Drug NANO multi-level structure coating and preparation method therefor

Abstract

A drug nano multi-level structure coating and a preparation method therefor. A polyphenol and a polyamine compound are subjected to oxidation, crosslinking and polymerization reactions under the action of an oxidizing agent to generate a polyphenol nanoparticle film layer outside a nano-drug carrier; then phenolic hydroxyl groups in the polyphenol nanoparticle film layer and metal ions undergo chelation to introduce the metal ions into the coating, thereby further improving the stability of the nano-drug carrier in the coating, reducing the degradation rate and the oxidation rate of phenolic hydroxyl groups, and endowing the coating with biological functions. In addition, because of the presence of cations, the coating can bind to water molecules, thereby enhancing the wettability of the coating.

Description

A drug nano multi-level structure coating and its preparation method

[0001] Related applications

[0002] This application claims priority to Chinese patent application No. 2023108595993, filed on July 13, 2023, entitled “A drug nano-multilevel structure coating and its preparation method,” the entire text of which is hereby incorporated by reference. Technical Field

[0003] The present application belongs to the technical field of biomedical functional materials, and specifically relates to a drug nano-multilevel structure coating and a preparation method thereof. Background Art

[0004] Surface engineering strategies are widely studied as an effective means of imparting multifunctional activities to the surfaces of biomedical materials and devices. Current approaches to achieving surface anticoagulation, anti-infection, anti-nonspecific protein adhesion, inflammation regulation, and selective cell growth promotion on medical materials primarily include passive and active defenses.

[0005] Passive defense surface engineering strategies have been widely studied. Compared with hydrophobic surfaces, hydrophilic surfaces have better biocompatibility. Therefore, the most researched coatings of this type are mainly hydrophilic surfaces, such as polyethylene glycol coatings and amphiphilic ion molecular brush surfaces. These two types of coatings effectively bind to water molecules to form a hydration layer on the surface, thereby resisting the nonspecific adhesion and proliferation of proteins, cells and bacteria, and giving the coating materials excellent anti-fouling properties, including resistance to protein adhesion, cell and bacterial adhesion and growth. The active defense strategy is mainly to load active ingredients into the coating, and achieve surface sterilization, anti-thrombosis, inflammation regulation and selective promotion of cell growth through the release of metal ions (Au, Ag+, Cu2+, etc.), bioactive molecules or drugs, proteins / peptides, etc.

[0006] Although both passive and active defense coatings have excellent biological properties, studies have found that the coatings face problems such as structural stability (such as the degradation of hydrophilic molecular brushes leading to poor surface wettability of the material), functional timeliness (such as the impedance performance will be greatly reduced after the hydration layer / air layer of the superhydrophilic / superhydrophobic surface is destroyed), and insufficient efficacy (once the drug loaded in the coating is completely released, the biological function maintained by the drug will also disappear) during long-term service, which ultimately leads to the failure of the implanted device and the inability to meet the therapeutic effect.

[0007] In addition, the methods that are currently being studied more for constructing topological structures on the surface of materials include: anodic oxidation, femtosecond laser etching, plasma etching, alkaline activation, sol-gel method, etc. However, these methods not only have requirements for the substrate material but also cause damage to it to a certain extent. Moreover, the micro / nano topological structures constructed by these methods are mostly constructed with inactive materials (such as nanotubes, silicon pillars or substrate materials, etc.) and do not have biological functionality.

[0008] Therefore, based on this, the technical solution of this application is proposed.

[0009] Summary of the Invention

[0010] Based on this, according to various embodiments of the present application, a drug nano-multilevel structure coating and a preparation method thereof are provided, and the technical solution is:

[0011] The present application provides a method for preparing a drug nano-multilevel structure coating, the preparation method comprising the following steps:

[0012] (1) dispersing the nano drug carrier in a solvent to obtain a nano drug carrier suspension;

[0013] (2) dissolving the polyphenol compound, the polyamine compound, the oxidant, and the metal ion in an acidic buffer solution to obtain a polyphenol buffer solution, a polyamine buffer solution, an oxidant buffer solution, and a metal ion buffer solution, respectively;

[0014] (3) adding the nano drug carrier suspension, the polyphenol buffer, the polyamine buffer, and the oxidant buffer in sequence to the surface of the substrate material, and washing the substrate material after the reaction to obtain a reaction sample;

[0015] (4) Immersing the reaction sample in the metal ion buffer solution, and washing and drying in sequence after the reaction to obtain the drug nano-multilevel structure coating.

