Multilayer microneedle patch and manufacturing method thereof

Abstract

The microneedle patch of the present invention comprises a base portion and a plurality of needle bodies formed by protrusions from the base portion. The base portion is formed by a barrier layer and a needle base layer. Each needle body portion is formed by a needle tip layer, a barrier layer, and a needle base layer. The barrier layer of each needle body portion is formed between the needle tip layer and the needle base layer of the corresponding needle body portion. The barrier layer of the base portion and the barrier layer of the needle body portion, and the needle base layer of the base portion and the needle base layer of the needle body portion are all integrally formed structures. The needle tip layer contains HA, PVP, and a first saccharide, the barrier layer contains a second saccharide, PVA, and HP-β-CD, and the needle base layer contains a third saccharide, PVA, and HP-β-CD. The barrier layer of the microneedle patch has a barrier effect, preventing the active ingredients of the needle tip layer from diffusing to the needle base layer, confining them to the needle tip and controlling the amount carried.

Description

Technical Field

[0001] The present invention relates to a microneedle patch structure and a manufacturing method thereof, and in particular to a medical aesthetics, medicine or vaccine microneedle patch and a manufacturing method thereof. Background Art

[0002] Transdermal drug delivery (TDD) has gained significant attention in recent years. It utilizes a non-invasive method to deliver active substances (e.g., drugs or vaccines) through the skin for absorption and efficacy. While TDD avoids the disruption of oral medications by the digestive system and liver during primary metabolism, and also eliminates the fear and pain associated with subcutaneous injections, the hydrophobic and negatively charged nature of the skin's stratum corneum makes it unsuitable for the delivery of water-soluble drugs or vaccines via traditional TDD systems.

[0003] To address these issues, existing technologies have developed microneedle patches, whose substrate is covered with multiple micron-sized needles that pierce the skin's stratum corneum and deliver drugs or vaccines to the epidermis for release. Using microneedle patches not only addresses many of the issues associated with oral administration or subcutaneous injections, but also expands the range of drugs or vaccines to include both fat-soluble and water-soluble drugs. These different types of drugs and vaccines can be delivered directly to the epidermis or dermis through the needles on the microneedle patch, delivering their efficacy without causing pain.

[0004] Due to the numerous advantages of microneedle patches, the industry is actively developing them. For example, Taiwan Invention Patent No. 201400140A discloses a method for fabricating a mosaic transdermal drug delivery patch. The method involves first applying a biodegradable polymer colloid containing the drug to a film to form multiple biodegradable carriers. Furthermore, a support substrate with multiple protruding support shafts is fabricated and pre-coated with an adhesive. The protruding support shafts on the surface of the support substrate are then aligned with the biodegradable carriers and bonded together to create the mosaic transdermal drug delivery patch.

[0005] However, the above-mentioned process method must additionally consider the spacing and alignment issues between the multiple protruding support shafts on the supporting substrate and the multiple carriers, which increases the difficulty of the process; and the production process requires a pre-adhesive coating step to bond the supporting substrate and the carrier, which increases the complexity of the process and production cost.

[0006] In addition, when the microneedle patch is particularly used to transmit active pharmaceutical ingredients or active vaccine ingredients, how to control the amount of active pharmaceutical ingredients or active vaccine ingredients carried becomes quite important. Generally speaking, the needle body length of the microneedle patch is between 100 microns (μm) and 1000 μm, and the thickness of the skin is not uniform depending on the body part, and the thickness of the epidermis can be only about 30 μm to 300 μm. If the expected effect of the amount of active substance carried by the microneedle patch is to be achieved, the active substance carried must be confined near the needle tip so that the active substance is accurately released to the epidermis to be acted upon. If the active substance carried is spread throughout the entire needle body, the expected effect cannot be achieved. In this case, if the predetermined effect is to be achieved, the content of the active substance carried must be increased, but this will result in a waste of active substances. The above-mentioned process method does not teach or suggest how to effectively control the amount of active pharmaceutical ingredients or active vaccine ingredients carried in the microneedle patch, so the existing process method still needs to be improved. Summary of the Invention

[0007] In view of the above technical problems, the purpose of the present invention is to effectively confine the active ingredients to the microneedle tip layer and accurately control the carrying amount, so that it can be used to make medical microneedle patches or vaccine microneedle patches.

[0008] To achieve the aforementioned objectives, the present invention provides a microneedle patch comprising a base portion and a plurality of needle body portions protruding from the base portion, the base portion being formed by a barrier layer and a needle bottom layer, and each needle body portion being formed by a needle tip layer, a barrier layer and a needle bottom layer, wherein the barrier layer of each needle body portion is formed between the needle tip layer and the needle bottom layer of the corresponding needle body portion, wherein the barrier layer of the base portion and the barrier layers of the plurality of needle body portions are an integrally formed structure, and the needle bottom layer of the base portion and the needle bottom layers of the plurality of needle body portions are an integrally formed structure; wherein the thickness of each needle body portion is 300 μm to 1000 μm, and the thickness of the base portion is 200 μm to 400 μm; with a tip of the needle bottom layer of the base portion toward the needle body portion as a thickness measurement line, the ratio of the thickness of the needle bottom layer of the needle body portion and the barrier layer of the needle body portion to the thickness of the needle body portion is 0.5 4 to 0.81; wherein, the material of the needle tip layer comprises hyaluronic acid, polyvinyl pyrrolidone and a first saccharide, wherein the molecular weight of the hyaluronic acid is between 2 kilodaltons and 500,000 daltons, and the weight ratio of the hyaluronic acid to the polyvinyl pyrrolidone is 1:0.8 to 1:2; the material of the barrier layer comprises a second saccharide, polyvinyl alcohol and 2-hydroxypropyl-β-cyclodextrin, wherein the weight ratio of the second saccharide to the polyvinyl alcohol is 1:1.8 to 1:3, and the weight ratio of the second saccharide to the 2-hydroxypropyl-β-cyclodextrin is 1:1.8 to 1:3; the material of the needle base layer comprises a third saccharide, polyvinyl alcohol and 2-hydroxypropyl-β-cyclodextrin, wherein the weight ratio of the third saccharide to the polyvinyl alcohol is 1:1.8 to 1:3, and the weight ratio of the third saccharide to the 2-hydroxypropyl-β-cyclodextrin is 1:1.8 to 1:3.

