared substrate layer mixture was placed in a centrifuge and poured into a microneedle mold. The microneedle mold was placed in a centrifuge and centrifuged at 4000 r / min for 3 minutes. Then, it was placed in a dryer and dried at 40°C for 6 hours to form a substrate layer, thereby preparing a microneedle patch.

[0161] Test example

[0162] Drug release experiment:

[0163] When the microneedle patch provided in the embodiment is placed in the blood, the half-life of sodium hyaluronate is 2 to 5 minutes, and its catabolism is a continuous and rapid process. The chitosan-encapsulated drug is released through the swelling and degradation mechanism of the chitosan matrix, resulting in a sustained release of the loaded drug for up to 28 days.

[0164] Example 1 Experiment of microneedle patch (using rhodamine staining):

[0165] Experiment 1: The microneedle patch provided in Example 1 was inserted into the pre-prepared hydrogel and the experimental phenomenon was recorded with an electron magnifying glass. It was found that the microneedle and the substrate layer could be 100% separated within two minutes, and it was observed that only the quick-release layer and the rhodamine in the quick-release layer dissolved in the water and continued to diffuse everywhere, while the sustained-release layer and the rhodamine in the sustained-release layer did not dissolve immediately and did not diffuse.

[0166] Experiment 2: A certain number of male C57BL / 6 mice were killed, and a 2cm×2cm area was shaved on the back with a pet shaver, and a depilatory cream was evenly applied. After a period of time, the depilatory cream and the back hair were washed off with water. The microneedle patch provided in Example 1 was successively applied to the back skin of the mouse, and the patch was left on the skin for 5 minutes, and then the skin punctured by the microneedle was removed for section observation, and it was found that there were many small holes marked with rhodamine in the mouse skin, and there was an undissolved sustained-release layer in the small holes.

[0167] Experiment of Comparative Example 1 Microneedle Patch (Quick Release Microneedle) (using Rhodamine dyeing):

[0168] Experiment 1: The microneedle patch provided in Comparative Example 1 was inserted into the pre-prepared hydrogel and the experimental phenomenon was recorded with an electronic magnifying glass. It was found that the microneedle tip and the substrate could be 100% separated within two minutes, and the polymer and rhodamine were observed to dissolve rapidly and diffuse continuously.

[0169] Experiment 2: A certain number of male C57BL / 6 mice were killed, and a 2cm×2cm area was shaved on the back with a pet shaver, and a depilatory cream was evenly applied. After a period of time, the depilatory cream and the back hair were washed off with water. The microneedle patch provided in Comparative Example 1 was successively applied to the back skin of the mouse, and the patch was left on the skin for 5 minutes, and then the skin punctured by the microneedle was removed for section observation, and it was found that there were many small holes marked with rhodamine in the mouse skin.

[0170] Comparative Example 2 Experiment of microneedle patch (sustained-release microneedle) (using rhodamine staining):

[0171] Experiment 1: The microneedle patch provided in Comparative Example 2 was inserted into the pre-prepared hydrogel and the experimental phenomenon was recorded with an electronic magnifying glass. It was found that the microneedle tip and the substrate could not be separated almost completely within two minutes, and it was observed that the polymer did not dissolve rhodamine and a small amount of diffusion was observed.

[0172] Experiment 2: A certain number of male C57BL / 6 mice were killed, and a 2cmX2cm area was shaved on the back with a pet shaver, and a depilatory cream was evenly applied. After a period of time, the depilatory cream and the back hair were washed off with water. The microneedle patch provided in Comparative Example 2 was successively attached to the back skin of the mouse, and the patch was left on the skin for 5 minutes, and then the skin punctured by the microneedle was removed for section observation, and it was found that there were many small holes in the mouse skin, but no rhodamine remained, indicating that the needle tip did not remain in the mouse skin.

