A microneedle patch loaded with multimodal driving complexes and preparation method and application thereof

Abstract

A microneedle patch loaded with a multimode driving complex, comprising a backing layer and a needle body arranged on the surface of the backing layer; the needle tip of the needle body is loaded with a multimode driving complex, the multimode driving complex comprises a magnetic nano core, a mesoporous shell layer modified on the surface of the magnetic nano core, a hydrophobic anti-inflammatory drug loaded in the channel of the mesoporous shell layer, a photothermal responsive polymer compound modified on the surface of the mesoporous shell layer, an inflammation targeting drug modified on the surface of the photothermal responsive polymer compound, and an inflammation responsive gas generating drug modified on the surface of the inflammation targeting drug; the photothermal responsive polymer compound comprises polydopamine; the inflammation responsive gas generating drug comprises L-arginine; the microneedle patch of the application can realize precise delivery of the multimode driving complex to the inflammatory tissue through the combined action of the magnetic nano core, the inflammation responsive gas generating drug and the inflammation targeting drug, and has good transdermal drug delivery effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of microneedle drug loading and release, in particular to a microneedle patch loaded with a multimodal driving compound and a preparation method and application thereof. BACKGROUND

[0002] Inflammatory diseases are a major disease that seriously threatens human life and health. The main treatment methods for inflammatory diseases in clinical practice include surgical treatment and drug treatment, but the commonly used drugs in clinical practice have problems such as low bioavailability and large toxic side effects.

[0003] In view of the problem of drug utilization, transdermal drug delivery has attracted widespread attention of researchers because it can avoid the liver first-pass effect and the degradation of drugs in the gastrointestinal tract. Microneedles, as a new method of site-specific transdermal drug delivery, have broad application prospects in local or systemic drug delivery. However, how the drugs that have entered the epidermis can continuously break through the layers of subcutaneous barriers to enter the target tissue is the main problem that limits the clinical application of transdermal drug delivery.

[0004] In view of the problem of treatment safety, studies have shown that local hyperthermia of the inflamed joint has the effects of improving local blood circulation, reducing joint inflammation and pain, regulating immunity, and promoting bone repair, and is a safe and effective adjuvant therapy. In addition, compared with non-steroidal anti-inflammatory drugs, slow-acting anti-rheumatic drugs, glucocorticoids, and biological agents commonly used in clinical practice, traditional Chinese medicine components with mild properties and good safety may play a more important role. SUMMARY

[0005] One object of the present application is to provide a microneedle patch loaded with a multimodal driving compound. The multimodal driving compound containing a magnetic nanometer core, a hydrophobic anti-inflammatory drug, an inflammation-targeting drug, and an inflammation-responsive gas-producing drug is loaded on the tip of the needle body of the microneedle patch. The good transdermal puncture ability of the needle tip, the magnetic targeting property of the magnetic nanometer core, the inflammation-responsive gas-producing property of the inflammation-responsive gas-producing drug, and the inflammation-targeting property of the inflammation-targeting drug form an ordered combination of transdermal drug delivery of the microneedle patch, i.e., "piercing, pulling, pushing, and targeting".

[0006] Another object of the present application is to provide a microneedle patch loaded with a multimodal driving compound. The multimodal driving compound is loaded with Chinese and Western medicine components and a light-heat-responsive polymer compound. The synergistic effect of the Chinese and Western medicine components improves the therapeutic effect and reduces the toxic side effects. The light-heat therapy property of the light-heat-responsive polymer compound down-regulates the expression of inflammatory factors and improves the therapeutic effect.

[0007] Another object of the present application is to provide a preparation method of the microneedle patch loaded with the multimodal driving compound.

[0008] Another object of the present application is to provide the use of the microneedle patch loaded with the multi-mode driven complex.

[0009] To achieve any of the above objects, the technical solution adopted by the present application is:

[0010] A microneedle patch loaded with a multi-mode driven complex, comprising a backing layer and a needle body arranged on the surface of the backing layer; the tip of the needle body is loaded with a multi-mode driven complex, the multi-mode driven complex comprising a magnetic nanometer core, a mesoporous shell layer modified on the surface of the magnetic nanometer core, a hydrophobic anti-inflammatory drug loaded in the channel of the mesoporous shell layer, a photothermal responsive polymer compound modified on the surface of the mesoporous shell layer, an inflammation targeting drug modified on the surface of the photothermal responsive polymer compound, and an inflammation responsive gas generating drug modified on the surface of the inflammation targeting drug.

[0011] Preferably, the magnetic nanometer core is a magnetic nanoparticle, and the magnetic nanoparticle comprises Fe3O4 or γ-Fe2O3.

[0012] Preferably, the magnetic nanoparticle further comprises a manganese iron nanocrystal or a manganese zinc iron nanocrystal.

[0013] Preferably, the mesoporous shell layer comprises mesoporous MnO2, mesoporous polydopamine, or mesoporous SiO2; when the material of the mesoporous shell layer is mesoporous SiO2, the mesoporous shell layer is etched after loading the hydrophobic anti-inflammatory drug.

[0014] Preferably, the hydrophobic anti-inflammatory drug comprises curcumin, paeoniflorin, methotrexate, tripterygium, or rapamycin.

[0015] Preferably, the inflammation targeting drug comprises hyaluronic acid, chondroitin sulfate, a neutrophil membrane, a neutrophil membrane protein, a macrophage membrane, or a macrophage membrane protein.

[0016] Preferably, the photothermal responsive polymer compound comprises polydopamine; and the inflammation responsive gas generating drug comprises L-arginine.

[0017] Preferably, the diameter of the magnetic nanometer core is 4-60 nm, the thickness of the mesoporous shell layer is 20-50 nm, the thickness of the photothermal responsive polymer compound is 2-5 nm, the thickness of the inflammation targeting drug is 1-3 nm, and the thickness of the inflammation responsive gas generating drug is 0.3-2 nm.

[0018] Further, the multi-mode driven complex can perform photothermal conversion on near-infrared light with a wavelength of 808 nm.

[0019] A preparation method of the microneedle patch loaded with the multi-mode driven complex, comprising the following steps:

[0020] (1) preparing magnetic nanoparticles, the magnetic nanoparticles comprising Fe3O4, γ-Fe2O3;

[0021] (2) coating mesoporous materials on the surface of the magnetic nanoparticles to obtain magnetic nanocomposites; the mesoporous materials comprising mesoporous SiO2, mesoporous MnO2, mesoporous polydopamine;

[0022] (3) dispersing the magnetic nanocomposites obtained in step (2) in deionized water at a concentration of 0.4-2 mg / mL, adding a hydrophobic anti-inflammatory drug to the deionized water at a concentration of 0.1-1 mg / mL, the hydrophobic anti-inflammatory drug comprising curcumin, paeoniflorin, methotrexate, tripterygium, rapamycin; physically stirring for 12-24 h to load the hydrophobic anti-inflammatory drug into the pores of the mesoporous shell layer, collecting the precipitate after centrifugal washing, and freeze-drying to obtain drug-loaded magnetic nanocomposites;

[0023] (4) dissolving dopamine hydrochloride in a deionized water / ethanol solution at a volume ratio of 1:0.5 to obtain a dopamine hydrochloride / water / ethanol solution at a concentration of 1.25-10 mg / mL; adding the drug-loaded magnetic nanocomposites obtained in step (3) to the dopamine hydrochloride / water / ethanol solution at a concentration of 2-10 mg / mL, and ultrasonically dispersing; then adding ammonia water to adjust the pH value of the solution to 8-10, and continuing to stir for 10-18 h; collecting the precipitate after centrifugal washing, and freeze-drying to obtain drug-loaded magnetic nanocomposites coated with a photothermal-responsive polymer compound; when the mesoporous material is mesoporous SiO2, the drug-loaded magnetic nanocomposites coated with the photothermal-responsive polymer compound obtained after the precipitate is collected are placed in an etching solution to etch the SiO2, and then centrifugally washed to collect the precipitate;

[0024] (5) adding the drug-loaded magnetic nanocomposites coated with the photothermal-responsive polymer compound obtained in step (4) to a mixed solution of EDC and NHS at a molar ratio of 5-1:1 at a concentration of 1-5 mg / mL to activate the hydroxyl groups; adding an inflammation-targeting drug to the mixed solution at a concentration of 0.5-10 mg / mL, the inflammation-targeting drug comprising hyaluronic acid, chondroitin sulfate, a neutrophil membrane, a neutrophil membrane protein, a macrophage membrane, and a macrophage membrane protein; reacting at room temperature for 24 h, collecting the precipitate after centrifugal washing, and freeze-drying to obtain drug-loaded magnetic nanocomposites coated with the photothermal-responsive polymer compound and the inflammation-targeting drug from the inside to the outside;

[0025] (6) adding the drug-loaded magnetic nano-composite coated with the photothermal responsive polymer compound and the inflammation-targeting drug from inside to outside obtained in step (5) into deionized water at a concentration of 2-10 mg / mL, ultrasonic dispersion, adding an inflammation-responsive gas-producing drug including L-arginine into the deionized water at a concentration of 0.5-5 mg / mL, collecting the precipitate after centrifugal washing, and freeze-drying to obtain a drug-loaded magnetic nano-composite coated with the photothermal responsive polymer compound, the inflammation-targeting drug, and the inflammation-responsive gas-producing drug from inside to outside, referred to as a multi-mode driven composite;

[0026] (7) dispersing the multi-mode driven composite prepared in step (6) into a needle tip material at a concentration of 2-8 mg / mL, preparing a microneedle using the needle tip material in which the multi-mode driven composite is dispersed and a needle body material in a microneedle mold, and making a backing using a backing material at the bottom of the microneedle to obtain a microneedle patch loaded with the multi-mode driven composite.

[0027] Preferably, in the step (1), the preparation method of the magnetic nanoparticles includes co-precipitation, thermal decomposition, hydrothermal method, microemulsion method, and sol-gel method.

[0028] Preferably, in the step (1), the magnetic nanoparticles further include manganese-iron nanocrystals and manganese-zinc-iron nanocrystals.

[0029] Preferably, in the step (2), the method for coating mesoporous SiO2 on the surface of the magnetic nanoparticles includes adding the magnetic nanoparticles prepared in step (1) into deionized water at a concentration of 1.5-2 mg / mL, ultrasonic dispersion for 30-60 min to obtain a dispersion liquid; adding cetyltrimethylammonium bromide (CTAB) into the dispersion liquid at a concentration of 0.01-0.025 mg / mL, and continuing ultrasonic dispersion for 30-60 min until the solution is clear and transparent; after the ultrasonic dispersion, moving the solution into a flask, stirring at 70-80°C for 10-20 min; preparing a mixed solution of ammonia water, ethylene glycol, and deionized water at a volume ratio of 0.7:10:30, and adding the mixed solution into the flask, and continuing stirring for 10-20 min; adding 1,3,5-trimethylbenzene (TMB) into the flask at a concentration of 1.5-3.5 μL / mL, and continuing reaction for 2-4 h; adding tetraethoxysilane (TEOS) into the flask at a concentration of 2.5-10.5 μL / mL, and heating at 70-80°C for 2-4 h; after cooling, centrifugal collection of the product, and vacuum drying to obtain the magnetic nanoparticles coated with mesoporous SiO2.

[0030] In the step (2), the method for coating mesoporous MnO2 on the surface of the magnetic nanoparticles is as follows: the magnetic nanoparticles prepared in the step (1) are added into deionized water at a concentration of 0.4-1 mg / mL, and then potassium permanganate is added at a concentration of 12-20 mg / mL, and stirred and dissolved, and then transferred into a polytetrafluoroethylene hydrothermal reactor, and reacted at 100-180 ℃ for 4-12 h, and then cooled to room temperature after the reaction is completed; the product is centrifuged at a speed of 3000-6000 rpm for 10-20 min by using a high-speed centrifuge, and washed with deionized water to obtain the magnetic nanoparticles coated with mesoporous MnO2.

[0031] In the step (2), the method for coating mesoporous polydopamine on the surface of the magnetic nanoparticles is as follows: the magnetic nanoparticles prepared in the step (1) are added into a mixed solution of deionized water and ethanol at a volume ratio of 1:1 at a concentration of 0.5-2 mg / mL, and ultrasonically dispersed; 1,3,5-trimethylbenzene (TMB) and dopamine hydrochloride are added into the solution at a concentration of 0.05-0.16 mL / mL and 0.02-0.065 mg / mL respectively, and stirred until the solution is clear and transparent; ammonia is added into the solution at a concentration of 7.5-21.5 μL / mL, and stirred for 2-6 h; the product is collected by alternately washing and centrifuging with water and ethanol, and vacuum dried to obtain the magnetic nanoparticles coated with mesoporous polydopamine.

[0032] Preferably, in the step (4), the etching solution is a NaOH solution, and the concentration of the NaOH solution is 0.03 g / L-0.08 g / L; the etching temperature is 40 ℃-60 ℃, and the etching time is 0.5 h-3 h.

[0033] Further, the step (7) comprises:

[0034] 1) the needle tip material is dissolved in deionized water to obtain a needle tip material aqueous solution; the multi-mode driving complex obtained in the step (6) is added into the needle tip material aqueous solution at a concentration of 2-8 mg / mL, and mixed, and the mixed solution is added into a microneedle mold, and centrifuged at 4 ℃ to fill the mixed solution into the needle tip part of the microneedle mold, and the process is repeated for more than 3 times to make the solution sufficiently compressed and deposited in the needle tip part; and after drying, the microneedle mold is ready for use;

[0035] 2) the needle body material is dissolved in deionized water to obtain a needle body material aqueous solution, and the needle body material aqueous solution is covered on the microneedle mold with needle tips prepared in the step 1) to fill the needle body solution into the needle body part of the microneedle mold; vacuum is applied for 10 minutes to remove micro-bubbles in the solution, and the needle tip is centrifuged at 4 ℃ to be compacted, and the process is repeated for several times to remove the excess solution.

[0036] ​3) Take the backing material, dissolve in deionized water to obtain a backing material aqueous solution, fill the backing material aqueous solution on the microneedle mold obtained in step 2) to fill the backing part of the microneedle mold, centrifuge at 4000 rpm for 5 min, repeat several times to remove excess solution, dry at room temperature for 48 h, demold to obtain a microneedle patch loaded with a multimodal driving composite.

[0037] Further, the needle tip material and the needle body material include hyaluronic acid, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, sucrose, chitosan, gelatin, polylactic acid-glycolic acid copolymer, and bletilla striata polysaccharide.

[0038] Further, the backing material includes HA, polyvinyl alcohol or its derivatives, PVP or its derivatives, sucrose, chitosan, gelatin, and PLGA.

[0039] Further, the drying method of the microneedle includes baking, vacuum drying, normal temperature drying, and freeze drying.

[0040] The application also provides a use of the microneedle patch loaded with the multimodal driving composite, including for magnetic resonance imaging to monitor the distribution of drugs in inflammatory lesions, diagnose and identify the boundary of localized inflammatory lesions, and for photothermal therapy, targeted therapy, and synergistic therapy of inflammatory diseases.

[0041] Preferably, the use of the microneedle patch loaded with the multimodal driving composite also includes photoacoustic imaging and fluorescence imaging.

[0042] Further, the application in magnetic resonance imaging refers to being used as a magnetic resonance T1 and T2 contrast material.

[0043] Further, the inflammatory diseases include rheumatoid arthritis.

[0044] Preferably, the inflammatory diseases also include arteritis, ulcerative colitis, Crohn's disease, gastritis, rhinitis, periodontitis, laryngopharyngitis, prostatitis, vaginitis, cervicitis, periarthritis of shoulder, cervical spondylosis, bursitis, dermatitis, conjunctivitis, and otitis media.

[0045] Compared with the prior art, the application has the following beneficial effects:

[0046] The novel multimodal driven microneedles of this invention can avoid the first-pass effect of drugs in the liver and the degradation of drugs in the gastrointestinal tract, and have good biosafety and stability. The magnetic nanocore, the inflammatory-responsive gas-generating drug, and the inflammatory-targeting drug can work together to achieve precise delivery of the multimodal driven complex to inflamed tissues, with good transdermal drug delivery effect. It is loaded with Chinese and Western medicine components, which can synergistically enhance the effect and have low toxicity and side effects. The loaded polydopamine has good photothermal conversion performance and can be used for local photothermal therapy to downregulate the expression of inflammatory factors and enhance the anti-inflammatory and immunomodulatory effects of Chinese and Western medicine. Attached Figure Description

[0047] Figure 1 This is a schematic diagram of the multimode driving complex structure of a microneedle patch loaded with a multimode driving complex according to the present invention.

[0048] Figure 2 This is a schematic diagram of a microneedle patch loaded with a multimodal driving complex according to the present invention.

[0049] Figure 3 Transmission electron microscopy (TEM) image of magnetic nanoparticles prepared according to Example 1 of the present invention, which is a microneedle patch loaded with a multimodal driving composite.

[0050] Figure 4 The XRD diffraction pattern of magnetic nanoparticles prepared in Example 1 of the present invention, which is a microneedle patch loaded with a multimode driving composite.

[0051] Figure 5 Transmission electron microscopy (TEM) image of a magnetic nanocomposite prepared according to Example 1 of the present invention, which is a microneedle patch loaded with a multimode driving composite.

[0052] Figure 6 Transmission electron microscopy (TEM) image of the multimode driving complex prepared in Example 12 of the present invention, which is a microneedle patch loaded with a multimode driving complex.

[0053] Figure 7 The image shows the hysteresis curve of the multimode driving composite prepared in Example 15 of the present invention, which is a microneedle patch loaded with a multimode driving composite.

