A method for preparing a hydrogel microneedle dressing

Abstract

The application relates to a preparation method of a hydrogel microneedle dressing, which comprises the following steps: S1, preparing a needle tip solution, wherein solutes of the needle tip solution comprise a combination of at least two of chitosan, Gantrez S-97 BF, hyaluronic acid, chondroitin sulfate sodium, polyvinylpyrrolidone and sodium carboxymethyl cellulose; S2, preparing a backing solution, wherein solutes of the backing solution are prepared from raw materials comprising hyaluronic acid, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, N-hydroxysuccinimide and polydopamine; S3, filling the needle tip solution and the backing solution into microneedle areas and backing areas of a microneedle mold respectively, and after freeze-drying demolding, coating an oxidizing agent on a backing layer surface formed by the backing solution to obtain the hydrogel microneedle dressing. The application has the advantages of good mechanical performance, good adhesion performance and liquid absorption capacity.

Description

Technical Field

[0001] The present invention relates to the technical field of medical dressings, and in particular to a method for preparing a hydrogel microneedle dressing. Background Art

[0002] Medical dressings are wound dressings used to cover sores, wounds, or other lesions. Currently, the main dressings used clinically are absorbent cotton gauze, non-woven dressings, film dressings, and hydrogel dressings. While absorbent cotton gauze and non-woven dressings offer excellent air and moisture permeability, they lack sufficient fluid absorption capacity and tend to adhere to the wound surface after absorbing fluid, hindering wound healing. Therefore, an ideal medical dressing should be soft, non-toxic, and have high fluid retention capacity. It should also exhibit non-cytotoxicity, high hemocompatibility, and maintain a moist environment, particularly for chronic wounds with exudates (such as venous, diabetic ulcers, and burns). Hydrogel dressings are water-insoluble, gel-like materials with a three-dimensional network structure formed from water-soluble polymers or their monomers. They possess a smooth surface, excellent biocompatibility, and the ability to undergo repeated hydration upon contact with the wound surface, absorbing exudate from the wound. Overall, hydrogel dressings are currently the best choice for this ideal dressing.

[0003] Currently, hydrogel dressings typically sprinkle the drug onto the wound-facing surface, allowing the drug to contact the wound surface during application. Alternatively, the drug is adsorbed into the dressing's adsorption layer. When applied to the wound, the dressing absorbs exudate from the wound, allowing the drug to dissolve in the exudate and migrate to the wound surface through molecular diffusion. This application method only allows the drug to contact the wound surface, making it less effective at repairing deeper tissue layers and resulting in prolonged wound recovery. To address this issue, the use of microneedles for transdermal delivery of macromolecules has gained increasing popularity in recent years. Specifically, microneedle dressings typically mix the drug with a shaped, solidifying component to create a microneedle-shaped drug. Upon application, the drug microneedles are embedded in the wound, where they come into contact with tissue fluid and dissolve and diffuse into the wound. Alternatively, the drug is loaded into the microneedles using a degradable / soluble material. During application, the drug gradually diffuses into the wound as the microneedles degrade / dissolve. Alternatively, the drug is directly coated onto the surface of the microneedles.

[0004] A Chinese patent with authorization publication number CN101687090B discloses a microneedle system, comprising a substrate and conical or polygonal microneedles for penetrating the skin surface bonded to the substrate, wherein the microneedles for penetrating the skin surface are made of a material containing 50-70% collagen and 50-30% hyaluronic acid by weight and capable of dissolving or swelling in vivo; the microneedles for penetrating the skin surface contain at least one of a water-soluble drug and a cosmetic ingredient; the substrate is a thin film substrate made of a material capable of dissolving or swelling in vivo; the substrate has a V-shaped portion formed by engraving a V-shaped cutting line; the microneedles for penetrating the skin surface are made by folding the V-shaped portion into a needle shape; a V-shaped cutting line is engraved on a thin film substrate made of a material capable of dissolving or swelling in vivo to form the V-shaped portion, and the microneedles for penetrating the skin surface are made by folding the V-shaped portion into a needle shape.

