Hydrogel microneedle for skin improvement and preparation method thereof

Abstract

The invention relates to the technical field of biomedical materials, in particular to a hydrogel microneedle for skin improvement and a preparation method thereof.The hydrogel microneedle for skin improvement comprises a microneedle matrix and fisetin, the microneedle matrix is a hydrogel matrix, and the fisetin is embedded in the microneedle matrix. According to the hydrogel microneedle for skin improvement, the hydrogel microneedle has good mechanical performance, biocompatibility and degradability, the effect of slowly releasing medicine can be achieved, the hydrogel matrix wraps fisetin, the targeting performance of anti-aging active ingredients can be effectively enhanced, and the anti-aging effect of the skin is improved. The anti-aging agent is slowly released in a corium layer to play an anti-aging role, and has a wide application prospect in medical beauty and skin care products.

Description

Technical Field

[0001] The present application relates to the technical field of biomedical materials, and in particular to a hydrogel microneedle for skin improvement and a preparation method thereof. Background Art

[0002] Skin aging is the result of the superposition of natural aging and external aging, which manifests as dry and loose skin, wrinkle formation, etc. The skin is composed of epidermis, dermis and subcutaneous tissue. With the increase of age and the influence of external factors (such as sunlight or ultraviolet radiation, pollutants, etc.), the collagen and elastic fibers in the dermis will become loose and decompose gradually faster. At the same time, the fat in the subcutaneous tissue is also reduced. Therefore, the skin elasticity becomes worse and worse, and wrinkles begin to appear.

[0003] There are two main methods for anti-aging and wrinkle removal: first, self-use skin care products such as external spraying, smearing, and patching; second, injection and filling medical beauty skin care products. The stratum corneum is the outermost part of the epidermis. The anti-aging active ingredients contained in self-use skin care products are often difficult to enter the dermis due to the obstruction of the stratum corneum, resulting in limited anti-aging effects. Local injection is currently the most commonly used medical beauty skin care product. The needle penetrates the tough stratum corneum to allow the injected drug active ingredients to play an anti-aging role, but it has the disadvantages of high trauma and many adverse reactions.

[0004] Gel microneedles have become a popular tool in precision medicine research due to their convenience, minimal invasiveness, and high efficiency. They are widely used in research on insulin delivery, immunotherapy, vaccine delivery, pain management, etc. Among them, hydrogel microneedles have the advantages of convenient administration, high permeability, and low toxic side effects. They have shown good diagnostic and therapeutic potential in the fields of diabetes, arthritis, and tumors. However, there is still a lack of corresponding research and application in the field of skin improvement.

[0005] In view of this, this application is specially filed. Summary of the invention

[0006] The present application provides a hydrogel microneedle for skin improvement and a preparation method thereof, which is used to solve the problem of how to enhance the targeting of anti-aging active ingredients so that they can be absorbed through the skin to exert anti-aging effects.

[0007] In one aspect, the present application provides a hydrogel microneedle for skin improvement, comprising:

[0008] A microneedle matrix, wherein the microneedle matrix is ​​a hydrogel matrix;

[0009] Fisetin, wherein the fisetin is embedded in the microneedle matrix.

[0010] In some embodiments, liposomes are dispersed in the microneedle matrix, the liposomes carry the fisetin, and the liposomes include a combination of two or more of hyaluronic acid, dioleoylphosphatidylethanolamine, and cholesterol.

[0011] In some of the embodiments, the ratio of the content of the liposome to the content of fisetin is no greater than 2.

[0012] In some embodiments, the hydrogel matrix is ​​a double-bond modified hydrogel, and the hydrogel matrix includes at least one of methacrylated silk fibroin and type XVII collagen.

[0013] On the other hand, the present application also provides a method for preparing a hydrogel microneedle for skin improvement, comprising the following steps:

[0014] Prepare fisetin solution;

[0015] preparing a hydrogel matrix solution;

[0016] adding the fisetin solution to the hydrogel matrix solution to obtain a fisetin-hydrogel matrix solution;

[0017] injecting the fisetin-hydrogel matrix solution into a microneedle mold, performing vacuum suction, and molding under ultraviolet irradiation;

[0018] After demolding, the hydrogel microneedles were obtained.

