Injectable drug-loaded adhesive hydrogel as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of drug-loaded adhesive hydrogel, and particularly relates to injectable drug-loaded adhesive hydrogel as well as a preparation method and application thereof. According to the hydrogel, dopamine hydrochloride modified biological macromolecules with amino groups and biological macromolecules with aldehyde groups serve as matrixes, a long-chain network structure is formed through a Schiff base reaction, and then iron ions serve as a complexing agent, so that the hydrogel is prepared. And complexing and cross-linking the dopamine hydrochloride modified carboxymethyl-beta-cyclodextrin and the long-chain network structure to form an ion dissipation network, thereby obtaining the injectable drug-loading adhesive hydrogel. Wherein the dopamine hydrochloride modified carboxymethyl-beta-cyclodextrin is loaded with antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecules. The hydrogel prepared by the invention consists of two networks, namely a long-chain network and an ion dissipation network, and has excellent bonding performance, drug-loading slow release is realized on the molecular level through hydrophilic molecule carboxymethyl-beta-cyclodextrin, and an injectable strong tissue bonding hydrogel drug-loading system is developed.

Description

Technical Field

[0001] The invention belongs to the technical field of drug-loaded adhesive hydrogels, and in particular relates to an injectable drug-loaded adhesive hydrogel and a preparation method and application thereof. Background Art

[0002] Oral administration is swallowed and the drug flows through the blood and liver, and is absorbed in different parts of the gastrointestinal tract to exert systemic effects. Common problems with traditional drug delivery methods include systemic metabolism of drugs, rapid decay of drug concentration, low bioavailability, and large toxic side effects. Hydrogel is a soft and wet material composed of a three-dimensional polymer network and water. The high water content makes the physical properties of hydrogels similar to those of tissues and gives hydrogels good biocompatibility. Hydrogels vary in size, structure, and function, with lengths ranging from nanometers to centimeters, and can be formed into almost any size and shape. Today, hydrogel drug delivery has been used in many branches of medicine. The advantages of hydrogel drug delivery include adjustable physical properties, spatial and temporal control of drug release, and protection of unstable drugs from degradation.

[0003] The strong adhesion technology between hydrogel and tissue has made great breakthroughs in recent years, and hydrogel can be used as a drug carrier, so strong tissue adhesion hydrogel shows great potential in drug delivery. In 2017, Science reported a strong tissue adhesion hydrogel with a bonding energy of 1000 J / m 2 , which marked the beginning of a breakthrough in hydrogel tissue adhesion. Strong tissue adhesion hydrogel drug delivery can promote drug diffusion from hydrogel to target tissue by increasing direct contact surface and reducing diffusion. Nature Biomedical Engineering first reported the application of a strong adhesive system to treat tendon injuries, with the hydrogel and tendon surface generating an adhesion energy greater than 1000 J / m 2 In addition to tissue bonding, the hydrogel can also be used for local drug release. This shows that strong tissue bonding hydrogels do have great advantages in drug delivery.

[0004] In recent years, hydrogels have been widely used in the treatment of oral diseases due to their characteristics, mainly in oral postoperative care, local oral anesthesia, oral mucosal diseases and cancer treatment. In existing studies, the weak adhesion of drug-loaded hydrogels in the oral environment leads to easy debonding of the hydrogels, and the physical embedding of drugs leads to the burst release of drugs. At the same time, the hydrogels cannot load drugs with poor water solubility. Summary of the invention

[0005] To this end, the present invention provides an injectable drug-loaded adhesive hydrogel and its preparation method and application, and designs from the molecular level to develop an injectable strong tissue adhesive hydrogel drug-loaded system to achieve long-term retention and stable sustained release of multiple types of hydrophobic drugs at the target site. The innovation lies in the excellent adhesive performance and drug-loading efficiency of the hydrogel, the ability to achieve slow and sustained release of drugs, and the ability to replace multiple types of hydrophobic drugs.

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] The first object of the present invention is to provide an injectable drug-loaded adhesive hydrogel, wherein the hydrogel uses dopamine hydrochloride-modified biomacromolecules with amino groups and biomacromolecules with aldehyde groups as a matrix, forms a long-chain network structure polymer layer through Schiff base reaction, and then uses iron ions as a complexing agent to complex and cross-link dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin and dopamine hydrochloride in the long-chain network structure polymer to form an ion dissipation polymer layer, thereby obtaining an injectable drug-loaded adhesive hydrogel; wherein the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin is loaded with antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecules, and then the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin is fixed on the long-chain network structure polymer layer under the complexing action of iron ions.

[0008] Furthermore, the preparation method of the biomacromolecule with amino group modified by dopamine hydrochloride comprises the following steps:

[0009] In a protective gas atmosphere, a biomacromolecule solution with amino groups and dopamine hydrochloride are mixed, and under the action of a condensing agent, dopamine hydrochloride and the biomacromolecule with amino groups undergo an amide reaction to obtain a biomacromolecule with amino groups modified by dopamine hydrochloride or a carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride.

