Modified chitosan hydrogel microneedle patch as well as preparation method and application thereof

Abstract

The invention relates to a modified chitosan hydrogel microneedle patch and a preparation method and application thereof.The hydrogel microneedle patch comprises an ion-enhanced modified hydrogel microneedle matrix and a supporting substrate, and the ion-enhanced hydrogel microneedle matrix comprises a hydrogel microneedle matrix and introduced enhanced ions; the hydrogel microneedle matrix is prepared from temperature-sensitive chitosan, the enhanced ions comprise anions and / or cations, the anions comprise tripolyphosphate ions, citrate ions, carbonate ions and sulfate ions, and the cations comprise sodium ions, calcium ions, iron ions and zinc ions. The supporting substrate is prepared from chitosan. Compared with the prior art, ions are introduced to enhance the dendronized chitosan hydrogel, so that the chitosan hydrogel of which the mechanical property is remarkably improved and which has temperature responsiveness and pH responsiveness is obtained, and then the chitosan hydrogel microneedle of which the mechanical property is remarkably improved and the drug release performance is excellent is obtained.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a modified chitosan hydrogel microneedle patch and a preparation method and application thereof. Background Art

[0002] Microneedle drug delivery is a novel transdermal drug delivery technology that uses reversible microchannels formed by the needle tips penetrating the skin's stratum corneum to deliver drugs loaded into the microneedle array directly to the epidermis or upper dermis, achieving efficient drug delivery. These transdermal drug delivery methods offer advantages such as non-invasiveness, high compliance, and stable dosage, and have been applied in medical aesthetics, vaccination, and drug delivery.

[0003] To date, developed microneedles can be categorized by their characteristics into solid microneedles, hollow microneedles, coated microneedles, soluble microneedles, and hydrogel microneedles. These microneedles still face the following challenges: ① Solid microneedles lack drug-carrying capabilities; drugs passively penetrate the skin through their microchannels, making it difficult to accurately control drug delivery. ② Hollow microneedles offer high drug loading capacity and precise drug delivery, but are limited by the complex and costly preparation process and the risk of needle pore clogging. ③ Coated microneedles are limited by low drug loading capacity, making it susceptible to drug blockage by the skin's stratum corneum, thus reducing drug delivery. ④ Soluble microneedles suffer from the disadvantage of uncontrolled rapid drug release. These challenges have hindered their development and widespread application in practical production. In recent years, a class of hydrogel microneedles has been developed to address these challenges. These microneedles possess a three-dimensional network structure that swells without dissolving, endowing them with the ability to release drugs continuously and providing the necessary prerequisite for controlled release. Among them, hydrogel microneedles prepared with synthetic polymers have the advantages of easy processing, short processing cycle and low cost, which make them have extremely high commercial value. However, the toxic low-molecular substances remaining in the polymerization or preparation process of synthetic materials, the pollution in the processing process and the degradation products with toxic side effects significantly reduce their safety. In addition, it is valuable to give this type of microneedle the ability to control drug release, such as through the stimulus responsiveness of the system, especially through temperature-sensitive response or pH response mechanism to achieve sustained release of drugs. This type of hydrogel microneedle can achieve the purpose of controlled drug release within a temperature range close to the physiological temperature of the human body or within the pH change range of the skin. Therefore, it is of great significance to develop a class of natural polymer materials with good biocompatibility, biodegradability and intelligent response characteristics, and use them as substrates to prepare corresponding hydrogel microneedles.

[0004] In recent years, a variety of microneedles using natural polymers such as chitosan as substrates have been developed. These natural molecules have advantages such as good biocompatibility and biodegradability, no toxic side effects of degradation products on the human body, natural antibacterial properties that can promote wound recovery, and a large number of amino and carboxyl functional groups available for modification in the molecules, which are easy to modify to expand their scope of application. However, these chitosan microneedles still have problems such as low mechanical strength and poor drug controlled release effect, which limits the practical application potential of such microneedles. Therefore, by chemically modifying chitosan with functional elements, the development of multifunctional hydrogel microneedles with good mechanical properties and intelligent controlled release effects has important research value and application prospects. Among them, chitosan is modified with alkoxy ether dendrimers to synthesize dendritic chitosan (DCs) with temperature-responsive characteristics. The polymer can form a high-transparency hydrogel and achieve sol-gel state conversion by changing the temperature (see the document Letian Feng, et al. ACS Appl. Mater. Interfaces, 2021, 13, 49369-49379 for details). However, this type of thermosensitive hydrogel still has the problem of relatively weak mechanical properties, which hinders its wider application in practice. Summary of the Invention