[0019] In some embodiments, the fisetin is a fisetin liposome carried by liposomes, and the preparation of the fisetin solution specifically includes:

[0020] Prepare fisetin liposomes, wherein the fisetin liposomes include fisetin and liposomes carrying the fisetin, and the liposomes include a combination of two or more of hyaluronic acid, dioleoylphosphatidylethanolamine, and cholesterol;

[0021] The fisetin liposomes are weighed and dissolved to obtain a fisetin solution.

[0022] In some embodiments, the preparation of fisetin liposomes specifically comprises:

[0023] Preparation of HA-DOPE: Weigh and dissolve dioleoylphosphatidylethanolamine to obtain solution phase A;

[0024] Weigh hyaluronic acid, NHS and EDC, mix and activate to obtain solution phase B;

[0025] The solution phase A is added to the solution phase B, and a hyaluronic acid phospholipid complex, namely HA-DOPE, is obtained through dialysis and freeze-drying;

[0026] Preparation of HA-LIP@Fis: Fisetin, dioleoylphosphatidylethanolamine and cholesterol were weighed and mixed and dissolved to obtain a solution phase C;

[0027] The solution phase C is subjected to ultrasonic dispersion treatment to obtain a liposome membrane;

[0028] Weigh the HA-DOPE and dissolve it to obtain a solution phase D;

[0029] The liposome membrane is transferred into the solution phase D, and fisetin liposomes, namely HA-LIP@Fis, are obtained through hydration, ultrasound and freeze-drying.

[0030] In some of the embodiments, the concentration of fisetin in the fisetin-hydrogel matrix solution is 2.5 umol / L to 50 umol / L.

[0031] In some embodiments, the preparation of the hydrogel matrix solution specifically includes:

[0032] The hydrogel matrix is ​​weighed and dissolved to obtain a hydrogel matrix solution, wherein the hydrogel matrix includes at least one of silk fibroin and recombinant type XVII collagen.

[0033] In some embodiments, the silk fibroin is modified silk fibroin modified with glycidyl methacrylate; and / or

[0034] The recombinant type XVII collagen is modified type XVII collagen modified by methacrylic anhydride.

[0035] After adopting the above technical solution, the present application has the following beneficial effects compared with the prior art.

[0036] 1. The hydrogel microneedles for skin improvement in the present application not only have good mechanical properties, biocompatibility and degradability, but also can achieve the effect of slow drug release. Moreover, by encapsulating fisetin in the hydrogel matrix, the targeting of anti-aging active ingredients can be effectively enhanced, so that it can be slowly released in the dermis to exert anti-aging effects, and has broad application prospects in medical beauty and skin care products.

[0037] 2. The preparation method of the hydrogel microneedles for skin improvement of the present application can obtain hydrogel microneedles with high transdermal efficiency, strong drug loading capacity and efficiency, and anti-aging effect, which solves the research and application gap of hydrogel microneedles containing fisetin in skin beauty, especially in the field of anti-skin aging. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1Schematic diagram of the structure of the hydrogel microneedle for skin improvement prepared in Example 1 of the present application;

[0039] Figure 2 This is a scanning electron microscope image of the hydrogel microneedle for skin improvement prepared in Example 1 of the present application at 1000 μm;

[0040] Figure 3 This is a scanning electron microscope image of the hydrogel microneedle for skin improvement prepared in Example 1 of the present application at 500 μm;

[0041] Figure 4 This is a scanning electron microscope image of the hydrogel microneedle for skin improvement prepared in Example 1 of the present application at 200 μm;

[0042] Figure 5 Flow chart of the method for preparing hydrogel microneedles for skin improvement in the embodiment of the present application. DETAILED DESCRIPTION

[0043] The technical solution of the present application will be described clearly and completely below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.

[0044] First, as Figure 1 As shown, an embodiment of the present application provides a hydrogel microneedle for skin improvement, which includes a microneedle matrix and fisetin, wherein the microneedle matrix is ​​a hydrogel matrix, and fisetin is embedded in the microneedle matrix.