[0010] Furthermore, the mass ratio of the biomacromolecule with an amino group, dopamine hydrochloride and the condensing agent is 20 to 200:1:4, the biomacromolecule with an amino group is chitosan, gelatin or collagen, the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, and the mass ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is 1 to 1.5:1; the temperature of the amide reaction is 37° C., the reaction time is 12 h to 24 h, and the protective gas is nitrogen.

[0011] Furthermore, the preparation method of dopamine hydrochloride modified carboxymethyl-β-cyclodextrin comprises the following steps:

[0012] In a protective gas atmosphere, a carboxymethyl-β-cyclodextrin solution and dopamine hydrochloride are mixed, and under the action of a condensing agent, dopamine hydrochloride and carboxymethyl-β-cyclodextrin undergo an amide reaction to obtain carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride.

[0013] Furthermore, the mass ratio of the carboxymethyl-β-cyclodextrin, dopamine hydrochloride and the condensing agent is 13-40:13:5, the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, and the mass ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is 1-1.5:1; the temperature of the amide reaction is room temperature, the reaction time is 12h-24h, and the protective gas is nitrogen.

[0014] The second object of the present invention is to provide a method for preparing the above-mentioned injectable drug-loaded adhesive hydrogel, comprising the following steps:

[0015] Adding a biomacromolecule with an amino group modified by dopamine hydrochloride to a toughening agent solution, then adding a carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride, and adding an antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecule, reacting and mixing at 37° C., so that the hydrophobic drug molecule is loaded on the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride, to form a reaction solution A;

[0016] The biomacromolecules with aldehyde groups and iron ions are mixed at room temperature to form a reaction solution B;

[0017] The reaction solution A and the reaction solution B are mixed at room temperature, and the biomacromolecules with amino groups modified by dopamine hydrochloride react with the biomacromolecules with aldehyde groups to form a long-chain network structure polymer layer. At the same time, under the action of iron ions, the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride and the long-chain network structure polymer are complexed and cross-linked to form an ion dissipation polymer layer, thereby obtaining an injectable drug-loaded adhesive hydrogel.

[0018] Furthermore, the mass ratio of the dopamine hydrochloride-modified biomacromolecule with amino group to the toughening agent solution is 19:65:1-5, the concentration of the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin is 1%wt.%-50%wt.%, and the anti-tumor hydrophobic drug molecule includes one of camptothecin, resveratrol, dexamethasone or paclitaxel.

[0019] Furthermore, the mass ratio of the biomacromolecule with aldehyde group and the biomacromolecule with amino group modified by dopamine hydrochloride is 0.1-0.2:1, the biomacromolecule with aldehyde group is oxidized dextran, oxidized hyaluronic acid, oxidized cellulose, the volume ratio of iron ion and carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride is 1-5:1-5, the concentration of the biomacromolecule with aldehyde group is 5wt%, and the molar concentration of the iron ion is 0.0001mol / l~0.03mol / l.

[0020] Furthermore, the mass ratio of reaction liquid A to reaction liquid B is 5 to 10:1.

[0021] The third object of the present invention is to provide the use of the above-mentioned injectable drug-loaded adhesive hydrogel in the preparation of oral antibacterial, anti-inflammatory or anti-tumor drugs.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) The injectable drug-loaded adhesive hydrogel provided by the present invention is composed of two layers of networks, a long-chain network polymer and an ion-dissipating polymer. The long-chain network polymer uses a biomacromolecule with an amino group modified with dopamine hydrochloride as a matrix and a biomacromolecule with an aldehyde group as a cross-linking agent, and cross-linking is generated by a Schiff base reaction between the amino group and the aldehyde group; the ion-dissipating network polymer is formed by the complexation of dopamine hydrochloride with iron ions. The biomacromolecule with an amino group and carboxymethyl-β-cyclodextrin are both modified and grafted with dopamine hydrochloride. After the addition of iron ions, the dopamine hydrochloride is mutually complexed, and the carboxymethyl-β-cyclodextrin loaded with hydrophobic drug molecules can be cross-linked with the long-chain network polymer to form a drug-loaded adhesive hydrogel. The bonding energy between the hydrogel and biological tissue comes from three parts: the rapid action of hydrogen bonds and the complexation of covalent bonds and iron ions; the aldehyde groups in the network and the tissue The amino groups on the hydrochloride undergo Schiff base reaction; at the same time, due to the characteristics of the dopamine hydrochloride molecules themselves, the hydrogel can also have a certain adhesion ability in a humid environment, increase the adhesion of the hydrogel, and make the hydrogel have excellent adhesion; and the carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride is loaded with antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecules, the hydrophobic molecules are coated to form inclusion compounds, and the carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride is fixed on the long-chain network polymer by complexation under iron ions, thereby achieving slow drug release and multiple drug loading; in summary, the present invention is designed at the molecular level to develop an injectable strong tissue adhesion hydrogel drug loading system, which can achieve long-term residence and stable sustained release of multiple types of hydrophobic drugs at the target, the hydrogel has excellent adhesion performance and drug loading efficiency, can achieve slow and sustained drug release, and can replace multiple types of hydrophobic drugs.