[0005] The aforementioned existing technology solutions have the following drawbacks: In solutions where a small amount of water-soluble drug is carried by a microneedle system, the drug mixes with components such as collagen and hyaluronic acid, which not only affects the drug's repair properties, but also suffers from poor retention at the wound site, easy detachment, low adhesion, and a high reliance on auxiliary equipment (such as medical tape) for ideal puncture and fixation. This also leads to low drug bioavailability, an increased risk of wound adhesion, and problems with frequent use. Therefore, it is necessary to design a microneedle dressing with excellent mechanical properties, good adhesion, and liquid absorption capacity. Summary of the Invention

[0006] The problem to be solved by the present invention is to provide a method for preparing a hydrogel microneedle dressing in view of the above-mentioned deficiencies in the prior art, which has the advantages of good mechanical properties, good adhesion properties, and liquid absorption capacity.

[0007] The above-mentioned object of the present invention is achieved through the following technical solutions:

[0008] A method for preparing a hydrogel microneedle dressing comprises the following steps:

[0009] S1. preparing a needle tip solution, wherein the solute of the needle tip solution comprises a combination of at least two of chitosan, Gantrez S-97 BF, hyaluronic acid, sodium chondroitin sulfate, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose;

[0010] S2: preparing a backing solution, wherein the solute of the backing solution is made of raw materials including hyaluronic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, and polydopamine;

[0011] S3 fills the needle tip solution and the backing solution into the microneedle area and the backing area of ​​the microneedle mold respectively, freeze-dries and demoulds, and then coats the surface of the backing layer formed by the backing solution with an oxidant to obtain a hydrogel microneedle dressing.

[0012] Furthermore, in S1, the solvent of the needle tip solution includes water, and the solute of the needle tip solution includes 10-30 g / mL chitosan and 30-40 g / mL Gantrez S-97 BF, or 10-30 g / mL hyaluronic acid and 40-50 g / mL sodium chondroitin sulfate.

[0013] Furthermore, in S2, the solvent of the backing solution includes water, and the solute concentration of the backing solution is 10-30 g / mL.

[0014] Furthermore, in S2, the molar ratio of hyaluronic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, and polydopamine is 1:1.0~2.0:1.0~2.0:1.0~2.0.

[0015] Furthermore, in said S2, the process of preparing the solute of the backing solution includes,

[0016] S21: Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysuccinimide to a 0.5-1.5 g / mL hyaluronic acid solution, adjust the pH to 4.5-5.5 with hydrochloric acid, and react in a sealed environment for 25-35 minutes to obtain a first reaction solution;

[0017] S22: adding polydopamine to the first reaction solution, adjusting the pH to 4.5-5.5 with hydrochloric acid, and reacting in a sealed environment for 10-15 hours to obtain a second reaction solution;

[0018] S33: The second reaction solution is first dialyzed against a PBS buffer solution with a pH of 5.0 for 3 to 5 times, each time for 5 to 7 hours, and then dialyzed against distilled water for several times, each time for 3 to 5 hours, and then freeze-dried for 10 to 15 hours to obtain the solute of the backing solution.

[0019] Furthermore, in S3, the oxidant includes 4.0-5.0 mg / mL of sodium periodate and 0.3-0.5 mol / mL of sodium hydroxide.