[0016] To facilitate understanding of the present application, the reaction principle of the present application is described:

[0017] The present application firstly disperses the nano drug carrier particles uniformly in a solvent, and then, in an acidic environment, oxidizes, crosslinks, and polymerizes polyphenol compounds and polyamine compounds under the action of an oxidant to generate a polyphenol nanoparticle (tens of nanometers) structural membrane layer. The nano membrane layer uniformly wraps the nano drug carrier (hundreds of nanometers) and firmly fixes it to the surface of the substrate material; then, in an acidic solution, the metal ions are chelated with the phenolic hydroxyl groups in the nano membrane protective layer. At this time, the metal ions can act as a "screw" connection and increase the structural and functional stability of the nano drug carrier protective layer, ultimately forming a drug nano multi-level structure coating with the drug as the main body.

[0018] Preferably, in step (1), the nano drug carrier is one of polymer nanoparticles (polymer nanospheres and nanocapsules), solid lipid nanoparticles, nanoliposomes, polymer micelles, dendrimers, and inorganic nanoparticles.

[0019] Preferably, in step (1), the solvent is one of an aqueous solution, an ethanol solution, and an ethanol / water mixture; in the ethanol / water mixture, the volume ratio of ethanol to water is 0.1-5:0.1-5.

[0020] Preferably, in step (2), the polyphenol compound is one or a combination of two or more of tannic acid, gallic acid, salvianolic acid B, epigallocatechin gallate, epicatechin gallate, epicatechin, epigallocatechin, catechol, pyrogallol, and flavonoids; the polyamine compound is one or a combination of two or more of ethylenediamine, pentamethylenediamine, 2,2,4-trimethylhexamethylenediamine, 1,8-diaminooctane, methylcyclohexanediamine, 1,3-diaminomethylcyclohexane, 2,4,6-triaminomethylcyclohexane, 1,4-bis(diaminohexyl)cyclohexane, and 2-(3,4-dihydroxyphenyl)ethylamine; the oxidant is one or a combination of two or more of hydrogen peroxide, ammonium persulfate, concentrated nitric acid, sodium periodate, potassium permanganate, and potassium dichromate; and the metal ion is one or a combination of two or more of copper ion, silver ion, zinc ion, and iron ion.

[0021] Preferably, in step (2), the pH of the acidic buffer solution is 3 to 7; the acidic buffer solution is one of acetic acid-acetate buffer solution, 2-(N-morpholinoline)ethanesulfonic acid buffer solution, glycine-hydrochloric acid buffer solution, phthalic acid-hydrochloric acid buffer solution, potassium hydrogen phthalate-sodium hydroxide buffer solution, disodium hydrogen phosphate-citric acid buffer solution, citric acid-sodium hydroxide-hydrochloric acid buffer solution, and citric acid-sodium citrate buffer solution.

[0022] Preferably, in step (3), in the mixed solution consisting of the nano drug carrier suspension, the polyphenol buffer, the polyamine buffer, and the oxidant buffer, the concentration of the nano drug carrier is 0.5-10 mg / mL, the concentration of the polyphenol compound is 0.5-20 mg / mL, the concentration of the polyamine compound is 0.1-10 mg / mL, and the concentration of the oxidant is 0.1-10 mg / mL. More preferably, in the mixed solution, the concentration of the nano drug carrier is 2 mg / mL, the concentration of the polyphenol compound is 1 mg / mL, the concentration of the polyamine compound is 0.5 mg / mL, and the concentration of the oxidant is 0.5 mg / mL.

[0023] Preferably, in step (3), the base material is one of metal-based biomaterials, ceramic-based biomaterials, polymer-based biomaterials, and composite biomaterials.

