Multi-drug truncation microneedle, preparation method and application of multi-drug truncation microneedle in promoting diabetic wounds

Abstract

The invention discloses a multi-drug truncation microneedle, a preparation method and application of the multi-drug truncation microneedle in promoting diabetic wounds, and belongs to the technical field of drugs. Comprising a backing (1) and an array composed of a plurality of multi-drug cutting needles (2) on the backing, each multi-drug cutting needle is of a microneedle structure and comprises a gel slow-release needle tip (21) and a water-soluble instant needle body (22), the gel slow-release needle tip (21) and the water-soluble instant needle body (22) form a complete microneedle, and the water-soluble instant needle body (22) and the backing (1) are fixedly connected into a whole. The space-time delivery of the angiogenesis promoting medicine and the angiogenesis maturing promoting medicine is realized, and the angiogenesis and angiogenesis maturing processes in the chronic wound of diabetes mellitus can be accurately regulated and controlled.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a multi-drug truncated microneedle, a preparation method and application thereof in promoting diabetic wounds. Background Art

[0002] In modern medicine, drug controlled release systems play a key role in disease treatment. Especially for complex diseases that require multi-drug combined treatment, how to accurately control the release time and dosage of different drugs, maximize the efficacy and reduce side effects, and make the drug release meet the progress of disease treatment is still a major challenge faced by scientists and workers. Microneedle drug delivery, as an emerging transdermal drug delivery method, penetrates the stratum corneum of the skin through a tiny needle array and delivers the drug directly to the microcirculation under the skin, thus overcoming many limitations of traditional oral or injectable drugs, such as first-pass effect and low bioavailability. In addition, microneedle delivery is non-invasive, easy to use, and can deliver drugs locally, significantly reducing systemic side effects, thus attracting widespread attention. However, microneedle systems for single drugs can usually only achieve instantaneous or short-term drug release, which cannot meet the complex treatment needs of certain diseases. Diseases such as chronic inflammation, cancer, and diabetes require multiple drugs to be released in a specific order and time to coordinate the therapeutic effects of different drugs and meet the dynamic needs in the process of disease treatment.

[0003] Diabetes is a chronic metabolic disease that is prevalent worldwide. Its hyperglycemia can cause a variety of complications, among which impaired diabetic wound healing is one of the most challenging complications. The lack of effective local vascularization, especially the formation and maintenance of functional blood vessels, leads to insufficient blood supply to the wound area, which severely limits the regenerative capacity of the tissue. Therefore, the coordinated release of angiogenesis and vascular maturation in time is the key to diabetic wound repair. Angiogenic drugs need to be delivered quickly in the early stages of wound healing to initiate angiogenesis, while angiogenic maturation drugs play a role in the later stages to promote the stabilization and maturation of new blood vessels. Therefore, how to precisely control the temporal release of multiple drugs to ensure that new blood vessels can not only form quickly but also maintain their functions continuously and stably is a key scientific issue in promoting diabetic wound healing.

[0004] Prior to the present invention, Chinese invention patent CN 113750079A disclosed a double-layer microneedle array, which can realize the layered differential release of vaccine / drug, which is conducive to the sequential delivery to meet the medication needs. However, this preparation method mixes the drug and the needle material together, and scrapes off the drug material solution many times in the middle. The drug loading is not accurate and causes drug waste. In addition, its outer layer is a sustained-release structure that reaches the release platform on the 7th day, and the sustained-release maintenance time is too short. Due to the presence of in vivo, the release platform period will be reached faster under the action of various enzymes and immune cells when used in vivo. It is not suitable for diseases with trace medication, expensive drugs, and long-term sustained release. Chinese invention patent CN 108392728A discloses a method for preparing a multilayer composite microneedle of silk fibroin, which changes the crystal structure of each layer of silk fibroin by a water treatment method to achieve different release rates of loaded drugs, but the silk fibroin structure adjustment process is not only complicated and cumbersome, but also not conducive to industrialization, and the method of crystal structure regulation is limited to the material of silk fibroin, and has no economic promotion value. Summary of the invention