[0020] Furthermore, in said S3, it includes:

[0021] S31 After adding the needle tip solution to the microneedle area of ​​the microneedle mold, centrifuge at 10-20°C and 3000-4000 rpm for 8-12 minutes, repeating at least 4 times, with the two adjacent centrifugation directions in opposite directions and the centrifugation speed and time remaining unchanged, so that the needle tip solution is filled into the microneedle area of ​​the microneedle mold;

[0022] S32: removing the needle tip solution from the backing area of ​​the microneedle mold and adding the backing solution, centrifuging at 10-20° C. and 500-3000 rpm for 1-10 minutes, repeating at least 12 times, with the two adjacent centrifugation directions being opposite, and the centrifugation speed and time being gradually reduced, so that the backing solution is filled into the backing area of ​​the microneedle mold;

[0023] S33 placing the microneedle mold with the needle tip solution and the backing solution in a freeze dryer, setting the freeze drying temperature to -80 to -20°C, the freeze drying pressure to 0.001 to 6.1 mbar, and the freeze drying time to 2 to 24 hours, and demolding after the freeze drying to obtain a microneedle patch; wherein the microneedle patch includes a microneedle layer composed of the needle tip solution and a backing layer composed of the backing solution;

[0024] S34: an oxidant is coated on the surface of the backing layer of the microneedle patch, and after oxidation, a post-treatment is performed to obtain a hydrogel microneedle dressing.

[0025] Furthermore, in the S3, the microneedle mold is made of polydimethylsiloxane, the microneedle density in the microneedle area is 100 / cm2, these microneedles are truncated cone-shaped and arranged in a two-dimensional array, the microneedle length is 600~800μm, the diameter of the bottom end of the microneedle is 300~350μm, and the diameter of the top end of the microneedle is 5~15μm.

[0026] Furthermore, in the S32, the centrifugal process includes: centrifugal running at 3000 r / min for 10 minutes and then changing the direction and continuing for 10 minutes, centrifugal running at 2500 r / min for 5 minutes and then changing the direction and continuing for 5 minutes, centrifugal running at 2000 r / min for 5 minutes and then changing the direction and continuing for 5 minutes, centrifugal running at 1500 r / min for 3 minutes and then changing the direction and continuing for 3 minutes, centrifugal running at 1000 r / min for 3 minutes and then changing the direction and continuing for 3 minutes, and centrifugal running at 500 r / min for 1 minute and then changing the direction and continuing for 1 minute.

[0027] In summary, the beneficial technical effects of the present invention are:

[0028] The present invention uses chitosan and Gantrez S-97 BF, or hyaluronic acid and sodium chondroitin sulfate, as raw materials for the microneedle layer. The resulting microneedles have good mechanical properties, good needle tip hardness, and are not prone to brittle cracking. The microneedle layer is prepared using a freeze-drying method. These microneedles have a loose porous structure and good water solubility, achieving the purpose of drug loading and accelerated drug release. At the same time, the porous structure of the freeze-dried microneedles increases the contact area between the microneedles and the skin, improving the adhesion and fit between the microneedles and the skin. The porous structure can also increase the drug loading capacity of the microneedles. In addition, the prepared microneedles are complete, smooth, neatly arranged, have good mechanical properties and adhesion, and the needle tips are tightly fitted to the backing, and can be completely dissolved in about 40 seconds.

[0029] The present invention uses hyaluronic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, and polydopamine to prepare a hyaluronic acid-grafted dopamine polymer, which is the solute of the backing solution. The hyaluronic acid-grafted dopamine polymer has higher biocompatibility, better tissue adhesion, and greater mechanical strength, and can enhance the adhesion between the microneedle layer, the backing layer, and the skin. Because active oxygen can be scavenged by catechol groups, it can be studied as a wound healing material and can replace sutures to achieve wound healing.

[0030] The hyaluronic acid of the present invention plays a key role in wound healing by regulating cell proliferation, migration and differentiation, as well as the growth and metabolism of the extracellular matrix. High-molecular-weight hyaluronic acid (HA) inhibits the proliferation and migration of most cell types, while low-molecular-weight forms of HA (<300kDa) promote cell proliferation and exhibit angiogenic properties. Using hyaluronic acid as the needle tip material and backing material is expected to achieve better wound healing effects.

