Hydrogel microneedle patch for treating oral ulcer and preparation method thereof

Abstract

The invention provides a hydrogel microneedle patch for treating oral ulcer and a preparation method, and belongs to the technical field of biomedical engineering. The technical problems that in the traditional oral ulcer administration process, medicine is difficult to retain at the focus for a long time, is easily scoured by saliva and is influenced by tongue and cheek movement are solved. According to the technical scheme, the method comprises the following steps: 1) designing and preparing a microneedle patch mold; (2) synthesizing drug-loaded polydopamine nano particles; (3) preparing a microneedle patch; and 4) evaluating the performance of the microneedle patch. The invention has the following beneficial effects: on one hand, the combination of the drug-loaded nanoparticles and the hydrogel microneedle array can reduce the dosage through drug sustained release; and on the other hand, the problems of high drug instability, low targeting property, poor bioavailability and hindering treatment effect are effectively solved, and the preparation can be widely applied to the fields of drug sustained release, wound healing, tissue engineering and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical engineering, and particularly relates to a hydrogel microneedle patch for treating oral ulcers and a preparation method thereof. Background Art

[0002] Hydrogel is a kind of polymer material with a three-dimensional cross-linked network structure. It has excellent water absorption performance and can maintain a stable coagulation structure while absorbing a large amount of water, playing an important role in the fields of biomedicine, life science, tissue engineering, flexible electronics, environmental engineering, etc. Microneedle technology is an interdisciplinary technology that combines microfabrication processes and biomedical applications, mainly used in the fields of drug delivery, vaccination, biosensing, disease diagnosis, and beauty. Its core principle is to use micron-sized needle tips to penetrate the skin stratum corneum to form microchannels, thereby achieving the efficient delivery of drugs or bioactive substances. However, in some special application scenarios, such as the oral cavity environment with characteristics of large movement, humidity, microorganisms, and inflammation, oral diseases are not only common but also quite difficult to treat, which poses new challenges to microneedle patches for oral disease treatment.

[0003] In recent years, polydopamine has been widely used in the fields of biomedicine, surface coating for anti-corrosion, environmental governance, etc. It is a bio-inspired synthetic polymer material that mimics the characteristics of mussel adhesion proteins and has strong adhesion, self-assembly ability, and multifunctional surface modification characteristics. Due to its biomimetic characteristics, versatility, and compatibility, polydopamine has become the focus of interdisciplinary research. With the further development of nanotechnology, polymer nanoparticles have become a new drug delivery carrier. They are formed by the self-assembly of polymer materials and have the characteristics of small particles, can penetrate the biological membrane barrier, reach specific parts of the human body that traditional drugs cannot reach, can significantly improve the solubility, stability, and targeting of drugs, and at the same time can reduce the distribution of drugs in non-target tissues, thereby reducing its toxic and side effects; on the other hand, due to the strong adhesion performance of polydopamine, using it as the coating of microneedles can significantly improve the adhesion of microneedle patches in complex environments. Summary of the Invention

[0004] The purpose of the present invention is to provide a hydrogel microneedle patch for treating oral ulcers and a preparation method thereof. The combination of drug-loaded nanoparticles and the hydrogel microneedle array can, on the one hand, reduce the dosage of drugs through drug sustained release; on the other hand, effectively overcome the problems of high drug instability, low targeting, and poor bioavailability, which hinder the treatment effect; in addition, the nanoparticles can also simultaneously load drugs with multiple functions to achieve the purpose of synergistic treatment, accelerate the recovery of diseases, and provide a new solution for the delivery of traditional drugs.