[0005] The purpose of the present invention is to overcome the defects of relatively weak mechanical properties in the above-mentioned prior art and to provide a modified chitosan hydrogel microneedle patch and its preparation method and application. Ions are introduced to enhance and modify the thermosensitive chitosan hydrogel to obtain a chitosan hydrogel with significantly improved mechanical properties, temperature responsiveness and pH responsiveness, and thus obtain chitosan hydrogel microneedles with significantly improved mechanical properties and excellent drug release performance.

[0006] The purpose of the present invention can be achieved by the following technical solutions:

[0007] One of the technical solutions of the present invention is to provide a modified chitosan hydrogel microneedle patch, which includes an ion-enhanced modified hydrogel microneedle matrix and a supporting substrate. The ion-enhanced modified hydrogel microneedle matrix includes a hydrogel microneedle matrix and introduced enhancing ions. The hydrogel microneedle matrix is ​​prepared using thermosensitive chitosan. The enhancing ions include anions and / or cations. The anions include tripolyphosphate ions, citrate ions, carbonate ions, and sulfate ions. The cations include sodium ions, calcium ions, iron ions, and zinc ions. The supporting substrate is prepared using chitosan.

[0008] Furthermore, the temperature-sensitive chitosan is alkoxy ether dendronized chitosan.

[0009] Furthermore, the alkoxy ether dendronized chitosan has the following structure:

[0010]

[0011] in, or—COO - H3N + -, R2=H or

[0012] X is methoxy, ethoxy, propoxy or hydroxy, Y is methoxy, ethoxy, propoxy or hydroxy; n=0-4, m=0-4, q=0-6500, z=0-6500, r=10-6500.

[0013] Furthermore, n=1-4, m=1-4, q=350, z=350, r=300.

[0014] Furthermore, the substitution degree of R2 is 0 to 0.95, preferably 0.05 to 0.95; the substitution degree of R3 is 0 to 0.95, preferably 0.05 to 0.95.

[0015] Furthermore, the microneedle patch is loaded with a pH indicator.

[0016] Furthermore, the pH indicator comprises phenol red.

[0017] Furthermore, the pH indicator loading method is: immersing the microneedle patch in a solution containing the pH indicator to uniformly dye the solution, thereby obtaining a microneedle patch loaded with the pH indicator.

[0018] Furthermore, the concentration of the solution containing the pH indicator is the highest and the lowest is 0. When it is 0, it means that no pH indicator is loaded.

[0019] The second technical solution of the present invention is to provide a method for preparing a modified chitosan hydrogel microneedle patch, comprising the following steps:

[0020] S1. Dissolve thermosensitive chitosan in water, mix well, and then vacuum to remove bubbles to obtain a hydrogel microneedle matrix solution. Fill the microneedle mold with the hydrogel microneedle matrix solution, centrifuge until the microneedle portion is completely filled, and remove excess solution to obtain a hydrogel microneedle matrix.

[0021] S2. placing the hydrogel microneedle matrix in an enhanced ion solution and fully immersing it at a certain temperature to obtain an ion-enhanced modified hydrogel microneedle matrix;

[0022] S3. Dissolve chitosan in water, mix well, and then vacuum to remove bubbles to obtain a supporting base solution. Fill the remaining space of the microneedle mold with the supporting base solution, and perform demolding after forming to obtain a hydrogel microneedle patch.

[0023] Further, in step S1, the microneedle mold includes a microneedle matrix portion and a microneedle base portion.

[0024] Furthermore, the microneedle matrix portion is composed of a plurality of microneedles distributed in an array.

[0025] Furthermore, the microneedle shape is a pyramid, a truncated cone or other special-shaped structures with sharp tips, the microneedle height is 1 to 1000 μm, the bottom diameter is 1 to 1000 μm, and the distance between the needle tips of two adjacent microneedles is 1 to 1000 μm.