[0009] By simultaneously controlling the composition of the three layers of the microneedle patch, namely the needle tip layer, the barrier layer and the needle base layer, the thickness of the needle body, the thickness of the base portion, and the thickness of the needle base layer and the barrier layer in the needle body and the ratio of the thickness to the needle body, the barrier layer can exert a barrier effect, confining the active ingredients to the needle tip layer and preventing the active ingredients in the needle tip layer from diffusing to the needle base layer. This is beneficial for controlling the amount of active ingredients carried in the microneedle patch to achieve the desired effect.

[0010] According to the present invention, the "thickness measurement line along a needle base layer of the base portion toward a tip of the needle body portion" refers to the shortest distance extending from the projection point of the needle body tip onto the base portion to the tip of the needle body portion as the thickness measurement line. More specifically, the base portion has a bottom surface relative to the needle body portion, and the shortest distance extending from the projection point of the needle body tip onto the bottom surface to the tip of the needle body portion is the thickness measurement line. It should be understood that the thicknesses of the base base layer, the base base layer, the barrier layer of the needle body portion, and the tip layer described herein are all measured along the thickness measurement line.

[0011] According to the present invention, the needle tip layer further comprises glycerol and polysorbate 20.

[0012] According to the present invention, the first sugar of the needle tip layer is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, dextrin, maltodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, dextran and combinations thereof.

[0013] According to the present invention, the second carbohydrate of the barrier layer is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof.

[0014] According to the present invention, the third sugar of the needle bottom layer is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan and combinations thereof.

[0015] According to the present invention, the needle tip layer further comprises an active ingredient. The active ingredient may be a pharmaceutical active ingredient or a vaccine active ingredient. Specifically, the pharmaceutical active ingredient may be a small molecule compound, a biological agent, a biosimilar drug, a protein drug, a botanical drug, etc. Specifically, the vaccine active ingredient may be an attenuated vaccine, an inactivated vaccine, a virus-like particle (VLP), a purified subunit antigen, a recombinant antigen, a synthetic peptide, a recombinant vector, a DNA vaccine, a nucleic acid vaccine, mucosal immunization, a combined vaccine, and the like.

[0016] According to the present invention, the mechanical strength of the needle body of the microneedle patch is greater than 0.058 Newtons per needle (N / needle), enabling the microneedle patch of the present invention to puncture the stratum corneum without breaking. Preferably, the mechanical strength of the needle body of the microneedle patch is greater than 0.14 N / needle. More preferably, the mechanical strength of the needle body of the microneedle patch is greater than 0.20 N / needle.

[0017] According to the present invention, the weight ratio of the hyaluronic acid to the first saccharide is 1:5 to 1:8.

[0018] In one embodiment, the thickness of the needle body (ie, the needle length of the needle body) is 400 μm to 1000 μm. In another embodiment, the thickness of the needle body is 600 μm to 900 μm.

[0019] In one embodiment, the needle tip layer has a thickness of 170 μm to 190 μm. In another embodiment, the needle tip layer has a thickness of 210 μm to 240 μm. In another embodiment, the needle tip layer has a thickness of 170 μm to 265 μm. In another embodiment, the needle tip layer has a thickness of 200 μm to 265 μm.

[0020] In one embodiment, the thickness of the barrier layer of the base portion is 110 μm to 210 μm. It should be understood that the barrier layer of the base portion herein refers to the portion outside the area where the molded needle portion is protruding from the base portion.

[0021] In one embodiment, the thickness of the base portion is 200 μm to 360 μm. In another embodiment, the thickness of the base portion is 210 μm to 360 μm.

[0022] In one embodiment, the total thickness of the needle base layer of the base portion, the needle base layer of the body portion, and the barrier layer of the body portion is 550 μm to 1100 μm. In another embodiment, the total thickness of the needle base layer of the base portion, the needle base layer of the body portion, and the barrier layer of the body portion is 570 μm to 1100 μm.

[0023] According to the present invention, the method for preparing the aforementioned microneedle patch comprises the following steps:

[0024] Step (a): providing a mother mold, wherein the mother mold has a reference surface and a plurality of holes, wherein the plurality of holes are concavely formed downward from the reference surface;

[0025] Step (b): Filling the plurality of cavities of the master mold with a needle tip mixture, wherein the needle tip mixture has a solid content greater than 5 weight percent (wt%) and less than 40 wt%, and comprises hyaluronic acid, polyvinyl pyrrolidone, and a first saccharide, wherein the hyaluronic acid has a molecular weight ranging from 2 kilodaltons to 500,000 daltons, and the weight ratio of the hyaluronic acid to the polyvinyl pyrrolidone is 1:0.8 to 1:2;

[0026] Step (c): drying the needle tip mixture to form a needle tip layer, wherein the surface of the needle tip layer is lower than the reference surface of the master mold;

[0027] Step (d): Filling a barrier mixture into the plurality of holes of the master mold, covering the needle tip layer and the base surface of the master mold so that the vertical distance between the liquid level of the barrier mixture and the base surface of the master mold is 600 μm to 1500 μm, wherein the barrier mixture has a solid content greater than 30 wt% and less than or equal to 45 wt%, and the barrier mixture comprises a second saccharide, polyvinyl alcohol, and 2-hydroxypropyl-β-cyclodextrin, wherein the weight ratio of the second saccharide to the polyvinyl alcohol is 1:1.8 to 1:3, and the weight ratio of the second saccharide to the 2-hydroxypropyl-β-cyclodextrin is 1:1.8 to 1:3;

[0028] Step (e): drying the barrier mixture to form a barrier layer, wherein the barrier layer is formed on the needle tip layer and the reference surface of the master mold;

[0029] Step (f): Filling a needle bottom mixture into the plurality of holes of the master mold, covering the barrier layer in the plurality of holes and the barrier layer on the reference surface of the master mold, so that the vertical distance between the liquid level of the needle bottom mixture and the reference surface of the master mold is 450 μm to 850 μm, wherein the needle bottom mixture has a solid content of greater than or equal to 30 wt% and less than 45 wt%, and comprises a third saccharide, polyvinyl alcohol, and 2-hydroxypropyl-β-cyclodextrin, the weight ratio of the third saccharide to the polyvinyl alcohol is 1:1.8 to 1:3, and the weight ratio of the third saccharide to the 2-hydroxypropyl-β-cyclodextrin is 1:1.8 to 1:3, and the solid content of the needle bottom mixture is less than the solid content of the barrier mixture;

[0030] Step (g): drying the needle base mixture to form a needle base layer, so that the barrier layer is adhered between the needle tip layer and the needle base layer; and

[0031] Step (h): removing the mutually bonded needle tip layer, the barrier layer and the needle bottom layer from the mother mold to obtain the microneedle patch.