[0024] Preferably, in step (4), the concentration of the metal ions in the metal ion buffer is 0.05 to 5 mg / mL. More preferably, the concentration of the metal ions is 0.5 mg / mL.

[0025] Preferably, in step (3) and step (4), the reaction temperature is 10-40°C, and the reaction time is 0.1-10 hours. More preferably, in step (3), the reaction temperature is 30°C, and the reaction time is 1 hour; in step (4), the reaction temperature is 30°C, and the reaction time is 2 hours.

[0026] Based on the same technical concept, another solution of the present application is to provide a drug nano-multilevel structure coating obtained by the above preparation method.

[0027] The beneficial effects of this application include:

[0028] 1. The present application is based on the oxidation, cross-linking, polymerization and deposition of polyphenols and polyamine compounds under the action of an oxidant. Only a simple "one-pot" method is needed to form a uniform polyphenol nanoparticle film layer on the surface of a nanodrug carrier. The polyphenol nanoparticle film layer not only increases the stability of the nanodrug carrier, but also firmly fixes the nanodrug carrier on the surface of the substrate material, realizing a body material constructed with the drug as the coating. As long as the coating exists, the drug exists and can exert its biological function for a long time. In addition, the polyphenol nanoparticle film layer is independent of material and can be modified on the surface of substrate materials of different shapes and properties (such as the surface of materials and devices such as catheters, cardiovascular stents, orthopedics, ophthalmology, wound dressings, etc.), and has a wide range of applicability.

[0029] 2. Different from the traditional topological structure preparation method, the size of the polyphenol / metal composite nanoparticles in the drug nano-multilevel structure coating described in this application is in the order of tens of nanometers, while the size of the nano-drug carrier is in the order of hundreds of nanometers. Nanoparticles of different sizes together give the coating a topological structure, and the constructed topological structure will not damage the substrate and has biological activity and biological functions.

[0030] 3. The polyphenol / metal composite nanoparticles in the drug nano-multilevel structure coating described in this application contain a large number of hydrophilic groups such as phenolic hydroxyl groups, carboxyl groups, amino groups, etc., which, together with the multilevel nanostructure, can make the drug structure coating have excellent hydrophilicity, and the coating surface is negatively charged, which can synergistically improve its biocompatibility in the body.

[0031] 4. In the pathological tissue environment of the body, there are often a large number of reactive oxygen free radicals and inflammatory cell infiltration. The polyphenol nanoparticle membrane layer has biological functions related to polyphenol compounds, such as anti-oxidation, free radical scavenging, and inflammation regulation. It can regulate the pathological microenvironment and synergistically exert a therapeutic effect with the drugs in the nanodrug carrier.

[0032] 5. The chelation of metal ions and phenolic hydroxyl groups in the drug nano-multilevel structure coating described in the present application has many functions: the biological function of the metal ions themselves (such as copper ions have the function of catalyzing the release of NO from nitric oxide donors in the blood, giving the coating excellent blood compatibility and antibacterial properties, etc.); the chelated metal ions act as a rivet to further connect the polyphenol nanoparticles, increase the structural stability of the nano drug carrier protective layer, and delay the drug release rate in the coating; the oxidation rate of the phenolic hydroxyl groups after chelation with the metal ions is slowed down, thereby extending their shelf life and the biological function of the polyphenols; the metal ions exist in the coating as cations and can bind to water molecules, synergistically enhancing the wettability of the coating.

[0033] 6. The polyphenol nanoparticle / metal composite layer in the drug nano-multilevel structure coating described in this application is pH-responsive, which can accelerate the dissociation of polyphenol / metal composite nanoparticles in a bacterial infection environment (weakly acidic), open the release window of the drug in the nano-drug carrier, and the released drug and polyphenol can synergistically treat pathological tissues.

[0034] 7. The preparation method described in this application is simple to operate, has efficient reaction, mild conditions, and has broad-spectrum practicality. Different nano-drug carriers can be modified on the surface of substrates of different materials and shapes, and can prepare drug nano-multilevel structure coatings that have drugs present as long as the coating exists and exert long-term biological functions. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0036] FIG1 is a scanning electron microscope (SEM) image of the morphology of the drug nanoscale multi-level structure prepared in Example 1 (scale 10 μm).