[0024] (2) The carboxymethyl-β-cyclodextrin in the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin of the present invention is similar to a hollow truncated cone, and its outer hydrophilicity is relatively strong, and it is easy to attract hydrophilic molecules, while its inner hydrophobicity is relatively strong, and it can encapsulate hydrophobic molecules; when the dopamine-modified carboxymethyl-β-cyclodextrin is mixed with hydrophobic drug molecules, the dopamine-modified carboxymethyl-β-cyclodextrin encapsulates the hydrophobic drug molecules to form an inclusion complex, which can prolong the retention time of the drug in the body and enhance the targeting of the drug.

[0025] (3) The drug-loaded adhesive hydrogel of the present invention is an injectable in situ formed hydrogel, which responds to changes in injection shear force and gels through covalent bonds and complex interactions. It can be easily injected and adhered to the target site. It is simple to operate, has arbitrary shaping, and is less traumatic. The preparation conditions are mild and no harmful substances are produced. It is easy to carry out large-scale industrial production. Nanocellulose is added to the preparation of the drug-loaded adhesive hydrogel for toughening, which improves the mechanical properties of the hydrogel. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The present invention is a process flow chart for preparing the injectable drug-loaded adhesive hydrogel.

[0027] Figure 2 This is a graph showing the bonding performance of the hydrogel at different dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin concentrations of the present invention.

[0028] Figure 3 This is a drug release curve diagram of the injectable drug-loaded adhesive hydrogel according to Example 1 of the present invention.

[0029] Figure 4 This is a graph showing the solubilization ability of dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin for resveratrol. DETAILED DESCRIPTION

[0030] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] It should be noted that the professional terms used in the present invention are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention. Unless otherwise specifically stated, the various raw materials, reagents, instruments and equipment used in the following embodiments of the present invention can be purchased from the market or prepared by existing methods.

[0032] The existing drug-loaded hydrogels in the oral environment mainly face the following problems: (1) Weak adhesion makes the hydrogel easy to debond; (2) Physical encapsulation leads to the rapid release of drugs, and the hydrogel cannot load drugs with poor water solubility; (3) Most of the drug-loaded hydrogels are patch-type and cannot conform to the structure of the oral cavity.

[0033] In view of the above problems, the present invention is designed from the molecular level to develop an injectable strong tissue adhesive hydrogel drug-carrying system. On the one hand, the present invention provides an injectable drug-carrying adhesive hydrogel, wherein the hydrogel is based on a biomacromolecule with an amino group and a biomacromolecule with an aldehyde group modified by dopamine hydrochloride as a matrix, and a long-chain network structure polymer layer is formed by a Schiff base synthesis reaction, and at the same time, iron ions are used as a complexing agent to complex and cross-link the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride and the dopamine hydrochloride in the long-chain network structure polymer to form an ion dissipation polymer layer, thereby obtaining an injectable drug-carrying adhesive hydrogel; wherein the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride is loaded with antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecules, and then the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride is fixed on the long-chain network structure polymer layer under the complexation of iron ions.

[0034] The hydrogel provided by the present invention is composed of two layers of networks, a long-chain network polymer and an ion dissipation polymer. The long-chain network polymer uses a biomacromolecule with an amino group modified by dopamine hydrochloride as a matrix, and the biomacromolecule with an aldehyde group undergoes a Schiff base reaction with the amino group and the aldehyde group to generate crosslinking; the ion dissipation network polymer is formed by the complexation of dopamine hydrochloride with iron ions. The biomacromolecule with an amino group and carboxymethyl-β-cyclodextrin are both modified and grafted with dopamine hydrochloride, and then iron ions are added to form a complexation of dopamine hydrochloride with the dopamine hydrochloride. The carboxymethyl-β-cyclodextrin loaded with drugs can be crosslinked with the long-chain network polymer to form a drug-loaded adhesive hydrogel. The adhesive energy between the hydrogel and the biological tissue comes from three parts: the rapid action of hydrogen bonds and the complexation of covalent bonds and iron ions; the Schiff base reaction between the aldehyde groups in the network and the amino groups on the tissue; and the addition of salts. Due to its own characteristics, the acid dopamine molecule can also allow the hydrogel to have a certain adhesion ability in a humid environment, increase the adhesion of the hydrogel, and make the hydrogel have excellent adhesion; and the carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride is loaded with antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecules, the hydrophobic molecules are coated to form inclusion compounds, and the hydrophilic carrier molecules (carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride) are fixed on the long-chain network polymer by complexation under iron ions, thereby achieving slow drug release and multiple drug loading; in summary, the present invention is designed at the molecular level to develop an injectable strong tissue adhesion hydrogel drug loading system, which can achieve long-term residence and stable sustained release of multiple types of hydrophobic drugs at the target, the hydrogel has excellent adhesion performance and drug loading efficiency, can achieve slow and sustained drug release, and can replace multiple types of hydrophobic drugs.

[0035] The drug-loaded adhesive hydrogel of the present invention is an injectable in situ formed hydrogel, which responds to changes in injection shear force and gels through covalent bonds and complex interactions, can be conveniently injected and adhered to the target site, is simple to operate, has arbitrary shaping, and has little trauma, etc., has mild preparation conditions, and does not produce harmful substances, and is easy to carry out large-scale industrial production.