[0005] Based on the above scientific understanding and clinical needs, the purpose of the present invention is to provide a multi-drug truncated microneedle patch. The multi-drug truncated microneedle provided by the present invention realizes the spatiotemporal delivery of angiogenesis-promoting drugs and vascular maturation-promoting drugs, which is conducive to the precise regulation of angiogenesis and vascular maturation processes in chronic diabetic wounds. The present invention provides the following technical solutions:

[0006] A multi-drug truncated microneedle patch, comprising a backing (1) and an array of a plurality of multi-drug truncated needles (2) on the backing, each multi-drug truncated needle being a microneedle structure, comprising a gel sustained-release needle tip (21) and a water-soluble fast-dissolving needle body (22), the gel sustained-release needle tip (21) and the water-soluble fast-dissolving needle body (22) forming a complete microneedle, and the water-soluble fast-dissolving needle body (22) being fixedly connected to the backing (1) as a whole;

[0007] The multi-drug truncated microneedle patch has an area of ​​1 cm 2 -4cm 2 , an array of 100-400 microneedles (e.g., a 10*10-20*20 array), each microneedle has a height of 600-1000 μm, a needle tip distance of 600-800 μm, and a height ratio of a gel sustained-release needle tip (21) to a water-soluble fast-dissolving needle body (22) of 1:1-1:4; the fast-dissolving needle body (22) is connected to the backing with a square base, and the side length of the square base is 300-500 μm.

[0008] The gel sustained-release needle tip (21) is loaded with a first drug, namely, a drug that promotes vascular maturation, and the water-soluble fast-dissolving needle body (22) is loaded with a second drug, namely, a drug that promotes angiogenesis. In other clinical applications, the first drug and the second drug may be the same or different.

[0009] The material of the gel sustained-release needle tip (21) is a sustained-release gel material; the material of the water-soluble quick-dissolving needle body (22) is a water-soluble polymer material.

[0010] The material of the backing and the connection between the backing and the quick-dissolving needle body (22) is a high molecular polymer.

[0011] The method for preparing the multi-drug truncated microneedle patch is characterized by comprising the following steps:

[0012] (1) filling the needle tip of the microneedle mold with a first drug solution that promotes angiogenesis by suction filtration;

[0013] (2) preparing a sustained-release gel needle tip polymer solution, mixing natural biomacromolecules, a crosslinking agent and an initiator to obtain a mixed solution, injecting the mixed solution into a microneedle mold so that the mixed solution fills the entire microneedle mold, filtering the polymer solution to the tip and mixing it with the first drug at the same time, irradiating with ultraviolet light, and causing a crosslinking reaction for 30 seconds to 5 minutes;

[0014] (3) filling the remaining part of the microneedle mold in step (2) except the needle tip with a second drug solution for promoting angiogenesis by suction filtration;

[0015] (4) preparing a fast-dissolving needle body polymer solution, and filling the entire microneedle mold except the needle tip with the water-soluble polymer solution by suction filtration, and at the same time, the water-soluble polymer solution is mixed with the second drug by suction filtration, and after drying, the corresponding material solution of the backing is added; after drying, the microneedle is peeled off from the mold to obtain a multi-drug truncated microneedle patch.

[0016] The first drug and the second drug include, but are not limited to, therapeutic structural molecules or drugs such as growth factors, small molecule compounds, monoclonal antibodies, and mRNA.

[0017] In step (2), the mass ratio of the natural biomacromolecule, the crosslinking agent, the initiator and the first drug in the natural biomacromolecule gel sustained-release needle tip is: (500-6000): (5000-40000): (500-8000): (0.1-1); the mass ratio of the fast-soluble high molecular polymer and the second drug is (500-80000): (0.1-1).

[0018] Preferably, the natural biomacromolecules in the natural biomacromolecule gel sustained-release needle tip body are one or more of hyaluronic acid, silk protein, chitosan and gelatin.

[0019] Preferred crosslinking agents include, but are not limited to, divinyl compounds, epoxy compounds, isocyanate compounds, aldehyde compounds, siloxane compounds, and carboxylic acid and acetic acid compounds.

