Injectable drug-loaded adhesive hydrogel and its preparation method and application

Abstract

The present invention belongs to the technical field of drug-loaded adhesive hydrogels, and in particular to a kind of injectable drug-loaded adhesive hydrogel and its preparation method and application. 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 is formed by Schiff base reaction. Then, iron ions are used as a complexing agent to make the carboxymethyl β-cyclodextrin modified by dopamine hydrochloride and the long-chain network structure complexed and cross-linked to form an ion dissipation network, 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. The hydrogel prepared by the present invention is composed of two networks, a long-chain network and an ion dissipation network, with excellent bonding performance, and drug-loaded sustained release is achieved at the molecular level by the hydrophilic molecule carboxymethyl β-cyclodextrin, and an injectable strong tissue adhesive hydrogel drug-loading system is developed.

Description

Technical Field

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

[0002] Oral administration means swallowing the drug, which 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. Hydrogel can be used as a drug carrier, so strong tissue adhesion hydrogel has shown great potential in drug delivery. In 2017, Science reported a strong tissue adhesion hydrogel with a bonding energy of 1000 J / m 2 This marked the beginning of a breakthrough in hydrogel tissue adhesion. Strong tissue-adhesive hydrogel drug delivery can promote drug diffusion from the hydrogel to the target tissue by increasing the direct contact surface and reducing diffusion. Nature Biomedical Engineering reported for the first time the application of a strong adhesive system to treat tendon injuries, with the hydrogel and tendon surface generating a bonding energy greater than 1000 J / m 2 In addition to tissue adhesion, the hydrogel can also be used for local drug release, demonstrating that strong tissue-adhesive hydrogels offer significant advantages in drug delivery.

[0004] In recent years, hydrogels have been widely used in the treatment of oral diseases due to their unique properties, primarily in oral postoperative care, local oral anesthesia, oral mucosal diseases, and cancer treatment. However, existing research has shown that drug-loaded hydrogels in the oral environment exhibit weak adhesion, leading to easy debonding. Physically encapsulated drug loading also results in burst release, and hydrogels are unable to load poorly water-soluble drugs. Summary of the Invention

[0005] To this end, the present invention provides an injectable drug-loaded adhesive hydrogel, its preparation method, and its application. Designed at the molecular level, this system develops an injectable, highly tissue-adhesive hydrogel drug delivery system, enabling the prolonged retention and stable sustained release of multiple hydrophobic drugs at the target site. The hydrogel's innovation lies in its excellent adhesive properties and drug-loading efficiency, enabling slow, sustained drug release, and adaptability to multiple 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, which 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 a 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 complexation action of iron ions.

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

[0009] Under a protective gas atmosphere, a biomacromolecule solution with amino groups and dopamine hydrochloride are mixed. 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 with dopamine hydrochloride or a carboxymethyl-β-cyclodextrin modified with 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 12h to 24h, 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 dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin.

[0013] Furthermore, the mass ratio of the carboxymethyl-β-cyclodextrin, dopamine hydrochloride and condensing agent is 13 to 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 to 1.5:1; the temperature of the amide reaction is room temperature, the reaction time is 12h to 24h, and the protective gas is nitrogen.

[0014] A 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] A biomacromolecule with an amino group modified with dopamine hydrochloride is added to a toughening agent solution, followed by a carboxymethyl-β-cyclodextrin solution modified with dopamine hydrochloride and a hydrophobic drug molecule having antibacterial, anti-inflammatory or anti-tumor properties. The mixture is reacted and mixed at 37° C. to load the hydrophobic drug molecule onto the carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride, thereby forming a reaction solution A.

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

[0017] Reaction liquid A and reaction liquid 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 groups 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 an aldehyde group and the biomacromolecule with an amino group modified by dopamine hydrochloride is 0.1 to 0.2:1, the biomacromolecule with an aldehyde group is oxidized dextran, oxidized hyaluronic acid, or oxidized cellulose, the volume ratio of the iron ion and the carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride is 1 to 5:1 to 5, the concentration of the biomacromolecule with an aldehyde group is 5 wt%, and the molar concentration of the iron ion is 0.0001 mol / l to 0.03 mol / 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 amino groups modified with dopamine hydrochloride as a matrix and a biomacromolecule with aldehyde groups as a cross-linking agent, and cross-linking is generated by Schiff base reaction between amino groups and aldehyde groups; the ion-dissipating network polymer is formed by the complexation of dopamine hydrochloride with iron ions. After the biomacromolecule with amino groups and carboxymethyl-β-cyclodextrin are modified and grafted with dopamine hydrochloride, the dopamine hydrochloride is complexed with each other after the addition of iron ions. 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 hydrogels 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 an inclusion complex, and the carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride is fixed to the long-chain network polymer by complexation under iron ions, thereby realizing 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 realizes long-term residence and stable sustained release of multiple types of hydrophobic drugs at the target site, 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. Its exterior is highly hydrophilic and easily attracts hydrophilic molecules, while its interior is highly hydrophobic and 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 the change of 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 invasive. 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 flow chart of the process for preparing the injectable drug-loaded adhesive hydrogel.