[0031] The present invention oxidizes the surface of the backing layer by sodium periodate and sodium hydroxide, thereby further improving the hygroscopicity of the backing layer and the adhesive force between the backing layer and the skin;

[0032] The hydrogel microneedle dressing prepared by the present invention is beneficial to increasing the stability and storage time of drugs, and can be applied to protein polypeptide drugs, vaccines, chemical drugs, gene therapy drugs, cells, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Schematic diagram of the morphology of the hydrogel microneedle dressing prepared in Example 1 of the present invention.

[0034] Figure 2 This is a graph showing the ultraviolet absorption of the solutes in the backing solution prepared in Example 12 of the present invention; wherein, from bottom to top, they are HA, PDA, and PDA-HA.

[0035] Figure 3 This is a FESEM side view of a single needle of the hydrogel microneedle dressing prepared in Example 16 of the present invention.

[0036] Figure 4 This is a diagram of the local pores of the microneedles of the hydrogel microneedle dressing prepared in Example 16 of the present invention.

[0037] Figure 5 This is a FESEM test image of multiple microneedles of the hydrogel microneedle dressing prepared in Example 16 of the present invention.

[0038] Figure 6 This is a microneedle solubility test diagram of the hydrogel microneedle dressing prepared in Example 16 of the present invention.

[0039] Figure 7 This is the frequency-modulus rheological diagram of the polydopamine-hyaluronic acid hydrogel microneedle dressing prepared in Example 16 of the present invention.

[0040] Figure 8 This is a microneedle adhesion diagram of the hydrogel microneedle dressing prepared in Example 16 of the present invention.

[0041] Figure 9 This is a graph showing the microneedle liquid absorption capacity of the hydrogel microneedle dressing prepared in Example 16 of the present invention. DETAILED DESCRIPTION

[0042] In order to make the technical means, creative features, objectives and functions achieved by the present invention clearer and easier to understand, the present invention is further explained below with reference to the accompanying drawings and specific implementation methods.

[0043] Example 1: A method for preparing a hydrogel microneedle dressing disclosed in the present invention, comprising the following steps:

[0044] S1: preparing a needle tip solution, wherein the solvent of the needle tip solution includes water, and the solute of the needle tip solution includes 20 g / mL chitosan and 40 g / mL Gantrez S-97 BF;

[0045] S2: preparing a backing solution, wherein the solvent of the backing solution includes water, the solute concentration of the backing solution is 20 g / mL, and the solute of the backing solution is made from raw materials including hyaluronic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, and polydopamine, and the molar ratio of hyaluronic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, and polydopamine is 1:1.5:1.5:1.5;

[0046] S3 fills the needle tip solution and the backing solution into the microneedle area and the backing area of ​​the microneedle mold respectively, sets the freeze-drying temperature to -80°C, the freeze-drying pressure to 0.1 mbar, and the freeze-drying time to 4 hours. After freeze-drying and demolding, an oxidant is coated on the surface of the backing layer formed by the backing solution. The oxidant includes 4.5 mg / mL sodium periodate and 0.4 mol / mL sodium hydroxide to obtain a hydrogel microneedle dressing.

[0047] Figure 1 The image below shows the appearance of the freeze-dried soluble microneedle array prepared in this example. It can be seen that the microneedle surface is porous, without any cracks, and has a complete morphology and no bubbles.

[0048] Examples 2 to 11 are methods for preparing a hydrogel microneedle dressing disclosed in the present invention. The difference from Example 1 is that, in S1, the components, concentrations, and hardness of the solute in the needle tip solution are as shown in Table 1.