[0026] Furthermore, in step S1, the solid content of the hydrogel microneedle matrix solution is 1 wt% to 15 wt%.

[0027] Furthermore, in step S1, the conditions for vacuuming and removing bubbles are as follows: a vacuum value of 0.04 to 0.08 MPa, a stirring rate of 500 to 1000 rpm, maintaining pressure for 20 to 40 minutes, releasing air, and repeating 2 to 3 times.

[0028] Furthermore, in step S1, the rotation speed of the centrifugal treatment is 3000-10000 rpm, and the time is 5-60 min.

[0029] Furthermore, in step S2, the gelling temperature (T gel ) is used as a reference, and the temperature is the temperature at which the hydrogel microneedle matrix is ​​in a sol state or a gel state.

[0030] Furthermore, in step S2, reinforcing ions are introduced into the hydrogel system by immersion. The reinforcing ions have an enhancing effect on the hydrogel system due to the Hofmeister effect. Different ions have different charge distributions, sizes and polarization abilities, which differentially affect the arrangement of polymer chains in the system. Their different hydration abilities induce different degrees of tight aggregation between chains, promote dehydration and shrinkage of polymer chains, and enhance interchain interactions, thereby improving the mechanical strength of the hydrogel. In the Hofmeister effect, the effect of anions is stronger than that of cations. However, the amino groups in the chitosan system can produce metal complexation with cations, so there is a synergistic effect of the Hofmeister effect and ion complexation in the process of strengthening the hydrogel.

[0031] Furthermore, the temperature can be selected from 0°C to T gel (sol state) or T gel ~80℃(gel state).

[0032] Furthermore, the concentration of the enhanced ion solution can be as high as the saturation concentration corresponding to each ion and as low as 0.01M.

[0033] Furthermore, in step S3, the solid content of the supporting substrate solution is 1 wt% to 15 wt%.

[0034] Furthermore, in step S3, the conditions for vacuuming and removing bubbles are as follows: a vacuum value of 0.04 to 0.08 MPa, a stirring rate of 500 to 1000 rpm, maintaining pressure for 20 to 40 minutes, releasing air, and repeating 2 to 3 times.

[0035] Furthermore, in steps S1 to S3, ultrapure water is used to prepare the solution.

[0036] The third technical solution of the present invention is to provide an application of a modified chitosan hydrogel microneedle patch in the preparation of drug delivery products.

[0037] Compared with the prior art, the present invention has the following advantages:

[0038] (1) The present invention enhances the hydrogel microneedle matrix by introducing reinforcing ions, and prepares a series of ion-enhanced hydrogel microneedle patches with significantly improved mechanical properties, good biocompatibility, pH responsiveness and temperature responsiveness. Its stimulus responsiveness can be applied to the intelligent controlled release of drugs.

[0039] (2) The anion pair system introduced in the present invention produces a Hofmeister effect, while the cation pair system produces a Hofmeister effect and ion complexation. By causing varying degrees of close aggregation between polymer chains, this promotes dehydration and shrinkage of the polymer chains, thereby improving the mechanical strength of the hydrogel. This ion enhancement method can effectively enhance the mechanical properties of the hydrogel without introducing complex chemical crosslinking or changing the original process flow, avoiding the biocompatibility issues that may be caused by traditional chemical crosslinking.

[0040] (3) The present invention achieves precise control of the hydrophilicity and hydrophobicity of dendritic chitosan by adjusting the modification ratio of the two dendritic moieties. Compared with dendritic chitosan modified with a single dendritic moiety, the present dendritic chitosan has a wider range of concentration and gelation temperature adjustment, thereby achieving wide-range tunability of mechanical strength.

[0041] (4) The dendritic chitosan hydrogel of the present invention can undergo sol-gel transition under the mediation of temperature. When the temperature rises and it transforms into a gel, the thermosensitive effect and ion enhancement effect in the system work together to give the hydrogel a denser network structure, thereby improving its mechanical properties.