[0005] The inventive concept of the present invention is as follows: by combining a hydrogel microneedle array and drug-loaded polydopamine nanoparticles, a hydrogel microneedle patch for treating oral ulcers is developed. On the one hand, the sustained release of drugs for treating oral ulcers can be achieved through the microneedle array, reducing the dosing frequency and improving the utilization rate of drugs; on the other hand, due to the presence of polydopamine, the adhesion of the microneedle patch is enhanced, overcoming the problems of difficult drug retention and easy flushing; in addition, the microneedle patch can improve the targeting of drugs, reduce the toxic and side effects of drugs, reduce the dosing frequency, promote wound healing and tissue repair, thereby providing an improved technical solution for non-invasive or minimally invasive disease treatment.

[0006] In order to achieve the above-mentioned invention purpose, the technical solution adopted by the present invention is specifically as follows: a hydrogel microneedle patch for treating oral ulcers and a preparation method thereof, comprising the following steps:

[0007] S1. Design and prepare a microneedle patch mold;

[0008] S2. Synthesize drug-loaded polydopamine nanoparticles;

[0009] S3. Prepare the microneedle patch;

[0010] S4. Evaluate the performance of the microneedle patch.

[0011] Further, the step S1 includes the following steps:

[0012] S11. Construct a size diagram of the microneedle patch. The microneedle array is located at the center of the substrate. The shape of the microneedle array is square, and the array form is 6×6, 7×7 or 8×8; the substrate is cylindrical, with a diameter D1 of 7.5-9.5 mm and a height of 1-3 mm; the microneedles are conical, with a bottom diameter D2 of 300-450 μm and a height H of 500-900 μm, and the distance L between the microneedles is 350-450 μm;

[0013] S12. Spin-coat a photoresist on a hard substrate of quartz, glass or metal, and prepare a mask plate by means of photolithography, electron beam etching or ion beam etching;

[0014] S13. Pour polydimethylsiloxane PDMS, polystyrene PS or polyethylene PE onto the mask plate, remove the bubbles, and then heat and cure at a temperature of 40-70 °C for a curing time of 4-6 h; after removing the mask plate, a microneedle patch mold is obtained.

[0015] Further, the step S2 includes the following steps:

[0016] S21. Dissolve 300-600 mg of dopamine powder in a mixed solution of 130 mL of ethanol and ammonia water. After 24 h, centrifuge and separate the precipitate to obtain polydopamine nanoparticles;

[0017] S22. Mix 6 - 12 mg of drug I for treating oral ulcers with 0.6 - 1 mg / mL polydopamine nanoparticle solution; or mix 3 - 6 mg of drug I for treating oral ulcers and 3 - 6 mg of drug II for treating oral ulcers with 0.6 - 1 mg / mL polydopamine nanoparticle solution, stir for 4 h, then centrifuge to separate the precipitate to obtain drug - loaded polydopamine nanoparticles.

[0018] Further, the drug I for treating oral ulcers and the drug II for treating oral ulcers in step S22 are triamcinolone acetonide, lidocaine, acyclovir or rosmarinic acid.

[0019] Further, step S3 includes the following two - step preparation steps:

[0020] S31. Thoroughly mix 1 - 10 mg of drug - loaded polydopamine nanoparticles with a hydrogel prepolymer solution having a mass fraction of 8 - 15% or pure hydrogel prepolymer solution, and pour this mixed solution into a microneedle patch mold.

[0021] S32. Place the mold loaded with the mixed solution in a vacuum environment for a period of time to remove the air bubbles in the mold loaded with the mixed solution; then pour the mixed solution in S31 into the mold loaded with the mixed solution again; evacuate again, and this process is repeated 2 - 4 times.

[0022] S33. Suck out the excess mixed liquid in the mold loaded with the mixed solution; cure the mixed solution by heating or ultraviolet light to obtain a mold loaded with a microneedle array.

[0023] S34. Add a hydrogel prepolymer solution having a mass fraction of 8 - 15% or pure hydrogel prepolymer solution to the mold loaded with the microneedle array, maintain it in a vacuum environment for 2 - 5 min, remove the air bubbles, and then cure it by heating or ultraviolet light to obtain a mold loaded with a microneedle patch; after demolding, obtain the final microneedle patch.