[0049] Table 1

[0050] Solute 1 Solute 1 concentration (g / mL) Solute 2 Solute 2 concentration (g / mL) hardness Example 1 Chitosan 20 Gantrez S-97 BF 40 hard Example 2 Chitosan 10 Gantrez S-97 BF 20 Moderate Example 3 Chitosan 10 Gantrez S-97 BF 30 Harder Example 4 Chitosan 10 Gantrez S-97 BF 40 hard Example 5 Chitosan 20 Gantrez S-97 BF 20 Moderate Example 6 Chitosan 20 Gantrez S-97 BF 30 Harder Example 7 Hyaluronic acid 20 Chondroitin sulfate 40 hard Example 8 Hyaluronic acid 20 Chondroitin sulfate 50 hard Example 9 Chitosan 10 Gantrez S-97 BF 10 soft Example 10 Chitosan 20 Gantrez S-97 BF 10 soft Example 11 Hyaluronic acid 20 Chondroitin sulfate 30 soft

[0051] As can be seen from Table 1, the hardness of the needle tip materials prepared in Examples 1, 4, 7, and 8 is better. These four groups are selected as the microneedle layer, and the hyaluronic acid grafted dopamine material is used as the backing layer to prepare the microneedle. The formability and mechanical strength of these four groups of microneedles were tested. The microneedle prepared in Example 1 has better formability and mechanical properties. It can still maintain a relatively complete needle shape after puncturing the three layers of sealing film. The microneedle tip using a composite material has better formability and mechanical properties than the microneedle tip using a single material. Through screening and comparison, the optimal prescription for the microneedle tip of this embodiment is a compound of 20% chitosan and 40% Gantrez S-97 BF.

[0052] Example 12: A method for preparing a hydrogel microneedle dressing disclosed in the present invention, which is different from Example 1 in that S2 includes the following steps:

[0053] S21: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysuccinimide were added to a 1.0 g / mL hyaluronic acid solution, and the pH was adjusted to 5.0 with hydrochloric acid. The mixture was reacted in a sealed environment for 30 minutes to obtain a first reaction solution.

[0054] S22: adding polydopamine to the first reaction solution, adjusting the pH to 5.0 with hydrochloric acid, and reacting in a sealed environment for 12 hours to obtain a second reaction solution;

[0055] S33: The second reaction solution is first dialyzed against a PBS buffer solution with a pH of 5.0 for 4 times, each time for 6 hours, and then dialyzed against distilled water for several times, each time for 4 hours, and then freeze-dried for 12 hours to obtain the solute of the backing solution.

[0056] Figure 2 The UV spectrum of the solute in the backing solution shows a maximum absorption peak at 278 nm. Polydopamine, due to its benzene ring structure, exhibits a strong UV absorption peak at 280 nm. The benzene ring structure of the dopamine-hyaluronic acid conjugate results in an absorption peak at 275 nm. This slight shift in absorption peak may be related to differences in solution pH. Hyaluronic acid exhibits no absorption peak in this range, indicating successful grafting.

[0057] Examples 13 to 15 are methods for preparing a hydrogel microneedle dressing disclosed in the present invention. The difference from Example 12 is that in S2, the solute concentration of the backing solution is 10, 15, and 30 g / mL.

[0058] Microneedles were prepared using 20 g / mL chitosan as the tip layer and the four backing solutions of Examples 12 to 15 as backing layers. Comparison of the four microneedle groups revealed that Example 13 had a softer backing, resulting in better microneedle formability but poor hardness; Example 14 had a moderate backing, resulting in better microneedle formability but average hardness; Example 12 had a harder backing, resulting in both good microneedle formability and good hardness; and Example 15 had a harder backing, with no discernible needle shape observed under a microscope.

[0059] Using 20 g / mL chitosan and 40 g / mL Gantrez S-97 BF as the needle tip layer, compared with the backing layers prepared in Examples 12 to 15, the microneedles of Example 13 have good formability and average hardness, and can only pierce one layer of sealing film; the microneedles of Example 14 have good formability and average hardness, and can only pierce one layer of sealing film; the microneedles of Example 12 have good formability and good hardness, and can maintain a good needle shape after piercing three layers of sealing film.