[0036] In a specific embodiment, the method for preparing a biomacromolecule modified with dopamine hydrochloride and having an amino group comprises the following steps:

[0037] In a protective gas atmosphere, a biomacromolecule solution with amino groups and dopamine hydrochloride are mixed, and under the action of a condensation agent, dopamine hydrochloride and the biomacromolecule with amino groups undergo an amide reaction to obtain a biomacromolecule with amino groups modified with dopamine hydrochloride.

[0038] In the process of preparing the biomacromolecule with amino group modified by dopamine hydrochloride, the mass ratio of the biomacromolecule with amino group, dopamine hydrochloride and condensation agent is 20-200:1:4, the biomacromolecule with amino group is chitosan, gelatin or collagen, the condensation agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, and the mass ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is 1-1.5:1; the temperature of amide reaction is 37°C, the reaction time is 12h-24h, and the protective gas is nitrogen.

[0039] In a specific embodiment, the preparation method of dopamine hydrochloride modified carboxymethyl-β-cyclodextrin comprises the following steps:

[0040] In a protective gas atmosphere, a carboxymethyl-β-cyclodextrin solution and dopamine hydrochloride are mixed, and under the action of a condensing agent, dopamine hydrochloride and carboxymethyl-β-cyclodextrin undergo an amide reaction to obtain dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin.

[0041] Wherein, in the process of preparing dopamine hydrochloride modified carboxymethyl-β-cyclodextrin, the mass ratio of the carboxymethyl-β-cyclodextrin, dopamine hydrochloride and the condensing agent is 13-40:13:5, the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, and the mass ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is 1-1.5:1; the temperature of the amide reaction is room temperature, the reaction time is 12h-24h, and the protective gas is nitrogen.

[0042] In a specific embodiment, the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin is loaded with antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecules, and the anti-tumor active ingredients include one of camptothecin, resveratrol, dexamethasone and paclitaxel. Carboxymethyl-β-cyclodextrin is similar to a hollow frustum, and its external hydrophilicity is strong, which easily attracts hydrophilic molecules, while its internal hydrophobicity is strong, which can wrap hydrophobic molecules; when the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin cyclodextrin is mixed with hydrophobic drug molecules, the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin coats the hydrophobic drug molecules to form an inclusion complex, which can prolong the retention time of the drug in the body and enhance the targeting of the drug; the complexation of dopamine hydrochloride under iron ions fixes the hydrophilic carrier molecules on the long-chain network, thereby introducing them into the system.

[0043] On the other hand, the present invention provides a method for preparing the above-mentioned injectable drug-loaded adhesive hydrogel, the process flow is as follows Figure 1 As shown, the following steps are included:

[0044] Adding a biomacromolecule with an amino group modified by dopamine hydrochloride to a toughening agent solution, then adding a carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride, and adding an antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecule, reacting and mixing at 37° C., the hydrophobic drug molecule is loaded on the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride to form a reaction solution A;

[0045] The biomacromolecules with aldehyde groups and iron ions are mixed at room temperature to form a reaction solution B;

[0046] The reaction solution A and the reaction solution B are mixed at room temperature, and the biomacromolecules with amino groups modified by dopamine hydrochloride react with the biomacromolecules with aldehyde groups to form a long-chain network structure polymer layer. At the same time, under the action of iron ions, the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride and the long-chain network structure polymer are complexed and cross-linked to form an ion dissipation polymer layer, thereby obtaining an injectable drug-loaded adhesive hydrogel.

[0047] In the present invention, the dopamine hydrochloride solution first modifies the biomacromolecules with amino groups and carboxymethyl-β-cyclodextrin, respectively. When the reaction solution A and the reaction solution B are mixed, the amino group and the aldehyde group react to produce crosslinking, that is, the Schiff base synthesis reaction forms a long-chain network structure polymer layer. Under the action of iron ions, the dopamine hydrochloride molecules are complexed, and the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride and the long-chain network structure polymer are complexed. In addition, the bonding energy of biological tissues comes partly from the rapid action of hydrogen bonds, and partly from the Schiff base reaction between the aldehyde groups in the network and the amino groups on the tissue. The dopamine hydrochloride molecules can also allow the hydrogel to have a certain bonding ability in a humid environment due to their own characteristics. In addition, nanocellulose is added to toughen the hydrogel when preparing the hydrogel, which improves the mechanical properties of the hydrogel.

[0048] In a specific embodiment, the mass ratio of the biomacromolecule with amino group modified by dopamine hydrochloride and the toughening agent solution is 19:65:1-5, and the concentration of the carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride is 1%wt.%-50%wt.%. Among them, the drug loading of the injectable drug-loaded adhesive hydrogel can be increased by adjusting the ratio of the carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride, and the more carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride, the greater the drug loading of the hydrogel. At the same time, carboxymethyl-β-cyclodextrin will affect the mechanical properties of the hydrogel. As a preferred embodiment of the present invention, the mass ratio of the biomacromolecule with amino group modified by dopamine hydrochloride, the toughening agent and the carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride is 19:65:1.