[0024] Further, another one - step preparation method for step S3 includes the following steps:

[0025] S31 - 1. Thoroughly mix 1 - 10 mg of drug - loaded polydopamine nanoparticles with a hydrogel prepolymer solution having a mass fraction of 8 - 15% or pure hydrogel prepolymer solution, and pour this mixed solution into a microneedle patch mold.

[0026] S32 - 1. Place the mold loaded with the mixed solution in a vacuum environment for a period of time to remove the air bubbles in the mold loaded with the mixed solution; then pour the mixed solution in S31 - 1 into the mold loaded with the mixed solution again; evacuate again, and this process is repeated 2 - 4 times; after removing the air bubbles, cure it by heating or ultraviolet light to obtain a mold loaded with a microneedle patch; after demolding, obtain the final microneedle patch.

[0027] Further, another deposition preparation method for step S3 includes the steps of:

[0028] S31-2: Infuse a hydrogel prepolymer solution with a mass fraction of 8-15% or pure into a microneedle patch mold.

[0029] S32-2: Place the mold loaded with the hydrogel prepolymer solution in a vacuum environment for a period of time to remove the air bubbles in the mold loaded with the hydrogel prepolymer solution; then infuse the hydrogel prepolymer solution with a mass fraction of 8-15% or pure into the mold loaded with the hydrogel prepolymer solution again; evacuate again, and this process is repeated 2-4 times; after removing the air bubbles, cure it by heating or ultraviolet light to obtain a mold loaded with a microneedle patch; after demolding, obtain a blank microneedle patch.

[0030] S33-2: Drop a solution containing 1-10 mg of drug-loaded polydopamine nanoparticles onto the blank microneedle patch and let it stand for 5-10 h to obtain the final microneedle patch.

[0031] Further, the hydrogel prepolymer solutions in steps S31, S34, S31-1, and S31-2 are gelatin, polyvinyl alcohol PVA, chitosan, hyaluronic acid, polyethylene glycol diacrylate PEGDA, or methacrylated gelatin GelMA.

[0032] Further, the time for placing the mold loaded with the mixed solution in steps S32 and S32-1 and the mold loaded with the hydrogel prepolymer solution in S32-2 in a vacuum environment is maintained at 15-30 min.

[0033] Further, the heating temperature in steps S33, S34, S32-1, and S32-2 is 37-70 °C, and the time is 5-7 h; the wavelength of ultraviolet light is 365 nm, and the irradiation time is 2-5 min.

[0034] Further, step S4 includes the following steps:

[0035] S41: Apply the microneedle patch to the oral cavity of a rat with an oral ulcer model.

[0036] S42: Observe the healing condition of the rat's oral cavity every day.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] 1. The present invention combines drug-loaded polydopamine nanoparticles with hydrogel microneedles. The polydopamine nanoparticles are used as an adhesion interface material to achieve stable adhesion in a complex environment with high humidity and frequent activities, effectively solving the problems of difficult retention and easy flushing of traditional medicaments.

[0039] 2. The microneedle array structure in the present invention realizes targeted drug delivery and slow release, continuously maintains the therapeutic efficacy locally, thereby reducing the frequency of drug administration and improving the drug utilization rate.

[0040] 3. The drug-loaded nanoparticles in the present invention can simultaneously load a variety of drugs for the treatment of oral ulcers, achieving a synergistic effect and meeting the core treatment requirements of "less drug administration times and faster recovery speed" for oral ulcers.

[0041] 4. The microneedle patch in the present invention is prepared by a template replication method, with low production cost; compared with multiple drug administrations for traditional oral ulcers, the microneedle patch can significantly reduce the number of drug administrations, thereby greatly reducing the treatment cost. Description of the Drawings

[0042] The drawings are used to provide a further understanding of the present invention, and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation to the present invention.

[0043] Figure 1 It is the size diagram of the microneedle patch in the present invention.

[0044] Figure 2 It is the preparation flow chart of the mask template in the present invention.

