Multifunctional composite hydrogel microneedle patch as well as preparation method and application thereof

Abstract

The invention discloses a multifunctional composite hydrogel microneedle patch as well as a preparation method and application thereof. The method comprises the following steps: firstly, preparing a hyaluronic acid needle body by taking hyaluronic acid as a needle body matrix and mesoporous polydopamine as a drug carrier; in addition, gelatin, common polydopamine and polyacrylamide composite hydrogel is used as a bottom patch, and the microneedle is fixed, so that the microneedle patch with a double-layer structure is obtained. Due to the structure, the hydrogel has excellent comprehensive properties such as adhesion, mechanical strength, antibiosis, photothermal, antioxidation and biocompatibility, and is expected to be applied to the fields of transdermal drug delivery, wound repair, skin and wound sensing detection and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of functional polymer materials and also to the field of biomedical materials, and specifically relates to a multifunctional composite hydrogel microneedle patch and its preparation method and application. Background Art

[0002] In recent years, as a highly potential general technology, microneedles have attracted extensive attention and application research in the fields of biomedicine and sensors. Microneedle patches can pierce the skin under minimally invasive and painless conditions, bypass tissue barriers, and inject drugs into the body efficiently, greatly improving the drug delivery efficiency. If an environment-responsive structure or biosensor function is integrated into the microneedle patch, on-demand precise drug delivery can be further achieved.

[0003] However, the adhesion of ordinary microneedle patches to the skin is limited, and they cannot act firmly and stably on the skin surface, easily causing detachment. For microneedle patches that need to act for a long time, during the use process by patients, various activities will inevitably cause them to be damaged, loosened or even detached under external forces, and ultimately the expected treatment or monitoring effects cannot be achieved. In addition, microneedles piercing the skin tissue may also pose a certain risk of bacterial infection. Therefore, it is necessary to increase their antibacterial properties.

[0004] Therefore, due to the above-mentioned usage problems, the application market requires microneedle patches with comprehensive properties such as excellent adhesion, mechanical strength, antibacterial, photothermal, antioxidant and biocompatibility to achieve better therapeutic effects. Summary of the Invention

[0005] The purpose of the present invention is to solve the problems existing in the prior art, and provides a multifunctional composite hydrogel microneedle patch and its preparation method and application. The present invention first uses hyaluronic acid as the matrix of the needle body, and composes mesoporous polydopamine to generate the first layer of microneedle structure; and uses gelatin, ordinary polydopamine and polyacrylamide composite hydrogel to form the bottom patch as the second layer structure and fix the microneedles. Among them, mesoporous polydopamine in the needle body serves as a drug carrier, while ordinary polydopamine in the bottom patch can endow the microneedle patch with adhesion, antioxidant, antibacterial and photothermal properties; polyacrylamide can improve the mechanical properties of the microneedle patch.

[0006] To achieve the above purpose, the technical solutions designed by the present invention are as follows:

[0007] The present invention provides a multifunctional composite hydrogel microneedle patch, which is characterized in that: the raw materials of the microneedle patch include gelatin, hyaluronic acid, acrylamide, mesoporous polydopamine, initiator, crosslinking agent and catalyst; wherein, the initiator is ammonium persulfate, the crosslinking agent is N,N'-methylenebisacrylamide, and the catalyst is tetramethylethylenediamine.

[0008] Further, the dosage of hyaluronic acid is 20% - 40% of the mass of gelatin. Preferably, the dosage of hyaluronic acid is 40% of the mass of gelatin, the dosage of mesoporous polydopamine is 0.4% of the mass of gelatin, and the dosage of acrylamide is 150% of the mass of gelatin; the initiator is ammonium persulfate, the crosslinking agent is N,N'-methylenebisacrylamide, and the catalyst is tetramethylethylenediamine; the dosage of ammonium persulfate is 2% of the mass of gelatin, the dosage of N,N'-methylenebisacrylamide is 0.06% of the mass of gelatin, and the dosage of tetramethylethylenediamine is 0.78% of the mass of gelatin.

[0009] Still further, the raw materials of the microneedle patch further include ordinary polydopamine and / or protocatechuic aldehyde, wherein the dosage of ordinary polydopamine is 1% - 50% of the mass of gelatin, and the dosage of protocatechuic aldehyde is 1% - 50% of the mass of gelatin.