[0042] (5) The ion-enhanced hydrogel microneedle matrix used in the present invention has good transparency. After being loaded with a pH indicator, the pH of the wound site can be visually monitored during the microneedle drug delivery process. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 Schematic diagram of the preparation process of the hydrogel microneedle patch shown in Example 1, including: (A) coating the hydrogel microneedle matrix solution on the microneedle mold; (B) centrifugally filling the hydrogel microneedle matrix solution into the mold; (C) removing excess solution; (D) soaking in ionic solution to enhance the mechanical properties of the hydrogel; (E) filling with supporting substrate solution; (F) molding; and (G) forming the hydrogel microneedle patch.

[0044] Figure 2 3 is a morphological diagram of the hydrogel microneedle patch shown in Example 1;

[0045] Figure 3 This is a polarizing microscope image of the hydrogel microneedle patch shown in Example 1;

[0046] Figure 4 Comparison of the compressive strength of the hydrogel microneedle patch: (A) without reinforcing ions, with TPP and Cit as reinforcing ions; (B) without reinforcing ions, with Ca as reinforcing ions. 2+ ;

[0047] Figure 5 This is the pH-responsive drug release curve of the gel microneedle patch shown in Example 1;

[0048] Figure 6 Schematic diagram of pH monitoring of the gel microneedle patch shown in Example 2, (A) The microneedle determines the wound status by monitoring the wound pH, (B) Schematic diagram of the ion-enhanced dendritic chitosan thermosensitive hydrogel, (C) Molecular structure of dendritic chitosan and enhancing ions;

[0049] Figure 7 The gel microneedle patch (A) shown in Example 2 and its photos at pH 6.0 and 8.0 (B).

[0050] Description of the marks in the figure:

[0051] 1-hydrogel microneedle patch, 11-ion-enhanced hydrogel microneedle matrix, 111-hydrogel microneedle matrix, 12-support substrate;

[0052] 2-microneedle mold, 21-microneedle part, 22-bottom part;

[0053] 3-hydrogel microneedle matrix solution;

[0054] 4-support substrate solution;

[0055] 5- Enhanced ionic solution. DETAILED DESCRIPTION

[0056] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the scope of protection of the present invention is not limited to the following embodiments. Based on the given embodiments, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0057] Unless otherwise specified, the reagents, methods, instruments and equipment used in the present invention are conventional reagents, methods, instruments and equipment in the art.

[0058] In the following examples, chitosan was purchased from McLean with a product number of C850346, a molecular weight of 150,000, and a degree of deacetylation ≥95%; sodium tripolyphosphate (TPP) was purchased from McLean with a product number of S817361; sodium citrate was purchased from McLean with a product number of S425417; and phenol red was purchased from McLean with a product number of P6066.

[0059] In the following examples, the preparation method of alkoxy ether dendronized chitosan is the same as that in the literature (Letian Feng, et al. ACS Appl. Mater. Interfaces, 2021, 13, 49369-49379), except that the modified dendrons are changed to diethylene glycol dendrons and triethylene glycol dendrons, and the amino feed ratio of the dendrons to chitosan is 0.35:0.35:1. The sol-gel transition temperature of the finally prepared alkoxy ether dendronized chitosan hydrogel is 41°C.

[0060] Example 1

[0061] A modified chitosan hydrogel microneedle patch, the hydrogel microneedle patch 1 comprising an ion-enhanced modified hydrogel microneedle matrix 11 and a supporting substrate 12, the ion-enhanced modified hydrogel microneedle matrix 11 comprising a hydrogel microneedle matrix 111 and introduced enhancing ions, the hydrogel microneedle matrix 111 being made of thermosensitive chitosan having a sol-gel transition temperature of 41°C, the enhancing ions being TPP, and the supporting substrate 12 being prepared from chitosan.

[0062] In this embodiment, the alkoxy ether dendronized chitosan has the following structure:

[0063]

[0064] in, —COO - H3N + -, R2=H,

[0065] X and Y are ethoxy; n=2, m=3, q=350, z=350, r=300.

[0066] In this embodiment, the degree of substitution of R2 is 0.3, and the degree of substitution of R3 is 0.35.

[0067] In this embodiment, TPP induces tight aggregation between chains through the Hofmeister effect, causing dehydration and shrinkage of the polymer chains, thereby improving the mechanical strength of the hydrogel.