[0045] Figure 3 It is the synthesis schematic diagram of the drug-loaded polydopamine nanoparticles in the present invention.

[0046] Figure 4 It is the flow chart of the two-step method for preparing the microneedle patch in the present invention.

[0047] Figure 5 It is the flow chart of the one-step method for preparing the microneedle patch in the present invention.

[0048] Figure 6 It is the flow chart of the deposition method for preparing the microneedle patch in the present invention.

[0049] Figure 7 It is the schematic diagram of the microneedle patch attached to the rat's oral cavity in the present invention.

[0050] Figure 8 It is the optical photograph of the microneedle patch mold in the present invention.

[0051] Figure 9 It is the TEM image of the polydopamine particles in the present invention.

[0052] Figure 10 It is the TEM image of the drug-loaded polydopamine particles in the present invention.

[0053] Figure 11 It is the optical photograph of the blank microneedle patch in the present invention.

[0054] Figure 12 This is an optical photograph of the side of the blank microneedle patch in the present invention.

[0055] Figure 13 This is a microscopic optical photograph of the blank microneedle patch in the present invention.

[0056] Figure 14 This is a TEM image of the side of the blank microneedle patch in the present invention.

[0057] Figure 15 This is a TEM image of the front of the blank microneedle patch in the present invention.

[0058] Figure 16 This is an optical photograph of the microneedle patch prepared by the deposition method in the present invention.

[0059] Figure 17 This is an optical photograph of the microneedle patch prepared by the one-step method in the present invention.

[0060] Among them, the reference numerals are: 1, microneedle array; 2, substrate; 3, microneedle; 4, hard substrate of quartz, glass or metal; 5, spin coating; 6, photoresist; 7, photolithography, electron beam lithography or ion beam etching; 8, mask; 9, perfusion; 10, polydimethylsiloxane PDMS, polystyrene PS or polyethylene PE; 11, heat curing; 12, microneedle patch mold; 13, dopamine; 14, mixed solution of ethanol and ammonia water; 15, polydopamine nanoparticles; 16, drug I for treating oral ulcers; 17, drug II for treating oral ulcers; 18, drug-loaded polydopamine nanoparticles; 19, hydrogel prepolymer solution; 20, mixed solution; 21, mold loaded with the mixed solution; 22, curing by heating or ultraviolet; 23, mold loaded with the microneedle array, 24, mold loaded with the microneedle patch; 25, demolding; 26, microneedle patch; 27, mold loaded with the hydrogel prepolymer solution; 28, blank microneedle patch; 29, rat with oral ulcer model. Detailed implementation manners

[0061] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Of course, the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0062] Example 1

[0063] A hydrogel microneedle patch for treating oral ulcers and a preparation method thereof, comprising the following steps:

[0064] S1. Design and prepare a microneedle patch mold;

[0065] S2. Synthesize drug-loaded polydopamine nanoparticles;

[0066] S3. Preparation of the microneedle patch;

[0067] S4. Performance evaluation of the microneedle patch.

[0068] Among them, step S1 includes the following steps:

[0069] S11. As Figure 1 shown, construct the dimensional drawing of the microneedle patch. The microneedle array 1 is located at the center of the substrate 2. The shape of the microneedle array 1 is square, and the array form is 7×7; the substrate 2 is cylindrical, with a diameter D1 of 8.5 mm and a height of 3 mm; the microneedles 3 are conical, with a bottom diameter D2 of 360 μm and a height H of 800 μm, and the distance L between the microneedles 3 is 400 μm;

[0070] S12. As Figure 2 shown, spin-coat the photoresist 6 on the hard substrate 4 of quartz, and prepare the mask 8 by photolithography 7;

[0071] S13. Pour the polydimethylsiloxane (PDMS) 10 into the mask 8, remove the bubbles, and then heat and cure 11 at a temperature of 60 °C for 4 h; after removing the mask 8, obtain the microneedle patch mold 12 ( Figure 8 ).