[0010] The present invention also provides a preparation method of a multifunctional composite hydrogel microneedle patch. The preparation method is to first use hyaluronic acid as the needle body matrix and mesoporous polydopamine as the drug carrier to prepare modified microneedles; then use a gelatin and polyacrylamide composite hydrogel as the bottom patch to fix the microneedles; under the action of an initiator, a crosslinking agent and a catalyst, a hydrogel is generated on the bottom patch to prepare the multifunctional composite hydrogel microneedle patch.

[0011] Further, the preparation method of the multifunctional composite hydrogel microneedle patch includes the following steps:

[0012] (1) Dissolve hyaluronic acid in deionized water and stir to form a uniform solution;

[0013] (2) Mix mesoporous polydopamine with the hyaluronic acid solution obtained in step (1) evenly to obtain a blend solution;

[0014] (3) Pour the blend solution of step (2) into a microneedle mold and use a centrifuge to centrifuge to fill the mold cavity;

[0015] (4) Remove the residual needle tip matrix on the surface of the mold and place it in an oven for curing to obtain the needle tip part;

[0016] (5) Add gelatin to deionized water and stir to form a gelatin solution;

[0017] Or, add gelatin to deionized water and stir to form a gelatin solution, and then add protocatechuic aldehyde to the obtained gelatin solution to obtain a gelatin Schiff base solution;

[0018] (6) Add acrylamide alone or acrylamide and ordinary polydopamine in a two-component manner to the gelatin Schiff base solution or gelatin solution obtained in step (5), and mix well to obtain a mixed solution;

[0019] (7) Prepare an N,N'-methylenebisacrylamide solution, and successively add the N,N'-methylenebisacrylamide solution, tetramethylethylenediamine, and ammonium persulfate to the mixed solution obtained in step (6), and stir evenly to obtain a prepolymer solution of the hydrogel patch;

[0020] (8) Pour the hydrogel prepolymer solution into a mold and centrifuge again, and raise the temperature to form a hydrogel;

[0021] (9) Use a surgical blade to peel the microneedle patch from the mold to obtain a multifunctional composite hydrogel microneedle patch.

[0022] Furthermore, in the above step (1), the dosage of hyaluronic acid is 20% - 40% of the mass of gelatin. Preferably, the dosage of hyaluronic acid is 40% of the mass of gelatin;

[0023] In the above step (2), the dosage of mesoporous polydopamine is 0.4% of the mass of gelatin;

[0024] In the above step (3), the rotation speed of the centrifuge is 4000 revolutions per minute, and the centrifugation time is 10 minutes;

[0025] In the above step (4), the curing temperature is 37°C, and the curing time is 4 hours.

[0026] Furthermore, in the above step (5), the concentration of the gelatin solution is 0.2 g·mL -1 ; the dosage of protocatechuic aldehyde is 1% - 50% of the mass of gelatin.

[0027] Furthermore, in the above step (6), the dosage of acrylamide is 150% of the mass of gelatin, and the dosage of ordinary polydopamine is 1% - 50% of the mass of gelatin.

[0028] Furthermore, in the above step (7), the concentration of N,N'-methylenebisacrylamide is 0.01 g·mL -1 , the dosage is 0.06% of the mass of gelatin, the dosage of tetramethylethylenediamine is 0.78% of the mass of gelatin, and the dosage of ammonium persulfate is 2% of the mass of gelatin. In the above step (8), the temperature increase is 60°C.

[0029] The present invention also provides an application of the above multifunctional composite hydrogel microneedle patch in the preparation of transdermal drug delivery, wound repair, and skin and wound sensing detection materials.

[0030] The preparation mechanism of the multifunctional composite hydrogel microneedle patch of the present invention:

[0031] The multifunctional composite hydrogel microneedle patch of the present invention has a bilayer structure. The microneedle part uses mesoporous polydopamine as a drug carrier, and realizes sustained and controlled release through the dissolution of the microneedles and the interaction between mesoporous polydopamine and the drug. The patch part is based on the physical network of gelatin with a triple helix structure and the chemical network of polyacrylamide to construct a high-strength double-network hydrogel. In order to improve its comprehensive properties such as adhesion, mechanical strength, antibacterial, photothermal, antioxidant and biocompatibility at the same time, protocatechuic aldehyde is used to modify gelatin to obtain gelatin Schiff base, and ordinary polydopamine is introduced into this system as the back patch of the microneedles. A composite hydrogel patch is obtained through various interactions formed between polydopamine, gelatin Schiff base and the groups in polyacrylamide.