[0032] According to the method for preparing a microneedle patch of the present invention, the prepared microneedle patch can confine the active ingredients to the needle tip layer, preventing the active ingredients in the needle tip layer from diffusing to the needle bottom layer, thereby facilitating precise control of the amount of active ingredients carried in the microneedle patch and avoiding waste of active substances.

[0033] According to the present invention, the master mold can be a hard master mold, and the material of the hard master mold can be glass, quartz, silicon wafer, metal, metal oxide, or metal alloy; the metal material can be aluminum, copper, or nickel, but is not limited to these. In another embodiment, the master mold can be a soft master mold, and the material of the soft master mold can be a polymer, metal foil, or flexible glass; the polymer can be polydimethylsiloxane (PDMS), polymethyl methacrylate (PMMA), polycarbonate (PC), polyethersulfone (PES), etc., but is not limited to these.

[0034] According to the present invention, the shape of the holes in the master mold can be conical, square-conical, or spire-shaped, but is not limited thereto. The master mold comprises a reference surface and a plurality of holes, each recessed downward from the reference surface. The depth of each hole ranges from 75 μm to 1500 μm, preferably from 150 μm to 1200 μm, more preferably from 175 μm to 1000 μm, and even more preferably from 200 μm to 1000 μm. The maximum width of each hole ranges from 38 μm to 800 μm, preferably from 75 μm to 650 μm, and even more preferably from 85 μm to 550 μm.

[0035] In the microneedle patch, the shape of each needle body can be conical, square-conical, or spire-shaped, but is not limited thereto.

[0036] In the microneedle patch, the density of the needle body can be between 1 needle / cm2. 2 ) to 1000 needles / cm 2 ; preferably 1 needle / cm 2 Up to 500 needles / cm 2 .

[0037] According to the present invention, the needle tip mixture further comprises glycerol and polysorbate 20.

[0038] According to the present invention, based on the total weight of the needle tip mixture, the content of glycerol is 0.005 wt % to 0.2 wt %, and the content of polysorbate 20 is 0.001 wt % to 0.1 wt %.

[0039] According to the present invention, the needle tip mixture is heated at 25°C and a shear rate of 1s -1 The viscosity measured under the conditions of FIG. 1 is 8 centipoise (cP) to 25,000 cP, preferably 8 cP to 20,000 cP.

[0040] According to the present invention, the barrier mixture is heated at 25°C and a shear rate of 1s -1 The viscosity measured under the conditions of FIG. 5 is 5000 cP to 220000 cP, preferably 10000 cP to 200000 cP, and more preferably 30000 cP to 200000 cP.

[0041] According to the present invention, the needle bottom mixed liquid is heated at 25°C and a shear rate of 1s -1 The viscosity measured under the following conditions is 3000 cP to 100000 cP, preferably 5000 cP to 100000 cP, more preferably 7000 cP to 90000 cP.

[0042] According to the present invention, the needle tip mixture, barrier mixture and needle base mixture can all be polymer aqueous solutions, and the needle tip mixture is a polymer aqueous solution containing active ingredients. Preferably, the solid content of the needle tip mixture is 10wt% to 35wt%.

[0043] According to the present invention, the polymer materials contained in the tip mixture, barrier mixture, and base mixture can be dissolvable or swellable materials. More specifically, the polymer materials can be biocompatible or biodegradable. For example, the polymer material may be amylopectin, starch, sodium hyaluronate, poly(methyl vinyl ether-alt-maleic anhydride) (PMVE / MA), sodium carboxymethylcellulose (CMC), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, poly(vinylalcohol) (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polylactic acid (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), chitosan, or a combination thereof, but is not limited thereto. Here, when the polymer material includes glucose, galactose, lactose, sucrose, trehalose, maltose, dextrin, maltodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, dextran, etc., it can help improve the mechanical strength of the microneedle patch. In addition, when making vaccine microneedle patches, the aforementioned glucose, galactose, lactose, sucrose, trehalose, maltose, dextrin, etc. can also serve as antigen protective agents.

[0044] Preferably, the aforementioned step (b) may include:

[0045] Step (b1): first forming a needle tip mixture on the master mold, and then allowing the needle tip mixture to flow into the plurality of holes, thereby allowing the needle tip mixture to cover the base surface and the plurality of holes of the master mold; and

[0046] Step (b2): removing the needle tip mixed liquid on the reference surface, thereby making the liquid surface of the needle tip mixed liquid flush with the reference surface of the master mold.

[0047] According to the present invention, in the above-mentioned step (b), the method for filling the needle tip mixture into the multiple holes of the master mold includes a vacuum extraction method and a centrifugation method. In one embodiment, the present invention can place the needle tip mixture and the master mold in an oven to extract air, thereby allowing the needle tip mixture to cover the base surface and multiple holes of the master mold; in another embodiment, the present invention can centrifuge the needle tip mixture and the master mold together, thereby allowing the needle tip mixture to cover the base surface and multiple holes of the master mold. Here, the pressure in the oven can be controlled at -700 mmHg to -800 mmHg, preferably -710 mmHg to -760 mmHg. The speed of the centrifugation step can be controlled at 20 times gravity (xg) to 20,000 xg, preferably 20 xg to 12,000 xg.

[0048] Preferably, the aforementioned step (d) may include:

[0049] Step (d1): first forming a barrier mixture on the master mold, and then allowing the barrier mixture to flow into the plurality of holes, thereby allowing the barrier mixture to cover the base surface and the plurality of holes of the master mold; and

[0050] Step (d2): removing a portion of the barrier mixture on the reference surface so that the vertical distance between the liquid level of the barrier mixture and the reference surface of the master mold is 600 μm to 1500 μm.

[0051] According to the present invention, in step (d), the method for filling the plurality of holes of the master mold with the barrier mixture includes vacuum extraction and centrifugation. In one embodiment, the present invention can place the barrier mixture and the master mold in an oven for vacuum extraction, thereby allowing the barrier mixture to cover the base surface and the plurality of holes of the master mold. In another embodiment, the present invention can centrifuge the barrier mixture and the master mold together, thereby allowing the barrier mixture to cover the base surface and the plurality of holes of the master mold. In this case, the pressure in the oven can be controlled within a range of -700 mmHg to -800 mmHg, preferably -710 mmHg to -760 mmHg. The speed of the centrifugation step can be controlled within a range of 20 x g to 20,000 x g, preferably 20 x g to 12,000 x g.