[0072] Step S2 includes the following steps:

[0073] S21. As Figure 3 shown, dissolve 500 mg of dopamine 13 powder in a mixed solution 14 of 130 mL of ethanol and ammonia water. After 24 h, centrifuge and separate the precipitate to obtain polydopamine nanoparticles 15 ( Figure 9 );

[0074] S22. Mix 8 mg of the drug rosmarinic acid 16 for treating oral ulcers with the solution of 0.8 mg / mL of polydopamine nanoparticles 15, stir for 4 h, and then centrifuge and separate the precipitate to obtain the drug-loaded polydopamine nanoparticles 18 ( Figure 10 ).

[0075] Step S3 includes the following preparation steps by deposition method:

[0076] S31. As Figure 6 shown, pour the pure PEGDA hydrogel prepolymer solution 19 into the microneedle patch mold 12;

[0077] S32. The mold 27 loaded with the hydrogel prepolymer solution is placed in a vacuum environment for 30 minutes to remove the air bubbles in the mold 27 loaded with the hydrogel prepolymer solution; then the pure PEGDA hydrogel prepolymer solution 19 is poured into the mold 27 loaded with the hydrogel prepolymer solution again; vacuum is applied again, and this process is repeated 4 times; after removing the air bubbles, it is cured 22 by ultraviolet curing, the wavelength of the ultraviolet is 365 nm, and the irradiation time is 5 minutes to obtain the mold 24 loaded with the microneedle patch; after demolding 25, the blank microneedle patch 28 is obtained. Figures 11 - 15 )

[0078] S33. The solution containing 1 mg of drug-loaded polydopamine nanoparticles 18 is dropped onto the blank microneedle patch 28 and left standing for 10 h to obtain the final microneedle patch 26. Figure 16 )

[0079] Step S4 includes the following steps:

[0080] S41. As Figure 7 shown, the microneedle patch 26 is attached to the oral cavity of the rat 29 with oral ulcer model.

[0081] S42. Observe the healing condition of the rat's oral cavity every day.

[0082] Example 2

[0083] A hydrogel microneedle patch for treating oral ulcers and a preparation method thereof include the following steps:

[0084] S1. Design and prepare a microneedle patch mold.

[0085] S2. Synthesize drug-loaded polydopamine nanoparticles.

[0086] S3. Preparation of the microneedle patch.

[0087] S4. Performance evaluation of the microneedle patch.

[0088] Among them, step S1 includes the following steps:

[0089] S11. As Figure 1 shown, construct the size diagram of the microneedle patch. The microneedle array 1 is located at the center of the substrate 2. The shape of the microneedle array 1 is square, and the array form is 7×7; the substrate 2 is cylindrical, the diameter D1 is 8.5 mm, and the height is 3 mm; the microneedle 3 is conical, the bottom diameter D2 is 360 μm, the height H is 800 μm, and the distance L between the microneedles 3 is 400 μm.

[0090] S12. As Figure 2 shown, spin-coat 5 photoresist 6 on the hard metal substrate 4, and prepare a mask plate 8 by electron beam lithography 7.

[0091] S13. Pour 9 polydimethylsiloxane (PDMS) 10 onto the mask 8, remove the bubbles, and then cure it by heating 11 at a temperature of 60 °C for 4 h. After removing the mask 8, a microneedle patch mold 12 is obtained ( Figure 8 ).

[0092] Step S2 includes the following steps:

[0093] S21. As Figure 3 shown, 500 mg of dopamine 13 powder is dissolved in a mixed solution 14 of 130 mL of ethanol and ammonia water. After 24 h, the precipitate is separated by centrifugation to obtain polydopamine nanoparticles 15 ( Figure 9 );

[0094] S22. 8 mg of rosmarinic acid 16, a drug for treating oral ulcers, is mixed with a solution of 0.8 mg / mL of polydopamine nanoparticles 15. After stirring for 4 h, the precipitate is separated by centrifugation to obtain drug-loaded polydopamine nanoparticles 18 ( Figure 10 ).