[0032] Advantages of the present invention:

[0033] 1. The microneedle patch provided by the present invention is a novel hydrogel composite bilayer structure.

[0034] 2. The multifunctional composite hydrogel microneedle patch provided by the present invention has multiple functional characteristics at the same time, including excellent antibacterial, drug release, photothermal, adhesion, swelling, mechanical, antioxidant and biocompatibility, etc.

[0035] 3. The multifunctional composite hydrogel microneedle patch provided by the present invention has excellent adhesion, so that the microneedle patch can be effectively fixed to avoid falling off under force during use.

[0036] 4. The multifunctional composite hydrogel microneedle patch provided by the present invention has outstanding mechanical properties, thus preventing damage caused by force during use.

[0037] 5. The multifunctional composite hydrogel microneedle patch provided by the present invention has significant photothermal characteristics.

[0038] 6. The multifunctional composite hydrogel microneedle patch provided by the present invention has excellent antibacterial activity against both Gram-positive and Gram-negative bacteria. When combined with the photothermal characteristics, the antibacterial effect is more significant, thus avoiding wound infection.

[0039] 7. The multifunctional composite hydrogel microneedle patch provided by the present invention is suitable for transdermal drug delivery. Its microneedles are soluble, which is convenient for controlling the release of drugs.

[0040] 8. The mesoporous polydopamine in the multifunctional composite hydrogel microneedle patch provided by the present invention can be used as a drug carrier for sustained and controlled release of drugs.

[0041] 9. The multifunctional composite hydrogel microneedle patch provided by the present invention has good swelling performance, and the swelling can be adjusted through process parameters to realize the regulation of drug release.

[0042] 10. The multifunctional composite hydrogel microneedle patch provided by the present invention has excellent antioxidant performance, which is beneficial to scavenging free radicals at the wound surface, thereby promoting wound healing.

[0043] 11. The multifunctional composite hydrogel microneedle patch provided by the present invention has good biocompatibility and is suitable for wound repair materials.

[0044] 12. The preparation process of the multifunctional composite hydrogel microneedle patch provided by the present invention is simple and convenient for industrial production.

[0045] In summary, the multifunctional composite hydrogel microneedle patch of the present invention has comprehensive properties such as excellent adhesion, mechanical strength, antibacterial, photothermal, antioxidant and biocompatibility, thus better meeting the actual needs. Brief Description of the Drawings

[0046] Figure 1 It is the microscopic structure of the multifunctional composite hydrogel microneedle patch. Detailed Description of the Invention

[0047] The present invention will be further described in detail below in conjunction with specific embodiments for those skilled in the art to understand.

[0048] Example 1

[0049] (1) Dissolve 0.4 g of hyaluronic acid in 2 mL of deionized water and stir to form a homogeneous solution;

[0050] (2) Mix 4 mg of mesoporous polydopamine with the hyaluronic acid solution obtained in step (1) evenly;

[0051] (3) Pour the blended solution in step (2) into a microneedle mold and centrifuge at 4000 revolutions per minute for 10 minutes to fill the mold cavity;

[0052] (4) Remove the residual tip matrix on the surface of the mold and place it in an oven at 37 °C for 4 hours to obtain the tip part;

[0053] (5) Add 1 g of gelatin to 5 mL of deionized water and stir to form a gelatin solution;

[0054] (6) Add 0.2 g of protocatechuic aldehyde to the gelatin solution obtained in step (5) to obtain a gelatin Schiff base solution;

[0055] (7) Add 1.5 g of acrylamide monomer and 0.3 g of ordinary polydopamine to the gelatin Schiff base solution obtained in step (6) and mix well;

[0056] (8) Add 60 μL of a solution with a concentration of 0.01 g·mL -1An N,N'-methylenebisacrylamide solution, 10 μL of tetramethylethylenediamine, and 0.02 g of ammonium persulfate were stirred evenly to obtain a prepolymer solution of the hydrogel patch;

[0057] (9) The hydrogel prepolymer solution was poured into a mold and centrifuged again, and a hydrogel was formed at 60 °C;

[0058] (10) The microneedle patch was peeled off from the mold with a surgical blade to obtain the multifunctional composite hydrogel microneedle patch 1.