[0054] Figure 8 This is a magnetic resonance image of the multimode driving complex obtained in Example 6 of the present invention, which is a microneedle patch loaded with a multimode driving complex.

[0055] Figure 9 Infrared images of ultrapure water and multimode driving complexes of different concentrations after laser irradiation at different times, representing Example 28 of the present invention, which is a microneedle patch loaded with a multimode driving complex.

[0056] Figure 10The fluorescence microscopy image of the microneedle patch loaded with the multi-mode driven complex of Example 29, Step 1 of the present application.

[0057] Figure 11 The optical image of the microneedle patch without the multi-mode driven complex of Example 30 of the present application.

[0058] Figure 12 The transmission electron microscopy photo of the microneedle patch without the multi-mode driven complex of Example 30 of the present application.

[0059] Figure 13 The skin redness condition over time graph of Example 30 of the present application, a microneedle patch loaded with a multi-mode driven complex.

[0060] Figure 14 The right foot mirco-CT image of the CIA model rat after 30 days of Example 31 of the present application, a microneedle patch loaded with a multi-mode driven complex.

[0061] Figure 15 The right foot mirco-CT image of the CIA model rat after treatment of Example 31 of the present application, a microneedle patch loaded with a multi-mode driven complex.

[0062] Figure No. 1, magnetic nanoparticles; 2, mesoporous shell layer; 3, hydrophobic anti-inflammatory drug; 4, photothermal responsive polymer compound; 5, inflammation targeting drug; 6, inflammation responsive gas generating drug; 7, backing; 8, needle body; 9, needle tip; 10, multi-mode driven complex. DETAILED DESCRIPTION

[0063] The present application will be further described in detail below with reference to the accompanying drawings.

[0064] The drugs involved in the examples are abbreviated as follows:

[0065] C: curcumin; P: paeonol; A: methotrexate; B: tripterygium; D: rapamycin; HA: hyaluronic acid; CS: chondroitin sulfate; E: neutrophil membrane; F: neutrophil membrane protein; G: macrophage membrane; H: macrophage membrane protein; I: phospholipid membrane; L: L-arginine.

[0066] Example 1

[0067] A method for preparing a new multi-mode driven microneedle, comprising the following steps:

[0068] (1) Preparation of Fe3O4 magnetic nanoparticles by chemical co-precipitation method: 8.1087 g of FeCl3·6H2O and 5.56 g of FeSO4·7H2O were dispersed in 50 mL of deionized water, respectively, and transferred to a 250 mL round-bottom flask for thorough mixing. Under nitrogen protection, the solution was stirred for 30 min to remove oxygen. 15 mL of ammonia water was quickly injected, and stirring was continued for 30 min. Then 1.92 g of citric acid was added, and stirring was continued for 30 min. The temperature was then raised to 85°C for 2 h of curing. After washing with water and ethanol solution by centrifugation, vacuum drying was performed to obtain Fe3O4 magnetic nanoparticles.

[0069] (2) Coating mesoporous material on the surface of magnetic nanoparticles to obtain magnetic nanocomposites: 10 mg of Fe3O4 prepared in step (1) was dispersed in 5 mL of deionized water, and ultrasonic dispersion was performed for 30 min. 0.1 g of cetyltrimethylammonium bromide (CTAB) was added, and ultrasonic dispersion was continued for 30 min until the solution was clear and transparent. After ultrasonic dispersion, the solution was transferred to a flask and stirred at 70°C for 10 min. A mixed solution of ammonia water, ethylene glycol and deionized water with a volume ratio of 0.7:10:30 was prepared, and was added to the above flask and stirred for 10 min. 150 μL of 1,3,5-trimethylbenzene (TMB) was added to the above flask and the reaction was continued for 2 h. 400 μL of tetraethoxysilane (TEOS) was added to the above flask, and heating was performed at 70°C for 3 h. After cooling, the product was collected by centrifugation, and vacuum drying was performed to obtain Fe3O4@mSiO2.

[0070] (3) Fe3O4@mSiO2 prepared in step (2) was dispersed in 15 mL of deionized water with 3 g of paeoniflorin (P) and 4 g of curcumin (C), and physical stirring was performed at room temperature for 12-24 h to load paeoniflorin and curcumin into the pores of mesoporous silica. The product was collected by centrifugal washing and freeze-drying to obtain Fe3O4@C / P-mSiO2. Paeoniflorin and curcumin can be used for the treatment of rheumatoid arthritis, arteritis, ulcerative colitis, Crohn's disease, gastritis, rhinitis, periodontitis, laryngopharyngitis, prostatitis, vaginitis, cervicitis, periarthritis of shoulder, cervical spondylosis, bursitis, dermatitis, conjunctivitis, and otitis media.

[0071] (4) 65 mg of dopamine hydrochloride was dissolved in 35 mL of deionized water and ethanol solution with a volume ratio of 1:0.5, and Fe3O4@C / P-mSiO2 prepared in step (3) was added thereto. Ultrasonic dispersion was performed for 30 min, and ammonia water was added to adjust the pH value of the solution to 8-10. Stirring was continued for 15 h, and the precipitate was collected by centrifugation and freeze-drying to obtain Fe3O4@C / P-mSiO2@PDA.

[0072] (5) The Fe3O4@C / P-mSiO2@PDA prepared in step (4) was dispersed in 50 mL of 0.055 g / L NaOH solution, and heated at 45°C for 1.5 h. After centrifugal washing, the precipitate was collected and freeze-dried to obtain Fe3O4@C / P@PDA.

[0073] (6) The Fe3O4@C / P@PDA prepared in step (5) was added to a mixed solution of EDC and NHS with a molar ratio of 2.5:1, to activate the hydroxyl group. Then 75 mg of hyaluronic acid was added, and the reaction was carried out at room temperature for 24 h. After centrifugal washing, the precipitate was collected and freeze-dried to obtain Fe3O4@C / P@PDA-HA.

[0074] (7) The Fe3O4@C / P@PDA-HA prepared in step (6) was ultrasonically dispersed in 15 mL of deionized water, and 25 mg of L-arginine was added. After centrifugal washing, the precipitate was collected and freeze-dried to obtain a multi-mode driven composite Fe3O4@C / P@PDA-HA / L.

[0075] (8) A needle tip solution containing polyvinyl alcohol and polyvinyl pyrrolidone K30 was prepared with deionized water, with the concentration of polyvinyl alcohol being 30 mg / mL and the concentration of polyvinyl pyrrolidone K30 being 45 mg / mL. The multi-mode driven composite Fe3O4@C / P@PDA-HA / L obtained in step (7) was mixed in the above needle tip solution at a concentration of 4 mg / ml, and the mixed solution was added to a microneedle mold. Centrifugation was carried out at 4°C to fill the mixed solution into the needle tip part of the microneedle mold. The process was repeated more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part. The microneedle mold was placed in an oven and dried at 37°C for 5 min to evaporate the water in the needle tip part.

[0076] (9) A needle body solution containing polyvinyl alcohol and polyvinyl pyrrolidone K30 was prepared with deionized water, with the concentration of polyvinyl alcohol being 150 mg / mL and the concentration of polyvinyl pyrrolidone K30 being 250 mg / mL. The above needle body solution was taken and covered on the microneedle mold with needle tips prepared in step (8) to fill the needle body solution into the needle body part of the microneedle mold. Vacuum was applied for 10 min to remove microbubbles in the solution, and the needle tip was compacted by centrifugation at 4°C for 5 min. The process was repeated several times to remove the excess solution.

[0077] (10) A PVA solution with a concentration of 100 mg / mL was prepared with deionized water, and the solution was filled into the microneedle mold obtained in step (9) to fill the backer part of the microneedle mold. Centrifugation was carried out at 4000 rpm for 5 min, and the process was repeated several times to remove the excess solution. The microneedle patch loaded with the multi-mode driven composite was obtained after drying at room temperature for 48 h and demolding.

[0078] As Figure 1As shown, the obtained multi-mode driven complex 10 includes a magnetic nano core 1, a mesoporous shell layer 2 modified on the surface of the magnetic nano core 1, a hydrophobic anti-inflammatory drug 3 loaded in the channel of the mesoporous shell layer 2, a photothermal responsive polymer compound 4 modified on the surface of the mesoporous shell layer 3, an inflammation targeting drug 5 modified on the surface of the photothermal responsive polymer compound 4, and an inflammation responsive gas generating drug 6 modified on the surface of the inflammation targeting drug 5.

[0079] As shown in the figure, the obtained multi-mode driven complex 10 includes a magnetic nano core 1, a mesoporous shell layer 2 modified on the surface of the magnetic nano core 1, a hydrophobic anti-inflammatory drug 3 loaded in the channel of the mesoporous shell layer 2, a photothermal responsive polymer compound 4 modified on the surface of the mesoporous shell layer 3, an inflammation targeting drug 5 modified on the surface of the photothermal responsive polymer compound 4, and an inflammation responsive gas generating drug 6 modified on the surface of the inflammation targeting drug 5. Figure 2 As shown, the obtained multi-mode driven complex 10 includes a magnetic nano core 1, a mesoporous shell layer 2 modified on the surface of the magnetic nano core 1, a hydrophobic anti-inflammatory drug 3 loaded in the channel of the mesoporous shell layer 2, a photothermal responsive polymer compound 4 modified on the surface of the mesoporous shell layer 3, an inflammation targeting drug 5 modified on the surface of the photothermal responsive polymer compound 4, and an inflammation responsive gas generating drug 6 modified on the surface of the inflammation targeting drug 5.

[0080] Embodiment 2

[0081] A preparation method of a new multi-mode driven microneedle, comprising the following steps:

[0082] (1) Fe3O4 magnetic nanoparticles were prepared by sol-gel method: 1 mM PAA was dissolved in 50 mL deionized water, and nitrogen was bubbled for 30 min to remove oxygen; the solution was heated to 100°C; 0.5 mmol FeCl3 and 0.28 mmol FeCl2 were dissolved in 2 mL 1M concentrated hydrochloric acid solution; the above solution was quickly added to the heated PAA solution and stirred vigorously; 15 mL of ammonia was added to adjust the solution pH to 9-10; after refluxing for 6 h, the precipitate was collected to obtain Fe3O4 nanoparticles.

[0083] (2) The surface of the magnetic nanoparticles was coated with mesoporous material to obtain a magnetic nano composite: 9 mg of Fe3O4 prepared in step (1) was dispersed in 20 mL deionized water, then 250 mg of potassium permanganate was added and stirred to dissolve, and then transferred to a 50 mL polytetrafluoroethylene hydrothermal reactor, and reacted at 120°C for 2 h. After the reaction was completed, it was cooled to room temperature; the product was centrifuged at 3000 rpm for 5 min using a high-speed centrifuge, washed with deionized water, and dried at 60°C for 48 h to obtain Fe3O4@MnO2.

[0084] (3) Fe3O4@MnO2 prepared in step (2) and 3 mg of methotrexate (A) and 3 mg of tripterygium (B) were dispersed in 14 mL deionized water, and physically stirred at room temperature for 12-24 h to load methotrexate and tripterygium into the channels of the mesoporous MnO2; the product was collected by centrifugation and washing, and freeze-dried to obtain Fe3O4@A / B-MnO2; wherein, methotrexate and tripterygium can be used for the treatment of rheumatoid arthritis, arteritis, ulcerative colitis, Crohn's disease, gastritis, rhinitis, periodontitis, laryngopharyngitis, prostatitis, vaginitis, cervicitis, periarthritis of shoulder, cervical spondylosis, bursitis, dermatitis, conjunctivitis, and otitis media.

[0085] (4) Dissolve 62 mg of dopamine hydrochloride in 30 ml of a deionized water / ethanol solution with a volume ratio of 1:1, add the Fe3O4@A / B-MnO2 prepared in step (3) to it, ultrasonically disperse for 30 min, add 50-80 μL of ammonia water, adjust the pH of the solution to 8-10, continue to stir for 10-18 h, collect the precipitate by centrifugation, and obtain Fe3O4@A / B-MnO2@PDA after freeze-drying.

[0086] (5) Take the Fe3O4@A / B-MnO2@PDA prepared in step (4), add it to 18 ml of a mixed solution of EDC and NHS with a molar ratio of 3:1 to activate the hydroxyl group, then add 80 mg of neutrophil membranes (E), repeatedly extrude through a 200 nm-400 nm polycarbonate membrane for 20-30 times, collect the precipitate after centrifugal washing, and obtain Fe3O4@A / B-MnO2@PDA-E after freeze-drying.

[0087] (6) Ultrasonically disperse the Fe3O4@A / B-MnO2@PDA-E prepared in step (5) in 14 ml of deionized water, add 30 mg of L-arginine (L) to it, collect the precipitate after centrifugal washing, and obtain the multi-mode driven composite Fe3O4@A / B-MnO2@PDA-E / L after freeze-drying.

[0088] (7) Prepare a needle tip solution containing chitosan and gelatin by using deionized water, so that the concentration of chitosan is 60 mg / mL and the concentration of gelatin is 60 mg / mL; mix the multi-mode driven composite Fe3O4@A / B-MnO2@PDA-E / L obtained in step (5) in the needle tip solution at a concentration of 2 mg / ml, add the mixed solution to a microneedle mold, centrifuge at 4°C to fill the mixed solution into the needle tip part of the microneedle mold, repeat the process for more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part; place it in an oven and dry at 37°C for 5 min to evaporate the water contained in the needle tip part;

[0089] (8) Prepare a needle body solution containing chitosan and gelatin by using deionized water, so that the concentration of chitosan is 80 mg / mL and the concentration of gelatin is 80 mg / mL; take the needle body solution, cover it on the microneedle mold with needle tips prepared in step (6), so that the needle body solution fills the needle body part of the microneedle mold; vacuum for 10 minutes to remove microbubbles in the solution, centrifuge the needle tip at 4°C, and remove the excess solution after repeating several times.

[0090] (9) PVP K90 solution with a concentration of 300 mg / mL was prepared with deionized water, and the solution was filled into the microneedle mold obtained in step (8) to fill the backing portion of the microneedle mold; centrifugation was repeated several times at 4000 rpm for 5 min to remove the excess solution, and the solution was dried at room temperature for 48 h to obtain a microneedle patch loaded with a multimode driving composite.

[0091] Example 3

[0092] A preparation method of a novel multimode driving microneedle, comprising the following steps:

[0093] (1) Fe3O4 magnetic nanoparticles were prepared by a chemical microemulsion method: 1.625 g of FeCl3·6H2O, 2.85 g of sodium citrate, and 2.5 g of sodium acetate were dispersed in 50 mL of ethylene glycol under magnetic stirring, and after being fully dissolved into a yellow transparent solution, the solution was transferred into a 100 mL polytetrafluoroethylene hydrothermal reactor, and reacted at 180-200°C overnight for 10-15 h; after being washed with water and ethanol solution alternately, vacuum drying was performed to obtain Fe3O4 magnetic nanoparticles.

[0094] (2) A magnetic nanoparticle composite was obtained by coating mesoporous material on the surface of the magnetic nanoparticles: 8 mg of Fe3O4 prepared in step (1) was ultrasonically dispersed in 5 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:1; 0.4 g of magnetic stirring was performed until the solution was clear and transparent; 0.7 mL of 1,3,5-trimethylbenzene (TMB) and 0.25 g of dopamine hydrochloride were added to the beaker, and stirring was continued for 30 min; 80 μL of ammonia water was added, and stirring was continued for 3 h; the product was collected by centrifugation after being washed with water and ethanol alternately, and vacuum drying was performed to obtain Fe3O4@mPDA.

[0095] (3) Fe3O4@mPDA prepared in step (2) and 2 mg of rapamycin (D) and 3 mg of paeonol (P) were dispersed in 13 mL of deionized water, and physical stirring was performed at room temperature for 12-24 h to load the rapamycin and paeonol into the pores of the mesoporous polydopamine; the product was collected by centrifugation and freeze-drying to obtain Fe3O4@D / P-mPDA.

[0096] (4) 59 mg of dopamine hydrochloride was dissolved in 25 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:0.5, and Fe3O4@D / P-mPDA prepared in step (3) was added thereto, ultrasonic dispersion was performed for 30 min, 50-80 μL of ammonia water was added to adjust the pH value of the solution to 8-10, and stirring was continued for 10-18 h; the precipitate was collected by centrifugation and freeze-drying to obtain Fe3O4@D / P-mPDA@PDA.

[0097] (5) Take Fe3O4@D / P-mPDA@PDA prepared in step (4) and add it to a mixed solution of 16 mL of EDC and NHS with a molar ratio of 3.5:1 to activate the hydroxyl group, then add 85 mg of macrophage membrane (G), and repeatedly extrude through a 200 nm polycarbonate membrane for 20 times. After centrifugal washing, the precipitate is collected, freeze-dried, and Fe3O4@D / P-mPDA@PDA-G is obtained.

[0098] (6) Ultrasonically disperse Fe3O4@D / P / HA-mPDA@PDA-G prepared in step (5) in 13 mL of deionized water, add 35 mg of L-arginine to it, centrifugal wash, collect the precipitate, and freeze-dry to obtain the multimodally driven composite Fe3O4@D / P-mPDA@PDA-G / L.

[0099] (7) Configure a needle tip solution, mix the multimodally driven composite Fe3O4@D / P-mPDA@PDA-G / L obtained in step (6) in the needle tip solution at a concentration of 2.2 mg / ml, and add the mixed solution to a microneedle mold. Centrifuge at 4°C to fill the mixed solution into the needle tip part of the microneedle mold. Repeat the process for more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part. Place it in an oven and dry it at room temperature for 5 min to evaporate the water in the needle tip part.