[0068] A method for preparing a modified chitosan hydrogel microneedle patch, such as Figure 1 As shown, the following steps are included:

[0069] S1. At room temperature, the alkoxy ether dendronized chitosan is dissolved in ultrapure water, mixed evenly, and then vacuumed to remove bubbles. The conditions for vacuuming and removing bubbles are as follows: a vacuum value of 0.05 MPa, a stirring rate of 750 rpm, maintaining the pressure for 30 minutes, releasing the air, and repeating 3 times to obtain a hydrogel microneedle matrix solution 3 with a solid content of 10 wt%. The hydrogel microneedle matrix solution 3 is filled into the microneedle mold 2, and the solution is centrifuged at a speed of 5000 rpm for 30 minutes until the microneedle portion 21 is completely filled. The excess solution is removed to obtain a hydrogel microneedle matrix 111, wherein the microneedle mold 2 includes a microneedle portion 21 and a bottom portion 22. The microneedle matrix portion is composed of a plurality of microneedles distributed in an array. The microneedles are pyramidal in shape, with a microneedle height of 800 μm, a bottom diameter of 360 μm, and a needle tip distance of 720 μm between two adjacent microneedles.

[0070] S2. At a temperature of 5° C., the hydrogel microneedle matrix 111 was fully immersed in a 0.3 M enhancing ion solution 5 (in this embodiment, a sodium tripolyphosphate (TPP) solution, and the solvent was ultrapure water) to obtain an ion-enhanced modified hydrogel microneedle matrix 11. To eliminate the interference of counterions when comparing the enhancing effects of anions and cations, all anions were in the form of their corresponding sodium salts, and all cations were in the form of their corresponding chloride salts.

[0071] S3, dissolving chitosan in ultrapure water, mixing well and then vacuuming to remove bubbles, the conditions for vacuuming and removing bubbles are as follows: vacuum value 0.05MPa, stirring speed 750rpm, pressure maintenance 30min, degassing, repeating 3 times to obtain a support base solution 4 with a solid content of 10wt%, filling the support base solution 4 into the remaining space of the microneedle mold 2, and performing demoulding after forming to obtain a hydrogel microneedle patch 1, as shown Figure 2 As shown. The polarizing microscope image of the hydrogel microneedle patch 1 is shown Figure 3 As shown in the figure, the hydrogel microneedles are arranged in a 15*15 square array, and the microneedles are pyramidal in shape.

[0072] Example 2

[0073] A modified chitosan hydrogel microneedle patch is similar to Example 1 in most aspects, except that the microneedle patch is loaded with a pH indicator, which is phenol red.

[0074] A method for preparing a modified chitosan hydrogel microneedle patch is similar to that of Example 1, except that step S4 is added, in which the hydrogel microneedle patch 1 prepared in step S3 is immersed in a 5 mg / mL phenol red solution (the solvent is ultrapure water) to uniformly dye it, thereby obtaining a phenol red-loaded microneedle patch.

[0075] Example 3

[0076] A modified chitosan hydrogel microneedle patch is similar to Example 2 in most aspects, except that the introduced enhancing ions are adjusted to citrate ions (sodium citrate (Cit) solution in this example, and the solvent is ultrapure water).

[0077] A method for preparing a modified chitosan hydrogel microneedle patch is similar to that of Example 2 in most aspects, except that the enhanced ion solution 5 in step S2 is adjusted to a sodium citrate solution with a citrate ion concentration of 0.3M.

[0078] Example 4

[0079] A modified chitosan hydrogel microneedle patch is similar to Example 2 except that the introduced enhancing ion is adjusted to Ca 2+ (This embodiment is a calcium chloride (CaCl2) solution, and the solvent is ultrapure water).

[0080] A method for preparing a modified chitosan hydrogel microneedle patch is similar to that of Example 2, except that the enhanced ions introduced are adjusted to CaCl2 solution, Ca 2+ The concentration is 0.3M.

[0081] Comparative Example 1

[0082] A chitosan hydrogel microneedle patch is provided, wherein no reinforcing ions are introduced, and the rest are the same as those in Example 2.