[0059] The bottom patch adhesion performance of the hydrogel microneedle patch 1 obtained by the above method reached 60.4 kPa, the swelling degree in deionized water was 342%, the tensile strength reached 273.1 kPa, and the toughness was 317.4 kJ / m 3 , and the compression modulus reached 259.1 kPa. After tensile and compressive deformation, the hydrogel could easily return to its original state, indicating its good recoverability. This advantage can protect the wound from external forces and provides a good basis for the application of the hydrogel in the skin wound environment. The microneedle patch had a significant scavenging rate for free radicals (1,1-diphenyl-2-picrylhydrazyl), all exceeding 80%, showing excellent antioxidant performance; the microneedles could be heated to 50 °C after 60 seconds of near-infrared light irradiation, indicating an outstanding photothermal conversion effect, and near-infrared light could be transdermally absorbed, and the microneedles could play a role under the skin; the microneedle patch had excellent antibacterial ability, with an antibacterial rate of 81.6% against Staphylococcus aureus and 92.2% against Escherichia coli; after near-infrared light irradiation, the antibacterial rates were further increased to 93.3% (Staphylococcus aureus) and 96.7% (Escherichia coli), respectively. Therefore, the hydrogel microneedle patch had an outstanding antibacterial effect and could effectively inhibit wound infection. In addition, the drug tetracycline hydrochloride was pre-loaded in mesoporous polydopamine, and other steps remained unchanged, and the drug transdermal sustained release exceeded 100 hours. The microneedle patch had good biocompatibility and was suitable as a wound dressing material.

[0060] Example 2

[0061] (1) 0.4 g of hyaluronic acid was dissolved in 2 mL of deionized water and stirred to form a homogeneous solution;

[0062] (2) 4 mg of mesoporous polydopamine was blended evenly with the hyaluronic acid solution obtained in step (1);

[0063] (3) The blended solution in step (2) was poured into a microneedle mold, and centrifuged at 4000 revolutions per minute for 10 minutes using a centrifuge to fill the mold cavity;

[0064] (4) The residual tip matrix on the surface of the mold was removed and placed in an oven at 37 °C for 4 hours to cure to obtain the tip part;

[0065] (5) Add 1 g of gelatin to 5 mL of deionized water and stir to form a gelatin solution;

[0066] (6) Add 0.3 g of protocatechuic aldehyde to the gelatin solution obtained in step (5) to obtain a gelatin Schiff base solution;

[0067] (7) Add 1.5 g of acrylamide monomer and 0.2 g of ordinary polydopamine to the gelatin Schiff base solution obtained in step (6) and mix well;

[0068] (8) Sequentially add 60 μL of N,N'-methylenebisacrylamide solution with a concentration of 0.01 g·mL -1 , 10 μL of tetramethylethylenediamine and 0.02 g of ammonium persulfate to the mixed solution obtained in step (7), stir evenly to obtain a prepolymer solution of the hydrogel patch;

[0069] (9) Pour the hydrogel prepolymer solution into a mold and centrifuge again, and form a hydrogel at 60 °C;

[0070] (10) Use a surgical blade to peel the microneedle patch from the mold to obtain the multifunctional composite hydrogel microneedle patch 2.

[0071] The bottom patch adhesion performance of the hydrogel microneedle patch 2 obtained by the above method reaches 53.8 kPa, the swelling degree in deionized water is 249%, the tensile strength reaches 207.6 kPa, and the toughness is 219.8 kJ / m 3 , and the compression modulus reaches 194.6 kPa.