[0100] (8) Configure a needle body solution, take the needle body solution, and cover it on the microneedle mold with needle tips prepared in step (7) to fill the needle body solution into the needle body part of the microneedle mold. Vacuum for 10 minutes to remove microbubbles in the solution, centrifuge the needle tip at 4°C, and repeat several times to remove the excess solution.

[0101] (9) Configure a backing solution, take the solution and fill it into the microneedle mold obtained in step (8) to fill the backing part of the microneedle mold. Centrifuge at 4000 rpm for 5 min, repeat several times to remove the excess solution, dry at room temperature for 48 h, demold, and obtain a microneedle patch loaded with a multimodally driven composite.

[0102] Example 4

[0103] (1) Prepare Fe3O4 magnetic nanoparticles by solvothermal method: Take 0.23 g of FeCl2, 0.56 g of TEA·HCl, and 0.9 g of NaOH and disperse them in 12 mL of a mixed solution of diethylene glycol and water, and ultrasonically until the solution is transparent. Take another 0.5 g of FeCl3, 0.56 g of TEA·HCl, and 0.9 g of NaOH and disperse them in 12 mL of a mixed solution of diethylene glycol and water, and ultrasonically until transparent. Transfer the above two to a high-temperature reaction kettle, react at 110°C for 1 h, and after the reaction is completed, centrifugal wash with water and ethanol solution alternately, and vacuum dry to obtain Fe3O4 magnetic nanoparticles.

[0104] (2) Coating mesoporous material on the surface of magnetic nanoparticles to obtain magnetic nanocomposites: 15 mg of Fe3O4 prepared in step (1) was taken in 8 mL of deionized water and ultrasonically dispersed for 30 min, 0.175 g of cetyltrimethylammonium bromide (CTAB) was added, and ultrasonic dispersion was continued for 30 min until the solution was clear and transparent; after ultrasonic dispersion, the solution was transferred into a flask, and stirring was carried out at 70°C for 15 min; a mixed solution of 40 mL of ammonia water, ethylene glycol and deionized water in a volume ratio of 0.7:10:30 was prepared and added to the above flask, and stirring was continued for 10 min; 150 μL of 1,3,5-trimethylbenzene (TMB) was added to the above flask, and reaction was continued for 2 h; 500 μL of tetraethoxysilane (TEOS) was added to the above flask, and heating reaction was carried out at 70°C for 3 h; after cooling, the product was collected by centrifugation, and vacuum drying was carried out to obtain Fe3O4@mSiO2.

[0105] (3) Fe3O4@mSiO2 prepared in step (2), 3 g of paeoniflorin (P), 3 g of curcumin (C) and 3 g of methotrexate (A) were dispersed in 20 mL of deionized water, and physical stirring was carried out at room temperature for 12-24 h to load paeoniflorin, curcumin and methotrexate into the pores of mesoporous silica; the product was collected by centrifugal washing, and freeze-drying was carried out to obtain Fe3O4@C / P-mSiO2.

[0106] (4) 80 mg of dopamine hydrochloride was dissolved in 20 mL of a deionized water-ethanol solution in a volume ratio of 1:0.5, Fe3O4@C / P-mSiO2 prepared in step (3) was added thereto, ultrasonic dispersion was carried out for 30 min, 50-80 μL of ammonia water was added to adjust the pH value of the solution to 8-10, stirring was continued for 10-18 h, the precipitate was collected by centrifugation, and freeze-drying was carried out to obtain Fe3O4@C / P-mSiO2@PDA.

[0107] (5) Fe3O4@C / P-mSiO2@PDA prepared in step (4) was taken and dispersed in 40 mL of a 0.08 g / L NaOH solution, heating reaction was carried out at 50°C for 2.5 h, the precipitate was collected by centrifugal washing after washing, and freeze-drying was carried out to obtain Fe3O4@C / P@PDA.

[0108] (6) Fe3O4@C / P@PDA prepared in step (5) was added to a mixed solution of EDC and NHS in a molar ratio of 4.5:1 to activate the hydroxyl group, and then 25 mg of neutrophil membrane protein (F) and 25 mg of macrophage membrane (G) were added, and repeated extrusion through a 200 nm polycarbonate membrane for 20 times, the precipitate was collected by centrifugal washing after washing, and freeze-drying was carried out to obtain Fe3O4@C / P@PDA-F / G.

[0109] (7) The Fe3O4@C / P@PDA-HA prepared in step (6) is ultrasonically dispersed in 20 mL of deionized water, 20 mg of L-arginine is added, and the precipitate is collected after centrifugal washing and freeze-dried to obtain the multi-mode driven composite Fe3O4@C / P@PDA-F / G / L.

[0110] (8) The needle tip solution is configured, the multi-mode driven composite obtained in step (7) is mixed in the needle tip solution at a concentration of 2.2 mg / ml, and the mixed solution is added to the microneedle mold. Centrifugation is performed at 4°C to fill the mixed solution into the needle tip part of the microneedle mold, and the process is repeated more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part. It is placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip part;

[0111] (9) The needle body solution is configured, the needle body solution is taken and covered on the microneedle mold with needle tips prepared in step (8) to fill the needle body solution into the needle body part of the microneedle mold. Vacuum is applied for 10 minutes to remove microbubbles in the solution, the needle tip is compacted by centrifugation at 4°C, and the excess solution is removed after repeating several times.

[0112] (10) The backing solution is configured, and the solution is filled into the microneedle mold obtained in step (9) to fill the backing part of the microneedle mold. Centrifugation is performed at 4000 rpm for 5 min, and the excess solution is removed after repeating several times. It is dried at room temperature for 48 h, demolded, and a microneedle patch loaded with a multi-mode driven composite is obtained.

[0113] Example 5

[0114] (1) Fe3O4 magnetic nanoparticles are prepared by sol-gel method: 1.625 g of FeCl3·6H2O, 2.85 g of sodium citrate, and 2.5 g of sodium acetate are dispersed in 50 mL of ethylene glycol under magnetic stirring, and a yellow transparent solution is obtained. The solution is transferred to a 100 mL polytetrafluoroethylene hydrothermal reactor, and reacted at 180-200°C overnight for 10-15 h. After washing with water and ethanol solution by centrifugation, vacuum drying is performed to obtain Fe3O4 magnetic nanoparticles.

[0115] (2) The surface of the magnetic nanoparticles is coated with mesoporous material to obtain a magnetic nanoparticle composite: 10 mg of Fe3O4 prepared in step (1) is ultrasonically dispersed in 6 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:1; 0.45 g of magnetic stirring until the solution is clear and transparent; 0.8 mL of 1,3,5-trimethylbenzene (TMB) and 0.3 g of dopamine hydrochloride are added to the beaker and continue to stir for 30 min; 80 μL of ammonia is added and continue to stir for 3 h; the product is collected by centrifugation after washing with water and ethanol alternately, and vacuum dried to obtain Fe3O4@mPDA.

[0116] (3) The Fe3O4@mPDA prepared in step (2) is dispersed in 17 mL of deionized water with 3 mg of curcumin (C), 3 mg of rapamycin (D), and 2 mg of paeonol (P), and physical stirring is performed at room temperature for 12-24 hours to load the curcumin, rapamycin, and paeonol into the pores of the mesoporous polydopamine, and the product is collected by centrifugation and freeze-dried to obtain Fe3O4@C / D / P-mPDA.

[0117] (4) 86 mg of dopamine hydrochloride is dissolved in 10 mL of a deionized water / ethanol solution with a volume ratio of 1:0.5, and Fe3O4@C / D / P-mPDA prepared in step (3) is added thereto, ultrasonic dispersion is performed for 30 min, 50-80 μL of ammonia water is added to adjust the pH of the solution to 8-10, and stirring is continued for 10-18 h, and the precipitate is collected by centrifugation and freeze-dried to obtain Fe3O4@C / D / P-mPDA@PDA.

[0118] (5) Fe3O4@C / D / P-mPDA@PDA prepared in step (4) is added to a mixed solution of EDC and NHS with a molar ratio of 3.5:1 to activate the hydroxyl group, and then 15 mg of neutrophil membrane (E), 15 mg of neutrophil membrane protein (F), and 10 mg of macrophage membrane (G) are added, and repeated extrusion through a 200 nm polycarbonate membrane is performed 20 times, and the precipitate is collected by centrifugation and freeze-dried to obtain Fe3O4@C / D / P-mPDA@PDA-E / F / G.

[0119] (6) Fe3O4@C / D / P-mPDA@PDA-E / F / G prepared in step (5) is ultrasonic dispersed in 11 mL of deionized water, and 30 mg of L-arginine is added thereto, and the precipitate is collected by centrifugation and freeze-dried to obtain a multi-mode driven complex Fe3O4@C / D / P-mPDA@PDA-E / F / G / L.

[0120] (7) A needle tip solution is prepared, and the multi-mode driven complex obtained in step (6) is mixed in the needle tip solution at a concentration of 3 mg / mL, and the mixed solution is added to a microneedle mold, and centrifugation is performed at 4°C to fill the mixed solution into the needle tip portion of the microneedle mold, and the process is repeated 3 times or more to allow the solution to be sufficiently compressed and deposited in the needle tip portion, and the microneedle mold is placed in an oven and dried at room temperature for 5 min to evaporate the water content in the needle tip portion.

[0121] (8) A needle body solution is prepared, and the needle body solution is applied to the microneedle mold with the needle tip prepared in step (7) to fill the needle body portion of the microneedle mold with the needle body solution, and vacuum is applied for 10 min to remove microbubbles in the solution, and the needle tip is compacted by centrifugation at 4°C, and the process is repeated several times to remove the excess solution.

[0122] (9) A backing solution was prepared and filled into the microneedle mold obtained in step (8) to fill the backing portion of the microneedle mold; centrifugation at 4000 rpm for 5 min was repeated several times to remove the excess solution, and the solution was dried at room temperature for 48 h to obtain a microneedle patch loaded with the multi-mode driven composite.

[0123] Example 6

[0124] A method for preparing a novel multi-mode driven microneedle includes the following steps:

[0125] (1) Fe3O4 magnetic nanoparticles were prepared by a chemical microemulsion method: 1.625 g of FeCl3·6H2O, 2.85 g of sodium citrate, and 2.5 g of sodium acetate were dispersed in 50 mL of ethylene glycol under magnetic stirring, and a yellow transparent solution was obtained and then transferred into a 100 mL polytetrafluoroethylene hydrothermal reactor, which was reacted at 180-200 °C overnight (10-15 h); the solution was washed with water and ethanol solution alternately and then vacuum dried to obtain Fe3O4 magnetic nanoparticles.

[0126] (2) The surface of the magnetic nanoparticles was coated with mesoporous material to obtain a magnetic nanoparticle composite: 4 mg of Fe3O4 prepared in step (1) was ultrasonically dispersed in 10 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:1; 0.35 g of magnetic stirring until the solution was clear and transparent; 0.6 mL of 1,3,5-trimethylbenzene (TMB) and 0.25 g of dopamine hydrochloride were added to the beaker and stirred for 30 min; 80 μL of ammonia was added and stirred for 3 h; the product was collected by centrifugation with water and ethanol alternately, and vacuum dried to obtain Fe3O4@mPDA.

[0127] (3) Fe3O4@mPDA prepared in step (2) and 1 mg of curcumin (C) were dispersed in 10 mL of deionized water, and physical stirring was performed at room temperature for 12-24 h to load curcumin into the pores of the mesoporous polydopamine; the product was collected by centrifugation and freeze-dried to obtain Fe3O4@C-mPDA.

[0128] (4) 50 mg of dopamine hydrochloride was dissolved in 40 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:0.5, and Fe3O4@C-mPDA prepared in step (3) was added thereto and ultrasonically dispersed for 30 min; 50-80 μL of ammonia was added to adjust the pH value of the solution to 8-10, and stirring was continued for 10-18 h; the precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@C-mPDA@PDA.

[0129] (5) Take Fe3O4@C-mPDA@PDA prepared in step (4), add it to a mixed solution of 10 mL of EDC and NHS with a molar ratio of 5:1 to activate the hydroxyl group, then add 100 mg of macrophage membrane protein (H), and repeatedly extrude it through a 200 nm polycarbonate membrane for 20 times. After centrifugal washing, the precipitate is collected, freeze-dried, and Fe3O4@C-mPDA@PDA-H is obtained.

[0130] (6) Ultrasonically disperse Fe3O4@C-mPDA@PDA-H prepared in step (5) in 10 mL of deionized water, add 50 mg of L-arginine to it, centrifugally wash it, collect the precipitate, freeze-dry it, and obtain the multimodal driving composite Fe3O4@C-mPDA@PDA-H / L.

[0131] (7) Configure a needle tip solution, mix the multimodal driving composite obtained in step (6) in the needle tip solution at a concentration of 3.5 mg / ml, add the mixed solution to a microneedle mold, centrifuge it at 4°C to fill the mixed solution into the needle tip part of the microneedle mold, repeat the process for more than 3 times to make the solution fully compressed and deposited in the needle tip part, and place it in an oven for drying at room temperature for 5 min to evaporate the water in the needle tip part.

[0132] (8) Configure a needle body solution, take the needle body solution, and cover it on the microneedle mold with needle tips prepared in step (7) to fill the needle body solution into the needle body part of the microneedle mold, vacuumize it for 10 min to remove microbubbles in the solution, centrifuge the needle tip at 4°C, and repeat the process for several times to remove the excess solution.

[0133] (9) Configure a backing solution, take the solution to fill it in the microneedle mold obtained in step (8) to fill the backing solution into the backing part of the microneedle mold, centrifuge it at 4000 rpm for 5 min, repeat the process for several times to remove the excess solution, dry it at room temperature for 48 h, demold it, and obtain the microneedle patch loaded with the multimodal driving composite.

[0134] Example 7

[0135] A preparation method of a novel multimodal driving microneedle, comprising the following steps:

[0136] (1) Prepare Fe3O4 magnetic nanoparticles by a chemical microemulsion method: take 1.625 g of FeCl3·6H2O, 2.85 g of sodium citrate, and 2.5 g of sodium acetate, disperse them in 50 mL of ethylene glycol under magnetic stirring, transfer the yellow transparent solution obtained by fully dissolving them into a 100 mL polytetrafluoroethylene hydrothermal reactor, and react it at 180°C-200°C overnight (10-15 h); centrifugally wash it with water and ethanol solution alternately, vacuumize and dry it, and obtain Fe3O4 magnetic nanoparticles.

[0137] (2) Coating mesoporous material on the surface of magnetic nanoparticles to obtain magnetic nanocomposites: 6 mg of Fe3O4 prepared in step (1) was ultrasonically dispersed in 9 mL of a mixed solution of deionized water and ethanol in a volume ratio of 1:1; 0.42 g of dopamine hydrochloride was added to the solution, and the mixture was stirred until the solution was clear and transparent; 0.75 mL of 1,3,5-trimethylbenzene (TMB) and 0.28 g of dopamine hydrochloride were added to the beaker, and the mixture was continuously stirred for 30 min; 100 μL of ammonia water was added, and the mixture was continuously stirred for 3 h; the product was collected by centrifugation and washed with water and ethanol alternately, and vacuum dried to obtain Fe3O4@mPDA. The solution was stirred by magnetic force until the solution was clear and transparent; 0.75 mL of 1,3,5-trimethylbenzene (TMB) and 0.28 g of dopamine hydrochloride were added to the beaker, and the mixture was continuously stirred for 30 min; 100 μL of ammonia water was added, and the mixture was continuously stirred for 3 h; the product was collected by centrifugation and washed with water and ethanol alternately, and vacuum dried to obtain Fe3O4@mPDA.

[0138] (3) Fe3O4@mPDA prepared in step (2) was dispersed in 11 mL of deionized water with 3 mg of paeoniflorin (P), and the mixture was physically stirred at room temperature for 12-24 h to load paeoniflorin into the pores of the mesoporous polydopamine; the product was collected by centrifugation and freeze-dried to obtain Fe3O4@P-mPDA.

[0139] (4) 53 mg of dopamine hydrochloride was dissolved in 15 mL of a mixed solution of deionized water and ethanol in a volume ratio of 1:0.5, and Fe3O4@D / P-mPDA prepared in step (3) was added to the solution, which was ultrasonically dispersed for 30 min; 50-80 μL of ammonia water was added to adjust the pH of the solution to 8-10, and the mixture was continuously stirred for 10-18 h; the precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@P-mPDA@PDA.

[0140] (5) Fe3O4@P-mPDA@PDA prepared in step (4) was added to 12 mL of a mixed solution of EDC and NHS in a molar ratio of 4.5:1 to activate the hydroxyl group; 95 mg of chondroitin sulfate (CS) was then added, and the mixture was reacted at room temperature for 24 h; the precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@P-mPDA@PDA-CS.

[0141] (6) Fe3O4@P-mPDA@PDA-CS prepared in step (5) was ultrasonically dispersed in 11 mL of deionized water, and 45 mg of L-arginine was added to the solution; the precipitate was collected by centrifugation and freeze-dried to obtain the multi-mode driven composite Fe3O4@P-mPDA@PDA-CS / L.

[0142] (7) A needle tip solution was prepared, and the multi-mode driven composite obtained in step (6) was mixed in the needle tip solution at a concentration of 4 mg / ml; the mixed solution was added to a microneedle mold, and the mixed solution was filled into the needle tip part of the microneedle mold by centrifugation at 4°C; the process was repeated for more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part; the mixture was placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip part;

[0143] (8) Prepare a needle body solution, take the needle body solution, and cover the micro-needle mold with the needle tip prepared in step (7) to fill the needle body part of the micro-needle mold with the needle body solution; vacuum for 10 minutes to remove micro-bubbles in the solution, and centrifuge the needle tip at 4°C to compact the needle tip; repeat several times to remove the excess solution.