[0052] Preferably, the aforementioned step (f) may include:

[0053] Step (f1): first forming a needle bottom mixture on the master mold, and then allowing the needle bottom mixture to flow into the plurality of holes, thereby allowing the needle bottom mixture to cover the barrier layer on the base surface of the master mold and the barrier layer in the plurality of holes; and

[0054] Step (f2): removing a portion of the needle bottom mixed liquid on the reference surface so that the vertical distance between the liquid level of the needle bottom mixed liquid and the reference surface of the master mold is 450 μm to 850 μm.

[0055] According to the present invention, in step (f), the method for filling the multiple pores of the master mold with the needle bottom mixture includes vacuum extraction and centrifugation. In one embodiment, the present invention can place the needle bottom mixture and the master mold in an oven for vacuum extraction, thereby allowing the needle bottom mixture to cover the barrier layer on the base surface of the master mold and the barrier layer within the multiple pores. In another embodiment, the present invention can centrifuge the needle bottom mixture and the master mold together, thereby allowing the needle bottom mixture to cover the barrier layer on the base surface of the master mold and the barrier layer within the multiple pores. In this case, the pressure in the oven can be controlled between -700 mmHg and -800 mmHg, preferably between -710 mmHg and -760 mmHg. The speed of the centrifugation step can be controlled between 20 x g and 20,000 x g, preferably between 20 x g and 12,000 x g.

[0056] Preferably, the aforementioned steps (b), (d) and (f) can each independently adopt slit or slotdie coating, blade coating, slide coating, dip coating, inkjet printing, nozzle printing, dispenser or their combinations to form the needle tip mixture, barrier mixture and needle bottom mixture on the master mold, but are not limited to the above methods. The method of forming the needle tip mixture on the master mold in step (b) can be the same as or different from the method of forming the barrier mixture on the master mold in step (d) and the method of forming the needle bottom mixture on the master mold in step (f). Preferably, the method for making the microneedle patch of the present invention can adopt a slit coating method to sequentially coat the needle tip mixture, barrier mixture and needle bottom mixture on the master mold. More preferably, the method for making the microneedle patch of the present invention adopts a dispensing method to sequentially form the needle tip mixture, the barrier mixture and the needle base mixture on a master mold.

[0057] In one embodiment, when the slit coating method is used to coat the needle tip mixture in step (b), the coating gap can be controlled to be 1 μm to 5000 μm, and the coating speed can be controlled to be 1 meter / minute (m / min) to 100 m / min; the above process parameters can be adjusted according to the characteristics of the selected needle tip mixture and the specifications of the microneedle patch. When the slit coating method is used to coat the barrier mixture in step (d), the coating gap can be controlled to be 1 μm to 3000 μm, and the coating speed can be controlled to be 1 m / min to 100 m / min. In addition, when the slit coating method is used to coat the needle base mixture in step (f), the coating gap can be controlled to be 1 μm to 3000 μm, and the coating speed can be controlled to be 1 m / min to 100 m / min; the above process parameters can be adjusted according to the characteristics of the selected barrier mixture, needle base mixture and the specifications of the microneedle patch.

[0058] Preferably, in the aforementioned step (b), the coating gap can be controlled at 100 μm to 5000 μm, and the coating speed can be controlled at 1 m / min to 100 m / min; in the aforementioned step (d), the coating gap can be controlled at 100 μm to 3000 μm, and the coating speed can be controlled at 1 m / min to 100 m / min; in the aforementioned step (f), the coating gap can be controlled at 100 μm to 3000 μm, and the coating speed can be controlled at 1 m / min to 100 m / min.

[0059] In this specification, the term "wet film thickness" refers to the vertical distance between the liquid level after the liquid is placed in the master mold and the base plane of the master mold, after the liquid covers the holes in the master mold. For example, "the wet film thickness of the barrier mixture is 600μm to 1500μm" means that after the barrier mixture fills the holes in the master mold and covers the needle tip layer, the vertical distance between the liquid level of the barrier mixture and the base plane of the master mold is 600μm to 1500μm. Preferably, in step (d), the vertical distance between the liquid level of the barrier mixture and the base plane of the master mold is 600μm to 850μm.

[0060] According to the present invention, the aforementioned steps (c), (e) and (g) can be carried out by freeze drying or room temperature drying. Preferably, the drying temperature of the aforementioned steps (c), (e) and (g) can be controlled at -80°C to 100°C. More specifically, when a medical microneedle patch is to be produced, the drying temperature of the aforementioned steps (c), (e) and (g) can be controlled at -80°C to 100°C to avoid the problem that a drying temperature above 100°C destroys the molecular structure of the active pharmaceutical ingredient and the active ingredient becomes ineffective. On the other hand, when a vaccine microneedle patch is to be produced, the drying temperature of the aforementioned steps (c), (e) and (g) can be controlled at -80°C to 40°C to avoid the vaccine from losing its activity due to a drying temperature above 40°C.

[0061] In this specification, the phrase "a wet film thickness of the needle bottom mixture of 450 μm to 850 μm" means that after the needle bottom mixture has filled the pores of the master mold and covered the barrier layer, the vertical distance between the liquid level of the needle bottom mixture and the reference plane of the master mold is 450 μm to 850 μm. Preferably, in step (f), the vertical distance between the liquid level of the needle bottom mixture and the reference plane of the master mold is 450 μm to 750 μm.

[0062] In application, by controlling the needle length of the microneedle patch, the microneedle patch can avoid touching the nervous system below the dermis during use, thereby reducing the user's fear and eliminating the pain.

[0063] In this specification, a range expressed as "from a smaller value to a larger value" unless otherwise specified indicates that the range is greater than or equal to the smaller value and less than or equal to the larger value. For example, a thickness of 300 μm to 1000 μm indicates a thickness range of "greater than or equal to 300 μm and less than or equal to 1000 μm." BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 Schematic diagram illustrating that the barrier layer in the microneedle patch of the embodiment has the expected barrier effect.

[0065] Figure 2 Schematic diagram illustrating that the barrier layer in the microneedle patch of the comparative example does not have the expected barrier effect.

[0066] Figures 3A to 3C It is a schematic diagram illustrating the meaning of wet film thickness in this specification. DETAILED DESCRIPTION

[0067] The following further describes the technical means adopted by the present invention to achieve the predetermined purpose of the invention with reference to the accompanying drawings and preferred embodiments of the present invention.