[0083] A method for preparing a chitosan hydrogel microneedle patch is similar to that of Example 2 in most aspects, except that step S2 is not performed, i.e., the hydrogel microneedle matrix is ​​not fully immersed in a 0.3 M TPP solution (the solvent is ultrapure water).

[0084] To explore the effect of enhancing the mechanical strength of the hydrogel microneedle patch with different anions, the hydrogel microneedle patch 1 in Examples 2 and 3 was compared with the hydrogel microneedle patch without the introduction of enhancing ions in Comparative Example 1. The compressive strength of a single needle body of the hydrogel microneedle patch when it was compressed to a certain distance was tested by a universal testing machine. The compressive strength was as follows: Figure 4 As shown in A. When the displacement continues to increase, the force-displacement curve of the microneedle does not show any discontinuity, which shows that the microneedle has good toughness and the needle tip bends but does not break under the application of external force. The compressive strength of the hydrogel microneedle without the introduction of reinforcing ions is 0.28N, the compressive strength of the hydrogel microneedle with the introduction of Cit as the reinforcing ion is 0.53N, and the compressive strength of the hydrogel microneedle with the introduction of TPP as the reinforcing ion is 0.78N. Therefore, after the introduction of the reinforcing ions Cit and TPP, the density of the polymer network of the hydrogel microneedle increases, thereby significantly enhancing the mechanical strength of the needle body, and the reinforcing effect of TPP is stronger than that of Cit.

[0085] To explore the enhancing effect of enhanced cations on the mechanical strength of the hydrogel microneedle patch, the hydrogel microneedle patch 1 in Example 4 was compared with the hydrogel microneedle patch without the introduction of enhanced ions in Comparative Example 1. The compressive strength of a single needle body of the hydrogel microneedle patch when it was compressed to a certain distance was tested by a universal testing machine. The compressive strength was as follows: Figure 4 As shown in B. When the displacement increases, the force-displacement curve of the microneedle does not show discontinuity, which shows that the microneedle has good toughness and the needle tip bends but does not break under the application of external force. The compressive strength of the hydrogel microneedle without the introduction of reinforcing ions is 0.28N. 2+ The compressive strength of the hydrogel microneedle is 0.35 N. Therefore, the introduction of reinforcing cations produces Hofmeister effect and metal complexation with the chitosan hydrogel network, which increases the density of the polymer network of the hydrogel microneedle and thus enhances the mechanical strength of the needle body.

[0086] The gel point temperature (37°C) was used to explore the drug release performance of the hydrogel microneedle patch 1 for guest molecules under different pH conditions (pH = 6.0, 7.0, 8.0). The hydrogel microneedle patch 1 in Example 2 was selected for the experiment, and the pH indicator phenol red dye was used as the drug model molecule to obtain a drug-loaded hydrogel microneedle patch. Using ultraviolet-visible spectrophotometry, the drug-loaded hydrogel microneedle patch was fully swollen at 37°C in the environment constructed by the model, and the changes in the drug absorbance in the system at different times were detected to track its release process. The release process of the hydrogel microneedle patch 1 is as follows. Figure 5As shown. In PBS solution with a pH of 6.0, the drug release rate and total drug release of the hydrogel were the lowest, with a total drug release of 74.8%. In PBS solutions with pH of 7.0 and 8.0, the drug release rate of the hydrogel was similar in the first 3 hours. After 3 hours, the drug release rate and total drug release of the former exceeded those of the latter, with total drug release of 93.5% and 83.5%, respectively. This is because when phenol red is used as a model drug, its release curve is significantly affected by pH, which is mainly related to changes in its molecular structure and solubility. Phenol red has low solubility in an acidic environment, resulting in a slow drug release rate. When the pH environment turns to alkaline, the solubility and diffusion rate of phenol red increase, and the drug release rate accelerates. Therefore, the drug release performance of ion-enhanced dendritic chitosan hydrogel at different pH is jointly regulated by its swelling properties and drug properties.