[0020] Preferably, the initiator includes, but is not limited to, one or more of a free radical initiator, a cationic initiator, an anionic initiator, a photoinitiator, a redox initiator, a thermal initiator, and a chemical initiator.

[0021] Preferably, the water-soluble high molecular polymer in step (4) is selected from one or more of hyaluronic acid, silk protein, polyglycolic acid, polyethylene oxide, polyacrylic acid, polyacrylamide, poly(methyl vinyl ether / maleic acid) half ester copolymer, polyvinyl pyrrolidone, polyethylene glycol or polyvinyl alcohol.

[0022] In the step (4), the mass ratio of the water-soluble high molecular polymer to the second drug is (500-80000):(0.1-1).

[0023] The mass percentage concentration of the water-soluble high molecular polymer solution and the corresponding material solution is 2%-40%.

[0024] Preferably, the filtration time in step (1) is 15 min-120 min.

[0025] Preferably, the filtration time in step (2) is 30 min-120 min.

[0026] Preferably, the light initiation time in step (2) is 30s-5min.

[0027] Preferably, the filtration time in step (3) is 15 min-120 min.

[0028] Preferably, the filtration time in step (4) is 30 min-120 min.

[0029] The preparation environment condition of the multi-drug truncated microneedle patch of the present invention is 2-8° C. or room temperature, and the humidity is maintained between 0% and 30%.

[0030] The multi-drug truncated microneedle patch prepared by the method also belongs to the protection scope of the present invention.

[0031] In general, the above technical solution conceived by the present invention has the following advantages compared with the prior art:

[0032] (1) The multi-drug truncated microneedle patch provided by the present invention has a gel sustained-release needle tip and a fast-dissolving needle body material, both of which are pharmaceutical excipients approved for use in the pharmacopoeia, are highly safe, and have application prospects for achieving clinical transformation.

[0033] (2) The multi-drug truncated microneedle patch provided in the present invention is prepared by a filtration method, which is simple and convenient. In addition, the drug is filtered into the microneedle body before the material solution, and the drug loading process greatly avoids drug waste.

[0034] (3) When the multi-drug truncated microneedle patch provided by the present invention is used, the quick-dissolving needle body dissolves quickly and leaves the gel needle tip body in the skin. The in vitro test did not reach the release plateau phase for 16 days ( Figure 7 is the corresponding in vitro release experiment), achieving long-term sustained delivery.

[0035] (4) The multi-drug truncated microneedle patch provided in the present invention realizes the layered differential release of multiple drugs, which is conducive to the sequential delivery that meets the medication needs. In addition, the multi-drug truncated microneedle patch increases the types of contents that can be carried in a single needle body, which is conducive to the co-delivery of two or more drugs.

[0036] (5) The multi-drug truncated microneedle patch provided by the present invention has good mechanical properties and can easily pierce pig skin. It also has a simple preparation process, a wide range of applications, does not require large-scale mechanical equipment, and has a low production cost, which is conducive to industrialization and clinical application.

[0037] The purpose of the multi-drug truncated microneedle patch provided by the present invention is to achieve different rates of release of drugs or contents loaded in the needle body from top to bottom. The tip has good mechanical properties; it is particularly suitable for multi-drug transdermal delivery in the treatment of chronic wound healing, psoriasis and epidermal tumors. The water-soluble polymer fast-dissolving needle body is loaded with angiogenic drugs, and the natural biogel sustained-release needle tip is loaded with angiogenic drugs, providing a minimally invasive and minimally painful double-layer microneedle patch with simple preparation, controllable delivery rate and good mechanical properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 It is a schematic diagram of the preparation process of the multi-drug truncated microneedle patch of the present invention.

[0039] Figure 2 This is a fluorescence microscope image of the multi-drug truncated microneedle patch of the present invention.

[0040] Figure 3 This is an electron scanning microscope image of the multi-drug truncated microneedle patch of the present invention

[0041] Figure 4 This is a confocal fluorescence microscope image of the multi-drug truncated microneedle patch of the present invention.