[0144] (9) Prepare a backing solution, take the solution to fill the micro-needle mold obtained in step (8) to fill the backing part of the micro-needle mold; centrifuge at 4000 rpm for 5 min, repeat several times to remove the excess solution, dry at room temperature for 48 h, demold, and obtain a micro-needle patch loaded with a multi-mode driving composite.

[0145] Example 8

[0146] A preparation method of a novel multi-mode driving micro-needle, comprising the following steps:

[0147] (1) Prepare Fe3O4 magnetic nanoparticles by a chemical microemulsion method: take 1.625 g of FeCl3·6H2O, 2.85 g of sodium citrate, and 2.5 g of sodium acetate, disperse them in 50 mL of ethylene glycol under magnetic stirring, transfer the yellow transparent solution to a 100 mL polytetrafluoroethylene hydrothermal reactor, and react at 180°C to 200°C overnight (10 to 15 h); wash with water and ethanol solution alternately, and vacuum dry to obtain Fe3O4 magnetic nanoparticles.

[0148] (2) Coat mesoporous material on the surface of the magnetic nanoparticles to obtain a magnetic nanoparticle composite: take 7 mg of Fe3O4 prepared in step (1) and ultrasonically disperse it in 4 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:1; add 0.4 g of magnetic stirring until the solution is clear and transparent; take 0.7 mL of 1,3,5-trimethylbenzene (TMB) and 0.3 g of dopamine hydrochloride, add them to the beaker, and continue stirring for 30 min; add 100 μL of ammonia water and continue stirring for 3 h; wash with water and ethanol alternately, centrifuge, collect the product, and vacuum dry to obtain Fe3O4@mPDA.

[0149] (3) Disperse Fe3O4@mPDA prepared in step (2) and 4 mg of methotrexate (A) in 12 mL of deionized water, physically stir at room temperature for 12 to 24 h, load methotrexate into the pores of the mesoporous polydopamine, centrifuge and wash to collect the product, and freeze-dry to obtain Fe3O4@A-mPDA.

[0150] (4) Dissolve 56 mg of dopamine hydrochloride in 20 ml of a deionized water / ethanol solution with a volume ratio of 1:0.5, add the Fe3O4@A-mPDA prepared in step (3) to the solution, ultrasonically disperse for 30 min, add 50-80 μL of ammonia water, adjust the pH of the solution to 8-10, continue to stir for 10-18 h, collect the precipitate by centrifugation, and freeze-dry to obtain Fe3O4@A-mPDA@PDA.

[0151] (5) Take the Fe3O4@A-mPDA@PDA prepared in step (4), add to 14 ml of a mixed solution of EDC and NHS with a molar ratio of 4:1 to activate the hydroxyl group, then add 90 mg of neutrophil membrane protein (F), repeatedly extrude through a 200 nm polycarbonate membrane for 20 times, collect the precipitate after centrifugal washing, and freeze-dry to obtain Fe3O4@A-mPDA@PDA-F.

[0152] (6) Ultrasonically disperse the Fe3O4@A-mPDA@PDA-F prepared in step (5) in 12 ml of deionized water, add 40 mg of L-arginine to the solution, collect the precipitate after centrifugal washing, and freeze-dry to obtain the multimode-driven composite Fe3O4@A-mPDA@PDA-F / L.

[0153] (7) Prepare a needle tip solution, mix the multimode-driven composite obtained in step (6) in the needle tip solution at a concentration of 4 mg / ml, add the mixed solution to a microneedle mold, centrifuge at 4°C to fill the mixed solution into the needle tip part of the microneedle mold, repeat the process for more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part, and place it in an oven for drying at room temperature for 5 min to evaporate the water in the needle tip part.

[0154] (8) Prepare a needle body solution, take the needle body solution, and cover the microneedle mold with the needle tip prepared in step (7) to fill the needle body solution into the needle body part of the microneedle mold, vacuumize for 10 min to remove microbubbles in the solution, centrifuge the needle tip at 4°C, and repeat several times to remove the excess solution.

[0155] (9) Prepare a backing solution, take the solution to fill in the microneedle mold obtained in step (8) to fill the backing solution into the backing part of the microneedle mold, centrifuge at 4000 rpm for 5 min, repeat several times to remove the excess solution, dry at room temperature for 48 h, demold, and obtain a microneedle patch loaded with the multimode-driven composite.

[0156] Example 9

[0157] A preparation method of a novel multimode-driven microneedle, comprising the following steps:

[0158] (1) Preparation of Fe3O4 magnetic nanoparticles by chemical microemulsion method: 1.625 g of FeCl3·6H2O, 2.85 g of sodium citrate, and 2.5 g of sodium acetate were dispersed in 50 mL of ethylene glycol under magnetic stirring, and a yellow transparent solution was obtained. The solution was transferred into a 100 mL polytetrafluoroethylene hydrothermal reactor, and reacted at 180-200 °C overnight (10-15 h). After being washed with water and ethanol solution by centrifugation, Fe3O4 magnetic nanoparticles were obtained by vacuum drying.

[0159] (2) Coating of mesoporous material on the surface of magnetic nanoparticles to obtain magnetic nanocomposites: 11 mg of Fe3O4 prepared in step (1) was ultrasonically dispersed in 5 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:1; 0.5 g of magnetic stirring until the solution was clear and transparent; 0.8 mL of 1,3,5-trimethylbenzene (TMB) and 0.3 g of dopamine hydrochloride were added to the beaker, and stirring was continued for 30 min; 120 μL of ammonia water was added, and stirring was continued for 3 h; the product was collected by centrifugation after washing with water and ethanol, and vacuum dried to obtain Fe3O4@mPDA.

[0160] (3) Fe3O4@mPDA prepared in step (2) was dispersed in 16 mL of deionized water with 2 mg of paeoniflorin (P) and 6 mg of methotrexate (A), and physical stirring was carried out at room temperature for 12-24 h to load paeoniflorin and methotrexate into the pores of mesoporous polydopamine. The product was collected by centrifugation and freeze-dried to obtain Fe3O4@A / P-mPDA.

[0161] (4) 68 mg of dopamine hydrochloride was dissolved in 40 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:0.5, and Fe3O4@D / P-mPDA prepared in step (3) was added thereto. Ultrasonic dispersion was carried out for 30 min, 50-80 μL of ammonia water was added to adjust the pH value of the solution to 8-10, and stirring was continued for 10-18 h. The precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@A / P-mPDA@PDA.

[0162] (5) Fe3O4@A / P-mPDA@PDA prepared in step (4) was added to 22 mL of a mixed solution of EDC and NHS with a molar ratio of 2:1 to activate the hydroxyl group. Then, 35 mg of hyaluronic acid (HA) and 35 mg of chondroitin sulfate (CS) were added, and the reaction was carried out at room temperature for 24 h. The precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@A / P-mPDA@PDA-HA / CS.

[0163] (6) The Fe3O4@A / P-mPDA@PDA-HA / CS prepared in step (5) is ultrasonically dispersed in 16 mL of deionized water, 20 mg of L-arginine is added, and the precipitate is collected after centrifugal washing and freeze-drying to obtain the multi-mode driven composite Fe3O4@A / P-mPDA@PDA-HA / CS / L.

[0164] (7) The needle tip solution is prepared, the multi-mode driven composite obtained in step (6) is mixed in the needle tip solution at a concentration of 2.2 mg / ml, the mixed solution is added to the microneedle mold, and the mixed solution is filled into the needle tip part of the microneedle mold under the condition of 4°C centrifugation. The process is repeated more than 3 times to make the solution fully compressed and deposited in the needle tip part; and it is placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip part.

[0165] (8) The needle body solution is prepared, the needle body solution is taken and covered on the microneedle mold with needle tips prepared in step (7), and the needle body solution is filled into the needle body part of the microneedle mold; vacuum is applied for 10 minutes to remove microbubbles in the solution, the needle tip is compacted by centrifugation at 4°C, and the excess solution is removed after repeating several times.

[0166] (9) The backing solution is prepared, the solution is filled into the microneedle mold obtained in step (8), and the backing part of the microneedle mold is filled with the solution; centrifugation is performed at 4000 rpm for 5 min, and the excess solution is removed after repeating several times, and the microneedle patch loaded with the multi-mode driven composite is obtained after drying at room temperature for 48 h and demolding.

[0167] Example 10

[0168] A preparation method of a novel multi-mode driven microneedle, comprising the following steps:

[0169] (1) Fe3O4 magnetic nanoparticles are prepared by a chemical microemulsion method: 1.625 g of FeCl3·6H2O, 2.85 g of sodium citrate, and 2.5 g of sodium acetate are dispersed in 50 mL of ethylene glycol under magnetic stirring, and a yellow transparent solution is obtained. After being transferred to a 100 mL polytetrafluoroethylene hydrothermal reactor, it is reacted at 180°C for 12 h; after being washed with water and ethanol solution by centrifugation, it is vacuum dried to obtain Fe3O4 magnetic nanoparticles.

[0170] (2) The surface of the magnetic nanoparticles is coated with mesoporous material to obtain a magnetic nanoparticle composite: 12 mg of Fe3O4 prepared in step (1) is ultrasonically dispersed in 9 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:1; 0.42 g of The magnetic stirring was continued until the solution was clear and transparent; 0.9 mL of 1,3,5-trimethylbenzene (TMB) and 0.3 g of dopamine hydrochloride were added to the beaker and stirring was continued for 30 min; 120 μL of ammonia water was added and stirring was continued for 3 h; the product was collected by centrifugation with water and ethanol, and vacuum dried to obtain Fe3O4@mPDA.

[0171] (3) Fe3O4@mPDA prepared in step (2) was dispersed in 17 mL of deionized water with 9 mg of rapamycin (D), and physical stirring was carried out at room temperature for 12-24 h to load the rapamycin into the pores of the mesoporous polydopamine; the product was collected by centrifugation and freeze-dried to obtain Fe3O4@D-mPDA.

[0172] (4) 71 mg of dopamine hydrochloride was dissolved in 35 mL of a deionized water / ethanol solution with a volume ratio of 1:0.5, and Fe3O4@D / P-mPDA prepared in step (3) was added thereto and ultrasonically dispersed for 30 min; 50-80 μL of ammonia water was added to adjust the pH of the solution to 8-10, and stirring was continued for 10-18 h; the precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@D-mPDA@PDA.

[0173] (5) Fe3O4@D / P-mPDA@PDA prepared in step (4) was added to 24 mL of a mixed solution of EDC and NHS with a molar ratio of 1.5:1 to activate the hydroxyl group, and then 30 mg of neutrophil membrane (E) and 35 mg of neutrophil membrane protein (F) were added; the mixture was repeatedly extruded through a 200 nm polycarbonate membrane for 20 times, and the precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@D-mPDA@PDA-E / F.

[0174] (6) Fe3O4@D-mPDA@PDA-E / F prepared in step (5) was ultrasonically dispersed in 17 mL of deionized water, and 15 mg of L-arginine was added thereto; the precipitate was collected by centrifugation and freeze-dried to obtain the multi-mode driven composite Fe3O4@D-mPDA@PDA-E / F / L.

[0175] (7) A needle tip solution was prepared, and the multi-mode driven composite obtained in step (6) was mixed in the needle tip solution at a concentration of 2.7 mg / ml; the mixed solution was added to a microneedle mold, and centrifugation was carried out at 4°C to fill the mixed solution into the needle tip part of the microneedle mold; the process was repeated for more than 3 times to allow the solution to be sufficiently compressed and deposited in the needle tip part; and the microneedle mold was placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip part.

[0176] (8) Prepare a needle body solution, take the needle body solution, and cover the micro-needle mold with the needle tip prepared in step (7) to fill the needle body part of the micro-needle mold with the needle body solution; vacuum for 10 minutes to remove micro-bubbles in the solution, and centrifuge the needle tip at 4°C to compact the needle tip; repeat several times to remove the excess solution.

[0177] (9) Prepare a backing solution, take the solution to fill the micro-needle mold obtained in step (8) to fill the backing part of the micro-needle mold; centrifuge at 4000 rpm for 5 min, repeat several times to remove the excess solution, dry at room temperature for 48 h, demold, and obtain a micro-needle patch loaded with a multi-mode driving composite.

[0178] Example 11

[0179] A preparation method of a novel multi-mode driving micro-needle, comprising the following steps:

[0180] (1) Prepare Fe3O4 magnetic nanoparticles by a chemical microemulsion method: take 1.625 g of FeCl3·6H2O, 2.85 g of sodium citrate, and 2.5 g of sodium acetate, disperse them in 50 mL of ethylene glycol under magnetic stirring, transfer the yellow transparent solution to a 100 mL polytetrafluoroethylene hydrothermal reactor, and react at 190°C overnight (10-15 h); centrifuge and wash with water and ethanol solution alternately, and vacuum dry to obtain Fe3O4 magnetic nanoparticles.

[0181] (2) Coat mesoporous material on the surface of the magnetic nanoparticles to obtain a magnetic nanoparticle composite: take 13 mg of Fe3O4 prepared in step (1) and ultrasonically disperse it in 10 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:1; add 0.5 g of magnetic stirring until the solution is clear and transparent; take 0.9 mL of 1,3,5-trimethylbenzene (TMB) and 0.3 g of dopamine hydrochloride, add them to the beaker, and continue stirring for 30 min; add 100 μL of ammonia water and continue stirring for 3 h; centrifuge and wash with water and ethanol alternately, collect the product, and vacuum dry to obtain Fe3O4@mPDA.

[0182] (3) Disperse Fe3O4@mPDA prepared in step (2) and 5 mg of tripterygium (B) and 5 mg of rapamycin (D) in 18 mL of deionized water, and physically stir at room temperature for 12-24 h to load tripterygium and rapamycin into the pores of the mesoporous polydopamine; centrifuge and wash to collect the product, and freeze-dry to obtain Fe3O4@B / D-mPDA.

[0183] (4) 74 mg of dopamine hydrochloride was dissolved in 30 ml of deionized water and ethanol solution with a volume ratio of 1:0.5, and Fe3O4@B / D-mPDA prepared in step (3) was added thereto and ultrasonically dispersed for 30 min, 50-80 μL of ammonia water was added to adjust the pH value of the solution to 8-10, and stirring was continued for 10-18 h. The precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@B / D-mPDA@PDA.

[0184] (5) Fe3O4@B / D-mPDA@PDA prepared in step (4) was added to 26 ml of a mixed solution of EDC and NHS with a molar ratio of 1:1 to activate the hydroxyl group, and then 25 mg of neutrophil membrane (E) and 35 mg of macrophage membrane (G) were added. The mixture was repeatedly extruded through a 200 nm polycarbonate membrane for 40 times, and the precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@B / D-mPDA@PDA-E / G.

[0185] (6) Fe3O4@B / D-mPDA@PDA-E / G prepared in step (5) was ultrasonically dispersed in 18 ml of deionized water, and 9 mg of L-arginine was added thereto. The precipitate was collected by centrifugation and freeze-dried to obtain a multi-mode driven composite Fe3O4@B / D-mPDA@PDA-E / G / L.

[0186] (7) A needle tip solution was prepared, and the multi-mode driven composite obtained in step (6) was mixed in the needle tip solution at a concentration of 2.9 mg / ml. The mixed solution was added to a microneedle mold, and the mixed solution was filled into the needle tip part of the microneedle mold by centrifugation at 4°C. The process was repeated more than 3 times to allow the solution to be sufficiently compressed and deposited in the needle tip part. The microneedle mold was placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip part.

[0187] (8) A needle body solution was prepared, and the needle body solution was applied to the microneedle mold with the needle tip prepared in step (7) to fill the needle body part of the microneedle mold. Vacuum was applied for 10 min to remove microbubbles in the solution, and the needle tip was compacted by centrifugation at 4°C. The process was repeated several times to remove excess solution.

[0188] (9) A backing solution was prepared, and the solution was filled into the microneedle mold obtained in step (8) to fill the backing part of the microneedle mold. Centrifugation was performed at 4000 rpm for 5 min, and the process was repeated several times to remove excess solution. The microneedle mold was dried at room temperature for 48 h, and the microneedle patch loaded with the multi-mode driven composite was gently demolded with tweezers.

[0189] Example 12

[0190] A method for preparing a novel multi-mode driven microneedle, comprising the following steps:

[0191] (1) Preparation of Fe3O4 magnetic nanoparticles by chemical microemulsion method: 1.625 g of FeCl3·6H2O, 2.85 g of sodium citrate, and 2.5 g of sodium acetate were dispersed in 50 mL of ethylene glycol under magnetic stirring, and a yellow transparent solution was obtained. The solution was transferred to a 100 mL polytetrafluoroethylene hydrothermal reactor, and reacted at 200°C overnight (10-15 h). After washing with water and ethanol solution by centrifugation, Fe3O4 magnetic nanoparticles were obtained by vacuum drying.

[0192] (2) Coating of mesoporous material on the surface of magnetic nanoparticles to obtain magnetic nanocomposites: 14 mg of Fe3O4 prepared in step (1) was ultrasonically dispersed in 10 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:1; 0.5 g of magnetic stirring until the solution was clear and transparent; 0.8 mL of 1,3,5-trimethylbenzene (TMB) and 0.4 g of dopamine hydrochloride were added to the beaker and stirring was continued for 30 min; 60 μL of ammonia was added and stirring was continued for 3 h; the product was collected by washing with water and ethanol by centrifugation, and vacuum dried to obtain Fe3O4@mPDA.