[0068] Several methods for making microneedle patches are listed below as examples to illustrate the embodiments of the present invention. Those skilled in the art can easily understand the advantages and effects that can be achieved by the present invention through the contents of this specification, and make various modifications and changes without departing from the spirit of the present invention to implement or apply the contents of the present invention.

[0069] Reagent Description

[0070] 1. Hyaluronic acid (HA), agent: Jingming Chemical Co., Ltd., molecular weight 100,000 Daltons.

[0071] 2. Polyvinylpyrrolidone (PVP), agent: Huimin Pharmaceutical Co., Ltd.

[0072] 3. Sucrose, agent: Jingming Chemical Co., Ltd.

[0073] 4. Trehalose, agent: Jingming Chemical Co., Ltd.

[0074] 5. Polyvinyl alcohol (PVA), agent: Yuansheng Applied Materials Co., Ltd.

[0075] 6. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) was purchased from Shangke Biomedical Industrial Co., Ltd. under the trade name Cavitron W7 HP7 Pharm.

[0076] 7. Glycerol, agent: Jingming Chemical Co., Ltd.

[0077] 8. Polysorbate 20 (Tween 20), purchased from Yuba Enterprise Co., Ltd., trade name MASEMUL PS 20.

[0078] Preparation example: polymer materials

[0079] The present invention first prepares three polymer materials of different compositions to prepare the tip mixture of the microneedle patch's tip layer, the barrier mixture of the barrier layer, and the base mixture of the base layer. Table 1 below shows the formula ingredients and weight ratios of polymer materials numbered A, B, and C.

[0080] Table 1: Formula ingredients and weight ratios of polymer materials

[0081] serial number Formula ingredients and weight ratios of polymer materials A 100,000 Dalton molecular weight hyaluronic acid: polyvinyl pyrrolidone: sucrose = 2:2:11 B 100,000 Dalton molecular weight hyaluronic acid: polyvinyl pyrrolidone: trehalose = 2:2:11 C Trehalose: polyvinyl alcohol: 2-hydroxypropyl-β-cyclodextrin = 1:2:2

[0082] Test Example 1: Viscosity Test

[0083] In this test example, appropriate amounts of polymers A, B, and C were weighed and dissolved in different solvents to prepare tip mixtures, barrier mixtures, and base mixtures with varying solid contents. Glycerol and polysorbate 20 (Tween 20) were added as appropriate, as shown in Table 2 below, to obtain the test samples. Polymer A was dissolved in phosphate-buffered saline (PBS), while polymers B and C were dissolved in deionized water (DI water). For example, the tip mixture of Example 1 contained 10 wt% polymer A, 0.0067 wt% glycerol, and 0.011 wt% polysorbate 20, with the remainder being PBS. For another example, the barrier mixture of Example 1 contained 40 wt% polymer C and 60 wt% DI water. For another example, the base mixture of Example 1 contained 35 wt% polymer C and 65 wt% DI water.

[0084] The viscosity of each sample was measured using a viscometer (model MCR302, purchased from Anton Paar) at 25°C for 1s. -1 The viscosity of each sample is shown in Table 2 below.

[0085] Examples 1 to 9: Microneedle Patches

[0086] As shown in Table 2, the aforementioned tip mixture, barrier mixture, and base mixture were used to prepare the microneedle patches of Examples 1 to 9 by the following methods.

[0087] First, a master mold with a reference surface and multiple holes is used. Each hole is recessed downward from the reference surface, and the holes are arranged in a matrix on the master mold. The master mold is made of polydimethylsiloxane (PDMS) and has a hole density of 266 holes / cm2. 2 ), the hole array is arranged in a circular pattern with a diameter of 1.5 centimeters (cm), and each hole is a square pyramid. The hole depth (i.e., the vertical distance between the hole tip and the master mold reference plane) used in the master molds of Examples 1 to 8 was approximately 580 μm to 620 μm, and the maximum hole width (i.e., the maximum inner diameter of the hole in a horizontal plane flush with the master mold reference plane) was approximately 290 μm to 310 μm. The hole depth (i.e., the vertical distance between the hole tip and the master mold reference plane) used in the master mold of Example 9 was approximately 880 μm to 920 μm, and the maximum hole width (i.e., the maximum inner diameter of the hole in a horizontal plane flush with the master mold reference plane) was approximately 440 μm to 460 μm.

[0088] Next, using a dispensing method, a volume of 0.1 ml of the needle tip mixture is dropped onto the master mold, and the needle tip mixture is allowed to cover the multiple holes on the master mold. The master mold containing the needle tip mixture is then placed in a vacuum oven and evacuated to reduce the pressure to -730 mmHg to -760 mmHg, thereby allowing the needle tip mixture to flow downward from the master mold base surface into the multiple holes of the master mold, covering the master mold base surface and all the holes. Here, this step can also be completed by centrifugation; for example, the master mold containing the needle tip mixture is placed in a centrifuge and centrifuged at a speed of 2300 x g for 6 minutes, allowing the needle tip mixture to flow downward from the master mold base surface into the multiple holes of the master mold, covering the master mold base surface and all the holes. Next, use a scraper to completely scrape off the needle tip mixture on the master mold reference surface, and then place the master mold containing the needle tip mixture in an environment of 30°C and a relative humidity of 20% to 65% for continuous drying for 1 hour, so that the needle tip mixture is dried into a needle tip layer, and the surface of the needle tip layer is lower than the master mold reference surface, thereby obtaining a master mold with a needle tip layer. Here, the thickness of the needle tip layer (dry film thickness) of the microneedle patch of Examples 1 to 9 is the vertical distance from the tip of the hole to the surface of the needle tip layer, wherein if the surface of the needle tip layer is not a flat surface but an inwardly concave plane, the thickness of the needle tip layer (dry film thickness) is the vertical distance from the tip of the hole to the lowest point of the needle tip layer surface. The ratio of the thickness of the needle tip layer of the microneedle patch of Examples 1 to 9 to the depth of the hole of the master mold (that is, the ratio of the thickness of the needle tip layer to the thickness of the needle body) is listed in Table 3 below.

[0089] Next, using a dispensing method, 0.8 ml of barrier mixture was dropped onto the master mold with the needle tip layer, covering the multiple holes. The master mold containing the barrier mixture was then centrifuged at 2300 x g for 6 minutes, allowing the barrier mixture to flow downward from the reference surface into the multiple holes of the master mold, covering the reference surface and the needle tip layer in all holes. A scraper was then used to scrape off a portion of the barrier mixture from the master mold reference surface, resulting in a wet film thickness as shown in Table 2. For example, if the barrier mixture wet film thickness is 700 μm, the vertical distance from the barrier mixture liquid surface to the master mold reference surface is 700 μm. The master mold containing the barrier mixture is then placed in an environment of 30°C and a relative humidity of 20% to 65% for continuous drying for 24 to 48 hours. This allows the barrier mixture to dry into a barrier layer that adheres to the needle tip layer and the master mold base surface, thereby obtaining a master mold with a needle tip layer and a barrier layer.