[0042] Figure 5 This is a methylene blue staining image of the multi-drug truncated microneedle patch of the present invention after being inserted into pig skin

[0043] Figure 6 This is a dissolution picture of the multi-drug truncated microneedle patch of the present invention after being dissolved in physiological saline

[0044] Figure 7 The in vitro release curve of the multi-drug truncated microneedle patch of the present invention is

[0045] Figure 8 This is a semi-quantitative graph of the maturation rate of new blood vessels in the diabetic chronic wound tissue of mice in Example 1 when the multi-drug truncated microneedle patch of the present invention is used.

[0046] Fig. 9 A schematic structural diagram of the multi-drug truncated microneedle patch of the present invention. DETAILED DESCRIPTION

[0047] The following is further described in conjunction with specific implementation cases and drawings of the specification, but the present invention is not limited to the following embodiments.

[0048] Example 1

[0049] The size of the multi-drug truncated microneedle patch used is 2.25 cm 2 It is a 15*15 array containing 225 microneedles. The connection between a single needle and the backing is a square with a side length of 320μm. The entire needle height is 800μm, of which the gel sustained-release needle tip is about 160μm high and the distance between two adjacent needle tips is 680μm.

[0050] This example provides a method for preparing a multi-drug truncated microneedle patch and investigates the therapeutic effect of the multi-drug truncated microneedle patch on promoting chronic wound healing in diabetic mice, including:

[0051] 1. Prepare the first drug solution: VEGF solution, the concentration of which is 0.1 mg / mL, and the solution is A;

[0052] 2. Prepare the gel sustained-release needle tip polymer solution: mix sodium hyaluronate (HA) modified with methacrylic anhydride, cross-linking agent ethylene glycol dimethacrylate (GDMA), and photoinitiator 2-hydroxy-4'-(2-hydroxyethoxy)-benzophenone (I2959) in a mass ratio of 1:2:3 to obtain a mixed solution B;

[0053] 3. Prepare a fast-dissolving water-soluble polymer solution: the mass concentration of polyvinyl alcohol (PVA) is 40%, and the solution is C;

[0054] 4. Prepare the second drug solution: PDGF solution, the concentration of which is 0.1 mg / mL.

[0055] 5. Preparation of multi-drug truncated microneedle patches Figure 1 As shown: Solution A was first injected into a customized polydimethylsiloxane (PDMS, Sylgard 184) microneedle array mold, and filtered for 30 minutes to fill the needle tip. Then the mixed solution B was added, filtered for 2 hours, the surface solution was scraped off, and UV light was irradiated for 30 seconds. Then solution D was injected into the microneedle array mold, filtered for 30 minutes to fill the needle body, and then solution C was added and filtered for 4 hours, and then solution C was added as a backing, placed in a silica gel dryer, and dried at 4°C for 24 hours to obtain a multi-drug truncated microneedle patch, and the single needle structure in the multi-drug truncated microneedle patch was: HA gel sustained-release needle tip loaded with VEGF, PVA fast-dissolving needle loaded with PDGF---PVA (V) + HA (P) and the connection between the PVA needle body backing.

[0056] Effect of promoting chronic wound healing in diabetic mice: Several 6-week-old male Balb / c male mice were selected, and the occurrence of diabetes was induced by streptozotocin (STZ). STZ was dissolved in citric acid buffer (pH 4.5) at a dose of 100-150 mg / kg per kilogram of body weight and administered by intraperitoneal injection for 5 consecutive days. After 7-10 days, the diabetic state was determined by measuring fasting blood glucose levels. Mice with fasting blood glucose values ​​exceeding 16.7 mmol / L can be considered to have successfully induced diabetes. The hair on the back of diabetic mice was removed by a shaver and depilatory cream. After 24 hours of observation, mice with no redness, swelling or damage on the back were selected for the experiment. Mice were anesthetized with isoflurane or sodium pentobarbital to ensure that the mice did not feel pain during surgery. The depth of anesthesia was detected by toe pinch pain reflex. The fur on the back (or flank) of the mouse was shaved to expose smooth skin. The surgical area was disinfected with iodine tincture and 70% alcohol. A 6 mm skin puncher was used to punch holes on the back (or flank) of mice to form full-thickness skin defects, and the mice were randomly divided into the following groups: PBS, PVA (P+V) - representing the whole needle is a PVA fast-dissolving needle body loaded with VEGF and PDGF; HA (P+V) - representing the whole needle is a HA gel sustained-release needle body loaded with VEGF and PDGF; PVA (P) + HA (V) - representing a gel sustained-release needle tip loaded with PDGF and a water-soluble polymer fast-dissolving needle body loaded with VEGF; PVA (V) + HA (P) - representing a gel sustained-release needle tip loaded with VEGF and a PVA fast-dissolving needle body loaded with PDGF. These five groups received corresponding microneedle patch treatments, and the mice were anesthetized and killed on the 7th and 14th days after treatment. The skin tissue at the wound modeling site of the mice was removed, and the neovascularization marker CD31 and smooth muscle cell marker a-SMA in the wound tissue were stained using immunofluorescence staining technology. After staining, the tissue sections were stained and the results were semi-quantitatively used to determine the proportion of mature blood vessels in different treatment groups.