[0037] FIG2 is an enlarged view of FIG1 (scale 1 μm).

[0038] Figure 3 is the distribution diagram of C, O, N and Cu elements in the coating detected by EDS spectrometer.

[0039] Figure 4 shows the content of C, O, N and Cu elements in the coating detected by EDS spectrometer. DETAILED DESCRIPTION

[0040] To make the purpose, technical solutions, and advantages of this application more clear, the technical solutions of this application will be described in detail below. Obviously, the embodiments described are only some of the embodiments of this application, rather than all of them. Based on the embodiments in this application, all other implementation methods obtained by ordinary technicians in this field without making any creative work are within the scope of protection of this application.

[0041] Example 1

[0042] This embodiment provides a method for preparing a drug nano-multilevel structure coating, the preparation method comprising the following steps:

[0043] (1) Dispersing the drug-loaded Tween-80 (polymer micelles) uniformly in an ethanol / water mixture to obtain a drug-loaded Tween-80 suspension; wherein the volume ratio of ethanol to water is 1:4;

[0044] (2) dissolving tannic acid, ethylenediamine, sodium periodate, and copper ions in a sodium acetate buffer solution having a pH of 5, respectively, to obtain a tannic acid buffer solution, an ethylenediamine buffer solution, a sodium periodate buffer solution, and a copper ion buffer solution;

[0045] (3) adding the drug-loaded Tween-80 suspension, the tannic acid buffer, the ethylenediamine buffer, and the sodium periodate buffer to the surface of the substrate in sequence, reacting at 25° C. on the surface of the substrate for 3 hours, and then washing with RO water to obtain a reaction sample; wherein, in the mixed solution consisting of the drug-loaded Tween-80 suspension, the tannic acid buffer, the ethylenediamine buffer, and the sodium periodate buffer, the concentration of the drug-loaded Tween-80 is 2 mg / mL, the concentration of tannic acid is 1 mg / mL, the concentration of ethylenediamine is 0.5 mg / mL, and the concentration of sodium periodate is 0.5 mg / mL;

[0046] (4) The reaction sample was immersed in the copper ion buffer solution with a concentration of 0.5 mg / mL, and reacted at a constant temperature of 25° C. for 3 h, and then fully washed with RO water and dried with nitrogen to obtain the drug nano-hierarchical structure coating.

[0047] Example 2

[0048] This embodiment provides a method for preparing a drug nano-multilevel structure coating, the preparation method comprising the following steps:

[0049] (1) uniformly dispersing drug-loaded polylactic acid nanospheres (polymer nanoparticles) in water to obtain a drug-loaded polylactic acid nanosphere suspension;

[0050] (2) dissolving epigallocatechin gallate, pentamethylenediamine, potassium permanganate, and copper ions in a sodium acetate buffer solution at pH 4, respectively, to obtain epigallocatechin gallate buffer solution, pentamethylenediamine buffer solution, potassium permanganate buffer solution, and copper ion buffer solution;

[0051] (3) adding the drug-loaded polylactic acid nanosphere suspension, the epigallocatechin gallate buffer, the pentamethylenediamine buffer, and the potassium permanganate buffer to the surface of the substrate material in sequence, reacting at 20° C. on the surface of the substrate material for 6 hours, and then washing with RO water to obtain a reaction sample; wherein, in the mixed solution consisting of the drug-loaded polylactic acid nanosphere suspension, the epigallocatechin gallate buffer, the pentamethylenediamine buffer, and the potassium permanganate buffer, the concentration of the drug-loaded polylactic acid nanosphere is 5 mg / mL, the concentration of epigallocatechin gallate is 2 mg / mL, the concentration of pentamethylenediamine is 2 mg / mL, and the concentration of potassium permanganate is 2 mg / mL;

[0052] (4) The reaction sample was immersed in the copper ion buffer solution with a concentration of 1 mg / mL, and reacted at a constant temperature of 20° C. for 6 h, and then fully washed with RO water and dried with nitrogen to obtain the drug nano-hierarchical structure coating.