[0072] Example 3

[0073] (1) Dissolve 0.4 g of hyaluronic acid in 2 mL of deionized water and stir to form a homogeneous solution;

[0074] (2) Blend 4 mg of mesoporous polydopamine with the hyaluronic acid solution obtained in step (1) evenly;

[0075] (3) Pour the blended solution in step (2) into a microneedle mold and centrifuge at 4000 revolutions per minute for 10 minutes to fill the mold cavity;

[0076] (4) Remove the residual tip matrix on the surface of the mold and place it in an oven at 37 °C for 4 hours to obtain the tip part;

[0077] (5) Add 1 g of gelatin to 5 mL of deionized water and stir to form a gelatin solution;

[0078] (6) Add 1.5 g of acrylamide monomer and 0.5 g of ordinary polydopamine to the gelatin solution obtained in step (5) and mix well;

[0079] (7) Add 60 μL of N,N'-methylenebisacrylamide solution with a concentration of 0.01 g·mL -1 in sequence to the mixed solution obtained in step (6), then add 10 μL of tetramethylethylenediamine and 0.02 g of ammonium persulfate, and stir evenly to obtain the prepolymer solution of the hydrogel patch;

[0080] (8) Pour the hydrogel prepolymer solution into a mold and centrifuge it again, and form a hydrogel at 60 °C;

[0081] (9) Use a surgical blade to peel the microneedle patch from the mold to obtain the multifunctional composite hydrogel microneedle patch 3.

[0082] The bottom patch adhesion performance of the hydrogel microneedle patch 3 obtained by the above method reaches 26.3 kPa, the swelling degree in deionized water is 151%, the tensile strength reaches 216.9 kPa, and the toughness is 202.8 kJ / m 3 , and the compression modulus reaches 218.9 kPa.

[0083] Example 4

[0084] (1) Dissolve 0.4 g of hyaluronic acid in 2 mL of deionized water and stir to form a uniform solution;

[0085] (2) Blend 4 mg of mesoporous polydopamine with the hyaluronic acid solution obtained in step (1) evenly;

[0086] (3) Pour the blended solution in step (2) into a microneedle mold, and centrifuge it at 4000 revolutions per minute for 10 minutes to fill the mold cavity;

[0087] (4) Remove the residual tip matrix on the surface of the mold, and put it into an oven to cure at 37 °C for 4 hours to obtain the tip part;

[0088] (5) Add 1 g of gelatin to 5 mL of deionized water and stir to form a gelatin solution;

[0089] (6) Add 0.5 g of protocatechuic aldehyde to the gelatin solution obtained in step (5) to obtain a gelatin Schiff base solution;

[0090] (7) Add 1.5 g of acrylamide monomer to the gelatin Schiff base solution obtained in step (6), and mix thoroughly;

[0091] (8) Add 60 μL of N,N'-methylenebisacrylamide solution with a concentration of 0.01 g·mL -1 in sequence to the mixed solution obtained in step (7), then add 10 μL of tetramethylethylenediamine and 0.02 g of ammonium persulfate, and stir evenly to obtain the prepolymer solution of the hydrogel patch;

[0092] (9) Pour the hydrogel prepolymer solution into the mold and centrifuge again to form a hydrogel at 60 °C;

[0093] (10) Use a surgical blade to peel the microneedle patch from the mold to obtain the multifunctional composite hydrogel microneedle patch 4.

[0094] The bottom patch adhesion performance of the hydrogel microneedle patch 4 obtained by the above method reaches 46.9 kPa, the swelling degree in deionized water is 215%, the tensile strength reaches 300.8 kPa, and the toughness is 244.8 kJ / m 3 , and the compression modulus reaches 153.0 kPa.

[0095] Other parts not described in detail are all prior arts. Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. People can also obtain other embodiments based on this embodiment without creative efforts, and these embodiments all belong to the protection scope of the present invention.

Claims

1. A multifunctional composite hydrogel microneedle patch, characterized in that: The raw materials of the microneedle patch include gelatin, hyaluronic acid, acrylamide, mesoporous polydopamine, initiator, cross-linking agent and catalyst; The initiator is ammonium persulfate, the cross-linking agent is N,N'-methylenebisacrylamide, and the catalyst is tetramethylethylenediamine.