[0057] The method for semi-quantification of the proportion of mature blood vessels is as follows:

[0058] (1) After immunofluorescence staining, confocal fluorescence microscopy can be used to observe that endothelial cells associated with blood vessel formation in the tissue are stained red, and smooth muscle cells associated with vascular maturation are stained green.

[0059] (2) Next, randomly search for 5 areas in the wound tissue slices, count the number of red fluorescent cells (new blood vessels) in the area, and then count the number of red fluorescent cells (mature blood vessels) surrounded by green fluorescent cells in the area.

[0060] (3) The number of mature blood vessels in the same area / the number of new blood vessels = the proportion of mature blood vessels in the area.

[0061] The results can be found in Figure 8 , PVA(V)+HA(P) corresponding to the embodiment of the present invention has the best effect.

[0062] In this embodiment, the double-bond grafted sodium hyaluronate may replace or further include one or more of silk protein, gelatin, carboxymethyl chitosan or quaternized chitosan.

[0063] In this embodiment, GDMA can be replaced by or further include one or more of bisphenol A epoxy resin, toluene diisocyanate (TDI), glutaraldehyde, methyltrimethoxysilane or maleic anhydride.

[0064] In this embodiment, I2959 can replace or further include one or more of benzoyl peroxide, ammonium persulfate, aluminum chloride, potassium (K) sodium (Na), 1-hydroxycyclohexyl phenyl ketone, hydrogen peroxide-sodium thiosulfate system, hydrogen peroxide (H2O2) or benzoyl peroxide.

[0065] In this embodiment, VEGF and PDGF can be replaced or further include bone morphogenetic protein-2 (BMP-2), anti-vascular endothelial growth factor receptor 2 antibody (anti-VEGFR-2), anti-programmed death receptor 1 antibody (anti-PD-1), oxaliplatin (OXA), interleukin 10 (IL10) or one or more thereof.

[0066] like Figure 2 , Figure 3 and Figure 4As shown, the present embodiment successfully prepared multi-drug truncated microneedles, and in a single needle, the height of the gel sustained-release needle tip and the height of the fast-dissolving needle body were about 1:4. Figure 5 As shown in the figure, the multi-drug truncated microneedle patch easily pierces the pig skin and has good mechanical properties. Figure 6 It can be seen that when the green fluorescent drug is loaded in the gel needle tip body, after the entire truncated microneedle patch is dissolved in water, the green fluorescence in the bottom gel needle tip is strong, indicating that the drug is not quickly released into the aqueous solution; and when the green fluorescent drug is loaded in the fast-dissolving needle body, after the entire truncated microneedle patch is dissolved in water, the fluorescence in the entire aqueous solution is strong and uniform, indicating that the drug is quickly released into the entire solution. Figure 7 The in vitro release experiments further confirmed Figure 6 The result, from Figure 7 It can be seen that the release rate of the drug loaded in the fast-dissolving needle body exceeds 75% after 24 hours, while the drug release rate in the gel sustained-release layer is less than 10% in the first 24 hours, and the drug release in the fast-dissolving needle body is basically completely released on the 6th day, reaching the release plateau, while the drug release in the gel sustained-release layer is still in a state of continuous slow release on the 16th day. Finally, after a single treatment of the chronic wounds of diabetic mice, the multi-drug truncated microneedle PVA (V) + HA (P) group used the water-soluble polymer fast-dissolving needle body to quickly deliver the angiogenic drug VEGF, and used the natural biogel sustained-release needle tip body to slowly deliver the angiogenic drug PDGF, so that the wounds of this group of mice had the highest proportion of vascular maturity on the 7th and 14th days after treatment, which means a good healing trend of the wound.