[0193] (3) Fe3O4@mPDA prepared in step (2) was dispersed in 19 mL of deionized water with 2 mg of rapamycin (D) and 6 mg of curcumin (C), and physical stirring was carried out at room temperature for 12-24 h to load rapamycin and curcumin into the pores of mesoporous polydopamine. The product was collected by centrifugal washing and freeze-drying to obtain Fe3O4@D / C-mPDA.

[0194] (4) 77 mg of dopamine hydrochloride was dissolved in 25 mL of a mixed solution of deionized water and ethanol with a volume ratio of 1:0.5, and Fe3O4@D / C-mPDA prepared in step (3) was added thereto. Ultrasonic dispersion was carried out for 30 min, 50-80 μL of ammonia was added to adjust the pH value of the solution to 8-10, and stirring was continued for 10-18 h. The precipitate was collected by centrifugal washing and freeze-drying to obtain Fe3O4@D / C-mPDA@PDA.

[0195] (5) Fe3O4@D / C-mPDA@PDA prepared in step (4) was added to 28 mL of a mixed solution of EDC and NHS with a molar ratio of 5:1 to activate the hydroxyl group. Then, 15 mg of neutrophil membrane (E) and 40 mg of macrophage membrane protein (H) were added, and the mixture was repeatedly extruded through a 200 nm polycarbonate membrane for 20 times. The precipitate was collected by centrifugal washing and freeze-drying to obtain Fe3O4@D / C-mPDA@PDA-E / H.

[0196] (6) The Fe3O4@D / C-mPDA@PDA-E / H prepared in step (5) is dispersed in 19 mL of deionized water by ultrasonic dispersion, 15 mg of L-arginine is added, and the precipitate is collected after centrifugal washing and freeze-drying to obtain the multi-mode driven composite Fe3O4@D / C-mPDA@PDA-E / H / L.

[0197] (7) The needle tip solution is prepared, the multi-mode driven composite obtained in step (6) is mixed in the needle tip solution at a concentration of 3.2 mg / ml, the mixed solution is added to the microneedle mold, and the mixed solution is filled into the needle tip part of the microneedle mold by centrifugation at 4°C. The process is repeated more than 3 times to make the solution fully compressed and deposited in the needle tip part; and the microneedle mold is placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip part.

[0198] (8) The needle body solution is prepared, the needle body solution is covered on the microneedle mold with needle tips prepared in step (7) to fill the needle body part of the microneedle mold with the needle body solution; vacuum is applied for 10 min to remove microbubbles in the solution, the needle tip is compacted by centrifugation at 4°C, and the excess solution is removed after repeating several times.

[0199] (9) The backing solution is prepared, the solution is filled in the microneedle mold obtained in step (8) to fill the backing part of the microneedle mold; centrifugation is performed at 4000 rpm for 5 min, and the excess solution is removed after repeating several times, and the microneedle patch loaded with the multi-mode driven composite is obtained by drying at room temperature for 48 h and gently demolding with tweezers.

[0200] Example 13

[0201] (1) Fe3O4 magnetic nanoparticles are prepared by a solvothermal method: 0.23 g of FeCl2, 0.56 g of TEA·HCl, and 0.9 g of NaOH are dispersed in 12 mL of a mixed solution of diethylene glycol and water, and ultrasonic dispersion is performed until the solution is transparent; 0.5 g of FeCl3, 0.56 g of TEA·HCl, and 0.9 g of NaOH are dispersed in 12 mL of a mixed solution of diethylene glycol and water, and ultrasonic dispersion is performed until the solution is transparent; the two solutions are transferred to a high-temperature reaction kettle, and reaction is performed at 110°C for 1 h; after the reaction is completed, the product is washed with water and ethanol solution by centrifugation, and vacuum dried to obtain Fe3O4 magnetic nanoparticles.

[0202] (2) Coating mesoporous material on the surface of magnetic nanoparticles to obtain magnetic nanocomposites: 18 mg of Fe3O4 prepared in step (1) was taken in 11 mL of deionized water and ultrasonically dispersed for 30 min, 0.18 g of cetyltrimethylammonium bromide (CTAB) was added and ultrasonic dispersion was continued for 30 min until the solution was clear and transparent; after ultrasonic dispersion, the solution was transferred into a flask and stirred at 70°C for 15 min; a mixed solution of 60 mL of ammonia water, ethylene glycol and deionized water in a volume ratio of 0.7:10:30 was prepared and added to the above flask and stirring was continued for 10 min; 125 μL of 1,3,5-trimethylbenzene (TMB) was added to the above flask and reaction was continued for 2 h; 500 μL of tetraethoxysilane (TEOS) was added to the above flask and reaction was carried out at 70°C for 3 h; after cooling, the product was collected by centrifugation and dried under vacuum to obtain Fe3O4@mSiO2.

[0203] (3) Fe3O4@mSiO2 prepared in step (2), 3 mg of paeoniflorin (P), 3 mg of methotrexate (A) and 3 mg of tripterygium (B) were dispersed in 16 mL of deionized water, and physical stirring was carried out at room temperature for 12-24 h to load paeoniflorin, methotrexate and tripterygium into the pores of mesoporous silica; the product was collected by centrifugal washing and freeze-dried to obtain Fe3O4@P / A / B-mSiO2; wherein paeoniflorin, methotrexate and tripterygium can be used for the treatment of rheumatoid arthritis, arteritis, ulcerative colitis, Crohn's disease, gastritis, rhinitis, periodontitis, laryngopharyngitis, prostatitis, vaginitis, cervicitis, periarthritis of shoulder, cervical spondylosis, bursitis, dermatitis, conjunctivitis and otitis media.

[0204] (4) 89 mg of dopamine hydrochloride was dissolved in 40 mL of a deionized water / ethanol solution in a volume ratio of 1:0.5, Fe3O4@P / A / B-mSiO2 prepared in step (3) was added thereto, ultrasonic dispersion was carried out for 30 min, 50-80 μL of ammonia water was added to adjust the pH value of the solution to 8-10, stirring was continued for 10-18 h, the precipitate was collected by centrifugation, and Fe3O4@P / A / B-mSiO2@PDA was obtained after freeze-drying.

[0205] (5) Fe3O4@P / A / B-mSiO2@PDA prepared in step (4) was dispersed in 60 mL of a 0.03 g / L NaOH solution, reaction was carried out at 40°C for 0.5 h, the precipitate was collected after centrifugal washing, and Fe3O4@P / A / B@PDA was obtained after freeze-drying.

[0206] (6) Take Fe3O4@P / A / B@PDA prepared in step (5) and add it to a mixed solution of 30 ml of EDC and NHS with a molar ratio of 3:1 to activate the hydroxyl group, then add 15 mg of phospholipid film (I), 10 mg of neutrophil membrane protein (F), and 10 mg of macrophage membrane protein (H), and repeatedly extrude through a 200 nm polycarbonate membrane for 35 times. After centrifugal washing, the precipitate is collected, freeze-dried, and Fe3O4@P / A / B@PDA-I / F / H is obtained.

[0207] (7) Take Fe3O4@P / A / B@PDA-I / F / H prepared in step (6) and ultrasonically disperse it in 12 mL of deionized water. Add 35 mg of L-arginine to the solution, centrifugally wash, collect the precipitate, and freeze-dry to obtain the multi-mode driven composite Fe3O4@P / A / B@PDA-I / F / H / L.

[0208] (8) Prepare a needle tip solution. Mix the multi-mode driven composite obtained in step (7) in the needle tip solution at a concentration of 3.5 mg / ml. Add the mixed solution to a microneedle mold and centrifuge at 4°C to fill the mixed solution into the needle tip part of the microneedle mold. Repeat the process for more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part. Place it in an oven and dry it at room temperature for 5 min to evaporate the water in the needle tip part.

[0209] (9) Prepare a needle body solution. Take the needle body solution and cover it on the microneedle mold with needle tips prepared in step (8) to fill the needle body solution into the needle body part of the microneedle mold. Vacuum for 10 minutes to remove microbubbles in the solution. Centrifuge at 4°C to compact the needle tip. Repeat several times to remove excess solution.

[0210] (10) Prepare a backing solution. Take the solution and fill it into the microneedle mold obtained in step (9) to fill the backing part of the microneedle mold. Centrifuge at 4000 rpm for 5 min. Repeat several times to remove excess solution. Dry at room temperature for 48 h. Gently demold with tweezers to obtain a microneedle patch loaded with a multi-mode driven composite.

[0211] Example 14

[0212] (1) Prepare Fe3O4 magnetic nanoparticles by solvothermal method: Take 0.23 g of FeCl2, 0.56 g of TEA·HCl, and 0.9 g of NaOH and disperse them in 12 mL of a mixed solution of diethylene glycol and water. Ultrasonicate until the solution is transparent. Take another 0.5 g of FeCl3, 0.56 g of TEA·HCl, and 0.9 g of NaOH and disperse them in 12 mL of a mixed solution of diethylene glycol and water. Ultrasonicate until the solution is transparent. Transfer the above two solutions to a high-temperature reaction kettle and react at 110°C for 1 h. After the reaction is completed, centrifugally wash with water and ethanol solutions alternately and vacuum dry to obtain Fe3O4 magnetic nanoparticles.

[0213] (2) Coating mesoporous material on the surface of magnetic nanoparticles to obtain magnetic nanocomposites: 18.2 mg of Fe3O4 prepared in step (1) was dispersed in 12 mL of deionized water by ultrasonic dispersion for 30 min, 0.2 g of cetyltrimethylammonium bromide (CTAB) was added, and ultrasonic dispersion was continued for 30 min until the solution was clear and transparent; after ultrasonic dispersion, the solution was transferred into a flask, and stirring was continued at 70°C for 15 min; a mixed solution of 60 mL of ammonia water, ethylene glycol and deionized water in a volume ratio of 0.7:10:30 was prepared and added to the above flask, and stirring was continued for 10 min; 150 μL of 1,3,5-trimethylbenzene (TMB) was added to the above flask, and reaction was continued for 2 h; 600 μL of tetraethoxysilane (TEOS) was added to the above flask, and reaction was continued at 70°C for 3 h; after cooling, the product was collected by centrifugation, and vacuum drying was performed to obtain Fe3O4@mSiO2.

[0214] (3) Fe3O4@mSiO2 prepared in step (2), 4 mg of paeoniflorin (P), 3 mg of methotrexate (A), and 3 mg of rapamycin (D) were dispersed in 15 mL of deionized water, and physical stirring was performed at room temperature for 12-24 h to load paeoniflorin, methotrexate and rapamycin into the pores of mesoporous silica; the product was collected by centrifugal washing, and freeze-drying was performed to obtain Fe3O4@P / A / D-mSiO2.

[0215] (4) 92 mg of dopamine hydrochloride was dissolved in 20 mL of a deionized water-ethanol solution in a volume ratio of 1:0.5, Fe3O4@P / A / D-mSiO2 prepared in step (3) was added thereto, ultrasonic dispersion was performed for 30 min, 50-80 μL of ammonia water was added to adjust the pH value of the solution to 8-10, stirring was continued for 10-18 h, the precipitate was collected by centrifugation, and freeze-drying was performed to obtain Fe3O4@P / A / D-mSiO2@PDA.

[0216] (5) Fe3O4@P / A / D-mSiO2@PDA prepared in step (4) was dispersed in 55 mL of a 0.04 g / L NaOH solution, and reaction was performed at 55°C for 0.9 h; after centrifugal washing, the precipitate was collected, and freeze-drying was performed to obtain Fe3O4@P / A / D@PDA.

[0217] (6) Take Fe3O4@P / A / D@PDA prepared in step (5), add to 35 ml of a mixed solution of EDC and NHS with a molar ratio of 1.5:1 to activate the hydroxyl group, then add 10 mg of neutrophil membrane (E), 10 mg of neutrophil membrane protein (F), 5 mg of macrophage membrane (G), and 5 mg of macrophage membrane protein (H), and repeatedly extrude through a 200 nm polycarbonate membrane for 20 times. After centrifugal washing, the precipitate is collected, freeze-dried, and Fe3O4@P / A / D@PDA-E / F / G / H is obtained.

[0218] (7) Take Fe3O4@P / A / D@PDA-E / F / G / H prepared in step (6), ultrasonically disperse in 13 mL of deionized water, and add 40 mg of L-arginine to the solution. After centrifugal washing, the precipitate is collected, freeze-dried, and a multimodal driving complex Fe3O4@P / A / D@PDA-E / F / G / H / L is obtained.

[0219] (8) Prepare a needle tip solution, mix the multimodal driving complex obtained in step (7) in the needle tip solution at a concentration of 3.7 mg / ml, and add the mixed solution to a microneedle mold. Centrifuge at 4°C to fill the mixed solution into the needle tip part of the microneedle mold. Repeat the process for more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part. Place it in an oven and dry at room temperature for 5 min to evaporate the water in the needle tip part.

[0220] (9) Prepare a needle body solution, take the needle body solution, and cover the microneedle mold with the needle tip prepared in step (8) to fill the needle body solution into the needle body part of the microneedle mold. Vacuum for 10 minutes to remove microbubbles in the solution, centrifuge the needle tip at 4°C, and repeat several times to remove excess solution.

[0221] (10) Prepare a backing solution, take the solution and fill it into the microneedle mold obtained in step (9) to fill the backing part of the microneedle mold. Centrifuge at 4000 rpm for 5 min, repeat several times to remove excess solution, and dry at room temperature for 48 h. Gently demold with tweezers to obtain a microneedle patch loaded with a multimodal driving complex.

[0222] Example 15

[0223] (1) Preparation of Fe3O4 magnetic nanoparticles by solvothermal method: 0.23 g of FeCl2, 0.56 g of TEA-HCl, and 0.9 g of NaOH were dispersed in 12 mL of a mixed solution of diethylene glycol and water, and ultrasonic treatment was performed until the solution became transparent; 0.5 g of FeCl3, 0.56 g of TEA-HCl, and 0.9 g of NaOH were dispersed in 12 mL of a mixed solution of diethylene glycol and water, and ultrasonic treatment was performed until the solution became transparent; the two solutions were transferred into a high-temperature reaction kettle, and reaction was performed at 110°C for 1 h; after the reaction was completed, the product was washed by centrifugation with water and an ethanol solution, and vacuum drying was performed, thereby obtaining Fe3O4 magnetic nanoparticles.

[0224] (2) Coating of mesoporous material on the surface of the magnetic nanoparticles to obtain a magnetic nanocomposite: 18.4 mg of Fe3O4 prepared in step (1) was dispersed in 12 mL of deionized water, and ultrasonic treatment was performed for 60 min; 0.1625 g of cetyltrimethylammonium bromide (CTAB) was added, and ultrasonic treatment was continued for 30 min until the solution became clear and transparent; after the ultrasonic treatment was completed, the solution was transferred into a flask, and stirring was performed at 70°C for 15 min; a mixed solution of 50 mL of ammonia water, ethylene glycol, and deionized water in a volume ratio of 0.7:10:30 was prepared, and was added to the above flask, and stirring was continued for 10 min; 150 μL of 1,3,5-trimethylbenzene (TMB) was added to the above flask, and reaction was continued for 2 h; 450 μL of tetraethoxysilane (TEOS) was added to the above flask, and reaction was performed at 70°C for 3 h; after cooling, the product was collected by centrifugation, and vacuum drying was performed, thereby obtaining Fe3O4@mSiO2.

[0225] (3) Fe3O4@mSiO2, 2 mg of methotrexate (A), 3 mg of tripterygium (B), and 4 mg of rapamycin (D) prepared in step (2) were dispersed in 14 mL of deionized water, and physical stirring was performed at room temperature for 12-24 h, so that methotrexate, tripterygium, and rapamycin were loaded into the pores of the mesoporous silica; the product was collected by centrifugation, and freeze-drying was performed, thereby obtaining Fe3O4@A / B / D-mSiO2.

[0226] (4) 95 mg of dopamine hydrochloride was dissolved in 18 mL of a deionized water-ethanol solution in a volume ratio of 1:0.5, and Fe3O4@A / B / D-mSiO2 prepared in step (3) was added thereto, and ultrasonic treatment was performed for 30 min; 50-80 μL of ammonia water was added, and the pH value of the solution was adjusted to 8-10; stirring was continued for 10-18 h, and the precipitate was collected by centrifugation, and freeze-drying was performed, thereby obtaining Fe3O4@A / B / D-mSiO2@PDA.

[0227] (5) The Fe3O4@A / B / D-mSiO2@PDA prepared in step (4) was dispersed in 60 mL of 0.05 g / L NaOH solution, and heated at 44°C for 1.3 h. After centrifugal washing, the precipitate was collected, and freeze-dried to obtain Fe3O4@A / B / D@PDA.

[0228] (6) The Fe3O4@A / B / D@PDA prepared in step (5) was added to a mixed solution of 36 ml of EDC and NHS with a molar ratio of 1:1 to activate the hydroxyl group, and then 5 mg of hyaluronic acid (HA), 10 mg of chondroitin sulfate (CS), and 20 mg of macrophage membrane protein (H) were added. The mixture was repeatedly extruded 40 times through a 400 nm polycarbonate membrane, and then centrifugally washed to collect the precipitate. After freeze-drying, Fe3O4@A / B / D@PDA-HA / CS / H was obtained.

[0229] (7) The Fe3O4@A / B / D@PDA-HA / CS / H prepared in step (6) was ultrasonically dispersed in 14 mL of deionized water, and 45 mg of L-arginine was added. After centrifugal washing, the precipitate was collected, and freeze-dried to obtain the multi-mode driven composite Fe3O4@A / B / D@PDA-HA / CS / H / L.

[0230] (8) A needle tip solution was prepared, and the multi-mode driven composite obtained in step (7) was mixed in the needle tip solution at a concentration of 3.9 mg / ml. The mixed solution was added to a microneedle mold, and centrifuged at 4°C to fill the mixed solution into the needle tip part of the microneedle mold. The process was repeated more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part. The microneedle mold was placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip part.