[0049] In a specific embodiment, the mass ratio of the biomacromolecule with aldehyde group and the biomacromolecule solution with amino group modified by dopamine hydrochloride is 0.1-0.2:1, the biomacromolecule with aldehyde group is oxidized dextran, oxidized hyaluronic acid, oxidized cellulose, the volume ratio of iron ion and carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride is 1-5:1-5, the concentration of the biomacromolecule with aldehyde group is 5wt%, and the molar concentration of the iron ion is 0.0001mol / l-0.03mol / l. Among them, the solid content of the injectable drug-loaded adhesive hydrogel is adjusted by the ratio of the biomacromolecule solution with amino group modified by dopamine hydrochloride and the biomacromolecule solution with aldehyde group, and the solid content affects the mechanical properties of the hydrogel and thus affects the adhesive properties of the hydrogel. As a preferred embodiment of the present invention, the mass ratio of the biomacromolecule with aldehyde group and the biomacromolecule solution with amino group modified by dopamine hydrochloride is 0.182:1.

[0050] In a specific embodiment, the mass ratio of reaction liquid A to reaction liquid B is 5 to 10: 1. As a preferred embodiment of the present invention, the mass ratio of reaction liquid A to reaction liquid B is 5.49:1.

[0051] The invention is further described below through specific examples.

[0052] Example 1

[0053] A method for preparing an injectable drug-loaded adhesive hydrogel, the process flow is as follows Figure 1 As shown, the following steps are included:

[0054] S1. Preparation of dopamine hydrochloride modified gelatin, comprising the following steps:

[0055] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0056] At 37°C, gelatin powder was added to the buffer solution and magnetically stirred until dissolved. NaOH solution was added dropwise to adjust the pH to about 4.5. EDC and NHS were then added and stirred for 20 minutes to activate the carboxyl groups to obtain a gelatin solution with a gelatin concentration of 1.39%. The mass ratio of gelatin, EDC and NHS was 100:1:1.

[0057] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution with a mass ratio of dopamine hydrochloride to gelatin of 1:200 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution is added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution is dialyzed and freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0058] The method for preparing dopamine-modified carboxymethyl-β-cyclodextrin comprises the following steps:

[0059] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0060] Add carboxymethyl-β-cyclodextrin to the buffer solution, stir magnetically until dissolved, adjust the pH to about 5.5 with a concentrated NaOH solution, then add EDC and NHS, stir for 20 minutes to activate the carboxyl group, and obtain a carboxymethyl-β-cyclodextrin solution. The concentration of carboxymethyl-β-cyclodextrin is 5%, and the mass ratio of carboxymethyl-β-cyclodextrin, EDC and NHS is 18:1:1.

[0061] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution, the mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin is 13:40, to form a dopamine hydrochloride solution, and the dopamine hydrochloride solution is added to the carboxymethyl-β-cyclodextrin solution, and the reaction is completed after stirring for 12 hours; the solution obtained by the sufficient reaction is dialyzed, and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride modified carboxymethyl-β-cyclodextrin.

[0062] S2. Add dopamine hydrochloride modified gelatin powder to a 5wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the nanocellulose aqueous solution is 19:65, then add a 30wt.% dopamine hydrochloride modified carboxymethyl-β-cyclodextrin aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin solution is 19:1, and add resveratrol, mix at 37°C to obtain reaction solution A.

[0063] S3. Mix an aqueous solution of oxidized dextran with a concentration of 5wt% and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001mol / l) at room temperature, wherein the mass ratio of oxidized dextran to the gelatin solution modified with dopamine hydrochloride is 0.182:1, and the volume ratio of iron ions to the carboxymethyl-β-cyclodextrin solution modified with dopamine hydrochloride is 1:1, to form a reaction solution B; mix the reaction solution A and the reaction solution B at a mass ratio of 5.49:1 at room temperature to obtain an injectable drug-loaded adhesive hydrogel.

[0064] Example 2

[0065] A method for preparing an injectable drug-loaded adhesive hydrogel, the process flow is as follows Figure 1 As shown, the following steps are included:

[0066] S1. Preparation of dopamine hydrochloride modified gelatin, comprising the following steps:

[0067] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0068] At 37°C, gelatin powder was added to the buffer solution and magnetically stirred until dissolved. NaOH solution was added dropwise to adjust the pH to about 4.5. EDC and NHS were then added and stirred for 20 minutes to activate the carboxyl groups to obtain a gelatin solution with a gelatin concentration of 1.39%. The mass ratio of gelatin, EDC and NHS was 100:1:1.

[0069] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution with a mass ratio of dopamine hydrochloride to gelatin of 1:200 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution is added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution is dialyzed and freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0070] The method for preparing dopamine-modified carboxymethyl-β-cyclodextrin comprises the following steps:

[0071] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0072] Add carboxymethyl-β-cyclodextrin to the buffer solution, stir magnetically until dissolved, adjust the pH to about 5.5 with a concentrated NaOH solution, then add EDC and NHS, stir for 20 minutes to activate the carboxyl group, and obtain a carboxymethyl-β-cyclodextrin solution. The concentration of carboxymethyl-β-cyclodextrin is 5%, and the mass ratio of carboxymethyl-β-cyclodextrin, EDC and NHS is 18:1:1.