[0067] Example 2

[0068] This embodiment provides a method for preparing a multi-drug truncated microneedle, comprising:

[0069] 1. Prepare the first drug solution: VEGF solution, the concentration of which is 0.1 mg / mL.

[0070] 2. Prepare the gel sustained-release needle tip polymer solution: Mix sodium hyaluronate (HA) modified with methacrylic anhydride, crosslinker ethylene glycol dimethacrylate (GDMA), and photoinitiator 2-hydroxy-4'-(2-hydroxyethoxy)-benzophenone (I2959) in a mass ratio of 1:1:4 to obtain a mixed solution B

[0071] 3. Prepare a quick-dissolving water-soluble polymer solution: polyvinyl alcohol (PVA) with a mass concentration of 30%.

[0072] 4. Prepare the first drug solution: PDGF solution, the concentration of which is 0.1 mg / mL.

[0073] 5. Preparation of truncated microneedle patch: First, inject solution A into the customized polydimethylsiloxane (PDMS, Sylgard 184) microneedle array mold, and filter for 30 minutes to fill the needle tip. Then add mixed solution B, filter for 2 hours, scrape the surface solution, and irradiate with ultraviolet light for 30 seconds. Then inject solution A into the microneedle array mold, filter for 30 minutes to fill the needle body, then add solution D and filter for 4 hours, place in a silica gel dryer, and dry at 4 degrees for 24 hours to obtain a truncated microneedle patch containing VEGF and PDGF called PVA (V) + HA (P).

[0074] In this embodiment, the double-bond grafted sodium hyaluronate may replace or further include one or more of silk protein, gelatin, carboxymethyl chitosan or quaternized chitosan.

[0075] In this embodiment, the cross-linking agent GDMA can be replaced by or further include one or more of bisphenol A epoxy resin, toluene diisocyanate (TDI), glutaraldehyde, methyltrimethoxysilane or maleic anhydride.

[0076] In this embodiment, initiator I2959 can replace or further include one or more of benzoyl peroxide, ammonium persulfate, aluminum chloride, potassium (K) sodium (Na), 1-hydroxycyclohexyl phenyl ketone, hydrogen peroxide-sodium thiosulfate system, hydrogen peroxide (H2O2) or benzoyl peroxide.

[0077] In this embodiment, the drugs VEGF and PDGF can be replaced or further include bone morphogenetic protein-2 (BMP-2), anti-vascular endothelial growth factor receptor 2 antibody (anti-VEGFR-2), anti-programmed death receptor 1 antibody (anti-PD-1), oxaliplatin (OXA), interleukin 10 (IL10) or one or more thereof.

Claims

1. A multi-drug truncated microneedle patch, characterized in that: The invention comprises a backing (1) and an array of a plurality of multi-drug truncated needles (2) on the backing, each of the multi-drug truncated needles is a microneedle structure, comprising a gel sustained-release needle tip (21) and a water-soluble fast-dissolving needle body (22), the gel sustained-release needle tip (21) and the water-soluble fast-dissolving needle body (22) form a complete microneedle, and the water-soluble fast-dissolving needle body (22) is fixedly connected to the backing (1) as a whole.

2. A multi-drug truncated microneedle patch according to claim 1, characterized in that: The multi-drug truncated microneedle patch has an area of ​​1 cm 2 -4cm 2 , an array of 100-400 microneedles (e.g., a 10*10-20*20 array), each microneedle has a height of 600-1000 μm, a needle tip distance of 600-800 μm, and a height ratio of a gel sustained-release needle tip (21) to a water-soluble fast-dissolving needle body (22) of 1:1-1:4; the fast-dissolving needle body (22) is connected to the backing with a square base, and the side length of the square base is 300-500 μm.