[0231] (9) A needle body solution was prepared, and the needle body solution was covered on the microneedle mold with needle tips prepared in step (8) to fill the needle body solution into the needle body part of the microneedle mold. Vacuum was applied for 10 min to remove microbubbles in the solution, and the needle tip was compacted by centrifugation at 4°C. After repeating several times, the excess solution was removed.

[0232] (10) A backing solution was prepared, and the solution was filled into the microneedle mold obtained in step (9) to fill the backing solution into the backing part of the microneedle mold. Centrifugation was performed at 4000 rpm for 5 min, and the excess solution was removed by repeating several times. The microneedle mold was dried at room temperature for 48 h, and then gently demolded with tweezers to obtain a microneedle patch loaded with the multi-mode driven composite.

[0233] Example 16

[0234] (1) Preparation of Fe3O4 magnetic nanoparticles by solvothermal method: 0.23 g of FeCl2, 0.56 g of TEA-HCl, and 0.9 g of NaOH were dispersed in 12 mL of a mixed solution of diethylene glycol and water, and ultrasonic treatment was performed until the solution became transparent; 0.5 g of FeCl3, 0.56 g of TEA-HCl, and 0.9 g of NaOH were dispersed in 12 mL of a mixed solution of diethylene glycol and water, and ultrasonic treatment was performed until the solution became transparent; the two solutions were transferred into a high-temperature reaction kettle, and reaction was performed at 110°C for 1 h; after the reaction was completed, the product was washed by centrifugation with water and ethanol solutions, and vacuum drying was performed to obtain Fe3O4 magnetic nanoparticles.

[0235] (2) Coating of mesoporous material on the surface of the magnetic nanoparticles to obtain a magnetic nanocomposite: 18.6 mg of Fe3O4 prepared in step (1) was dispersed in 10 mL of deionized water, and ultrasonic treatment was performed for 30 min; 0.2 g of cetyltrimethylammonium bromide (CTAB) was added, and ultrasonic treatment was continued for 30 min until the solution became clear and transparent; after the ultrasonic treatment was completed, the solution was transferred into a flask, and stirring was performed at 70°C for 15 min; a mixed solution of 50 mL of ammonia water, ethylene glycol, and deionized water in a volume ratio of 0.7:10:30 was prepared, and was added into the above flask, and stirring was continued for 10 min; 165 μL of 1,3,5-trimethylbenzene (TMB) was added into the above flask, and reaction was continued for 2 h; 550 μL of tetraethoxysilane (TEOS) was added into the above flask, and reaction was performed at 70°C for 3 h; after cooling, the product was collected by centrifugation, and vacuum drying was performed to obtain Fe3O4@mSiO2.

[0236] (3) Fe3O4@mSiO2 prepared in step (2), 3 mg of curcumin (C), 3 mg of methotrexate (A), and 3 mg of tripterygium (B) were dispersed in 13 mL of deionized water, and physical stirring was performed at room temperature for 12-24 h, so that curcumin, methotrexate, and tripterygium were loaded into the pores of the mesoporous silica; the product was collected by centrifugal washing, and freeze-drying was performed to obtain Fe3O4@C / A / B-mSiO2.

[0237] (4) 96 mg of dopamine hydrochloride was dissolved in 16 mL of a deionized water-ethanol solution in a volume ratio of 1:0.5, and Fe3O4@C / A / B-mSiO2 prepared in step (3) was added thereto, and ultrasonic treatment was performed for 30 min; 50-80 μL of ammonia water was added, and the pH value of the solution was adjusted to 8-10; stirring was continued for 10-18 h, and the precipitate was collected by centrifugation, and freeze-drying was performed to obtain Fe3O4@C / A / B-mSiO2@PDA.

[0238] (5) Fe3O4@C / A / B-mSiO2@PDA prepared in step (4) was dispersed in 50 mL of a 0.06 g / L NaOH solution, and reaction was performed at 60°C for 3 h; after centrifugal washing, the precipitate was collected, and freeze-drying was performed to obtain Fe3O4@C / A / B@PDA.

[0239] (6) Take Fe3O4@C / A / B@PDA prepared in step (5) and add it to a mixed solution of 37 ml of EDC and NHS with a molar ratio of 5:1 to activate the hydroxyl group, then add 10 mg of hyaluronic acid (HA) and 25 mg of neutrophil membrane (E), and repeatedly extrude through a 200 nm polycarbonate membrane for 30 times. After centrifugal washing, the precipitate is collected, freeze-dried, and Fe3O4@C / A / B@PDA-HA / E is obtained.

[0240] (7) Ultrasonic dispersion of Fe3O4@C / A / B@PDA-HA / E prepared in step (6) in 15 mL of deionized water, and then 50 mg of L-arginine is added. After centrifugal washing, the precipitate is collected, freeze-dried, and the multi-mode driven composite Fe3O4@C / A / B@PDA-HA / E / L is obtained.

[0241] (8) Prepare a needle tip solution, mix the multi-mode driven composite obtained in step (7) in the needle tip solution at a concentration of 3.5 mg / ml, and add the mixed solution to the microneedle mold. Centrifugation is performed at 4°C to fill the mixed solution into the needle tip part of the microneedle mold. The process is repeated more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part. It is placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip part.

[0242] (9) Prepare a needle body solution, and take the needle body solution to cover the microneedle mold with needle tips prepared in step (8) to fill the needle body solution into the needle body part of the microneedle mold. Vacuum is applied for 10 minutes to remove microbubbles in the solution. The needle tip is compacted by centrifugation at 4°C. After repeating several times, the excess solution is removed.

[0243] (10) Prepare a backing solution, and take the solution to fill the microneedle mold obtained in step (9) to fill the backing part of the microneedle mold. Centrifugation is performed at 4000 rpm for 5 min. The excess solution is removed by repeating several times. It is dried at room temperature for 48 h. The microneedle patch loaded with the multi-mode driven composite is obtained by gently demolding with tweezers.

[0244] Example 17

[0245] (1) Fe3O4 magnetic nanoparticles were prepared by sol-gel method: 1 mM PAA was dissolved in 50 mL deionized water, and nitrogen was bubbled for 30 min to remove oxygen. The solution was heated to 100°C. 0.5 mmol FeCl3 and 0.28 mmol FeCl2 were dissolved in 2 mL of 1M concentrated hydrochloric acid solution. The above solution was quickly added to the heated PAA solution and stirred vigorously. 15 mL of ammonia was added to adjust the pH of the solution to 9-10. After refluxing for 6 h, the precipitate was collected and freeze-dried to obtain Fe3O4 nanoparticles.

[0246] (2) The magnetic nanoparticles surface is coated with mesoporous material to obtain magnetic nanocomposites: 16 mg of Fe3O4 prepared in step (1) is dispersed in 25 mL solution, then 300 mg of potassium permanganate is added and stirred to dissolve, and then transferred to a 50 mL polytetrafluoroethylene hydrothermal reactor, and reacted at 120°C for 2h. After the reaction is completed, cool to room temperature; centrifuge the product at 6000 rpm for 15 min, wash with deionized water, and dry at 60°C for 48h to obtain Fe3O4@MnO2.

[0247] (3) Fe3O4@MnO2 prepared in step (2) is dispersed in 18 mL deionized water with 3 mg curcumin (C), 3 mg paeoniflorin (P), and 4 mg tripterygium (B), and physically stirred at room temperature for 12-24h to load curcumin, paeoniflorin, and tripterygium into the pores of mesoporous MnO2. Centrifugal washing collects the product, and freeze-drying obtains Fe3O4@C / P / B-MnO2.

[0248] (4) 83 mg of dopamine hydrochloride is dissolved in 15 mL of deionized water and ethanol solution with a volume ratio of 1:1, and Fe3O4@C / P / B-MnO2 prepared in step (3) is added, ultrasonic dispersion for 30 min, 50-80 μL of ammonia is added, and the solution PH value is adjusted to 8-10, and then continue to stir for 10-18h. Centrifugal collection of the precipitate, freeze-drying obtains Fe3O4@C / P / B-MnO2@PDA.

[0249] (5) Fe3O4@C / P / B-MnO2@PDA prepared in step (4) is added to 32 ml of EDC and NHS mixed solution with a molar ratio of 4:1 to activate the hydroxyl group, and then 25 mg of neutrophil membrane protein (F) and 20 mg of macrophage membrane protein (H) are added. Repeat extrusion 20-30 times through a 200 nm-400 nm polycarbonate membrane, centrifugal washing collects the precipitate, and freeze-drying obtains Fe3O4@C / P / B-MnO2@PDA-F / H.

[0250] (6) Fe3O4@C / P / B-MnO2@PDA-F / H prepared in step (5) is ultrasonic dispersed in 10 mL deionized water, and 25 mg of L-arginine (L) is added. Centrifugal washing collects the precipitate, and freeze-drying obtains multi-mode driven composite Fe3O4@C / P / B-MnO2@PDA-F / H / L.

[0251] (7) Configuration of the tip solution, the multi-mode driven complex obtained in step (6) is mixed in the above-mentioned tip solution at a concentration of 3.4 mg / ml, the mixed solution is added to the microneedle mold, and the mixed solution is filled into the tip part of the microneedle mold under the condition of 4℃ centrifugation, and the process is repeated more than 3 times to make the solution fully compressed and deposited in the tip part; it is placed in an oven and dried at room temperature for 5 min to evaporate the water contained in the tip part;

[0252] (8) Configuration of the body solution, take the body solution, cover the microneedle mold containing the tip prepared in step (7), so that the body solution fills the body part of the microneedle mold; vacuum for 10 minutes to remove microbubbles in the solution, 4℃ centrifugation compaction tip, repeated several times to remove excess solution.

[0253] (9) Configuration of the backing solution, take the solution to fill the microneedle mold obtained in step (8), so that it fills the backing part of the microneedle mold; 4000 rpm centrifugation for 5 min, repeated several times to remove excess solution, room temperature drying for 48 h, gently demolding with tweezers to obtain a microneedle patch loaded with a multi-mode driven complex.

[0254] Example 18

[0255] (1) Preparation of Fe3O4 magnetic nanoparticles by sol-gel method: 1 mM PAA is dissolved in 50 mL deionized water, nitrogen is bubbled for 30 min to remove oxygen, and the solution is heated to 100℃; 0.5 mmol FeCl3 and 0.28 m mol FeCl2 are dissolved in 2 mL 1M concentrated hydrochloric acid solution; the above solution is quickly added to the heated PAA solution and stirred vigorously; 15 mL of low-value ammonia is added to adjust the solution PH to 9-10; after refluxing for 6 h, the precipitate is collected to obtain Fe3O4 nanoparticles.

[0256] (2) Coating mesoporous material on the surface of the magnetic nanoparticles to obtain a magnetic nanoparticle composite: 18.8 mg of Fe3O4 prepared in step (1) is dispersed in 20 mL solution, then 400 mg of potassium permanganate is added and stirred to dissolve, and then transferred to a 50 mL polytetrafluoroethylene hydrothermal reactor, and reacted at 120℃ for 2 h. After the reaction is completed, cool to room temperature; the product is centrifuged at 3000 rpm for 5 min with a high-speed centrifuge, washed with deionized water, and dried at 60℃ for 48 h to obtain Fe3O4@MnO2.

[0257] (3) The Fe3O4@MnO2 prepared in step (2) is dispersed in 12 mL of deionized water with 4 mg of curcumin (C), 4 mg of methotrexate (A), and 2 mg of rapamycin (D), and physical stirring is performed at room temperature for 12-24 h to load the curcumin, methotrexate, and rapamycin into the pores of the mesoporous MnO2. The product is collected by centrifugation and freeze-drying to obtain Fe3O4@C / A / D-MnO2.

[0258] (4) 97 mg of dopamine hydrochloride is dissolved in 14 mL of a deionized water / ethanol solution with a volume ratio of 1:1, and the Fe3O4@C / A / D-MnO2 prepared in step (3) is added thereto. Ultrasonic dispersion is performed for 30 min, 50-80 μL of ammonia water is added to adjust the pH of the solution to 8-10, and stirring is continued for 10-18 h. The precipitate is collected by centrifugation, and Fe3O4@C / A / D-MnO2@PDA is obtained after freeze-drying.

[0259] (5) The Fe3O4@C / A / D-MnO2@PDA prepared in step (4) is added to a mixed solution of EDC and NHS with a molar ratio of 4.5:1 to activate the hydroxyl group. Then, 15 mg of chondroitin sulfate (CS), 10 mg of macrophage membrane (G), and 10 mg of macrophage membrane protein (H) are added, and repeated extrusion through a 400 nm polycarbonate membrane is performed 40 times. The precipitate is collected by centrifugation and freeze-drying to obtain Fe3O4@C / A / D-MnO2@PDA-CS / G / H.

[0260] (6) The Fe3O4@A / B-MnO2@PDA-CS / G / H prepared in step (5) is ultrasonically dispersed in 16 mL of deionized water, and 45 mg of L-arginine (L) is added thereto. The precipitate is collected by centrifugation and freeze-drying to obtain the multi-mode driven complex Fe3O4@A / B-MnO2@PDA-CS / G / H / L.

[0261] (7) A needle tip solution is prepared, and the multi-mode driven complex obtained in step (6) is mixed in the needle tip solution at a concentration of 4.2 mg / mL. The mixed solution is added to a microneedle mold, and centrifugation is performed at 4°C to fill the mixed solution into the needle tip portion of the microneedle mold. The process is repeated more than 3 times to allow the solution to be sufficiently compressed and deposited in the needle tip portion. The microneedle mold is placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip portion.

[0262] (8) A needle body solution is prepared, and the needle body solution is applied to the microneedle mold with the needle tip prepared in step (7) to fill the needle body portion of the microneedle mold with the needle body solution. Vacuum is applied for 10 min to remove microbubbles in the solution, and the needle tip is compacted by centrifugation at 4°C. The process is repeated several times to remove the excess solution.

[0263] (9) Configuration of backing solution, take the solution to fill in the microneedle mold obtained in step (8), so that it fills the backing part of the microneedle mold; centrifugal 4000 rpm for 5 min, repeat several times to remove excess solution, dry at room temperature for 48 h, gently demold with forceps, get loaded with multimode driving compound microneedle patch.

[0264] Example 19

[0265] (1) Fe3O4 magnetic nanoparticles were prepared by sol-gel method: 1 mM PAA was dissolved in 50 mL deionized water, and nitrogen was bubbled for 40 min to remove oxygen; the solution was heated to 100°C; 0.5 mmol FeCl3 and 0.28 mmol FeCl2 were dissolved in 2 mL 1M concentrated hydrochloric acid solution; the above solution was quickly added to the heated PAA solution and stirred vigorously; 16 mL of ammonia was added to adjust the solution PH to 9-10; after refluxing for 6 h, the precipitate was collected to obtain Fe3O4 nanoparticles.

[0266] (2) The surface of the magnetic nanoparticles was coated with mesoporous material to obtain a magnetic nanocomposite: 18.9 mg of Fe3O4 prepared in step (1) was dispersed in 20 mL solution, then 350 mg of potassium permanganate was added and stirred to dissolve, and then transferred to a 50 mL polytetrafluoroethylene hydrothermal reactor, and reacted at 120°C for 2h. After the reaction was completed, it was cooled to room temperature; the product was centrifuged at 3000 rpm for 5 min with a high-speed centrifuge, washed with deionized water, and dried at 60°C for 48h to obtain Fe3O4@MnO2.

[0267] (3) Fe3O4@MnO2 prepared in step (2) was dispersed in 11 mL deionized water with 1 mg of curcumin (C), 3 mg of tripterygium (B), and 4 mg of rapamycin (D), and physically stirred at room temperature for 12-24 h to load curcumin, tripterygium, and rapamycin into the pores of mesoporous MnO2. The product was collected by centrifugation and freeze-dried to obtain Fe3O4@C / B / D-MnO2.

[0268] (4) 98 mg of dopamine hydrochloride was dissolved in 12 mL of deionized water and ethanol solution with a volume ratio of 1:1, and Fe3O4@C / B / D-MnO2 prepared in step (3) was added, ultrasonic dispersion for 30 min, 50-80 μL of ammonia was added, and the solution PH value was adjusted to 8-10, and the stirring was continued for 10-18 h. The precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@C / B / D-MnO2@PDA.

[0269] (5) Take Fe3O4@C / B / D-MnO2@PDA prepared in step (4) and add it to a mixed solution of 39 ml of EDC and NHS with a molar ratio of 4:1 to activate the hydroxyl group, then add 20 mg of hyaluronic acid (HA) and 15 mg of neutrophil membrane protein (F), and repeatedly extrude through a 200 nm polycarbonate membrane for 20 times. After centrifugal washing, the precipitate is collected, freeze-dried, and Fe3O4@C / B / D-MnO2@PDA-HA / F is obtained.

[0270] (6) Take Fe3O4@A / B-MnO2@PDA-E prepared in step (5) and ultrasonically disperse it in 17 mL of deionized water, then add 40 mg of L-arginine (L) to it. After centrifugal washing, the precipitate is collected, freeze-dried, and the multi-mode driven composite Fe3O4@C / B / D-MnO2@PDA-HA / F / L is obtained.

[0271] (7) Configure a needle tip solution, mix the multi-mode driven composite obtained in step (6) in the needle tip solution at a concentration of 3.1 mg / ml, and add the mixed solution to a microneedle mold. Centrifuge at 4°C to fill the mixed solution into the needle tip part of the microneedle mold. Repeat the process more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part. Place it in an oven and dry it at room temperature for 5 min to evaporate the water in the needle tip part.