[0095] Step S3 includes the following one-step preparation steps:

[0096] S31. As Figure 5 shown, 10 mg of drug-loaded polydopamine nanoparticles 18 is thoroughly mixed with a 10% mass fraction PVA hydrogel prepolymer solution 19, and this mixed solution 20 is poured into the microneedle patch mold 12;

[0097] S32. The mold 21 loaded with the mixed solution is placed in a vacuum environment for 20 min to remove the bubbles in the mold 21 loaded with the mixed solution; then the mixed solution 20 in S31 is poured into the mold 21 loaded with the mixed solution again; vacuumize again, and this process is repeated 3 times; after removing the bubbles, cure it by heating 22 at a heating temperature of 60 °C for 6 h to obtain a mold 24 loaded with a microneedle patch; after demolding 25, the final microneedle patch 26 is obtained ( Figure 17 ).

[0098] Step S4 includes the following steps:

[0099] S41. As Figure 7 shown, the microneedle patch 26 is attached to the oral cavity of a rat 29 with an oral ulcer model;

[0100] S42. Observe the healing condition of the rat's oral cavity every day.

[0101] Example 3

[0102] A hydrogel microneedle patch for treating oral ulcers and a preparation method thereof, including the following steps:

[0103] S1. Design and fabricate a microneedle patch mold;

[0104] S2. Synthesize drug-loaded polydopamine nanoparticles;

[0105] S3. Prepare the microneedle patch;

[0106] S4. Evaluate the performance of the microneedle patch.

[0107] Among them, step S1 includes the following steps:

[0108] S11. As Figure 1 shown, construct the dimensional drawing of the microneedle patch. The microneedle array 1 is located at the center of the substrate 2. The shape of the microneedle array 1 is square, and the array form is 8×8; the substrate 2 is cylindrical, with a diameter D1 of 7.5 mm and a height of 1 mm; the microneedles 3 are conical, with a bottom diameter D2 of 300 μm and a height H of 500 μm, and the distance L between the microneedles 3 is 350 μm;

[0109] S12. As Figure 2 shown, spin-coat photoresist 6 on the hard substrate 4 of glass, and prepare a mask plate 8 by means of ion beam etching 7;

[0110] S13. Pour polystyrene (PS) 10 onto the mask plate 8. After removing the bubbles, heat and cure 11 at a temperature of 40 °C for a curing time of 6 h; after removing the mask plate 8, obtain the microneedle patch mold 12.

[0111] Step S2 includes the following steps:

[0112] S21. As Figure 3 shown, dissolve 300 mg of dopamine 13 powder in a mixed solution 14 of 130 mL of ethanol and ammonia water. After 24 h, centrifuge and separate the precipitate to obtain polydopamine nanoparticles 15;

[0113] S22. Mix 4 mg of triamcinolone acetonide 16 for treating oral ulcers and 4 mg of lidocaine 17 for treating oral ulcers with 1 mg / mL of polydopamine nanoparticle 15 solution. After stirring for 4 h, centrifuge and separate the precipitate to obtain drug-loaded polydopamine nanoparticles 18.

[0114] Step S3 includes the following two-step preparation steps:

[0115] S31. As Figure 4 shown, fully mix 5 mg of drug-loaded polydopamine nanoparticles 18 with an 8% chitosan hydrogel prepolymer solution 19 by mass fraction, and pour this mixed solution 20 into the microneedle patch mold 12;

[0116] S32. The mold 21 loaded with the mixed solution is placed in a vacuum environment for 15 min to remove the bubbles in the mold 21 loaded with the mixed solution; then the mixed solution 20 in S31 is poured into the mold 21 loaded with the mixed solution again; vacuum is applied again, and this process is repeated 2 times;

[0117] S33. Suck out the excess mixed liquid 20 in the mold 21 loaded with the mixed solution; cure the mixed solution 20 by heating, the heating temperature is 37 °C, and the time is 5 h to obtain the mold 23 loaded with the microneedle array;

[0118] S34. Add the chitosan hydrogel prepolymer solution 19 with a mass fraction of 8% to the mold 23 loaded with the microneedle array, maintain it in a vacuum environment for 5 min, remove the bubbles, and then cure it by heating, the heating temperature is 37 °C, and the time is 7 h to obtain the mold 24 loaded with the microneedle patch; after demolding 25, the final microneedle patch 26 is obtained.