[0073] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution, the mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin is 13:40, to form a dopamine hydrochloride solution, and the dopamine hydrochloride solution is added to the carboxymethyl-β-cyclodextrin solution, and the reaction is completed after stirring for 12 hours; the solution obtained by the sufficient reaction is dialyzed, and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride modified carboxymethyl-β-cyclodextrin.

[0074] S2. Add dopamine hydrochloride modified gelatin powder to a 5wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the nanocellulose aqueous solution is 19:65, then add a 30wt.% dopamine hydrochloride modified carboxymethyl-β-cyclodextrin aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin solution is 19:2, and add resveratrol, mix at 37°C to obtain reaction solution A.

[0075] S3. Mix an aqueous solution of oxidized dextran with a concentration of 5wt% and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001mol / l) at room temperature, wherein the mass ratio of oxidized dextran to the gelatin solution modified with dopamine hydrochloride is 0.182:1, and the volume ratio of iron ions to the carboxymethyl-β-cyclodextrin solution modified with dopamine hydrochloride is 1:2, to form a reaction solution B; mix the reaction solution A and the reaction solution B at a mass ratio of 5.49:1 at room temperature to obtain an injectable drug-loaded adhesive hydrogel.

[0076] Example 3

[0077] A method for preparing an injectable drug-loaded adhesive hydrogel, the process flow is as follows Figure 1 As shown, the following steps are included:

[0078] S1. Preparation of dopamine hydrochloride modified gelatin, comprising the following steps:

[0079] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0080] At 37°C, gelatin powder was added to the buffer solution and magnetically stirred until dissolved. NaOH solution was added dropwise to adjust the pH to about 4.5. EDC and NHS were then added and stirred for 20 minutes to activate the carboxyl groups to obtain a gelatin solution with a gelatin concentration of 1.39%. The mass ratio of gelatin, EDC and NHS was 100:1:1.

[0081] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution with a mass ratio of dopamine hydrochloride to gelatin of 1:200 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution is added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution is dialyzed and freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0082] The method for preparing dopamine-modified carboxymethyl-β-cyclodextrin comprises the following steps:

[0083] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0084] Add carboxymethyl-β-cyclodextrin to the buffer solution, stir magnetically until dissolved, adjust the pH to about 5.5 with a concentrated NaOH solution, then add EDC and NHS, stir for 20 minutes to activate the carboxyl group, and obtain a carboxymethyl-β-cyclodextrin solution. The concentration of carboxymethyl-β-cyclodextrin is 5%, and the mass ratio of carboxymethyl-β-cyclodextrin, EDC and NHS is 18:1:1.

[0085] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution, the mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin is 13:40, to form a dopamine hydrochloride solution, and the dopamine hydrochloride solution is added to the carboxymethyl-β-cyclodextrin solution, and the reaction is completed after stirring for 12 hours; the solution obtained by the sufficient reaction is dialyzed, and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride modified carboxymethyl-β-cyclodextrin.

[0086] S2. Add dopamine hydrochloride modified gelatin powder to a 5wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the nanocellulose aqueous solution is 19:65, then add a 30wt.% dopamine hydrochloride modified carboxymethyl-β-cyclodextrin aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin solution is 19:3, and add resveratrol, mix at 37°C to obtain reaction solution A.

[0087] S3. Mix an aqueous solution of oxidized dextran with a concentration of 5wt% and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001mol / l) at room temperature, wherein the mass ratio of oxidized dextran to the gelatin solution modified with dopamine hydrochloride is 0.182:1, and the volume ratio of iron ions to the carboxymethyl-β-cyclodextrin solution modified with dopamine hydrochloride is 1:3, to form a reaction solution B; mix the reaction solution A and the reaction solution at a mass ratio of 5.49:1 at room temperature to obtain an injectable drug-loaded adhesive hydrogel.

[0088] Comparative Example 1

[0089] A method for preparing an injectable drug-loaded adhesive hydrogel, the process flow is as follows Figure 1 As shown, the following steps are included:

[0090] S1. Preparation of dopamine hydrochloride modified gelatin, comprising the following steps:

[0091] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0092] At 37°C, gelatin powder was added to the buffer solution and magnetically stirred until dissolved. NaOH solution was added dropwise to adjust the pH to about 4.5. EDC and NHS were then added and stirred for 20 minutes to activate the carboxyl groups to obtain a gelatin solution with a gelatin concentration of 1.39%. The mass ratio of gelatin, EDC and NHS was 100:1:1.

[0093] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution with a mass ratio of dopamine hydrochloride to gelatin of 1:200 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution is added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution is dialyzed and freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0094] The method for preparing dopamine-modified carboxymethyl-β-cyclodextrin comprises the following steps:

[0095] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0096] Add carboxymethyl-β-cyclodextrin to the buffer solution, stir magnetically until dissolved, adjust the pH to about 5.5 with a concentrated NaOH solution, then add EDC and NHS, stir for 20 minutes to activate the carboxyl group, and obtain a carboxymethyl-β-cyclodextrin solution. The concentration of carboxymethyl-β-cyclodextrin is 5%, and the mass ratio of carboxymethyl-β-cyclodextrin, EDC and NHS is 18:1:1.