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

[0028] Figure 3 This is a drug release curve 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 clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall 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 specified, 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 embedding of drugs 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 response to the above problems, the present invention is designed at the molecular level to develop an injectable strong tissue adhesion 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. At the same time, iron ions are used as a complexing agent to complex and cross-link the carboxymethyl-β-cyclodextrin modified with 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 with dopamine hydrochloride is loaded with antibacterial, anti-inflammatory or anti-tumor hydrophobic drug molecules, and then the carboxymethyl-β-cyclodextrin modified with 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-dissipating polymer. The long-chain network polymer uses a biomacromolecule with amino groups modified with dopamine hydrochloride as a matrix, and the biomacromolecule with aldehyde groups undergoes a Schiff base reaction with the amino groups to generate crosslinks. The ion-dissipating network polymer is formed by the complexation of dopamine hydrochloride with iron ions. After the biomacromolecule with amino groups and carboxymethyl-β-cyclodextrin are modified and grafted with dopamine hydrochloride, iron ions are added to form a complexation between dopamine hydrochloride, and the carboxymethyl-β-cyclodextrin loaded with drugs can be cross-linked with the long-chain network polymer to form a drug-loaded adhesive hydrogel. The adhesive energy between the hydrogel and biological tissue comes from three parts: the rapid action of hydrogen bonds and the complexation of covalent bonds with 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 an inclusion complex, 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 realizing slow drug release and multiple drug loading; in summary, the present invention is designed from the molecular level to develop an injectable strong tissue adhesion hydrogel drug loading system, which realizes long-term residence and stable sustained release of multiple types of hydrophobic drugs at the target site, 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 that responds to changes in injection shear force through covalent bonds and complex interactions and gels. It can be conveniently injected and adhered to the target site. It is simple to operate, has arbitrary shaping, and is less invasive. The preparation conditions are mild, and no harmful substances are produced, making it easy to carry out large-scale industrial production.

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

[0037] Under a protective gas atmosphere, a biomacromolecule solution with amino groups and dopamine hydrochloride are mixed. 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 with dopamine hydrochloride.

[0038] In the process of preparing the biomacromolecule with amino group modified with dopamine hydrochloride, the mass ratio of the biomacromolecule with amino group, dopamine hydrochloride and condensing agent is 20-200:1:4, the biomacromolecule with 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 1-1.5:1; the temperature of the amide reaction is 37° C., the reaction time is 12 h to 24 h, and the protective gas is nitrogen.

[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 dopamine-modified carboxymethyl-β-cyclodextrin.

[0041] 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 to 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 to 1.5:1; the temperature of the amide reaction is room temperature, the reaction time is 12h to 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 ingredient includes one of camptothecin, resveratrol, dexamethasone and paclitaxel. Carboxymethyl-β-cyclodextrin is similar to a hollow frustum. Its exterior is highly hydrophilic and easily attracts hydrophilic molecules, while its interior is highly hydrophobic and can encapsulate hydrophobic molecules. When the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin is mixed with the hydrophobic drug molecules, the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin encapsulates the hydrophobic drug molecules to form an inclusion complex, which can prolong the drug's retention time in the body and enhance the drug's targeting. 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] A biomacromolecule with an amino group modified with dopamine hydrochloride is added to a toughening agent solution, followed by a carboxymethyl-β-cyclodextrin solution modified with dopamine hydrochloride and a hydrophobic drug molecule having antibacterial, anti-inflammatory or anti-tumor properties. The mixture is reacted and mixed at 37° C. The hydrophobic drug molecule is loaded on the carboxymethyl-β-cyclodextrin modified with dopamine hydrochloride to form a reaction solution A.

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

[0046] Reaction liquid A and reaction liquid 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, dopamine hydrochloride solution is first modified respectively to the biomacromolecule and carboxymethyl-β-cyclodextrin with amino group, after reaction solution A and reaction solution B are mixed, amino group and aldehyde group reaction produce crosslinking, i.e. Schiff base synthesis reaction forms long-chain network structure polymer layer, under the action of iron ion, complexation between dopamine hydrochloride molecules, by dopamine hydrochloride modified carboxymethyl-β-cyclodextrin and long-chain network structure polymer complexation, in addition, the bonding energy of biological tissue comes from the rapid action of hydrogen bond, and a part comes from the aldehyde group in the network and the amino group on the tissue Schiff base reaction occurs, and dopamine hydrochloride molecule can also allow hydrogel to have certain bonding ability in a humid environment due to its own characteristics. In addition, nanocellulose is added to strengthen the toughness when preparing hydrogel, which improves the mechanical properties of hydrogel.