[0090] Next, using the same dispensing method, 0.8 ml of the needle-base mixture was dropped onto the master mold with the needle tip layer and barrier layer, covering the multiple holes. The master mold containing the needle-base mixture was then placed in a centrifuge and centrifuged at 2300 x g for 40 minutes. The mixture flowed downward from the base surface into the multiple holes of the master mold, covering the barrier layer on the base surface and the barrier layer in all holes. A scraper was then used to scrape off a portion of the needle-base mixture on the base surface of the master mold, resulting in the wet film thickness of the needle-base mixture for each example as shown in Table 2. The master mold containing the base mixture was then placed in an environment of 30°C and a relative humidity of 20% to 65% for continuous drying for 24 to 48 hours. The base mixture dried to form a base layer, which then adhered to the barrier layer. The barrier layer of the body was then bonded between the tip layer and the base layer of the body, thereby obtaining a finished master mold. The shortest distance from the projection of the hole tip onto the base layer surface to the tip was used as the thickness measurement line. The ratio of the sum of the thicknesses of the base layer and barrier layer of the body of the microneedle patches of Examples 1 to 9 (i.e., the perpendicular distance from the master mold reference plane to the tip layer surface) to the thickness of the body (i.e., the depth of the master mold hole) measured along this thickness measurement line is shown in Table 3 below. Furthermore, the thickness of the base portion of the microneedle patches of Examples 1 to 9 (i.e., the perpendicular distance from the base layer surface to the master mold reference plane) is also listed in Table 3 below.

[0091] Finally, the finished product is removed from the master mold to obtain the microneedle patches of Examples 1 to 9. It should be noted that in the above-mentioned method for preparing the microneedle patch, the needle tip mixture may contain a pharmaceutical active ingredient or a vaccine active ingredient.

[0092] like Figure 1 As shown, the microneedle patch 1 of the present invention includes a base portion 12 and a plurality of needle bodies 11 formed by protruding from the base portion 12. The base portion 12 is formed by a barrier layer 122 of the base portion and a needle base layer 123 of the base portion. Each needle body portion 11 is formed by a needle tip layer 111, a barrier layer 112 of the needle body portion, and a needle base layer 113 of the needle body portion. The barrier layer 112 of the needle body portion is formed between the needle tip layer 111 and the needle base layer 113 of the needle body portion. The barrier layer 122 of the base portion and the barrier layer 112 of the needle body portion are integrally formed, and the needle base layer 123 of the base portion and the needle base layer 113 of the needle body portion are integrally formed. The thickness measurement line L is the shortest distance from the tip of the needle body portion to the projection point of the base relative to the bottom surface of the needle body portion, and is used to measure the thickness H of the needle base layer 123 of the base portion. 123 , the thickness H of the needle bottom layer 113 of the needle body 113 , the thickness H of the barrier layer 112 of the needle body 112 and the thickness H of the needle tip layer 111111 The baseline. Figure 1 As shown, the thickness H of the needle bottom layer 123 of the base portion measured along the thickness measurement line L is 123 The thickness of the base portion 12 is equal to the sum of the thickness of the barrier layer 122 and the needle bottom layer 123 of the base portion, referred to as the thickness of the base portion 12; and the thickness H of the needle bottom layer 113 of the needle body portion measured along the thickness measurement line L is 113 , the thickness H of the barrier layer 112 of the needle body 112 and the thickness H of the needle tip layer 111 111 The sum of the thicknesses of the three is the thickness of the needle body 11. The thickness H of the needle base layer 113 of the needle body of the microneedle patch of Examples 1 to 9 is 113 and the thickness H of the barrier layer 112 of the needle body 112 The ratio of the sum of the depth of the hole of the master mold (i.e., the thickness of the needle body) is also listed in Table 3 below. In addition, the thickness H of the needle bottom layer 123 of the base portion measured along the thickness measurement line L is 123 , the thickness H of the needle bottom layer 113 of the needle body 113 and the thickness H of the barrier layer 112 of the needle body 112 The total of the three is 550μm to 1100μm.

[0093] In addition, in order to further explain the meaning of wet film thickness, the following is an example of the preparation process of the barrier layer and the needle bottom layer in the microneedle patch and the preparation process of the barrier layer and the needle bottom layer. Figures 3A to 3C Provide explanation.

[0094] like Figure 3A As shown, a mother mold 30 containing a needle layer has a reference surface 301 , a plurality of holes 302 recessed downward from the reference surface 301 , and needle tip layers 311 formed in the holes 302 .

[0095] Then, if Figure 3B As shown, a barrier mixture 32A is injected into the hole 302 and covers the surface of the needle tip layer 311 and the reference surface 301 of the master mold. At this time, the vertical distance H1 between the liquid surface 32B of the barrier mixture 32A and the reference surface 301 of the master mold is the wet film thickness of the barrier mixture 32A.

[0096] Then, if Figure 3CAs shown, the aforementioned barrier mixture will then form a needle body barrier layer 312 on the surface of the needle tip layer 311 and a base barrier layer 322 on the reference surface 301 of the master mold. Then, a needle bottom mixture 33A is injected into the hole 302 and covers the surface of the needle body barrier layer 312 and the surface of the base barrier layer 322. At this time, the vertical distance H2 between the liquid surface 33B of the needle bottom mixture 33A and the reference surface 301 of the master mold is the wet film thickness of the needle bottom mixture 33A.

[0097] Comparative Examples 1 and 2: Microneedle Patches

[0098] The microneedle patches of Comparative Examples 1 and 2 are prepared in roughly the same manner as the microneedle patch of Example 8, except that the wet film thickness of the needle-bottom mixture of the microneedle patches of Comparative Examples 1 and 2 is different from the wet film thickness of the needle-bottom mixture of the microneedle patch of Example 8.

[0099] Table 2: Composition and viscosity of the tip mixture, composition and viscosity and wet film thickness of the barrier mixture, and composition and viscosity and wet film thickness of the base mixture used to prepare the microneedle patches of Examples 1 to 9.