[0053] Example 3

[0054] This embodiment provides a method for preparing a drug nano-multilevel structure coating, the preparation method comprising the following steps:

[0055] (1) uniformly dispersing drug-loaded lecithin (solid lipid nanoparticles) in water to obtain a drug-loaded lecithin suspension;

[0056] (2) Gallic acid, 2,2,4-trimethylhexamethylenediamine, sodium periodate, and iron ions (Fe3+) were dissolved in a phthalic acid-hydrochloric acid buffer solution with a pH of 3.5 to obtain gallic acid buffer, 2,2,4-trimethylhexamethylenediamine buffer, sodium periodate buffer, and iron ion buffer, respectively;

[0057] (3) adding the drug-loaded lecithin suspension, the gallic acid buffer, the 2,2,4-trimethylhexamethylenediamine buffer, and the sodium periodate buffer to the surface of the substrate material in sequence, reacting at 15° C. on the surface of the substrate material for 10 h, and then washing with RO water to obtain a reaction sample; wherein, in the mixed solution consisting of the drug-loaded lecithin suspension, the gallic acid buffer, the 2,2,4-trimethylhexamethylenediamine buffer, and the sodium periodate buffer, the concentration of the drug-loaded lecithin is 6 mg / mL, the concentration of gallic acid is 3 mg / mL, the concentration of 2,2,4-trimethylhexamethylenediamine is 3 mg / mL, and the concentration of sodium periodate is 3 mg / mL;

[0058] (4) The reaction sample was immersed in the iron ion buffer solution with a concentration of 1 mg / mL, and reacted at a constant temperature of 10° C. for 10 h, and then fully washed with RO water and dried with nitrogen to obtain the drug nano-hierarchical structure coating.

[0059] Example 4

[0060] This embodiment provides a method for preparing a drug nano-multilevel structure coating, the preparation method comprising the following steps:

[0061] (1) uniformly dispersing the drug-loaded nanoliposomes in water to obtain a drug-loaded nanoliposome suspension;

[0062] (2) dissolving pyrogallol, 1,8-diaminooctane, ammonium persulfate and silver ions in a citric acid-sodium citrate buffer solution at pH 4, respectively, to obtain pyrogallol buffer solution, 1,8-diaminooctane buffer solution, ammonium persulfate buffer solution and silver ion buffer solution;

[0063] (3) adding the drug-loaded nanoliposome suspension, the pyrogallol buffer, the 1,8-diaminooctane buffer, and the ammonium persulfate buffer on the surface of the substrate in sequence, reacting at 35° C. on the surface of the substrate for 1 hour, and then washing with RO water to obtain a reaction sample; wherein, in the mixed solution consisting of the drug-loaded nanoliposome suspension, the pyrogallol buffer, the 1,8-diaminooctane buffer, and the ammonium persulfate buffer, the concentration of the drug-loaded nanoliposome is 2 mg / mL, the concentration of pyrogallol is 2 mg / mL, the concentration of 1,8-diaminooctane is 1.5 mg / mL, and the concentration of ammonium persulfate is 2 mg / mL;

[0064] (4) The reaction sample was immersed in the silver ion buffer solution with a concentration of 0.1 mg / mL, and reacted at a constant temperature of 35° C. for 1 hour, and then fully washed with RO water and dried with nitrogen to obtain the drug nano-hierarchical structure coating.

[0065] Example 5

[0066] This embodiment provides a method for preparing a drug nano-multilevel structure coating, the preparation method comprising the following steps:

[0067] (1) uniformly dispersing drug-loaded porous silica nanoparticles (inorganic nanoparticles) in water to obtain a drug-loaded porous silica nanoparticle suspension;

[0068] (2) epicatechin gallate, 1,3-diaminomethylcyclohexane, potassium dichromate, and zinc ion are dissolved in a glycine-hydrochloric acid buffer solution at pH 6, respectively, to obtain epicatechin gallate buffer solution, 1,3-diaminomethylcyclohexane buffer solution, potassium dichromate buffer solution, and zinc ion buffer solution;