[0119] Step S4 includes the following steps:

[0120] S41. As shown in Figure 7 the microneedle patch 26 is attached to the oral cavity of the rat 29 with an oral ulcer model;

[0121] S42. Observe the healing condition of the rat's oral cavity every day.

[0122] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A hydrogel microneedle patch for treating oral ulcers and a preparation method thereof, characterized in that, It includes the following steps: S1. Design and prepare a microneedle patch mold; S2. Synthesize drug-loaded polydopamine nanoparticles; S3. Prepare the microneedle patch; S4. Evaluate the performance of the microneedle patch.

2. The hydrogel microneedle patch for treating oral ulcers and its preparation method according to claim 1, characterized in that, The step S1 includes the following steps: S11. Construct a size diagram of the microneedle patch. The microneedle array (1) is located at the central position of the substrate (2). The shape of the microneedle array (1) is square, and the array form is 6×6, 7×7 or 8×8. The substrate (2) is cylindrical, with a diameter D1 of 7.5 - 9.5 mm and a height of 1 - 3 mm. The microneedle (3) is conical, with a bottom diameter D2 of 300 - 450 μm and a height H of 500 - 900 μm. The distance L between the microneedles (3) is 350 - 450 μm; S12. Spin-coat (5) a photoresist (6) on a hard substrate (4) of quartz, glass or metal, and prepare a mask plate (8) by means of photolithography, electron beam etching or ion beam etching (7); S13. Pour (9) polydimethylsiloxane PDMS, polystyrene PS or polyethylene PE (10) onto the mask plate (8). After removing the bubbles, heat and cure (11) at a temperature of 40 - 70 °C for a curing time of 4 - 6 h. After removing the mask plate (8), a microneedle patch mold (12) is obtained.

3. The hydrogel microneedle patch for treating oral ulcers and the preparation method according to claim 1, wherein, The step S2 includes the following steps: S21. Dissolve 300 - 600 mg of dopamine (13) powder in a mixed solution (14) of 130 mL of ethanol and ammonia water. After 24 h, centrifuge and separate the precipitate to obtain polydopamine nanoparticles (15); S22. Mix 6 - 12 mg of drug I (16) for treating oral ulcers with a solution of 0.6 - 1 mg / mL of polydopamine nanoparticles (15); or mix 3 - 6 mg of drug I (16) for treating oral ulcers and 3 - 6 mg of drug II (17) for treating oral ulcers with a solution of 0.6 - 1 mg / mL of polydopamine nanoparticles (15). After stirring for 4 h, centrifuge and separate the precipitate to obtain drug-loaded polydopamine nanoparticles (18).

4. The hydrogel microneedle patch for treating oral ulcers and the preparation method according to claim 3, wherein, The drug I (16) and drug II (17) for treating oral ulcers in the step S22 are triamcinolone acetonide, lidocaine, acyclovir or rosmarinic acid.