[0097] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution, the mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin is 13:40, to form a dopamine hydrochloride solution, and the dopamine hydrochloride solution is added to the carboxymethyl-β-cyclodextrin solution, and the reaction is completed after stirring for 12 hours; the solution obtained by the sufficient reaction is dialyzed, and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride modified carboxymethyl-β-cyclodextrin.

[0098] S2. Add dopamine hydrochloride modified gelatin powder to a 5wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the nanocellulose aqueous solution is 19:65, then add a 30wt.% dopamine hydrochloride modified carboxymethyl-β-cyclodextrin aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin solution is 19:4, and add resveratrol, mix at 37°C to obtain reaction solution A.

[0099] S3. Mix an aqueous solution of oxidized dextran with a concentration of 5wt% and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001mol / l) at room temperature, wherein the mass ratio of oxidized dextran to the gelatin solution modified with dopamine hydrochloride is 0.182:1, and the volume ratio of iron ions to the carboxymethyl-β-cyclodextrin solution modified with dopamine hydrochloride is 1:4, to form a reaction solution B; mix the reaction solution A and the reaction solution B at a mass ratio of 5.49:1 at room temperature to obtain an injectable drug-loaded adhesive hydrogel.

[0100] Comparative Example 2

[0101] A method for preparing an injectable drug-loaded adhesive hydrogel, the process flow is as follows Figure 1 As shown, the following steps are included:

[0102] S1. Preparation of dopamine hydrochloride modified gelatin, comprising the following steps:

[0103] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0104] At 37°C, gelatin powder was added to the buffer solution and magnetically stirred until dissolved. NaOH solution was added dropwise to adjust the pH to about 4.5. EDC and NHS were then added and stirred for 20 minutes to activate the carboxyl groups to obtain a gelatin solution with a gelatin concentration of 1.39%. The mass ratio of gelatin, EDC and NHS was 100:1:1.

[0105] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution with a mass ratio of dopamine hydrochloride to gelatin of 1:200 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution is added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution is dialyzed and freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0106] The method for preparing dopamine-modified carboxymethyl-β-cyclodextrin comprises the following steps:

[0107] MES and NaCl were dissolved in deionized water to prepare MES buffer. The mass ratio of MES, NaCl and deionized water was 7:1:360. NaOH was added dropwise using a pH meter to adjust the pH value to 5.1.

[0108] Add carboxymethyl-β-cyclodextrin to the buffer solution, stir magnetically until dissolved, adjust the pH to about 5.5 with a concentrated NaOH solution, then add EDC and NHS, stir for 20 minutes to activate the carboxyl group, and obtain a carboxymethyl-β-cyclodextrin solution. The concentration of carboxymethyl-β-cyclodextrin is 5%, and the mass ratio of carboxymethyl-β-cyclodextrin, EDC and NHS is 18:1:1.

[0109] Under a nitrogen atmosphere, dopamine hydrochloride is dissolved in a buffer solution, the mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin is 13:40, to form a dopamine hydrochloride solution, and the dopamine hydrochloride solution is added to the carboxymethyl-β-cyclodextrin solution, and the reaction is completed after stirring for 12 hours; the solution obtained by the sufficient reaction is dialyzed, and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride modified carboxymethyl-β-cyclodextrin.

[0110] S2. Add dopamine hydrochloride modified gelatin powder to a 5wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the nanocellulose aqueous solution is 19:65, then add a 30wt.% dopamine hydrochloride modified carboxymethyl-β-cyclodextrin aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin solution is 19:5, and add resveratrol, mix at 37°C to obtain reaction solution A.

[0111] S3. Mix an aqueous solution of oxidized dextran with a concentration of 5wt% and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001mol / l) at room temperature, wherein the mass ratio of oxidized dextran to the gelatin solution modified with dopamine hydrochloride is 0.182:1, and the volume ratio of iron ions to the carboxymethyl-β-cyclodextrin solution modified with dopamine hydrochloride is 1:5, to form a reaction solution B; mix the reaction solution A and the reaction solution B at a mass ratio of 5.49:1 at room temperature to obtain an injectable drug-loaded adhesive hydrogel.

[0112] The injectable drug-loaded adhesive hydrogels prepared in Examples 1 to 3 and Comparative Examples 1 to 2 were tested for performance, and the results are as follows:

[0113] Figure 2 Graph showing the bonding performance of the hydrogel at different dopamine hydrochloride modified carboxymethyl-β-cyclodextrin concentrations of the present invention. Figure 2 As shown, on the one hand, carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride is added to the hydrogel in the form of an aqueous solution, and the increase in water in the hydrogel will affect the mechanical properties of the hydrogel; on the other hand, carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride is a short molecular chain, and adding too much will occupy more dopamine hydrochloride molecules, affecting the cross-linking with long-chain molecules, so that carboxymethyl-β-cyclodextrin is not fixed in the hydrogel network at the molecular level, affecting the integrity of the hydrogel network, thereby affecting the mechanical properties and causing a decrease in adhesion energy.

[0114] Figure 3 Graph showing the drug release curve of the injectable drug-loaded adhesive hydrogel of Example 1 of the present invention. Figure 3 As shown, the injectable drug-loaded adhesive hydrogel of Example 1 has a certain sustained release effect within 3 days.