[0060] Example 16: A method for preparing a hydrogel microneedle dressing disclosed in the present invention, which is different from Example 1 in that S3 includes the following steps:

[0061] S31 After adding the needle tip solution to the microneedle area of ​​the microneedle mold, centrifuge at 3000 rpm for 10 min at 15° C., then change the direction and continue for another 10 min. Centrifuge at 3000 rpm for 10 min, then change the direction and continue for another 10 min, so that the needle tip solution fills the microneedle area of ​​the microneedle mold.

[0062] S32: removing the needle tip solution from the backing area of ​​the microneedle mold and adding the backing solution, then centrifuging at 3000 r / min for 10 min at 15° C., changing the direction and continuing for 10 min, centrifuging at 2500 r / min for 5 min, changing the direction and continuing for 5 min, centrifuging at 2000 r / min for 5 min, changing the direction and continuing for 5 min, centrifuging at 1500 r / min for 3 min, changing the direction and continuing for 3 min, centrifuging at 1000 r / min for 3 min, changing the direction and continuing for 3 min, and centrifuging at 500 r / min for 1 min, changing the direction and continuing for 1 min, so that the backing solution fills the backing area of ​​the microneedle mold;

[0063] S33 placing the microneedle mold with the needle tip solution and the backing solution in a freeze dryer, and demoulding after freeze drying to obtain a microneedle patch; wherein the microneedle patch includes a microneedle layer composed of the needle tip solution and a backing layer composed of the backing solution;

[0064] S34: an oxidant is coated on the surface of the backing layer of the microneedle patch, and after oxidation, a post-treatment is performed to obtain a hydrogel microneedle dressing.

[0065] The hydrogel microneedle dressing prepared in Example 16 was used for characterization testing:

[0066] (1) Mechanical properties test

[0067] Using a sealing film to mimic skin, three layers of sealing film were folded to represent skin of a certain thickness and elasticity. The microneedle patch prepared in Example 4 was pressed vertically onto the three layers of sealing film with a firm finger pressure for 2 minutes. It was observed that two layers of sealing film were completely punctured, and the third layer was mostly punctured. Microscopic observation of the microneedle patch after the penetration test showed that relatively intact needles were still present.

[0068] (2) Microneedle morphological characterization

[0069] The morphology of the freeze-dried microneedles was observed by field emission scanning electron microscopy under high vacuum conditions with an accelerating voltage of 10 kV, and the distribution of related elements was analyzed by energy dispersive X-ray spectrometry. Figures 3-5 As shown, Figure 3 This is the side view of a single needle of the freeze-dried excipient microneedle FESEM. Figure 4 The local pore structure of a single needle. Figure 5 This is a FESEM test image of multiple freeze-dried microneedles. It can be seen from the image that the microneedles prepared by the present invention are conical in shape, uniform in size, and accompanied by a large number of pore structures, and the needle body is tightly connected to the backing.

[0070] (3) Microneedle solubility test

[0071] After drying, the micro - needles were inverted with the tips downward on a pre - perforated polyethylene (PE) film, ensuring that only the tip part was exposed in PBS buffer at about pH 6.0 (simulating skin pH). Then they were placed in a constant - temperature shaking incubator at 37 °C and 50 r / min for the dissolution experiment. At regular intervals, the micro - needles were taken out, the moisture on the surface of the micro - needles was blotted dry with filter paper, and the dissolution of the micro - needles was observed under a microscope and photographed for record. Figure 6 This is a test chart for the water solubility of freeze - dried micro - needles. It can be seen that the micro - needles prepared by the present invention dissolve rapidly, starting to dissolve in about 10 s and being basically completely dissolved at 90 s. They have good dissolution performance, less irritation to the skin, and good safety.