[0100]

[0101]

[0102] Table 3: The polymer materials used for the tip layer, barrier layer and base layer of microneedle patch Examples 1 to 9, the ratio of the thickness of the tip layer to the thickness of the needle body, the thickness of the base, the thickness of the base layer and barrier layer of the needle body measured along the thickness measurement line and the ratio of the thickness of the base layer and barrier layer to the thickness of the needle body, mechanical strength and diffusion prevention test results.

[0103]

[0104] Test Example 2: Mechanical Strength Test of Microneedle Patch

[0105] The microneedle patches of Examples 1 to 9 and Comparative Examples 1 and 2 were placed in a moisture-proof cabinet for 2 days. The mechanical strength of each microneedle patch was then tested using a universal material testing machine (Instrument Model 3343, purchased from INSTRON). In this test, the displacement was set to 10 millimeters (mm), and the compression test was performed at a speed of 66 mm / min, with 500 compression stress values ​​collected per second. The mechanical strength of the microneedle patches of Examples 1 to 9 and Comparative Examples 1 and 2 is shown in Table 3 above.

[0106] As shown in Table 3, the mechanical strengths of the microneedle patches of Examples 1 to 9 were all higher than the mechanical strength required to penetrate the stratum corneum without breaking (0.058 N / needle). The mechanical strengths of the microneedle patches of Examples 2 to 9 were all higher than 0.20 N / needle, and the microneedle patch of Example 9 had the best mechanical strength (0.3 N / needle). In contrast, the microneedle patch of Comparative Example 2 had a mechanical strength of only 0.05 N / needle, which made it difficult to penetrate the stratum corneum and easily broke, making it difficult to apply the microneedle patch.

[0107] Test Example 3: Anti-diffusion effect test of microneedle patch

[0108] In this test example, a two-color fluorescence observation method was used to test whether the barrier layer effectively prevents the active ingredients of the needle tip layer from diffusing to the needle bottom layer, so as to control the amount of active ingredients carried by the needle tip layer in the microneedle patch. In the microneedle patches of Examples 1 to 9 and Comparative Examples 1 and 2, 29.6 micrograms / ml of green fluorescence was added to the needle tip mixture, and 29.6 micrograms / ml of red fluorescence was added to the needle bottom mixture. After the microneedle patches of Examples 1 to 9 and Comparative Examples 1 and 2 were prepared, each microneedle patch was placed under an inverted fluorescence microscope (instrument model NIB410-FL, purchased from NEXCOPE) to observe whether diffusion occurs between the layers. If the needle bottom layer still exhibits red fluorescence under observation using an inverted fluorescence microscope, it means that the green fluorescence of the needle tip layer has not diffused, as shown in FIG. Figure 1 As shown in the needle body 11 of the microneedle patch 1, the barrier layer 112 of the needle body has a barrier effect, which can confine the active ingredients to the needle tip layer 111, so it is represented by "○" in Table 3 above; if the needle bottom layer shows orange fluorescence, it means that the green fluorescence of the needle tip layer has diffused into the needle bottom layer and mixed with the red fluorescence of the needle bottom layer, as shown in the figure. Figure 2 As shown in the needle body portion 21 of the microneedle patch 2, the barrier layer 212 of the needle body portion does not have a barrier effect, so that the active ingredient diffuses from the needle tip layer 211 to the needle bottom layer 223 of the base portion, and is therefore represented by "╳" in Table 3 above.

[0109] As shown in Table 3, the microneedle patches of Examples 1 to 9 were all able to effectively prevent the active ingredient from diffusing from the needle tip layer to the needle base layer. In contrast, the microneedle patches of Comparative Examples 1 and 2 were unable to prevent the active ingredient from diffusing from the needle tip layer to the needle base layer. In particular, even though the microneedle patch of Comparative Example 2 had the mechanical strength to pierce the stratum corneum, it was still unable to prevent the active ingredient from diffusing from the needle tip layer to the needle base layer, thereby affecting the therapeutic effect of the microneedle patch containing the active ingredient.

[0110] In summary, by controlling the composition of the needle tip layer, barrier layer and needle bottom layer and the thickness of the layers, the present invention obtains a microneedle patch that not only has good mechanical strength and is conducive to the application of the microneedle patch, but also can effectively prevent the active ingredients from diffusing from the needle tip layer to the needle bottom layer, thereby being able to confine the carried active substances near the needle tip, so as to accurately release the active substances to the desired site of action, thereby ensuring that the predetermined therapeutic effect is achieved.

[0111] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as a preferred embodiment, it is not intended to limit the present invention. Any technician familiar with the present profession can make some changes or modifications to equivalent embodiments of the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A microneedle patch, characterized in that: The invention relates to a needle needle device comprising a base portion and a plurality of needle bodies formed by protruding from the base portion, wherein the base portion is formed by a barrier layer and a base layer, and each needle body portion is formed by a tip layer, a barrier layer, and a base layer, wherein the barrier layer of each needle body portion is formed between the tip layer and the base layer of the corresponding needle body portion, wherein the barrier layer of the base portion and the barrier layers of the plurality of needle bodies are integrally formed, and the base layer of the base portion and the base layers of the plurality of needle bodies are integrally formed; wherein the thickness of each needle body portion is 300 to 1000 microns, and the thickness of the base portion is 200 to 400 microns; and with a thickness measurement line from the base layer of the base portion toward a tip of the needle body portion, the ratio of the sum of the thickness of the base layer of the needle body portion and the barrier layer of the needle body portion to the thickness of the needle body portion is 0.54 to 0.81; The material of the needle tip layer includes hyaluronic acid, polyvinyl pyrrolidone and a first saccharide, wherein the molecular weight of the hyaluronic acid is between 2 kilodaltons and 500,000 daltons, and the weight ratio of the hyaluronic acid to the polyvinyl pyrrolidone is 1:0.8 to 1:2; the material of the barrier layer includes a second saccharide, polyvinyl alcohol and 2-hydroxypropyl-β-cyclodextrin, wherein the weight ratio of the second saccharide to the polyvinyl alcohol in the barrier layer material is 1:1.8 to 1:3, and the weight ratio of the second saccharide to the 2-hydroxypropyl-β-cyclodextrin in the barrier layer material is 1:1.8 to 1:3; the material of the needle base layer includes a third saccharide, polyvinyl alcohol and 2-hydroxypropyl-β-cyclodextrin, wherein the weight ratio of the third saccharide to the polyvinyl alcohol in the needle base material is 1:1.8 to 1:3, and the weight ratio of the third saccharide to the 2-hydroxypropyl-β-cyclodextrin in the needle base material is 1:1.8 to 1:

3.