[0173] From the comparison between Example 1 and Comparative Example 1 (fast-release microneedles) and Comparative Example 2 (sustained-release microneedles), it can be seen that the microneedle patch provided in the present application can achieve rapid separation of the microneedles from the substrate layer, and has a fast-release layer 150 that quickly dissolves and releases the drug and a sustained-release layer 160 that slowly dissolves and releases the drug, achieving good therapeutic effects on stubborn diseases that are difficult to eradicate and prone to recurrence.

[0174] The above description is only a specific embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a microneedle, characterized in that: The microneedle 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 the quick-release layer has a cavity inside; the inner core is disposed in the cavity, and the inner core includes a sustained-release layer; under the same dissolution environment, the dissolution rate of the quick-release layer is greater than the dissolution rate of the sustained-release layer; the quick-release layer is sodium hyaluronate, and the sustained-release layer is chitosan; The outer layer at the root has an opening communicating with the cavity, and the inner core and the root have a bubble layer at the opening; The preparation method comprises: S1, preparing a quick-release layer mixed solution: dissolving a solute for the quick-release layer in a polar solvent to prepare a quick-release layer mixed solution; the solute for the quick-release layer is sodium hyaluronate; S2, preparing a sustained-release layer mixed solution: dissolving a solute for the sustained-release layer in an organic acid or inorganic acid solution to obtain a sustained-release layer mixed solution; wherein the solute for the sustained-release layer is chitosan, and the mass fraction of the solute for the sustained-release layer in the sustained-release layer mixed solution is 4.8% to 6.25%; S3, placing the quick-release layer mixed solution prepared in step S1 in the microneedle mold, first centrifuging or vacuuming, and then drying to form the quick-release layer having a cavity; S4, placing the sustained-release layer mixture obtained in step S2 into the cavity of the quick-release layer in step S3, first centrifuging or vacuuming it, and then placing it in a dryer and drying it at 30°C to 100°C for 30min to 24h to form the sustained-release layer and obtain microneedles.

2. The method for preparing a microneedle according to claim 1, characterized in that: Also includes: S5, repeating steps S3 and S4 alternately to obtain microneedles with a layered structure in which the quick-release layer and the sustained-release layer are alternately distributed.

3. The method for preparing a microneedle according to claim 1, characterized in that: In the mixed solution for the quick-release layer, the mass fraction of the solute for the quick-release layer is 4.8% to 9.1%.

4. The method for preparing a microneedle according to claim 1, characterized in that: The polar solvent is one of water, methanol, ethanol, isopropanol, n-butanol, acetone, chloroform and tetrahydrofuran.

5. The method for preparing a microneedle according to claim 4, characterized in that: 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 cyclohexane acid; the inorganic acid solution is one of diluted hydrochloric acid, hypochlorous acid, nitric acid, chlorous acid, boric acid, carbonic acid, and silicic acid.

6. The method for preparing a microneedle according to claim 1, characterized in that: The sustained-release layer contains the loaded drug, and the sustained-release layer mixed solution prepared in step S2 also contains the loaded drug solution.

7. The method for preparing a microneedle according to claim 6, characterized in that: The quick-release layer contains loaded drugs, and the quick-release layer mixed solution prepared in step S1 also contains loaded drug solution.

8. The method for preparing a microneedle according to claim 6, characterized in that: The mass fraction of the solute for the quick-release layer in the quick-release layer mixture is 4.3% to 7.6%.

9. The method for preparing a microneedle according to claim 1, characterized in that: The centrifuge in S3 is centrifuged at a speed of 3000 r / min to 30000 r / min for 5 min to 90 min or vacuumed at -95 Kpa to -30 Kpa for 5 min to 60 min, and then placed in a dryer and dried at 30° C. to 200° C. for 10 min to 24 h.

10. The method for preparing a microneedle according to claim 1, characterized in that: The centrifuge in S4 is centrifuged at a speed of 3000 r / min to 30000 r / min for 1 min to 60 min or vacuumed at a condition of -95 Kpa to -30 Kpa for 1 min to 50 min.