[0072] (4)Rheological properties of the micro - needle backing

[0073] The frequency - modulus scan of the mixed solution was carried out at 1% strain to test the variation of the gel storage (G') and loss (G") moduli of the oxidized solution and the polymer with frequency. Figure 7 It shows that the frequency corresponding to the crossover of G' and G" is defined as the gel point. When G' (storage modulus) < G'' (loss modulus), the bulk phase is more偏向于viscoelastic liquid.

[0074] (5)Application of the hydrogel micro - needle dressing

[0075] On the micro - needle patch, 4.5 mg / mL of sodium periodate and 0.4 mol / mL of sodium hydroxide were dropped to fully oxidize the micro - needle patch. As Figure 8 shown, the oxidized and adhesive micro - needle patch can be closely adhered to the skin surface without falling off when applied.

[0076] To determine the liquid absorption capacity of the hydrogel micro - needle dressing, a sample of known weight was immersed in a beaker containing simulated wound fluid and placed in a constant - temperature shaking incubator at 37 °C and 50 r / min. After 24 h, the sample was taken out of the test solution and the excess liquid on the surface of the sample was gently blotted dry, and then re - weighed. Figure 9 It shows the swelling situation of the hydrogel micro - needle dressing after absorbing the wound - simulated fluid. The liquid absorption capacity of the dressing sample was calculated using the following formula: Liquid absorption capacity = (Ws−Wd)×100%, where Wd and Ws are the weights of the dry and wet samples respectively. The equilibrium swelling ratio of the hydrogel = Ws / Wd, where Ws is the weight of the hydrogel after swelling equilibrium; Wd is the dry weight of the gel. After the micro - needle patch was immersed in the wound - simulated fluid for 24 h, its size expanded from 1×1 cm to 1.5×1.5 cm, and the weight increased from 32.85 mg to 866.5 mg. The liquid absorption capacity was 25.38%, and the equilibrium swelling ratio was 833.65%. The dressing micro - needles have good liquid absorption capacity and adhesiveness. ​Example 17: A preparation method of a hydrogel microneedle dressing disclosed in the present invention. The difference from Example 16 is that the freeze-drying temperature is set to -20°C, the freeze-drying pressure is set to 0.1 mbar, and the freeze-drying time is set to 4 hours.

[0078] The morphology of microneedles was significantly different at different pre-freezing temperatures. The surface of the freeze-dried microneedles obtained at -80°C was smooth and dense, while the freeze-dried microneedles obtained at -20°C were loose and uneven, and contained a large number of bubbles inside. This may be because the dissolved solutes contained in the unfrozen water could not be decomposed in situ during the drying process, causing the material to melt and expand.

[0079] Examples 18 to 20 are methods for preparing a hydrogel microneedle dressing disclosed in the present invention. The difference from Example 16 is that the freeze-drying temperature is set to -80°C, the freeze-drying pressure is set to 0.1 mbar, and the freeze-drying time is set to 2, 8 or 12 hours.

[0080] This example examined the appearance and mechanical strength of the microneedles obtained after drying for 2, 4, 8, and 12 hours. Drying is divided into two stages: sublimation drying and desorption drying, which remove free water and bound water from the sample, respectively. The freeze dryer used in this example heats naturally, and it is impossible to manually set the temperature curve during the freeze-drying process. Therefore, the only way to ensure complete drying of the sample is to extend the drying time. Considering the experimental cost and machine wear, a freeze-drying time of 4 hours was selected as the optimal condition.