[0048] In a specific embodiment, the mass ratio of the biomacromolecule with amino groups 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 capacity of the injectable drug-loaded adhesive hydrogel can be increased by adjusting the ratio of the carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride. The more carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride, the greater the drug loading capacity of the hydrogel. At the same time, carboxymethyl-β-cyclodextrin affects the mechanical properties of the hydrogel. As a preferred embodiment of the present invention, the mass ratio of the biomacromolecule with amino groups 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 aldehyde-bearing biomacromolecule to the dopamine hydrochloride-modified biomacromolecule solution with an amino group is 0.1-0.2:1. The aldehyde-bearing biomacromolecule is oxidized dextran, oxidized hyaluronic acid, or oxidized cellulose. The volume ratio of the iron ion to the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin solution is 1-5:1-5. The concentration of the aldehyde-bearing biomacromolecule is 5 wt%, and the molar concentration of the iron ion is 0.0001 mol / l to 0.03 mol / l. The solid content of the injectable drug-loaded adhesive hydrogel is adjusted by adjusting the ratio of the dopamine hydrochloride-modified biomacromolecule solution with an amino group to the aldehyde-bearing biomacromolecule solution. The solid content affects the mechanical properties of the hydrogel, thereby affecting the adhesive properties of the hydrogel. As a preferred embodiment of the present invention, the mass ratio of the aldehyde-bearing biomacromolecule to the dopamine hydrochloride-modified biomacromolecule solution with an amino group 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 following is further described 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 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 was 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 was added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution was dialyzed and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0058] The preparation of 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 to 5.1.

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

[0061] Under a nitrogen atmosphere, dopamine hydrochloride was dissolved in a buffer solution in a mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin of 13:40 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution was added to the carboxymethyl-β-cyclodextrin solution and stirred for 12 hours to allow the reaction to be complete. The solution obtained by the sufficient reaction was 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 5 wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the nanocellulose aqueous solution is 19:65, then add a 30 wt.% 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, and mix at 37°C to obtain reaction solution A.

[0063] S3. A 5 wt% aqueous solution of oxidized dextran and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001 mol / l) are mixed 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; reaction solution A and reaction solution B are mixed 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 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 was 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 was added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution was dialyzed and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0070] The preparation of 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 to 5.1.

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

[0073] Under a nitrogen atmosphere, dopamine hydrochloride was dissolved in a buffer solution in a mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin of 13:40 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution was added to the carboxymethyl-β-cyclodextrin solution and stirred for 12 hours to allow the reaction to be complete. The solution obtained by the sufficient reaction was 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 5 wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the nanocellulose aqueous solution is 19:65, then add a 30 wt.% 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, and mix at 37°C to obtain reaction solution A.

[0075] S3. A 5 wt% aqueous solution of oxidized dextran and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001 mol / l) are mixed 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; reaction solution A and reaction solution B are mixed 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 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 was 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 was added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution was dialyzed and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0082] The preparation of 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 to 5.1.

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

[0085] Under a nitrogen atmosphere, dopamine hydrochloride was dissolved in a buffer solution in a mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin of 13:40 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution was added to the carboxymethyl-β-cyclodextrin solution and stirred for 12 hours to allow the reaction to be complete. The solution obtained by the sufficient reaction was 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 5 wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the nanocellulose aqueous solution is 19:65, then add a 30 wt.% 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, and mix at 37°C to obtain reaction solution A.

[0087] S3. A 5 wt% aqueous solution of oxidized dextran and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001 mol / l) are mixed 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; reaction solution A and the reaction solution are mixed 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 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 was 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 was added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution was dialyzed and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0094] The preparation of 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 to 5.1.

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

[0097] Under a nitrogen atmosphere, dopamine hydrochloride was dissolved in a buffer solution in a mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin of 13:40 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution was added to the carboxymethyl-β-cyclodextrin solution and stirred for 12 hours to allow the reaction to be complete. The solution obtained by the sufficient reaction was 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 5 wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder and the nanocellulose aqueous solution is 19:65, then add a 30 wt.% dopamine hydrochloride modified carboxymethyl-β-cyclodextrin aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder and the dopamine hydrochloride modified carboxymethyl-β-cyclodextrin solution is 19:4, and add resveratrol, and mix at 37°C to obtain reaction solution A.