3. A multi-drug truncated microneedle patch according to claim 1, characterized in that: The gel sustained-release needle tip (21) is loaded with a first drug, namely, a drug that promotes blood vessel maturation, and the water-soluble fast-dissolving needle body (22) is loaded with a second drug, namely, a drug that promotes angiogenesis.

4. A multi-drug truncated microneedle patch according to claim 1, characterized in that: The material of the gel sustained-release needle tip (21) is a sustained-release gel material; the material of the water-soluble quick-dissolving needle body (22) is a water-soluble polymer material; The backing and the connection between the backing and the quick-dissolving needle body (22) are made of high molecular polymer.

5. A method for preparing a multi-drug truncated microneedle patch according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) filling the needle tip of the microneedle mold with a first drug solution that promotes angiogenesis by suction filtration; (2) preparing a sustained-release gel needle tip polymer solution, mixing natural biomacromolecules, a crosslinking agent and an initiator to obtain a mixed solution, injecting the mixed solution into a microneedle mold so that the mixed solution fills the entire microneedle mold, filtering the polymer solution to the tip and mixing it with the first drug at the same time, irradiating with ultraviolet light, and causing a crosslinking reaction for 30 seconds to 5 minutes; (3) filling the remaining part of the microneedle mold in step (2) except the needle tip with a second drug solution for promoting angiogenesis by suction filtration; (4) preparing a fast-dissolving needle body polymer solution, and filling the entire microneedle mold except the needle tip with the water-soluble polymer solution by suction filtration, and at the same time, the water-soluble polymer solution is mixed with the second drug by suction filtration, and after drying, the corresponding material solution of the backing is added; after drying, the microneedle is peeled off from the mold to obtain a multi-drug truncated microneedle patch.

6. The method according to claim 5, characterized in that The first drug and the second drug include, but are not limited to, therapeutic structural molecules or drugs such as growth factors, small molecule compounds, monoclonal antibodies, and mRNA.

7. The method according to claim 5, characterized in that In step (2), the mass ratio of the natural biomacromolecule, the crosslinking agent, the initiator and the first drug in the natural biomacromolecule gel sustained-release needle tip is: (500-6000): (5000-40000): (500-8000): (0.1-1); the mass ratio of the fast-soluble high molecular polymer and the second drug is (500-80000): (0.1-1); Preferably, the natural biomacromolecules in the natural biomacromolecule gel sustained-release needle tip body are one or more of hyaluronic acid, silk protein, chitosan and gelatin; Preferred crosslinking agents include but are not limited to divinyl compounds, epoxy compounds, isocyanate compounds, aldehyde compounds, siloxane compounds and carboxylic acid acetic acid compounds; Preferably, the initiator includes, but is not limited to, one or more of a free radical initiator, a cationic initiator, an anionic initiator, a photoinitiator, a redox initiator, a thermal initiator, and a chemical initiator.

8. The method according to claim 5, characterized in that The water-soluble high molecular polymer in step (4) is selected from one or more of hyaluronic acid, silk protein, polyglycolic acid, polyethylene oxide, polyacrylic acid, polyacrylamide, poly(methyl vinyl ether / maleic acid) half ester copolymer, polyvinyl pyrrolidone, polyethylene glycol or polyvinyl alcohol; In the step (4), the mass ratio of the water-soluble high molecular polymer to the second drug is (500-80000):(0.1-1); The mass percentage concentration of the water-soluble high molecular polymer solution and the corresponding material solution is 2%-40%.

9. The method according to claim 5, characterized in that Preferably, the filtration time in step (1) is 15 min-120 min; the filtration time in step (2) is 30 min-120 min; the photoinitiation time in step (2) is 30 s-5 min; the filtration time in step (3) is 15 min-120 min; the filtration time in step (4) is 30 min-120 min; The preparation environment condition is 2-8°C and the humidity is maintained between 0% and 30%.

10. Use of the multi-drug truncated microneedle patch according to any one of claims 1 to 4 for preparing a microneedle patch for delivering angiogenesis-promoting drugs and vascular maturation-promoting drugs, and for preparing a drug for promoting diabetic wound healing.

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