[0115] Figure 4 The figure is a graph showing the solubilization ability of the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin on resveratrol. Figure 4 As shown, dopamine hydrochloride modified carboxymethyl-β-cyclodextrin increased the water solubility of the drug resveratrol by about 130 times.

[0116] It should be noted that when the present invention involves a numerical range, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as those in the embodiments, in order to avoid redundancy, the present invention describes a preferred embodiment. Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they know the basic creative concept. Therefore, the attached claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0117] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. An injectable drug-loaded adhesive hydrogel, characterized in that: The hydrogel uses biomacromolecules with amino groups and biomacromolecules with aldehyde groups modified by dopamine hydrochloride as a matrix, forms a long-chain network structure polymer layer through Schiff base reaction, and uses iron ions as a complexing agent to complex and cross-link carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride and dopamine hydrochloride in the long-chain network structure polymer layer to form an ion dissipation polymer layer, thereby obtaining an injectable drug-loaded adhesive hydrogel; wherein the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride is loaded with antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecules, and then the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride is fixed on the long-chain network structure polymer layer under the complexing action of iron ions.

2. The injectable drug-loaded adhesive hydrogel according to claim 1, characterized in that: The method for preparing a biomacromolecule modified with dopamine hydrochloride and having an amino group comprises the following steps: In a protective gas atmosphere, a biomacromolecule solution with amino groups and dopamine hydrochloride are mixed, and under the action of a condensation agent, dopamine hydrochloride and the biomacromolecule with amino groups undergo an amide reaction to obtain a biomacromolecule with amino groups modified by dopamine hydrochloride.

3. The injectable drug-loaded adhesive hydrogel according to claim 2, characterized in that: The mass ratio of the biomacromolecule with an amino group, dopamine hydrochloride and the condensing agent is 20 to 200:1:4, the biomacromolecule with an amino group is chitosan, gelatin or collagen, the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, and the mass ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is 1 to 1.5:1; the temperature of the amide reaction is 37° C., the reaction time is 12 h to 24 h, and the protective gas is nitrogen.

4. The injectable drug-loaded adhesive hydrogel according to claim 1, characterized in that: The preparation method of dopamine hydrochloride modified carboxymethyl-β-cyclodextrin comprises the following steps: In a protective gas atmosphere, a carboxymethyl-β-cyclodextrin solution and dopamine hydrochloride are mixed, and under the action of a condensing agent, dopamine hydrochloride and carboxymethyl-β-cyclodextrin undergo an amide reaction to obtain carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride.

5. The injectable drug-loaded adhesive hydrogel according to claim 4, characterized in that: The mass ratio of the carboxymethyl-β-cyclodextrin, dopamine hydrochloride and the condensing agent is 13-40:13:5, the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, and the mass ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is 1-1.5:1; the temperature of the amide reaction is room temperature, the reaction time is 12h-24h, and the protective gas is nitrogen.

6. A method for preparing an injectable drug-loaded adhesive hydrogel according to any one of claims 1 to 5, characterized in that: The steps include: Adding the biomacromolecule with amino group modified by dopamine hydrochloride to the toughening agent solution, then adding the carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride, and adding the antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecules, and mixing at 37° C. to form a reaction solution A; The biomacromolecules with aldehyde groups and iron ions are mixed at room temperature to form a reaction solution B; The reaction solution A and the reaction solution B are mixed at room temperature, and the biomacromolecules with amino groups modified by dopamine hydrochloride react with the biomacromolecules with aldehyde groups to form a long-chain network structure polymer layer. At the same time, under the action of iron ions, the carboxymethyl-β-cyclodextrin modified by dopamine hydrochloride and the long-chain network structure polymer are complexed and cross-linked to form an ion dissipation polymer layer, thereby obtaining an injectable drug-loaded adhesive hydrogel.

7. The method for preparing the injectable drug-loaded adhesive hydrogel according to claim 6, characterized in that: The mass ratio of the dopamine hydrochloride-modified biomacromolecule with amino group, toughening agent solution and dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin solution is 19:65:1-5, the concentration of the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin solution is 1%wt.%-50%wt.%, and the anti-tumor hydrophobic drug molecule includes one of camptothecin, resveratrol, dexamethasone or paclitaxel.

8. The method for preparing the injectable drug-loaded adhesive hydrogel according to claim 6, characterized in that: The mass ratio of the biomacromolecule solution with aldehyde groups to the biomacromolecule solution with amino groups modified by dopamine hydrochloride is 0.1-0.2:1, the biomacromolecule with aldehyde groups is oxidized dextran, oxidized hyaluronic acid, oxidized cellulose, the volume ratio of iron ions to the carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride is 1-5:1-5, the concentration of the biomacromolecule solution with aldehyde groups is 5wt%, and the molar concentration of the iron ions is 0.0001mol / l-0.03mol / l.

9. The method for preparing the injectable drug-loaded adhesive hydrogel according to claim 6, characterized in that: The mass ratio of reaction liquid A to reaction liquid B is 5 to 10:

1.

10. Use of the injectable drug-loaded adhesive hydrogel according to any one of claims 1 to 5 in the preparation of oral antibacterial, anti-inflammatory or anti-tumor drugs.

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