[0045] The hydrogel microneedles for skin improvement according to the present application, compared with traditional solid microneedles, not only have good mechanical properties, biocompatibility and degradability, but can also achieve the effect of slow drug release. Moreover, by encapsulating fisetin in the hydrogel matrix, the targeting of anti-aging active ingredients can be effectively enhanced, so that it can be slowly released in the dermis to exert anti-aging effects, and has broad application prospects in medical cosmetic skin care products.

[0046] In this embodiment, the fisetin-hydrogel matrix solution is injected into the microneedle mold, vacuum suction is performed, and molding is performed under ultraviolet irradiation, so that hydrogel microneedles embedded with fisetin are obtained after demolding. Among them, fisetin is not only a flavonoid plant antioxidant, but also a natural senescent cell scavenger. By controlling the concentration of fisetin in the fisetin-hydrogel matrix solution to 2.5umol / L~50umol / L, the hydrogel microneedles can significantly inhibit skin oxidative damage and cell apoptosis, and inhibit melanin formation.

[0047] In this embodiment, liposomes are dispersed in the microneedle matrix, and the liposomes carry fisetin. The liposomes include a combination of two or more of hyaluronic acid, dioleoylphosphatidylethanolamine, and cholesterol to form fisetin liposomes (HA-LIP@Fis). With CD44 as the target, the fisetin liposomes can target and bind to CD44 on the surface of the cell membrane of fibroblasts, keratinocytes, etc., which helps the anti-aging active ingredients to more efficiently bind to the corresponding cells and extracellular matrix, thereby exerting their biological effects to a greater extent.

[0048] In this embodiment, the ratio of the liposome content to the fisetin content is no more than 2. By controlling the ratio of the liposome content to the fisetin content, the fisetin liposomes can be targeted and bound to fibroblasts, making the local drug concentration higher and evenly distributed, thereby enhancing the effect of fisetin in inhibiting skin oxidative damage and cell apoptosis, and inhibiting melanin.

[0049] In this embodiment, the hydrogel matrix is ​​a double-bond modified hydrogel, and the hydrogel matrix includes at least one of double-bond modified silk fibroin and recombinant type XVII collagen, so that the hydrogel microneedles have the advantages of high transdermal efficiency, strong drug loading capacity and high drug loading efficiency, which helps to slowly release or degrade anti-aging active ingredients and inhibit the proliferation of fibroblasts and the deposition of collagen.

[0050] Preferably, the silk fibroin is modified silk fibroin (SFMA) modified by glycidyl methacrylate, which can enhance the tissue compatibility of the hydrogel microneedles, improve their mechanical strength, and further optimize the efficiency and stability of the gel microneedle characterization and drug delivery.

[0051] Preferably, the recombinant type XVII collagen is a modified recombinant type XVII collagen (rhCol17MA) modified with methacrylic anhydride, which has excellent biocompatibility and can supplement exogenous collagen XVII in human skin, thereby maintaining the biological functions of epidermal stem cells and hair follicle stem cells, mediating their interaction with surrounding cells and extracellular matrix, and thus inhibiting the aging process of the skin.

[0052] Second, as Figure 1 As shown, the present application embodiment also provides a method for preparing a hydrogel microneedle for skin improvement, comprising the following steps:

[0053] Step S1: preparing a fisetin solution;

[0054] Step S2: preparing a hydrogel matrix solution;

[0055] Step S3: adding the fisetin solution to the hydrogel matrix solution to obtain a fisetin-hydrogel matrix solution, wherein the concentration of fisetin in the fisetin-hydrogel matrix solution is 2.5 umol / L to 50 umol / L;

[0056] Step S4: injecting the fisetin-hydrogel matrix solution into the microneedle mold and molding it under ultraviolet irradiation;

[0057] Step S5: After demoulding, the hydrogel microneedles are obtained.

[0058] According to the preparation method of hydrogel microneedles for skin improvement of the present application, hydrogel microneedles with high transdermal efficiency, strong drug loading capacity and efficiency and anti-aging effect can be obtained, which solves the research and application gap of hydrogel microneedles containing fisetin in skin beauty, especially in the field of anti-skin aging.