[0272] (8) Configure a needle body solution, take the needle body solution, and cover it on the microneedle mold with needle tips prepared in step (7) to fill the needle body solution into the needle body part of the microneedle mold. Vacuum for 10 minutes to remove microbubbles in the solution, and centrifuge the needle tip at 4°C. Repeat several times to remove excess solution.

[0273] (9) Configure a backing solution, take the solution and fill it into the microneedle mold obtained in step (8) to fill the backing part of the microneedle mold. Centrifuge at 4000 rpm for 5 min, repeat several times to remove excess solution, and dry at room temperature for 48 h. Gently demold with tweezers to obtain a microneedle patch loaded with a multi-mode driven composite.

[0274] Example 20

[0275] (1) Prepare Fe3O4 magnetic nanoparticles by sol-gel method: take 1 mM PAA dissolved in 50 mL deionized water, and bubble nitrogen for 30 min to remove oxygen. Heat the solution to 100°C. Dissolve 0.5 mmol FeCl3 and 0.28 mmol FeCl2 in 2 mL of 1M concentrated hydrochloric acid solution. Quickly add the above solution to the heated PAA solution and stir vigorously. Add 15 mL of ammonia water to adjust the solution pH to 9-10. After refluxing for 6 h, cool and collect the precipitate to obtain Fe3O4 nanoparticles.

[0276] (2) Coating mesoporous material on the surface of magnetic nanoparticles to obtain magnetic nanocomposites: 20 mg of Fe3O4 prepared in step (1) was dispersed in 30 mL solution and ultrasonically dispersed for 60 min, then 380 mg of potassium permanganate was added and stirred to dissolve, and then transferred to a 50 mL polytetrafluoroethylene hydrothermal reactor, and reacted at 120°C for 2 h. After the reaction was completed, it was cooled to room temperature; the product was centrifuged at 3000 rpm for 5 min using a high-speed centrifuge, washed with deionized water, and dried at 60°C for 48 h to obtain Fe3O4@MnO2.

[0277] (3) Fe3O4@MnO2 prepared in step (2) was dispersed in 10 mL deionized water with 10 mg of tripterygium (B), and physical stirring was carried out at room temperature for 12-24 h to load tripterygium into the pores of mesoporous MnO2. The product was collected by centrifugation and freeze-dried to obtain Fe3O4@B-MnO2.

[0278] (4) 100 mg of dopamine hydrochloride was dissolved in 10 mL of a deionized water / ethanol solution with a volume ratio of 1:1, and Fe3O4@B-MnO2 prepared in step (3) was added thereto, ultrasonically dispersed for 30 min, 50-80 μL of ammonia was added to adjust the pH of the solution to 8-10, and stirring was continued for 10-18 h. The precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@B-MnO2@PDA.

[0279] (5) Fe3O4@B-MnO2@PDA prepared in step (4) was added to a 40 mL mixed solution of EDC and NHS with a molar ratio of 3.5:1 to activate the hydroxyl group, and then 7 mg of chondroitin sulfate (CS) and 13 mg of neutrophil membrane protein (F) were added. The mixture was repeatedly extruded 20-30 times through a 200 nm-400 nm polycarbonate membrane, and the precipitate was collected by centrifugation and freeze-dried to obtain Fe3O4@B-MnO2@PDA-CS / F.

[0280] (6) Fe3O4@B-MnO2@PDA-CS / F prepared in step (5) was ultrasonically dispersed in 18 mL of deionized water, and 36 mg of L-arginine (L) was added thereto. The precipitate was collected by centrifugation and freeze-dried to obtain a multi-mode driven composite Fe3O4@B-MnO2@PDA-CS / F / L.

[0281] (7) A needle tip solution was prepared, and the multi-mode driven composite obtained in step (6) was mixed in the needle tip solution at a concentration of 3.9 mg / ml. The mixed solution was added to a microneedle mold, and centrifugation was performed at 4°C to fill the mixed solution into the needle tip portion of the microneedle mold. The process was repeated more than 3 times to allow the solution to be sufficiently compressed and deposited in the needle tip portion. The mixture was placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip portion.

[0282] (8) Prepare a needle body solution, take the needle body solution, and cover the micro-needle mold containing the needle tip prepared in step (7) to fill the needle body part of the micro-needle mold with the needle body solution; vacuum for 10 minutes to remove micro-bubbles in the solution, and centrifuge the needle tip at 4°C to compact the needle tip; repeat several times to remove the excess solution.

[0283] (9) Prepare a backing solution, take the solution to fill the micro-needle mold obtained in step (8) to fill the backing part of the micro-needle mold; centrifuge at 4000 rpm for 5 min, repeat several times to remove the excess solution, dry at room temperature for 48 h, and gently demold with tweezers to obtain a micro-needle patch loaded with a multi-mode driving composite.

[0284] Example 21

[0285] (1) Prepare γ-Fe2O3 magnetic nanoparticles by co-precipitation: 27 g of (CH2)6N4, 6 g of NaNO3, and 21 g of FeCl2.4H2O are dispersed in 500 ml of deionized water under ultrasonic conditions, the solution is heated to 60°C after stirring for 1 h, and oxygen is continuously pumped into it for 8 h to achieve complete oxidation of the nanoparticles, then filtered through filter paper, and the precipitate remaining on the filter paper is washed with ethanol and deionized water three times to reduce the number of anions and organic impurities, and the precipitate is collected and dried at 70°C for 24 h. Finally, the dried sample is ground to obtain γ-Fe2O3 nanoparticles.

[0286] (2) Coat the magnetic nanoparticles with mesoporous material to obtain a magnetic nanocomposite: take 20 mg of γ-Fe2O3 prepared in step (1) and disperse it in 30 mL of solution, ultrasonic dispersion for 60 min, then add 380 mg of potassium permanganate and stir to dissolve, transfer to a 50 mL polytetrafluoroethylene hydrothermal reactor, and react at 120°C for 2 h; after the reaction is completed, cool to room temperature; centrifuge the product at 3000 rpm for 5 min using a high-speed centrifuge, wash with deionized water, and dry at 60°C for 48 h to obtain γ-Fe2O3@MnO2.

[0287] (3) Disperse γ-Fe2O3@MnO2 prepared in step (2) and 9 mg of Tripterygium (B) in 19 mL of deionized water, and physically stir at room temperature for 12-24 h to load Tripterygium into the pores of mesoporous MnO2, centrifuge and wash to collect the product, and freeze-dry to obtain γ-Fe2O3@B-MnO2.

[0288] (4) 100 mg of dopamine hydrochloride was dissolved in 100 ml of a deionized water / ethanol solution with a volume ratio of 1:1, and γ-Fe2O3@B-MnO2 prepared in step (3) was added thereto and ultrasonically dispersed for 30 min. 50-80 μL of ammonia water was added to adjust the pH of the solution to 8-10, and stirring was continued for 10-18 h. The precipitate was collected by centrifugation, and freeze-drying was performed to obtain γ-Fe2O3@B-MnO2@PDA.

[0289] (5) γ-Fe2O3@B-MnO2@PDA prepared in step (4) was taken and added to a mixed solution of EDC and NHS with a molar ratio of 3.5:1 to activate the hydroxyl group. Then, 3 mg of chondroitin sulfate (CS), 2 mg of phospholipid film (I), and 1.6 mg of neutrophil membrane protein (F) were added, and repeated extrusion through a 200 nm-400 nm polycarbonate membrane was performed 20-30 times. The precipitate was collected by centrifugation and freeze-drying was performed to obtain γ-Fe2O3@B-MnO2@PDA-CS / F / I. 34

[0290] (6) γ-Fe2O3@B-MnO2@PDA-CS / F / I prepared in step (5) was ultrasonically dispersed in 18 mL of deionized water, and 2.6 mg of L-arginine (L) was added thereto. The precipitate was collected by centrifugation and freeze-drying was performed to obtain a multimodal driving complex Fe3O4@B-MnO2@PDA-CS / F / I / L.

[0291] (7) A needle tip solution was prepared, and the multimodal driving complex obtained in step (6) was mixed in the needle tip solution at a concentration of 3.9 mg / ml. The mixed solution was added to a microneedle mold, and centrifugation was performed at 4°C to fill the mixed solution into the needle tip portion of the microneedle mold. The process was repeated 3 times or more to allow the solution to be sufficiently compressed and deposited in the needle tip portion. The microneedle mold was placed in an oven, and drying was performed at room temperature for 5 min to evaporate the water content in the needle tip portion.

[0292] (8) A needle body solution was prepared, and the needle body solution was taken and applied to the microneedle mold with the needle tip prepared in step (7) to fill the needle body solution into the needle body portion of the microneedle mold. Vacuum was applied for 10 min to remove microbubbles in the solution, and the needle tip was compacted by centrifugation at 4°C. The process was repeated several times to remove the excess solution.

[0293] (9) A backing solution was prepared, and the solution was taken and filled into the microneedle mold obtained in step (8) to fill the backing solution into the backing portion of the microneedle mold. Centrifugation was performed at 4000 rpm for 5 min, and the process was repeated several times to remove the excess solution. Drying was performed at room temperature for 48 h, and the microneedle patch loaded with the multimodal driving complex was gently demolded using tweezers.

[0294] Example 22

[0295] ​(1) Preparation of magnetic nanoparticles by co-precipitation method: first, 10.81 g of FeCl3 was ultrasonically dispersed in 50 mL of distilled water, and nitrogen was continuously introduced into the solution for 30 min to remove oxygen in the solution. 2.87 g of MnCl2 was dissolved in 30 mL of distilled water and added to the above solution. Then, a 4 mol / L NaOH solution was used to adjust the pH value to 10-12, and the solution was heated to 100°C and continuously stirred for 2 h. After the reaction was completed, it was naturally cooled and washed with a neodymium magnet for three times to obtain MnFe2O4 nanoparticles.

[0296] (2) Coating mesoporous material on the surface of magnetic nanoparticles to obtain magnetic nanocomposites: 16 mg of MnFe2O4 prepared in step (1) was ultrasonically dispersed in 5 mL of deionized water for 30 min, and 0.12 g of cetyltrimethylammonium bromide (CTAB) was added and ultrasonically dispersed for another 30 min until the solution was clear and transparent. After ultrasonic dispersion, the solution was transferred to a flask and stirred at 70°C for 10 min. A mixed solution of 50 mL of ammonia water, ethylene glycol and deionized water with a volume ratio of 0.7:10:30 was prepared and added to the above flask and stirred for another 10 min. 120 μL of 1,3,5-trimethylbenzene (TMB) was added to the above flask and reacted for 2 h. 400 μL of tetraethoxysilane (TEOS) was added to the above flask and heated at 70°C for 3 h. After cooling, the product was collected by centrifugation and vacuum dried to obtain MnFe2O4@mSiO2.

[0297] (3) MnFe2O4@mSiO2 prepared in step (2) was dispersed in 19 mL of deionized water with 9 mg of tripterygium (B), and physical stirring was carried out at room temperature for 12-24 h to load tripterygium into the pores of mesoporous SiO2. The product was collected by centrifugation and freeze-dried to obtain MnFe2O4@B-mSiO2.

[0298] (4) 100 mg of dopamine hydrochloride was dissolved in 100 mL of deionized water and ethanol solution with a volume ratio of 1.1:1, and MnFe2O4@B-mSiO2 prepared in step (3) was added thereto and ultrasonically dispersed for 30 min. 50-80 μL of ammonia water was added to adjust the pH value of the solution to 8-10, and stirring was continued for 10-18 h. The precipitate was collected by centrifugation and freeze-dried to obtain MnFe2O4@B-mSiO2@PDA.

[0299] (5) MnFe2O4@B-mSiO2@PDA prepared in step (4) was dispersed in 50 mL of 0.06 g / L NaOH solution and heated at 60°C for 3 h. After centrifugation and washing, the precipitate was collected and freeze-dried to obtain MnFe2O4@B@PDA.

[0300] (6) The MnFe2O4@B@PDA prepared in step (5) is added to a mixed solution of 45 ml of EDC and NHS with a molar ratio of 3.5:1 to activate the hydroxyl group, and then 3 mg of chondroitin sulfate (CS), 2 mg of phospholipid film (I), and 1.6 mg of neutrophil membrane protein (F) are added. The mixture is repeatedly extruded through a 200 nm-400 nm polycarbonate membrane for 20-30 times, and the precipitate is collected after centrifugal washing and freeze-drying to obtain MnFe2O4@B@PDA-CS / F / I.

[0301] (7) The γ-Fe2O3@B@PDA-CS / F / I prepared in step (6) is ultrasonically dispersed in 18 mL of deionized water, and 3.6 mg of L-arginine (L) is added. The precipitate is collected after centrifugal washing and freeze-drying to obtain a multimodal driving complex Fe3O4@B@PDA-CS / F / I / L.

[0302] (8) A needle tip solution is prepared, and the multimodal driving complex obtained in step (6) is mixed in the needle tip solution at a concentration of 3.9 mg / ml. The mixed solution is added to a microneedle mold, and the mixed solution is filled into the needle tip part of the microneedle mold by centrifugation at 4°C. The process is repeated for more than 3 times to allow the solution to be fully compressed and deposited in the needle tip part. The microneedle mold is placed in an oven and dried at room temperature for 5 min to evaporate the water in the needle tip part.

[0303] (9) A needle body solution is prepared, and the needle body solution is covered on the microneedle mold with needle tips prepared in step (7) to fill the needle body part of the microneedle mold with the needle body solution. Vacuum is applied for 10 minutes to remove microbubbles in the solution, and the needle tip is compacted by centrifugation at 4°C. The process is repeated for several times to remove the excess solution.

[0304] (10) A backing solution is prepared, and the solution is filled in the microneedle mold obtained in step (8) to fill the backing part of the microneedle mold. Centrifugation is performed at 4000 rpm for 5 min, and the process is repeated for several times to remove the excess solution. The microneedle mold is dried at room temperature for 48 h, and the microneedle patch loaded with the multimodal driving complex is obtained by gently demolding with tweezers.

[0305] Example 23

[0306] Structural characterization of magnetic nanoparticles

[0307] The magnetic nanoparticles prepared in step (1) in Examples 1 to 22 are subjected to structural characterization by a transmission electron microscope FEI Tecnai F20. The transmission electron microscope photograph of the magnetic nanoparticles prepared in Example 1 is taken as a representative, and the results are shown in FIG. 1, which shows that the magnetic nanoparticles prepared in the present application have regular morphology, uniform particle size, and good dispersibility. Figure 3

[0308] ​The magnetic nanoparticles prepared in step (1) in Examples 1 to 20 were subjected to XRD verification using an XRD diffractometer, and the diffraction pattern of the magnetic nanoparticles prepared in Example 1 was taken as a representative example, and the results are shown in Figure 4 Fig. 1. It was observed that the diffraction patterns of the magnetic nanoparticles prepared in Examples 1 to 20 were consistent with the Fe3O4 standard card, indicating that the prepared magnetic nanoparticles were Fe3O4. The magnetic nanoparticles prepared in Example 21 were subjected to XRD verification using an XRD diffractometer, and the diffraction pattern of the magnetic nanoparticles prepared in Example 21 was consistent with the γ-Fe2O3 standard card, indicating that the prepared magnetic nanoparticles were Fe3O4.

[0309] Example 24

[0310] Structural characterization of the magnetic nanocomposites

[0311] The magnetic nanocomposites prepared in step (2) in Examples 1 to 22 were subjected to structural characterization using a transmission electron microscope FEI Tecnai F20, and the transmission electron micrograph of the magnetic nanocomposite prepared in Example 1 was taken as a representative example, and the results are shown in Figure 5 Fig. 2. It was observed that the prepared magnetic nanocomposites had regular morphology, uniform particle size, and good dispersibility.

[0312] Structural characterization of the multimode driving composites

[0313] The multimode driving composites prepared in Examples 1 to 22 were subjected to structural characterization using a transmission electron microscope FEI Tecnai F20, and the multimode driving composite prepared in Example 12 was taken as a representative example, and the results are shown in Figure 6 Fig. 3. It was observed that the prepared multimode driving composites had regular shape and good uniformity; and had obvious core-shell structure, which was consistent with the multi-layer structure characteristics of the multimode driving composites prepared in the application.

[0314] Example 26

[0315] The multimode driving composites prepared in Examples 1 to 22 were subjected to hysteresis curve testing, and Example 15 was taken as a representative example, and the results are shown in Figure 7 Fig. 4. It was shown that the multimode driving composites prepared in the application had strong magnetism.

[0316] Example 27

[0317] In-vitro magnetic resonance imaging performance of the multimode driving composites

[0318] The multi-mode driven complex prepared in Example 1 to Example 22 was subjected to T1 and T2 weighted magnetic resonance imaging analysis on a 3.0T magnetic resonance imaging instrument, and the test conditions were T1: TR = 650 ms, TE = 200 ms; T2: TR = 4000 ms, TE = i3 / 26 / 39 / 52 ms, echo length = 13 ms, slice thickness = 3.0 mm, slice interval = 0 mm, signal acquisition times = 1, flip angle = 30°; as represented by the multi-mode driven complex prepared in Example 6, the results are shown in Figure 8 As shown in the figure, the prepared multi-mode driven complex has good T1 weighted imaging performance, and the brightness of the solution increases with the increase of the concentration; in T2 weighted imaging, the brightness of the solution becomes dark with the increase of the concentration, indicating that the multi-mode driven complex has good T2 weighted imaging performance; therefore, the multi-mode driven complex prepared in the application has good T1 and T2 dual-mode imaging performance, which can meet the needs of magnetic resonance imaging experiments.