[0087] The pH monitoring function of the phenol red loaded hydrogel microneedle patch 1 was investigated. PBS buffer solutions with pH values ​​of 6.0 and 8.0 were added dropwise to the phenol red loaded hydrogel microneedle patch 1 of Example 2. The hydrogel microneedle patch 1 was observed after its color stabilized. The pH monitoring diagram of the hydrogel microneedle patch 1 is shown in FIG. Figure 6 As shown, the top view and side view of the hydrogel microneedle patch 1 are as shown Figure 7 As shown. When the pH of the added PBS is 6.0, the hydrogel microneedle body is yellow, and when the pH of the added PBS is 8.0, the hydrogel microneedle body is red. The color of the hydrogel microneedle loaded with phenol red changes from yellow to red when the pH value changes from acidic to alkaline, which shows that the hydrogel microneedle can accurately reflect the pH changes at the wound. Since the pH value of chronic skin wounds is alkaline, when the wound gradually heals, the pH value of the wound surface transitions to neutral and eventually returns to physiological weak acidity. Real-time monitoring of the dynamic changes in the pH of the wound surface by hydrogel microneedles can not only provide early warning of infection risks, but also evaluate the healing stage, providing important assistance for precise wound management.

[0088] Although the present invention has been described in detail above using general explanations, specific embodiments, and experiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

Claims

1. A modified chitosan hydrogel microneedle patch, characterized in that: The hydrogel microneedle patch includes an ion-enhanced modified hydrogel microneedle matrix and a supporting substrate. The ion-enhanced modified hydrogel microneedle matrix includes a hydrogel microneedle matrix and introduced enhancing ions. The hydrogel microneedle matrix is ​​prepared using thermosensitive chitosan. The enhancing ions include anions and / or cations. The anions include tripolyphosphate ions, citrate ions, carbonate ions, and sulfate ions. The cations include sodium ions, calcium ions, iron ions, and zinc ions. The supporting substrate is prepared using chitosan.

2. A modified chitosan hydrogel microneedle patch according to claim 1, characterized in that: The temperature-sensitive chitosan is alkoxy ether dendronized chitosan.

3. A modified chitosan hydrogel microneedle patch according to claim 2, characterized in that: The alkoxy ether dendronized chitosan has the following structure: Where R1 = or -COO - H3N + -, R2=H or X is methoxy, ethoxy, propoxy or hydroxy, Y is methoxy, ethoxy, propoxy or hydroxy; n=0-4, m=0-4, q=0-6500, z=0-6500, r=10-6500.

4. A modified chitosan hydrogel microneedle patch according to claim 3, characterized in that: The substitution degree of R2 is 0 to 0.95, and the substitution degree of R3 is 0 to 0.

95.

5. The modified chitosan hydrogel microneedle patch according to claim 1, characterized in that: The microneedle patch is loaded with a pH indicator.

6. The modified chitosan hydrogel microneedle patch according to claim 5, characterized in that: The pH indicator includes phenol red, anthocyanin, and bromothymol blue.

7. The modified chitosan hydrogel microneedle patch according to claim 5, characterized in that: The pH indicator loading method is as follows: immersing the microneedle patch in a solution containing the pH indicator to uniformly dye the solution, thereby obtaining a microneedle patch loaded with the pH indicator.

8. The method for preparing a modified chitosan hydrogel microneedle patch according to any one of claims 1 to 7, characterized in that: The following steps are involved: S1. Dissolve thermosensitive chitosan in water, mix well, and then vacuum to remove bubbles to obtain a hydrogel microneedle matrix solution. Fill the microneedle mold with the hydrogel microneedle matrix solution, centrifuge until the microneedle portion is completely filled, and remove excess solution to obtain a hydrogel microneedle matrix. S2. placing the hydrogel microneedle matrix in an enhanced ion solution and fully immersing it at a certain temperature to obtain an ion-enhanced modified hydrogel microneedle matrix; S3. Dissolve chitosan in water, mix well, and then vacuum to remove bubbles to obtain a supporting base solution. Fill the remaining space of the microneedle mold with the supporting base solution, and perform demolding after forming to obtain a hydrogel microneedle patch.

9. The modified chitosan hydrogel microneedle patch according to claim 8, characterized in that: In step S2, the temperature is a temperature that makes the hydrogel microneedle matrix in a sol state or a gel state.

10. Use of the modified chitosan hydrogel microneedle patch according to any one of claims 1 to 7 in the preparation of drug delivery products.

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