[0059] In this embodiment, in step S1, fisetin is fisetin liposome carried by liposome, wherein the fisetin liposome includes fisetin and liposome carrying fisetin, and the liposome includes a combination of two or more of hyaluronic acid, dioleoylphosphatidylethanolamine, and cholesterol.

[0060] In this embodiment, step S1 specifically includes the following steps:

[0061] Step S11: Preparation of fisetin liposomes

[0062] ① Preparation of HA-DOPE: Weigh 30.0 mg of hyaluronic acid (HA), 576 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 65.0 mg of 1-hydroxypyrrolidine-25-dione (NHS) and dissolve them in 100 mL of distilled water. Adjust the pH to 7.5 with NaOH solution and react in a 37°C water bath for 3 hours. Add a solution containing 72.0 mg of dioleoylphosphatidylethanolamine (DOPE) to the reaction solution and react in a 37°C water bath for 24 hours. The reaction solution is dialyzed with distilled water and freeze-dried to obtain HA-DOPE.

[0063] ② Preparation of HA-LIP@Fis: Weigh 13.2mg HOPE, 9.4mg cholesterol and 16mg Fisetin and dissolve them in 30mL methanol. After ultrasonic dispersion, filter to remove the undissolved substances. After the methanol is evaporated in a rotary evaporator, a thin lipid film is obtained. Add 16mg HA-DOPE dissolved in 16mL deionized water to hydrate the film. Use an ultrasonic disperser to intermittently ultrasonicate for 10min at 4°C with an ultrasonic power of 40HZ to obtain non-chromone-encapsulated targeted liposomes (HA-LIP@Fis).

[0064] Step S12: Weigh and dissolve the fisetin liposomes to obtain a fisetin solution.

[0065] In this embodiment, CD44 is used as a target, HA-LIP@Fis is used to target and bind to CD44 on the cell membrane surface of fibroblasts, keratinocytes, etc., and fisetin is encapsulated in liposomes to act across the membrane in the cells, thereby regulating the relevant pathways of skin aging. In addition, the HA-CD44 interaction can affect the role of the immune system in the skin aging process, thereby inhibiting the process of skin aging. HA-targeted liposomes can make the anti-aging active ingredients more efficiently bind to the corresponding cells and extracellular matrix, thereby exerting their biological effects to a greater extent.

[0066] In this embodiment, step S2 specifically includes the following steps: weighing and dissolving the hydrogel matrix to obtain a microneedle matrix solution, wherein the hydrogel matrix includes at least one of silk fibroin and recombinant type XVII collagen.

[0067] In this embodiment, the silk fibroin is a modified silk fibroin modified with glycidyl methacrylate. Specifically, 10 g of silk cocoons are immersed in 1L 0.05M Na2CO3 solution and boiled at 100°C for 30 minutes, and washed with distilled water several times to obtain degummed silk fibroin. Then, the degummed silk fibroin (SFMA) is dried in a drying oven. Weigh 10 g of the above SF and dissolve it in lithium bromide (9.3M) solution at 60°C for 1 hour, and slowly add 6 mL of glycidyl methacrylate (GMA). After 8 hours of reaction, dialyze with distilled water for 3 days using a dialysis bag. The obtained SFMA solution is pre-frozen at -80°C and then freeze-dried to obtain a sponge-like SFMA.

[0068] In this embodiment, the recombinant type XVII collagen is a modified recombinant type XVII collagen (rhCol17MA) modified with methacrylic anhydride. Specifically, 10 g of recombinant type XVII collagen is weighed and dissolved in 500 mL of distilled water. After it is fully dissolved, the pH is adjusted to 7.0, and 10 mL of methacrylic anhydride (MA) is slowly added dropwise. The reaction is allowed to proceed overnight. After the reaction is completed, it is dialyzed (MW: 3500Da) for three days to fully remove the unreacted MA and then freeze-dried and collected.