[0069] (3) adding the drug-loaded porous silica nanoparticle suspension, the epicatechin gallate buffer, the 1,3-diaminomethylcyclohexane buffer, and the potassium dichromate buffer to the surface of the substrate material in sequence, reacting at 35° C. on the surface of the substrate material for 0.5 h, and then washing with RO water to obtain a reaction sample; wherein, in the mixed solution consisting of the drug-loaded porous silica nanoparticle suspension, the epicatechin gallate buffer, the 1,3-diaminomethylcyclohexane buffer, and the potassium dichromate buffer, the concentration of the drug-loaded porous silica nanoparticles is 6 mg / mL, the concentration of epicatechin gallate is 2 mg / mL, the concentration of 1,3-diaminomethylcyclohexane is 2 mg / mL, and the concentration of potassium dichromate is 2 mg / mL;

[0070] (4) The reaction sample was immersed in the zinc ion buffer solution with a concentration of 1.5 mg / mL, and the reaction was carried out at a constant temperature of 35° C. for 0.5 h. The reaction sample was then fully washed with RO water and dried with nitrogen to obtain the drug nano-hierarchical structure coating.

[0071] Example 6

[0072] This embodiment provides a method for preparing a drug nano-multilevel structure coating, the preparation method comprising the following steps:

[0073] (1) uniformly dispersing the drug-loaded poloxamer nanodrug carrier (polymer micelle) in water to obtain a drug-loaded poloxamer nanodrug carrier suspension;

[0074] (2) dissolving epigallocatechin, methylcyclohexanediamine, 30% hydrogen peroxide, and zinc ion in an acetic acid-acetate buffer solution at pH 6.5, respectively, to obtain epigallocatechin buffer solution, methylcyclohexanediamine buffer solution, 30% hydrogen peroxide buffer solution, and zinc ion buffer solution, respectively;

[0075] (3) adding the drug-loaded poloxamer nano-drug carrier suspension, the epigallocatechin buffer solution, the methylcyclohexanediamine buffer solution, and the 30% hydrogen peroxide buffer solution to the surface of the substrate material in sequence, reacting the mixture at 15° C. for 8 h on the surface of the substrate material, and then washing the mixture with RO water to obtain a reaction sample; wherein, in the mixed solution consisting of the drug-loaded poloxamer nano-drug carrier suspension, the epigallocatechin buffer solution, the methylcyclohexanediamine buffer solution, and the 30% hydrogen peroxide buffer solution, the concentration of the drug-loaded poloxamer nano-drug carrier is 8 mg / mL, the concentration of epigallocatechin is 6 mg / mL, the concentration of methylcyclohexanediamine is 4 mg / mL, and the concentration of 30% hydrogen peroxide is 5%;

[0076] (4) The reaction sample was immersed in the zinc ion buffer solution with a concentration of 4 mg / mL, and reacted at a constant temperature of 15° C. for 8 h, and then fully washed with RO water and dried with nitrogen to obtain the drug nano-hierarchical structure coating.

[0077] Experimental example

[0078] The drug nano-hierarchical structure coating obtained in Example 1 was observed by SEM. The results are shown in Figures 1 and 2. It can be seen from the figures that a layer of nano-hierarchical structure coating composed mainly of nano-drug carriers is generated on the surface of the base material. The outer surface of the nano-drug carrier in the coating is uniformly covered with polyphenol nanoparticles with a particle size of 10 to 20 nm. The reaction process does not change the morphology of the nano-drug carrier and has a nano-hierarchical structure.

[0079] From the EDS spectra of the drug nano-hierarchical structure coating in Figures 3 and 4, it can be seen that the metal Cu2+ is uniformly distributed in the coating.

[0080] The above description is merely a specific embodiment of the present application, but the scope of protection of the present application is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in this application should be included in the scope of protection of this application. Therefore, the scope of protection of this application should be based on the scope of protection of the claims.