2. The microneedle patch according to claim 1, wherein The needle tip layer further comprises glycerol and polysorbate 20.

3. The microneedle patch according to claim 1 or 2, wherein: The first saccharide is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, dextrin, 2-hydroxypropyl-β-cyclodextrin, dextran, and combinations thereof; the second saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof; and the third saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof.

4. The microneedle patch according to claim 1 or 2, wherein: The first saccharide is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, maltodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, dextran, and combinations thereof; the second saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof; and the third saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof.

5. The microneedle patch according to claim 3, wherein The needle tip layer contains an active ingredient, which includes attenuated vaccines, inactivated vaccines, virus-like particles, purified subunit antigens, genetically recombinantly expressed antigens, synthetic peptides, genetically recombinant vectors, gene vaccines, nucleic acid vaccines, mucosal immunization or combination vaccines.

6. The microneedle patch according to claim 1, wherein The weight ratio of the hyaluronic acid to the first saccharide is 1:5 to 1:

8.

7. A method for manufacturing a microneedle patch according to any one of claims 1 to 6, characterized in that: The following steps are involved: Step (a): providing a mother mold, wherein the mother mold has a reference surface and a plurality of holes, wherein the plurality of holes are concavely formed downward from the reference surface; Step (b): Filling the plurality of holes of the master mold with a needle tip mixture, wherein the needle tip mixture has a solid content greater than 5 weight percent and less than 40 weight percent, and comprises hyaluronic acid, polyvinyl pyrrolidone, and a first saccharide, wherein the molecular weight of the hyaluronic acid is between 2 kilodaltons and 500,000 daltons, and the weight ratio of the hyaluronic acid to the polyvinyl pyrrolidone is 1:0.8 to 1:2; Step (c): drying the needle tip mixture to form a needle tip layer, wherein the surface of the needle tip layer is lower than the reference surface of the master mold; Step (d): Filling a barrier mixture into the plurality of holes of the master mold, covering the needle tip layer and the base surface of the master mold, so that the vertical distance between the liquid level of the barrier mixture and the base surface of the master mold is 600 μm to 1500 μm, wherein the solid content of the barrier mixture is greater than 30 weight percent and less than or equal to 45 weight percent, and the barrier mixture comprises a second saccharide, polyvinyl alcohol, and 2-hydroxypropyl-β-cyclodextrin, and the weight ratio of the second saccharide to the polyvinyl alcohol in the barrier mixture is 1:1.8 to 1:3, and the weight ratio of the second saccharide to the 2-hydroxypropyl-β-cyclodextrin in the barrier mixture is 1:1.8 to 1:3; Step (e): drying the barrier mixture to form a barrier layer, wherein the barrier layer is formed on the needle tip layer and the reference surface of the master mold; Step (f): Filling a needle bottom mixture into the plurality of holes of the master mold, covering the barrier layer in the plurality of holes and the barrier layer on the base surface of the master mold, so that the vertical distance between the liquid level of the needle bottom mixture and the base surface of the master mold is 450 μm to 850 μm, wherein the needle bottom mixture has a solid content of greater than or equal to 30 weight percent and less than 45 weight percent, and the needle bottom mixture comprises a third saccharide, polyvinyl alcohol, and 2-hydroxypropyl-β-cyclodextrin, the weight ratio of the third saccharide to the polyvinyl alcohol in the needle bottom mixture is 1:1.8 to 1:3, and the weight ratio of the third saccharide to the 2-hydroxypropyl-β-cyclodextrin in the needle bottom mixture is 1:1.8 to 1:3, and the solid content of the needle bottom mixture is less than the solid content of the barrier mixture; Step (g): drying the needle base mixture to form a needle base layer, so that the barrier layer is adhered between the needle tip layer and the needle base layer; and Step (h): removing the mutually bonded needle tip layer, the barrier layer and the needle bottom layer from the mother mold to obtain the microneedle patch.

8. The method for manufacturing a microneedle patch according to claim 7, wherein: The needle tip mixture further comprises glycerol and polysorbate 20.

9. The method for manufacturing a microneedle patch according to claim 8, wherein: Based on the total weight of the needle tip mixture, the content of the glycerol is 0.005 weight percent to 0.2 weight percent, and the content of the polysorbate 20 is 0.001 weight percent to 0.1 weight percent.

10. The method for manufacturing a microneedle patch according to claim 8, wherein: The viscosity of the needle tip mixture ranges from 8 centipoise to 25,000 centipoise.

11. The method for manufacturing a microneedle patch according to claim 8, wherein: The viscosity of the barrier mixture is 5,000 centipoise to 220,000 centipoise.

12. The method for manufacturing a microneedle patch according to claim 8, wherein: The viscosity of the needle bottom mixture is 3000 centipoise to 100000 centipoise.

13. The method for manufacturing a microneedle patch according to claim 7, wherein: In step (b), the weight ratio of the hyaluronic acid to the first saccharide is 1:5 to 1:

8.

14. The method for manufacturing a microneedle patch according to claim 7, wherein: In step (d), the vertical distance between the liquid level of the barrier mixed liquid and the reference plane of the master mold is 600 μm to 850 μm.

15. The method for manufacturing a microneedle patch according to any one of claims 7 to 14, wherein: The first saccharide is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, dextrin, 2-hydroxypropyl-β-cyclodextrin, dextran, and combinations thereof; the second saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof; and the third saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof.

16. The method for manufacturing a microneedle patch according to any one of claims 7 to 14, wherein: The first saccharide is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, maltodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, dextran, and combinations thereof; the second saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof; and the third saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof.

17. The method for manufacturing a microneedle patch according to claim 7, wherein: In step (b), the method of filling the needle tip mixture into the multiple holes of the master mold includes vacuum pumping and centrifugation; in step (d), the method of filling the barrier mixture into the multiple holes of the master mold includes vacuum pumping and centrifugation; and in step (f), the method of filling the needle base mixture into the multiple holes of the master mold includes vacuum pumping and centrifugation.

18. The method for manufacturing a microneedle patch according to claim 7, wherein: The needle tip mixture contains an active ingredient, which includes attenuated vaccines, inactivated vaccines, virus-like particles, purified subunit antigens, genetically recombinantly expressed antigens, synthetic peptides, genetically recombinant vectors, gene vaccines, nucleic acid vaccines, mucosal immunization or combination vaccines.

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