[0069] In this embodiment, step S4 specifically includes the following steps: injecting the fisetin-hydrogel matrix solution into the microneedle mold, and then placing the microneedle mold in a vacuum drying oven, vacuuming at -0.1 MPa for 5 minutes at room temperature to remove bubbles and fill the needle tip, repeating 4 times, removing the bubbles on the surface and making the liquid level with the mold, and photocuring and cross-linking under ultraviolet light for 5 minutes.

[0070] In this embodiment, step S5 specifically includes the following steps: adding 1 mL of PVA solution to coat the surface of the solidified substrate, replenishing the PVA solution after 4 hours, and demolding the microneedle mold after the PVA solution forms a film and dries, thereby obtaining a hydrogel microneedle.

[0071] Example 1 Preparation of hydrogel microneedles

[0072] This embodiment provides a hydrogel microneedle for skin improvement, and the preparation method thereof comprises the following steps:

[0073] Step S1: preparing fisetin solution: weighing 100 mg of fisetin liposomes and dissolving them in PBS solution to obtain a fisetin solution.

[0074] Step S2: preparing the hydrogel matrix solution:

[0075] Weigh 1 g of modified silk fibroin (SFMA) and 1 g of modified recombinant type XVII collagen (rhCol 17 MA), 0.01 g LAP was dissolved in 10 ml pure water to obtain a hydrogel matrix solution;

[0076] Step S3: Add the fisetin liposome solution prepared in step S1 to the hydrogel matrix solution prepared in step S2 to obtain a fisetin-hydrogel matrix solution.

[0077] Step S4: inject the fisetin-hydrogel matrix solution into the microneedle mold, and then place the microneedle mold in a vacuum drying oven, vacuum pump at -0.1 MPa for 5 minutes at room temperature to remove bubbles and fill the needle tip, repeat 4 times, remove the bubbles on the surface and make the liquid level with the mold, and photocuring and cross-linking under ultraviolet light for 5 minutes;

[0078] Step S5: Add 1 mL of PVA solution and coat it on the surface of the cured substrate, and add PVA solution after 4 hours. After the PVA solution forms a film and dries, demould the microneedle mold to obtain a hydrogel microneedle.

[0079] Example 2

[0080] The difference between this embodiment and embodiment 1 is that:

[0081] Step S1: preparing fisetin solution: weighing 10 mg of fisetin liposomes and dissolving them in PBS solution to obtain a fisetin solution.

[0082] Example 3

[0083] The difference between this embodiment and embodiment 1 is that:

[0084] Step S1: preparing fisetin solution: weighing 300 mg of fisetin liposomes and dissolving them in PBS solution to obtain a fisetin solution.

[0085] Example 4

[0086] The difference between this embodiment and embodiment 1 is that:

[0087] Step S2: preparing a hydrogel matrix solution: weighing 0.5 g of modified silk fibroin (SFMA) and 1 g of modified recombinant type XVII collagen (rhCol17MA), dissolving them in a PBS solution, and obtaining a hydrogel matrix solution.

[0088] Example 5

[0089] The difference between this embodiment and embodiment 1 is that:

[0090] Step S2: preparing a hydrogel matrix solution: weighing 1 g of modified silk fibroin (SFMA) and 0.5 g of modified recombinant type XVII collagen (rhCol17MA), dissolving them in a PBS solution, and obtaining a hydrogel matrix solution.

[0091] Example 6

[0092] The difference between this embodiment and embodiment 1 is that:

[0093] Step S2: preparing a hydrogel matrix solution: weighing 1 g of modified silk fibroin (SFMA) and 1.5 g of modified recombinant type XVII collagen (rhCol17MA), dissolving them in a PBS solution, and obtaining a hydrogel matrix solution.

[0094] Example 7

[0095] The difference between this embodiment and embodiment 1 is that:

[0096] Step S2: preparing a hydrogel matrix solution: weighing 0.5 g of modified silk fibroin (SFMA) and 1.5 g of modified recombinant type XVII collagen (rhCol17MA), dissolving them in a PBS solution to obtain a hydrogel matrix solution.

[0097] Comparative Example 1

[0098] The difference between this comparative example and Example 1 is:

[0099] There is no step S1, that is, the prepared hydrogel microneedles do not contain fisetin liposomes.