Claims

1. A method for preparing a drug nano multi-level structure coating, characterized in that: The preparation method comprises the following steps: (1) dispersing the nano drug carrier in a solvent to obtain a nano drug carrier suspension; (2) dissolving the polyphenol compound, the polyamine compound, the oxidant and the metal ion in an acidic buffer respectively to obtain a polyphenol buffer, a polyamine buffer, an oxidant buffer and a metal ion buffer respectively; (3) adding the nano drug carrier suspension, the polyphenol buffer, the polyamine buffer, and the oxidant buffer in sequence to the surface of the substrate material, and washing the substrate material surface after the reaction to obtain a reaction sample; and (4) Immersing the reaction sample in the metal ion buffer solution, and washing and drying in sequence after the reaction, thereby obtaining the drug nano-multilevel structure coating.

2. The method for preparing the drug nano multi-level structure coating according to claim 1, characterized in that: In step (1), the nano drug carrier is one of polymer nanoparticles, solid lipid nanoparticles, nanoliposomes, polymer micelles, dendritic macromolecules and inorganic nanoparticles.

3. The method for preparing the drug nano multi-level structure coating according to claim 1 or 2, characterized in that: In step (1), the solvent is one of an aqueous solution, an ethanol solution, and an ethanol / water mixture; In the ethanol / water mixture, the volume ratio of ethanol to water is about 0.1-5:0.1-5.

4. The method for preparing the drug nano multi-level structure coating according to any one of claims 1 to 3, characterized in that: In step (2), the polyphenol compound is one or a combination of two or more of tannic acid, gallic acid, salvianolic acid B, epigallocatechin gallate, epicatechin gallate, epicatechin, epigallocatechin, catechol, pyrogallol and flavonoids; The polyamine compound is one or a combination of two or more of ethylenediamine, pentamethylenediamine, 2,2,4-trimethylhexamethylenediamine, 1,8-diaminooctane, methylcyclohexanediamine, 1,3-diaminomethylcyclohexane, 2,4,6-triaminomethylcyclohexane, 1,4-bis(diaminohexyl)cyclohexane and 2-(3,4-dihydroxyphenyl)ethylamine; The oxidant is one or a combination of two or more of hydrogen peroxide, ammonium persulfate, concentrated nitric acid, sodium periodate, potassium permanganate and potassium dichromate; The metal ions are one or a combination of two or more of copper ions, silver ions, zinc ions and iron ions.

5. The method for preparing the drug nano multi-level structure coating according to any one of claims 1 to 4, characterized in that: In step (2), the pH of the acidic buffer solution is about 3 to 7; The acidic buffer is one of acetic acid-acetate buffer, 2-(N-morpholine)ethanesulfonic acid buffer, glycine-hydrochloric acid buffer, phthalic acid-hydrochloric acid buffer, potassium hydrogen phthalate-sodium hydroxide buffer, disodium hydrogen phosphate-citric acid buffer, citric acid-sodium hydroxide-hydrochloric acid buffer and citric acid-sodium citrate buffer.

6. The method for preparing the drug nano multi-level structure coating according to any one of claims 1 to 5, characterized in that: In step (3), in the mixed solution consisting of the nano drug carrier suspension, the polyphenol buffer, the polyamine buffer and the oxidant buffer, the concentration of the nano drug carrier is about 0.5-10 mg / mL, the concentration of the polyphenol compound is about 0.5-20 mg / mL, the concentration of the polyamine compound is about 0.1-10 mg / mL, and the concentration of the oxidant is about 0.1-10 mg / mL.

7. The method for preparing the drug nano multi-level structure coating according to any one of claims 1 to 6, characterized in that: In step (3), the substrate material is one of metal-based biomaterials, ceramic-based biomaterials, polymer-based biomaterials and composite biomaterials.

8. The method for preparing the drug nano multi-level structure coating according to any one of claims 1 to 7, characterized in that: In step (4), the concentration of metal ions in the metal ion buffer is about 0.05 to 5 mg / mL.

9. The method for preparing the drug nano multi-level structure coating according to any one of claims 1 to 8, characterized in that: In step (3) and step (4), the reaction temperature is about 10 to 40° C., and the reaction time is about 0.1 to 10 h.

10. The drug nano multi-level structure coating obtained by the preparation method according to any one of claims 1 to 9.

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