[0099] S3. A 5 wt% aqueous solution of oxidized dextran and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001 mol / l) are mixed 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; reaction solution A and reaction solution B are mixed 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 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 was 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 was added to the gelatin solution and shaken for 12 hours to allow the reaction to be complete. The fully reacted solution was dialyzed and then freeze-dried in a freeze dryer for 2 days to obtain dopamine hydrochloride-modified gelatin.

[0106] The preparation of 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 to 5.1.

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

[0109] Under a nitrogen atmosphere, dopamine hydrochloride was dissolved in a buffer solution in a mass ratio of dopamine hydrochloride to carboxymethyl-β-cyclodextrin of 13:40 to form a dopamine hydrochloride solution. The dopamine hydrochloride solution was added to the carboxymethyl-β-cyclodextrin solution and stirred for 12 hours to allow the reaction to be complete. The solution obtained by the sufficient reaction was 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 5 wt% nanocellulose aqueous solution, the mass ratio of the dopamine hydrochloride modified gelatin powder to the nanocellulose aqueous solution is 19:65, then add a 30 wt.% 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, and mix at 37°C to obtain reaction solution A.

[0111] S3. A 5 wt% aqueous solution of oxidized dextran and an aqueous solution of ferric nitrate (the concentration of iron ions in the aqueous solution of ferric nitrate is 0.0001 mol / l) are mixed 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; reaction solution A and reaction solution B are mixed at a mass ratio of 5.49:1 at room temperature to obtain an injectable drug-loaded adhesive hydrogel.

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

[0113] Figure 2 Figure 2 is a graph showing the bonding performance of the hydrogel at different concentrations of dopamine hydrochloride modified carboxymethyl-β-cyclodextrin. 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. 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 The drug release curve of the injectable drug-loaded adhesive hydrogel of Example 1 of the present invention is shown in FIG. 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 shows the solubilization ability of dopamine hydrochloride modified carboxymethyl-β-cyclodextrin for 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 numerical ranges are mentioned in the present invention, it should be understood that both endpoints of each numerical range and any value between the two endpoints may 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 preferred embodiments. Although 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 understand the basic inventive concepts. Therefore, the appended 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 may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications fall within the scope of the claims and their equivalents, the present invention is intended to include such changes and modifications.

Claims

1. An injectable drug-loaded adhesive hydrogel, characterized in that: The hydrogel uses dopamine hydrochloride-modified biomacromolecules with amino groups and biomacromolecules with aldehyde groups as matrices, forms a long-chain network structure polymer layer through a Schiff base reaction, and simultaneously uses iron ions as a complexing agent to complex and cross-link dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin with the 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 dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin is loaded with hydrophobic drug molecules, and then the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin is fixed on the long-chain network structure polymer layer under the complexation effect of the iron ions; 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 volume ratio of the iron ion to the carboxymethyl-β-cyclodextrin solution modified by dopamine hydrochloride is 1-5:1-5; The hydrophobic drug molecule is resveratrol; The biomacromolecule with amino group is gelatin; The biological macromolecule with aldehyde groups is oxidized dextran.

2. The injectable drug-loaded adhesive hydrogel according to claim 1, characterized in that: The preparation method of a biomacromolecule modified with dopamine hydrochloride and having an amino group comprises the following steps: Under a protective gas atmosphere, a biomacromolecule solution with amino groups and dopamine hydrochloride are mixed. 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 with 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 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 12h to 24h, 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 dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin.

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 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 the injectable drug-loaded adhesive hydrogel according to any one of claims 1 to 5, characterized in that: The steps include: A biomacromolecule with an amino group modified with dopamine hydrochloride is added to a toughening agent solution, followed by a carboxymethyl-β-cyclodextrin solution modified with dopamine hydrochloride and a hydrophobic drug molecule, and the mixture is mixed at 37°C to form a reaction solution A; the toughening agent solution is a nanocellulose aqueous solution; The biomacromolecule with aldehyde group and iron ions are mixed at room temperature to form reaction solution B; Reaction solution A and 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 groups, the toughening agent solution and the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin solution is 19:65:1-5, and the concentration of the dopamine hydrochloride-modified carboxymethyl-β-cyclodextrin solution is 1%wt.%-50%wt.%.

8. The method for preparing the injectable drug-loaded adhesive hydrogel according to claim 6, characterized in that: The concentration of the biomacromolecule solution with aldehyde groups is 5 wt %, and the molar concentration of the iron ions is 0.0001 mol / l to 0.03 mol / 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.

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