[0100] Comparative Example 2

[0101] The difference between this comparative example and Example 1 is:

[0102] Step S2: preparing a hydrogel matrix solution: weighing 1 g of modified recombinant type XVII collagen (rhCol17MA) and dissolving it in a PBS solution to obtain a hydrogel matrix solution.

[0103] Comparative Example 3

[0104] The difference between this comparative example and Example 1 is:

[0105] Step S2: preparing a hydrogel matrix solution: weighing 1 g of silk fibroin (SFMA) and dissolving it in a PBS solution to obtain a hydrogel matrix solution.

[0106] Performance Testing

[0107] Scanning electron microscopy, appearance: After each hydrogel microneedle was demolded and dried, the surface of the microneedle was sprayed with gold for 30 seconds, and the surface morphology of the microneedle was observed using a scanning electron microscope. The test conditions were: 5kV electron beam.

[0108] Compression performance test: Place the hydrogel sample directly under the special gel strength probe. The gel probe squeezes the hydrogel until it breaks. The force required for the hydrogel to break is recorded, which is defined as the gel strength of the hydrogel.

[0109] Mechanical properties test: Take the microneedle sample prepared by hydrogel and stick it on the compression sensor of the texture analyzer with the needle tip facing down. Wash the pig skin to remove excess fat and moisture, fix it on the experimental table below the texture analyzer, and compress it at a uniform speed of 10mm / min. The maximum compression force of the microneedle patch is tested when the needle tip displacement is 0.4mm.

[0110] Table 1 Compressive performance test results of hydrogel microneedles in Examples 1 to 7 and Comparative Examples 1 to 3

[0111]

[0112] Table 2 Mechanical properties test results of hydrogel microneedles in Examples 1 to 7 and Comparative Examples 1 to 3

[0113]

[0114] Table 1 shows the compression performance test results of the hydrogel microneedles in Examples 1 to 7 and Comparative Examples 1 to 3. The greater the pressure required for the hydrogel to rupture, the higher the gel strength of the hydrogel microneedles. From the test results, it can be seen that the pressure required for the hydrogel microneedles to rupture in Examples 1 to 4, Example 6 and Example 7 is significantly greater than the pressure required for the hydrogel microneedles to rupture in Comparative Examples 1 to 3, that is, they have better gel strength, and through Figures 1 to 4 It can be seen that the hydrogel microneedles in Example 1 have regular shapes and good molding effects.

[0115] The penetration force required for the skin should exceed 0.1N / needle, that is, the breaking force of the microneedle is greater than 0.1N to overcome the stratum corneum barrier. Table 2 shows the mechanical property test results of the hydrogel microneedles in Examples 1 to 7 and Comparative Examples 1 to 3. The greater the compression force, the better the mechanical properties of the hydrogel microneedles. From the test results, it can be seen that when the displacement of the test needle tip is 0.4mm, the maximum compression force of the microneedle patch is greater than 1.8N, which can meet the requirements for piercing the skin.

[0116] It can be seen that the hydrogel microneedles for skin improvement provided by the present invention can effectively enhance the targeting of anti-aging active ingredients by encapsulating fisetin in the hydrogel matrix, so that fisetin is slowly released in the dermis to exert anti-aging effects, wherein the hydrogel matrix includes modified silk fibroin and recombinant type XVII collagen, and the modified silk fibroin has good mechanical properties, biocompatibility, biodegradability and drug delivery properties, and it synergizes with recombinant type XVII collagen, not only can the fisetin carried by liposomes be accurately delivered to the deep tissue of the skin, ensuring a high concentration and uniform distribution of fisetin, but also can supplement exogenous collagen XVII, maintain the biological functions of epidermal stem cells and hair follicle stem cells, mediate their interaction with surrounding cells and extracellular matrix, thereby inhibiting the aging process of the skin.

[0117] In the description of the present application, it should be understood that the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside", "clockwise", "counterclockwise", "axial", "radial", "circumferential" and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present application and simplifying the description, and do not indicate or imply that the referred device or element must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as a limitation on the present application.