11. The method for preparing a microneedle according to claim 1, characterized in that: In S4, the sustained-release layer mixed liquid is replaced by a sustained-release layer powder. The preparation method of the sustained-release layer powder is as follows: drying the sustained-release layer mixed liquid prepared in step S2, and grinding the dried solid with a grinding instrument to obtain the sustained-release layer powder.

12. The method for preparing a microneedle according to any one of claims 1 to 11, characterized in that: The inner core comprises at least one fast-release layer and at least one sustained-release layer.

13. The method for preparing a microneedle according to claim 12, characterized in that: Along the direction from the root to the tip, the sustained-release layer and the fast-release layer are alternately arranged.

14. The method for preparing a microneedle according to any one of claims 1 to 11, characterized in that: At least the sustained-release layer carries the drug.

15. The method for preparing a microneedle according to claim 14, characterized in that: The quick-release layer and the sustained-release layer both carry the drug.

16. The method for preparing a microneedle according to claim 15, characterized in that: The drug carried in the fast-release layer and the sustained-release layer is the same drug.

17. The method for preparing a microneedle according to claim 14, characterized in that: The microneedles are used to prevent or treat hair loss, and the carried drugs include small molecules that promote hair growth.

18. The method for preparing a microneedle according to claim 17, characterized in that: The hair growth promoting small molecules include one or more of minoxidil and its derivatives, capsaicin, Platycladus orientalis leaves, finasteride, valproic acid, deoxycortisone, SM04554, CB-03-01, triamcinolone acetonide, betamethasone, 17α-estradiol, adenosine, all-trans retinoic acid, fluoroidil, RU-58841, suberoxime acid, 2-cyano-3-(1-phenyl-1H-indol-3-yl)-2-propionic acid, (4-methoxycarbonyl)phenyl ester and ketoconazole.

19. A microneedle patch, characterized in that: The invention comprises a substrate layer and a microneedle prepared by the microneedle preparation method according to any one of claims 1 to 18, wherein the root is arranged on the substrate layer.

20. The microneedle patch according to claim 19, characterized in that: The roots of the plurality of microneedles are all arranged on the substrate layer, and the plurality of microneedles are distributed in an array.

21. The microneedle patch according to claim 20, characterized in that: The substrate layer ingredients include any one or more of polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid or its salt, lactose, sorbitol, dextran, trehalose and sucrose.

22. The microneedle patch according to claim 21, characterized in that The substrate layer is composed of a mixture of sodium hyaluronate and polyvinyl alcohol.

23. The microneedle patch according to claim 19, characterized in that The microneedles are connected to the substrate layer through the outer layer.

24. The microneedle patch according to claim 23, characterized in that The contact area between the microneedle and the substrate layer is smaller than the area of ​​the orthographic projection of the microneedle on the substrate layer.

25. The microneedle patch according to claim 23, characterized in that A bubble layer is provided at the connection between the microneedle and the substrate layer.

26. A method for preparing the microneedle patch according to any one of claims 19 to 25, characterized in that: include: P1, preparing a substrate layer mixed solution: dissolving a substrate layer solute in a polar solvent to prepare a substrate layer mixed solution; P2, pouring the substrate layer mixed solution described in step P1 into a mold with microneedles, first centrifuging or vacuuming, and then drying to obtain a microneedle patch.

27. The method for preparing a microneedle patch according to claim 26, characterized in that: 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 1:1 to 10:

1.

28. The method for preparing a microneedle patch according to claim 27, characterized in that: In the substrate layer mixed solution, the mass fractions of the sodium hyaluronate and polyvinyl alcohol are 4.8% to 6.3%.

29. The method for preparing a microneedle patch according to claim 26, characterized in that: In step P2, the centrifuge is centrifuged at a speed of 3000 r / min to 30000 r / min for 1 min to 60 min or vacuumed at a condition of -95 Kpa to -30 Kpa for 1 min to 50 min; then it is placed in a dryer or a vacuum oven, dried at room temperature for 5 h to 24 h, and then heated to 30° C. to 200° C. and dried for 0.5 h to 12 h.

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