[0081] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for preparing a hydrogel microneedle dressing, characterized in that: include, S1: preparing a needle tip solution, wherein the solvent of the needle tip solution includes water, and the solute of the needle tip solution consists of 10-30 g / mL chitosan and 30-40 g / mL Gantrez S-97 BF, or 10-30 g / mL hyaluronic acid and 40-50 g / mL sodium chondroitin sulfate; S2: preparing a backing solution, wherein the solute of the backing solution is made of raw materials including hyaluronic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, and polydopamine; In S2, the solvent of the backing solution includes water, the solute concentration of the backing solution is 10-20 g / mL, and the molar ratio of hyaluronic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, and polydopamine is 1:1.0-2.0:1.0-2.0:1.0-2.0; The process of preparing the solute for the backing solution includes, S21: Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysuccinimide to a 0.5-1.5 g / mL hyaluronic acid solution, adjust the pH to 4.5-5.5 with hydrochloric acid, and react in a sealed environment for 25-35 minutes to obtain a first reaction solution; S22: adding polydopamine to the first reaction solution, adjusting the pH to 4.5-5.5 with hydrochloric acid, and reacting in a sealed environment for 10-15 hours to obtain a second reaction solution; S23: The second reaction solution is first dialyzed against a pH 5.0 PBS buffer solution for 3 to 5 times, each time for 5 to 7 hours, and then dialyzed against distilled water for several times, each time for 3 to 5 hours, and then freeze-dried for 10 to 15 hours to obtain a solute of the backing solution; S3: filling the needle tip solution and the backing solution into the microneedle region and the backing region of the microneedle mold respectively, freeze-drying and demoulding, and coating the surface of the backing layer formed by the backing solution with an oxidant to obtain a hydrogel microneedle dressing; In the S3, the oxidant is composed of 4.0-5.0 mg / mL sodium periodate and 0.3-0.5 mol / mL sodium hydroxide, the freeze-drying temperature is set to -80°C, the freeze-drying pressure is set to 0.001-6.1 mbar, and the freeze-drying time is set to 2-24 h.

2. The method for preparing a hydrogel microneedle dressing according to claim 1, wherein: In said S3, including, S31 After adding the needle tip solution to the microneedle area of ​​the microneedle mold, centrifuge at 10-20°C and 3000-4000 rpm for 8-12 minutes, repeating at least 4 times, with the two adjacent centrifugation directions in opposite directions and the centrifugation speed and time remaining unchanged, so that the needle tip solution is filled into the microneedle area of ​​the microneedle mold; S32: removing the needle tip solution from the backing area of ​​the microneedle mold and adding the backing solution, centrifuging at 10-20° C. and 500-3000 rpm for 1-10 minutes, repeating at least 12 times, with the two adjacent centrifugation directions being opposite, and the centrifugation speed and time being gradually reduced, so that the backing solution is filled into the backing area of ​​the microneedle mold; S33 placing the microneedle mold with the needle tip solution and the backing solution in a freeze dryer, and demoulding after freeze drying to obtain a microneedle patch; wherein the microneedle patch includes a microneedle layer composed of the needle tip solution and a backing layer composed of the backing solution; S34: an oxidant is coated on the surface of the backing layer of the microneedle patch, and after oxidation, a post-treatment is performed to obtain a hydrogel microneedle dressing.

3. The method for preparing a hydrogel microneedle dressing according to claim 2, wherein: In the S3, the microneedle mold is made of polydimethylsiloxane, the microneedle density in the microneedle area is 100 / cm2, these microneedles are truncated cone-shaped and arranged in a two-dimensional array, the microneedle length is 600~800μm, the diameter of the bottom end of the microneedle is 300~350μm, and the diameter of the top end of the microneedle is 5~15μm.

4. The method for preparing a hydrogel microneedle dressing according to claim 2, wherein: In the S32, the centrifugal process includes: running at 3000 r / min for 10 minutes and then changing the direction for another 10 minutes, running at 2500 r / min for 5 minutes and then changing the direction for continuing to run for 5 minutes, running at 2000 r / min for 5 minutes and then changing the direction for continuing to run for 5 minutes, running at 1500 r / min for 3 minutes and then changing the direction for continuing to run for 3 minutes, running at 1000 r / min for 3 minutes and then changing the direction for continuing to run for 3 minutes, and running at 500 r / min for 1 minute and then changing the direction for continuing to run for 1 minute.

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