[0118] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of this application, the meaning of "plurality" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0119] In this application, unless otherwise clearly specified and limited, the terms "installed", "connected", "connected", "fixed" and the like should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection, an electrical connection, or communication with each other; it can be a direct connection, or an indirect connection through an intermediate medium, it can be the internal connection of two elements or the interaction relationship between two elements, unless otherwise clearly defined. For ordinary technicians in this field, the specific meanings of the above terms in this application can be understood according to specific circumstances.

[0120] In the present application, the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present application. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0121] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present application.

Claims

1. A hydrogel microneedle for skin improvement, characterized in that: include: A microneedle matrix, wherein the microneedle matrix is ​​a hydrogel matrix; Fisetin, wherein the fisetin is embedded in the microneedle matrix.

2. The hydrogel microneedle for skin improvement according to claim 1, characterized in that: Liposomes are dispersed in the microneedle matrix, the liposomes carry the fisetin, and the liposomes include a combination of two or more of hyaluronic acid, dioleoylphosphatidylethanolamine, and cholesterol.

3. The hydrogel microneedle for skin improvement according to claim 2, characterized in that: The ratio of the content of the liposome to the content of fisetin is no more than 2.

4. The hydrogel microneedle for skin improvement according to any one of claims 1 to 3, characterized in that: The hydrogel matrix is ​​a double-bond modified hydrogel, and the hydrogel matrix includes at least one of methacrylic-modified silk fibroin and type XVII collagen.

5. A method for preparing hydrogel microneedles for skin improvement, characterized in that: The following steps are involved: Prepare fisetin solution; preparing a hydrogel matrix solution; adding the fisetin solution to the hydrogel matrix solution to obtain a fisetin-hydrogel matrix solution; injecting the fisetin-hydrogel matrix solution into a microneedle mold, performing vacuum suction, and molding under ultraviolet irradiation; After demolding, the hydrogel microneedles were obtained.

6. The method for preparing hydrogel microneedles for skin improvement according to claim 5, characterized in that: The fisetin is a fisetin liposome carried by liposomes, and the preparation of the fisetin solution specifically includes: Prepare fisetin liposomes, wherein the fisetin liposomes include fisetin and liposomes carrying the fisetin, and the liposomes include a combination of two or more of hyaluronic acid, dioleoylphosphatidylethanolamine, and cholesterol; The fisetin liposomes are weighed and dissolved to obtain a fisetin solution.

7. The method for preparing hydrogel microneedles for skin improvement according to claim 6, characterized in that: The preparation of fisetin liposomes specifically comprises: Preparation of HA-DOPE: Weigh and dissolve dioleoylphosphatidylethanolamine to obtain solution phase A; Weigh hyaluronic acid, NHS and EDC, mix and activate to obtain solution phase B; The solution phase A is added to the solution phase B, and a hyaluronic acid phospholipid complex, namely HA-DOPE, is obtained through dialysis and freeze-drying; Preparation of HA-LIP@Fis: Fisetin, dioleoylphosphatidylethanolamine and cholesterol were weighed and mixed and dissolved to obtain a solution phase C; The solution phase C is subjected to ultrasonic dispersion treatment to obtain a liposome membrane; Weigh the HA-DOPE and dissolve it to obtain a solution phase D; The liposome membrane is transferred into the solution phase D, and fisetin liposomes, namely HA-LIP@Fis, are obtained through hydration, ultrasound and freeze-drying.

8. The hydrogel microneedle for skin improvement according to any one of claims 5 to 7, characterized in that: The concentration of fisetin in the fisetin-hydrogel matrix solution is 2.5umol / L to 50umol / L.

9. The method for preparing hydrogel microneedles for skin improvement according to any one of claims 5 to 7, characterized in that: The preparation of the hydrogel matrix solution specifically comprises: The hydrogel matrix is ​​weighed and dissolved to obtain a hydrogel matrix solution, wherein the hydrogel matrix includes at least one of silk fibroin and recombinant type XVII collagen.

10. The method for preparing hydrogel microneedles for skin improvement according to claim 9, characterized in that: The silk fibroin is modified silk fibroin modified by glycidyl methacrylate; and / or The recombinant type XVII collagen is modified type XVII collagen modified by methacrylic anhydride.

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