5. The hydrogel microneedle patch for treating oral ulcers and the preparation method according to claim 1, wherein The step S3 includes the following two-step preparation steps: S31. Thoroughly mix 1 - 10 mg of drug-loaded polydopamine nanoparticles (18) with a hydrogel prepolymer solution (19) with a mass fraction of 8 - 15% or pure, and pour this mixed solution (20) into the microneedle patch mold (12); S32. Place the mold (21) loaded with the mixed solution in a vacuum environment for a period of time to remove the bubbles in the mold (21) loaded with the mixed solution; then pour the mixed solution (20) in S31 into the mold (21) loaded with the mixed solution again; evacuate again, and this process is repeated 2 - 4 times; S33. Suck out the excess mixed liquid (20) in the mold (21) loaded with the mixed solution; cure (22) the mixed solution (20) by heating or ultraviolet light to obtain a mold (23) loaded with a microneedle array; S34. A hydrogel prepolymer solution (19) with a mass fraction of 8 - 15% or pure is added to a mold (23) loaded with a microneedle array, maintained in a vacuum environment for 2 - 5 min. After removing air bubbles, it is cured (22) by heating or ultraviolet light to obtain a mold (24) loaded with a microneedle patch; after demolding (25), the final microneedle patch (26) is obtained; Another one-step preparation method of the step S3 includes the following steps: S31-1. 1 - 10 mg of drug-loaded polydopamine nanoparticles (18) are fully mixed with a hydrogel prepolymer solution (19) with a mass fraction of 8 - 15% or pure, and this mixed solution (20) is poured into a microneedle patch mold (12); S32-1. The mold (21) loaded with the mixed solution is placed in a vacuum environment for a period of time to remove air bubbles in the mold (21) loaded with the mixed solution; then the mixed solution (20) in S31-1 is poured into the mold (21) loaded with the mixed solution again; vacuum is pumped again, and this process is repeated 2 - 4 times; after removing air bubbles, it is cured (22) by heating or ultraviolet light to obtain a mold (24) loaded with a microneedle patch; after demolding (25), the final microneedle patch (26) is obtained; Another deposition preparation method of the step S3 includes the steps: S31-2. A hydrogel prepolymer solution (19) with a mass fraction of 8 - 15% or pure is poured into a microneedle patch mold (12); S32-2. The mold (27) loaded with the hydrogel prepolymer solution is placed in a vacuum environment for a period of time to remove air bubbles in the mold (27) loaded with the hydrogel prepolymer solution; then a hydrogel prepolymer solution (19) with a mass fraction of 8 - 15% or pure is poured into the mold (27) loaded with the hydrogel prepolymer solution again; vacuum is pumped again, and this process is repeated 2 - 4 times; after removing air bubbles, it is cured (22) by heating or ultraviolet light to obtain a mold (24) loaded with a microneedle patch; after demolding (25), a blank microneedle patch (28) is obtained; S33-2. A solution containing 1 - 10 mg of drug-loaded polydopamine nanoparticles (18) is dropped onto the blank microneedle patch (28) and left standing for 5 - 10 h to obtain the final microneedle patch (26).

6. The hydrogel microneedle patch for treating oral ulcers and the preparation method according to claim 5, wherein, The hydrogel prepolymer solution (19) in the steps S31, S34, S31-1 and S31-2 is gelatin, polyvinyl alcohol PVA, chitosan, hyaluronic acid, polyethylene glycol diacrylate PEGDA or methacrylated gelatin GelMA.

7. The hydrogel microneedle patch for treating oral ulcers and the preparation method according to claim 5, wherein The time for the mold (21) loaded with the mixed solution in the steps S32 and S32-1 and the mold (27) loaded with the hydrogel prepolymer solution in S32-2 placed in the vacuum environment is maintained at 15 - 30 min.

8. The hydrogel microneedle patch for treating oral ulcers and the preparation method according to claim 5, wherein The heating temperature in the steps S33, S34, S32-1 and S32-2 is 37 - 70 °C, and the time is 5 - 7 h; the wavelength of ultraviolet light is 365 nm, and the irradiation time is 2 - 5 min.

9. The hydrogel microneedle patch for treating oral ulcers and the preparation method according to claim 1, characterized in that, The step S4 includes the following steps: S41. Apply the microneedle patch (26) to the oral cavity of the rat with oral ulcer model (29); S42. Observe the healing condition of the rat's oral cavity every day.

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