[0319] Example 28

[0320] In vitro photothermal performance of the multi-mode driven complex

[0321] The multi-mode driven complex prepared in Example 21 was prepared in an EP tube with ultrapure water to prepare aqueous solutions of the multi-mode driven complex with concentrations of 50 μg / mL, 100 μg / mL and 200 μg / mL, respectively, 0.2 mL of ultrapure water was used as a control, and the temperature change of the solution under laser irradiation was observed at 0 min, 1 min, 2 min, 5 min, 8 min and 10 min using a near-infrared thermal imager; the results are shown in Figure 9 As shown in the figure, the temperature of ultrapure water only slightly increased after 10 min of irradiation; with the increase of laser irradiation time, the temperature of the aqueous solution of the multi-mode driven complex increased significantly, and the temperature increased more obviously with the increase of the concentration of the multi-mode driven complex; it is shown that the multi-mode driven complex prepared in the application has a significant heating effect under laser irradiation, and the multi-mode driven complex prepared in the application has good photothermal performance, which can meet the needs of photothermal therapy.

[0322] Example 29

[0323] In vitro cell uptake

[0324] 1. Lipopolysaccharide-stimulated macrophages were activated into inflammatory macrophages; the multi-mode driven complex prepared in Example 1 was fluorescently labeled, and an equal amount of the fluorescently labeled multi-mode driven complex was added to the culture solution containing unactivated macrophages, the culture solution containing inflammatory macrophages, and the culture solution containing inflammatory macrophages pretreated with HA, respectively; after 4 h of incubation in an incubator, the uptake of the macrophages was observed under a fluorescence microscope, and the results are shown inFigure 10 As shown, the uptake of the fluorescently labeled multi-mode driven complex in the inflammatory macrophages is significantly increased, indicating that the multi-mode driven complex prepared in Example 1 has good inflammation targeting; while in the inflammatory macrophages pretreated with hyaluronic acid, the uptake of the fluorescently labeled multi-mode driven complex is significantly reduced, indicating that the inflammation targeting of the multi-mode driven complex prepared in Example 1 is mediated by hyaluronic acid.

[0325] 2. The macrophages were stimulated with lipopolysaccharide to activate the macrophages into inflammatory macrophages, and the multi-mode driven complex prepared in Example 7 was fluorescently labeled. Equal amounts of the fluorescently labeled multi-mode driven complex were added to the culture solution containing unactivated macrophages, the culture solution containing inflammatory macrophages, and the culture solution containing inflammatory macrophages pretreated with chondroitin sulfate, respectively. After incubation in the incubator for 4 h, the uptake of the macrophages was observed under a fluorescence microscope. The results were as follows: the uptake of the fluorescently labeled multi-mode driven complex in the inflammatory macrophages was significantly increased, indicating that the multi-mode driven complex prepared in Example 7 has good inflammation targeting; while in the inflammatory macrophages pretreated with chondroitin sulfate, the uptake of the fluorescently labeled multi-mode driven complex was significantly reduced, indicating that the inflammation targeting of the multi-mode driven complex prepared in Example 7 is mediated by chondroitin sulfate.

[0326] 3. The macrophages were stimulated with lipopolysaccharide to activate the macrophages into inflammatory macrophages, and the multi-mode driven complex prepared in Example 2 was fluorescently labeled. Equal amounts of the fluorescently labeled multi-mode driven complex were added to the culture solution containing unactivated macrophages, the culture solution containing inflammatory macrophages, and the culture solution containing inflammatory macrophages pretreated with neutrophil membranes, respectively. After incubation in the incubator for 4 h, the uptake of the macrophages was observed under a fluorescence microscope. The results were as follows: the uptake of the fluorescently labeled multi-mode driven complex in the inflammatory macrophages was significantly increased, indicating that the multi-mode driven complex prepared in Example 2 has good inflammation targeting; while in the inflammatory macrophages pretreated with neutrophil membranes, the uptake of the fluorescently labeled multi-mode driven complex was significantly reduced, indicating that the inflammation targeting of the multi-mode driven complex prepared in Example 2 is mediated by neutrophil membranes.

[0327] 4. Lipopolysaccharide was used to stimulate macrophages to activate them into inflammatory macrophages. The multi-mode driven complex prepared in Example 8 was fluorescently labeled. Equal amounts of the fluorescently labeled multi-mode driven complex were added to culture solution containing non-activated macrophages, culture solution containing inflammatory macrophages, and culture solution containing inflammatory macrophages pretreated with neutrophil membrane proteins. After 4 hours of incubation in an incubator, the uptake of the multi-mode driven complex by the macrophages was observed under a fluorescence microscope. The results showed that the uptake of the fluorescently labeled multi-mode driven complex by the inflammatory macrophages was significantly increased, indicating that the multi-mode driven complex prepared in Example 8 had good inflammatory targeting. The uptake of the fluorescently labeled multi-mode driven complex by the inflammatory macrophages pretreated with neutrophil membrane proteins was significantly reduced, indicating that the inflammatory targeting of the multi-mode driven complex prepared in Example 8 was mediated by neutrophil membrane proteins.

[0328] 5. Lipopolysaccharide was used to stimulate macrophages to activate them into inflammatory macrophages. The multi-mode driven complex prepared in Example 3 was fluorescently labeled. Equal amounts of the fluorescently labeled multi-mode driven complex were added to culture solution containing non-activated macrophages, culture solution containing inflammatory macrophages, and culture solution containing inflammatory macrophages pretreated with macrophage membrane proteins. After 4 hours of incubation in an incubator, the uptake of the multi-mode driven complex by the macrophages was observed under a fluorescence microscope. The results showed that the uptake of the fluorescently labeled multi-mode driven complex by the inflammatory macrophages was significantly increased, indicating that the multi-mode driven complex prepared in Example 3 had good inflammatory targeting. The uptake of the fluorescently labeled multi-mode driven complex by the inflammatory macrophages pretreated with macrophage membrane proteins was significantly reduced, indicating that the inflammatory targeting of the multi-mode driven complex prepared in Example 3 was mediated by macrophage membrane proteins.

[0329] 6. Lipopolysaccharide was used to stimulate macrophages to activate them into inflammatory macrophages. The multi-mode driven complex prepared in Example 6 was fluorescently labeled. Equal amounts of the fluorescently labeled multi-mode driven complex were added to culture solution containing non-activated macrophages, culture solution containing inflammatory macrophages, and culture solution containing inflammatory macrophages pretreated with macrophage membrane proteins. After 4 hours of incubation in an incubator, the uptake of the multi-mode driven complex by the macrophages was observed under a fluorescence microscope. The results showed that the uptake of the fluorescently labeled multi-mode driven complex by the inflammatory macrophages was significantly increased, indicating that the multi-mode driven complex prepared in Example 6 had good inflammatory targeting. The uptake of the fluorescently labeled multi-mode driven complex by the inflammatory macrophages pretreated with macrophage membrane proteins was significantly reduced, indicating that the inflammatory targeting of the multi-mode driven complex prepared in Example 6 was mediated by macrophage membrane proteins.

[0330] Example 30

[0331] This example is basically the same as Example 2, the difference is that the microneedle patch prepared in this example does not contain a multimode driving complex, the optical image thereof is as shown in Figure 11 The electron microscope results are as shown in Figure 12 The microneedle patch is attached to the arm, and after 1 min of pressing, the microneedle patch is removed, and at 0 min, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, and 30 min, the skin is observed, as shown in Figure 13 The skin appears slightly red and swollen within 0-9 min, and the redness and swelling gradually subside after 9 min, and most of the redness and swelling subside at 10 min, indicating that the microneedle patch of the application has less irritation to the skin.

[0332] Example 31

[0333] Take 9 CIA model rats, divide them into three groups of 1, 4, and 4 in turn, the first group is a blank group, and the CIA model rats therein are not treated; after 30 days, the rats are sacrificed, and the right foot is taken for observation by mirco-CT, the results are as shown in Figure 14 The first group of rats has severe joint bone destruction.

[0334] In the second group, the blank microneedle patch of Example 29 is attached to the skin of the right leg of each CIA model rat, pressed and kept for 30 s, and then the microneedle is fixed with a medical waistband; the blank microneedle patch is pressed once every 3 days according to the above steps, for a total of 3 times; 21 days after the end of pressing, the rats are sacrificed, and the right foot is taken for observation by mirco-CT, the results are that the joint bone destruction of the second group of rats is severe.

[0335] In the third group, the microneedle patch loaded with the multimode driving complex prepared in Example 2 is attached to the skin of the right leg of each CIA model rat, pressed and kept for 30 s, and then the microneedle is fixed with a medical waistband; the blank microneedle patch is pressed once every 3 days according to the above steps, for a total of 3 times; 21 days after the end of pressing, the rats are sacrificed, and the right foot is taken for observation by mirco-CT, the results are as shown in Figure 15 No obvious destruction of the joint bone of the rats is observed, indicating that the microneedle patch prepared by the application can effectively control the progression of rheumatoid arthritis and repair bone damage.

[0336] Finally, it should be noted that the above examples only illustrate the technical solutions of the application, but do not limit them; although the application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions described in the foregoing examples, or make equivalent substitutions for some of the technical features; and these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the application.

Claims

1. A microneedle patch loaded with a multimodal delivery complex comprising a backing layer and a needle body disposed on the surface of the backing layer; characterized in that, The needle tip of the needle body is loaded with a multi-mode driven complex, the multi-mode driven complex comprises a magnetic nano core, a mesoporous shell layer modified on the surface of the magnetic nano core, a hydrophobic anti-inflammatory drug loaded in the channel of the mesoporous shell layer, a photothermal responsive polymer compound modified on the surface of the mesoporous shell layer, an inflammation targeting drug modified on the surface of the photothermal responsive polymer compound, an inflammation responsive gas producing drug modified on the surface of the inflammation targeting drug, the magnetic nano core is a magnetic nanoparticle, the magnetic nanoparticle comprises Fe3O4 and γ-Fe2O3, the mesoporous shell layer comprises mesoporous MnO2, mesoporous polydopamine and mesoporous SiO2, when the material of the mesoporous shell layer is mesoporous SiO2, the mesoporous shell layer is etched after loading the hydrophobic anti-inflammatory drug, the inflammation targeting drug comprises hyaluronic acid, chondroitin sulfate, neutrophil membrane, neutrophil membrane protein, macrophage membrane and macrophage membrane protein, and the photothermal responsive polymer compound comprises polydopamine; and the inflammation responsive gas producing drug comprises L-arginine.

2. The microneedle patch loaded with multi-modal driven compounds according to claim 1, wherein, The hydrophobic anti-inflammatory drug comprises curcumin, paeoniflorin, methotrexate, tripterygium and rapamycin.

3. A method of preparing a microneedle patch loaded with a multimodal driving complex as claimed in any one of claims 1 to 2, characterized in that, The method comprises the following steps: (1) preparing a magnetic nanoparticle, the magnetic nanoparticle comprises Fe3O4 and γ-Fe2O3; (2) coating a mesoporous material on the surface of the magnetic nanoparticle to obtain a magnetic nano composite; the mesoporous material comprises mesoporous SiO2, mesoporous MnO2 and mesoporous polydopamine; (3) dispersing the magnetic nano composite obtained in step (2) in deionized water at a concentration of 0.4-2 mg / mL, adding a hydrophobic anti-inflammatory drug to the deionized water at a concentration of 0.1-1 mg / mL, the hydrophobic anti-inflammatory drug comprises curcumin, paeoniflorin, methotrexate, tripterygium and rapamycin, and physically stirring for 12-24 h to load the hydrophobic anti-inflammatory drug into the channel of the mesoporous shell layer, collecting the precipitate after centrifugal washing, and freeze-drying to obtain a drug-loaded magnetic nano composite; (4) dissolving dopamine hydrochloride in a deionized water / ethanol solution with a volume ratio of 1:0.5 at a concentration of 1.25-10 mg / mL to configure a dopamine hydrochloride / water / ethanol solution; adding the drug-loaded magnetic nano composite obtained in step (3) to the dopamine hydrochloride / water / ethanol solution at a concentration of 2-10 mg / mL, and ultrasonic dispersing; then adding ammonia water to adjust the pH value of the solution to 8-10, and continuing to stir for 10-18 h, collecting the precipitate after centrifugal washing, and freeze-drying to obtain a drug-loaded magnetic nano composite coated with a photothermal responsive polymer compound; when the mesoporous material is mesoporous SiO2, the obtained drug-loaded magnetic nano composite coated with the photothermal responsive polymer compound needs to be placed in an etching solution to etch the SiO2 after collecting the precipitate, and then centrifugal washing and collecting the precipitate. (5) The drug-loaded magnetic nanocomposite coated with the photothermal responsive polymer compound prepared in step (4) is added to a mixed solution of EDC and NHS in a molar ratio of 5-1:1 at a concentration of 1-5 mg / mL to activate the hydroxyl group; an inflammation-targeting drug is added thereto at a concentration of 0.5-10 mg / mL, the inflammation-targeting drug including hyaluronic acid, chondroitin sulfate, a neutrophil membrane, a neutrophil membrane protein, a macrophage membrane, and a macrophage membrane protein; and the reaction is performed at room temperature for 24 h, after which the precipitate is collected after washing by centrifugation, and freeze-drying is performed to obtain a drug-loaded magnetic nanocomposite coated with a photothermal responsive polymer compound and an inflammation-targeting drug from the inside to the outside; (6) The drug-loaded magnetic nanocomposite coated with a photothermal responsive polymer compound and an inflammation-targeting drug from the inside to the outside obtained in step (5) is added to deionized water at a concentration of 2-10 mg / mL, and is dispersed by ultrasonic waves, and an inflammation-responsive gas-producing drug is added thereto at a concentration of 0.5-5 mg / mL, the inflammation-responsive gas-producing drug including L-arginine; and the precipitate is collected after washing by centrifugation, and freeze-drying is performed to obtain a drug-loaded magnetic nanocomposite coated with a photothermal responsive polymer compound, an inflammation-targeting drug, and an inflammation-responsive gas-producing drug from the inside to the outside, which is referred to as a multi-mode driven composite; (7) The multi-mode driven composite prepared in step (6) is dispersed in a needle tip material at a concentration of 2-8 mg / mL, and a microneedle is prepared in a microneedle mold using the needle tip material in which the multi-mode driven composite is dispersed and a needle body material, and a backing is made at the bottom of the microneedle using a backing material to obtain a microneedle patch loaded with the multi-mode driven composite.

4. The method of claim 3, wherein the multi-modal delivery complex is loaded into the microneedle patch by, In step (2), the method for coating the magnetic nanoparticles with mesoporous SiO2 is as follows: the magnetic nanoparticles prepared in step (1) are added to deionized water at a concentration of 1.5-2 mg / mL, and are dispersed by ultrasonic waves for 30-60 min to obtain a dispersion liquid; cetyltrimethylammonium bromide (CTAB) is added to the dispersion liquid at a concentration of 0.02-0.05 mg / mL, and the ultrasonic wave treatment is continued for 30-60 min until the solution is clear and transparent; after the ultrasonic wave treatment, the solution is transferred to a flask, and stirring is performed at 70-80°C for 10-20 min; a mixed solution of ammonia, ethylene glycol, and deionized water in a volume ratio of 0.7:10:30 is prepared, and is added to the flask, and stirring is continued for 10-20 min; 1,3,5-trimethylbenzene (TMB) is added to the flask at a concentration of 2-5 μL / mL, and the reaction is continued for 2-4 h; tetraethoxysilane (TEOS) is added to the flask at a concentration of 4-12 μL / mL, and the reaction is performed at 70-80°C for 2-4 h; after cooling, the product is collected by centrifugation, and is dried under vacuum to obtain magnetic nanoparticles coated with mesoporous SiO2; In the step (2), the method for coating the magnetic nanoparticles with mesoporous MnO2 is as follows: the magnetic nanoparticles prepared in the step (1) are added into deionized water at a concentration of 1-4 mg / mL, and then potassium permanganate is added at a concentration of 10-20 mg / mL, and stirred and dissolved, and then transferred into a polytetrafluoroethylene hydrothermal reactor, and reacted at 100-180 ℃ for 4-12 h, and then cooled to room temperature after the reaction is completed; the product is centrifuged at a speed of 3000-6000 rpm for 10-20 min by using a high-speed centrifuge, and washed with deionized water to obtain the magnetic nanoparticles coated with mesoporous MnO2; The method for coating the magnetic nanoparticles with mesoporous polydopamine in step (2) is as follows: the magnetic nanoparticles prepared in step (1) are added into a mixed solution of deionized water and ethanol in a volume ratio of 1:1 at a concentration of 1-4 mg / mL, and ultrasonic dispersion is performed; 1,3,5-trimethylbenzene (TMB) and dopamine hydrochloride are added into the above flask at a concentration of 20-30 mg / mL and 0.02-0.06 mL / mL, respectively, and stirring is continued for 30-60 min; ammonia is added into the above flask at a concentration of 3-8 μL / mL, and stirring is continued for 2-6 h; the product is collected by alternately washing and centrifuging with water and ethanol, and vacuum drying is performed to obtain the magnetic nanoparticles coated with mesoporous polydopamine. F-127, magnetic stirring until the solution is clear and transparent; 1,3,5-trimethylbenzene (TMB) and dopamine hydrochloride are added into the above flask at a concentration of 20-30 mg / mL and 0.02-0.06 mL / mL, respectively, and stirring is continued for 30-60 min; ammonia is added into the above flask at a concentration of 3-8 μL / mL, and stirring is continued for 2-6 h; the product is collected by alternately washing and centrifuging with water and ethanol, and vacuum drying is performed to obtain the magnetic nanoparticles coated with mesoporous polydopamine.

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