2. The multifunctional composite hydrogel microneedle patch according to claim 1, characterized in that: The amount of hyaluronic acid used is 20% to 40% of the mass of gelatin, the amount of mesoporous polydopamine used is 0.4% of the mass of gelatin, and the amount of acrylamide used is 150% of the mass of gelatin; the initiator is ammonium persulfate, the cross-linking agent is N,N'-methylenebisacrylamide, and the catalyst is tetramethylethylenediamine; the amount of ammonium persulfate used is 2% of the mass of gelatin, the amount of N,N'-methylenebisacrylamide used is 0.06% of the mass of gelatin, and the amount of tetramethylethylenediamine used is 0.78% of the mass of gelatin.

3. The multifunctional composite hydrogel microneedle patch according to claim 1 or 2, characterized in that: The raw materials of the microneedle patch also include common polydopamine and / or protocatechuic aldehyde, wherein the amount of common polydopamine is 1% to 50% of the mass of gelatin, and the amount of protocatechuic aldehyde is 1% to 50% of the mass of gelatin.

4. A method for preparing a multifunctional composite hydrogel microneedle patch, characterized in that: The preparation method comprises the following steps: firstly using hyaluronic acid as a needle matrix and mesoporous polydopamine as a drug carrier to prepare a modified microneedle; then using gelatin and polyacrylamide composite hydrogel as a bottom patch to fix the microneedle; and generating a hydrogel on the bottom patch under the action of an initiator, a crosslinking agent and a catalyst to prepare a multifunctional composite hydrogel microneedle patch.

5. The preparation method according to claim 4, characterized in that: The following steps are involved: (1) dissolving hyaluronic acid in deionized water and stirring to form a uniform solution; (2) uniformly mixing the mesoporous polydopamine and the hyaluronic acid solution obtained in step (1) to obtain a blended solution; (3) pouring the blended solution of step (2) into the microneedle mold and centrifuging it to fill the mold cavity; (4) removing the needle tip matrix remaining on the surface of the mold and placing it in an oven for curing to obtain the needle tip portion; (5) adding gelatin into deionized water and stirring to form a gelatin solution; Alternatively, gelatin is added to deionized water and stirred to form a gelatin solution, and then protocatechuic aldehyde is added to the gelatin solution obtained in the step to obtain a gelatin Schiff base solution; (6) adding acrylamide as a single component or acrylamide and ordinary polydopamine as two components to the gelatin Schiff base solution or gelatin solution obtained in step (5), and mixing them thoroughly to obtain a mixed solution; (7) preparing an N,N'-methylenebisacrylamide solution, adding the N,N'-methylenebisacrylamide solution, tetramethylethylenediamine and ammonium persulfate to the mixed solution obtained in step (6) in sequence, stirring evenly, to obtain a prepolymer solution for a hydrogel patch; (8) pouring the hydrogel prepolymer solution into the mold, centrifuging again, and heating to form a hydrogel; (9) Use a surgical blade to peel the microneedle patch from the mold to obtain a multifunctional composite hydrogel microneedle patch.

6. The preparation method according to claim 5, characterized in that: In the step (1), the amount of hyaluronic acid used is 20% to 40% of the mass of gelatin; In the step (2), the amount of mesoporous polydopamine used is 0.4% of the mass of gelatin; In the step (3), the centrifuge speed is 4000 rpm and the centrifugation time is 10 minutes; In the step (4), the curing temperature is 37° C. and the curing time is 4 hours.

7. The preparation method according to claim 5, characterized in that: In step (5), the concentration of the gelatin solution is 0.2 g·mL -1 ; The amount of protocatechuic aldehyde used is 1% to 50% of the mass of gelatin.

8. The preparation method according to claim 5, characterized in that: In the step (6), the amount of acrylamide used is 150% of the mass of gelatin, and the amount of common polydopamine used is 1% to 50% of the mass of gelatin.

9. The preparation method according to claim 5, characterized in that: In step (7), the concentration of N,N'-methylenebisacrylamide is 0.01 g·mL -1 , the amount used is 0.06% of the mass of gelatin, the amount of tetramethylethylenediamine used is 0.78% of the mass of gelatin, and the amount of ammonium persulfate used is 2% of the mass of gelatin; in the step (8), the heating temperature is 60°C.

10. Use of the multifunctional composite hydrogel microneedle patch according to claim 1 in the preparation of transdermal drug delivery, wound repair, and skin and wound surface sensing and detection materials.

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