A hydrogel composite, preparation method and application

Abstract

The present invention discloses a hydrogel composite, a preparation method and an application, belonging to the technical field of hydrogels; the hydrogel composite provided by the present invention comprises the following raw materials: a hydrogel matrix, sodium glycerophosphate pentahydrate and a functional drug; the hydrogel matrix comprises chitosan, hydroxybutyl chitosan and methacrylated gelatin; the functional drug comprises cannabidiol, tobramycin and acetylsalicylic acid; the hydrogel composite provided by the present invention has excellent mechanical properties and water vapor permeability, and also has excellent sustained release properties and wound healing ability, and can be widely applied to the preparation of drugs for treating wounds. Moreover, the preparation method of the hydrogel composite provided by the present invention is simple to operate and is beneficial to practical application.

Description

Technical Field

[0001] The present invention belongs to the technical field of hydrogels, and in particular relates to a hydrogel composite, a preparation method and an application thereof. Background Art

[0002] Chitosan has characteristics such as biocompatibility, biodegradability, antibacterial property and hemostatic property, and also has the function of promoting cells to produce growth factors and forming an environment required for wound healing. In the prior art, it is widely used as a material for preparing hydrogels. A hydrogel is a three-dimensional network or interpenetrating network between a solid and a liquid. The hydrogel prepared with chitosan as the material also has good biocompatibility, and can be prepared into products such as thermosensitive or photosensitive hydrogels by combining with other different components, so that it can be injected in the form of a solution or applied to human wounds or defects, and rapidly complete gelation under the irradiation of human body temperature or visible light.

[0003] However, relying solely on the antibacterial and hemostatic properties of chitosan and the promotion of cells to produce growth factors is not sufficient to effectively promote wound healing, and the current chitosan-based hydrogels may have problems with poor air permeability on the basis of good adhesion. In addition, the mechanical strength of the three-dimensional network or interpenetrating network formed by chitosan-based hydrogels is insufficient, and although the three-dimensional network or interpenetrating network can load drugs to further enhance the corresponding efficacy of the hydrogel to a certain extent, due to the differences in physical properties caused by the differences in the structures of drug molecules, such as hydrophilicity and hydrophobicity, etc., it will affect the interaction between drugs and the release rate and the degree of efficacy of the drugs. Summary of the Invention

[0004] The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art and provide a hydrogel composite, a preparation method and an application thereof with excellent mechanical properties, water vapor permeability, sustained release property and wound healing promotion efficacy.

[0005] To achieve the above purpose, in the first aspect of the present invention, the present invention provides a hydrogel composite, and the hydrogel composite includes the following raw materials: a hydrogel matrix, sodium glycerophosphate pentahydrate and a functional drug;

[0006] The hydrogel matrix includes chitosan, hydroxybutyl chitosan and methacrylated gelatin;

[0007] The functional drug includes cannabidiol, tobramycin and acetylsalicylic acid.

[0008] The hydrogel composite provided by the present invention selects the compound of chitosan, hydroxybutyl chitosan and methacrylated gelatin as the hydrogel matrix, so that the obtained hydrogel composite has good mechanical properties on the premise of having basic adhesion properties; specifically, it has excellent tensile strength and elongation at break; and, the compound of chitosan, hydroxybutyl chitosan and methacrylated gelatin can also make the obtained hydrogel composite have excellent water vapor transmittance, thereby further enhancing the antibacterial property of the product and accelerating the wound healing. At the same time, the present invention introduces sodium glycerophosphate pentahydrate. On the one hand, it can provide thermosensitivity for the hydrogel composite, and on the other hand, it can also help the hydrogel matrix to quickly crosslink into a network structure, so as to efficiently load drugs and achieve the slow release effect of drugs. In addition, the present invention selects functional drugs including cannabidiol, tobramycin and acetylsalicylic acid. On the one hand, the compound of the three can better achieve antibacterial, hemostatic, anti-inflammatory and cell growth promotion, so as to achieve a more excellent effect of promoting wound healing; on the other hand, the three can have a strong hydrogen bond connection with the hydrogel matrix and sodium glycerophosphate pentahydrate, so as to achieve a stable and long-term slow release effect and strengthen the promotion effect on wound healing.

[0009] As a preferred embodiment of the hydrogel composite of the present invention, the hydrogel matrix comprises the following components in parts by mass: 1 part of chitosan, 0.2-0.8 parts of hydroxybutyl chitosan, and 0.04-0.15 parts of methacrylated gelatin.

[0010] Exemplarily, the hydroxybutyl chitosan can be any point value or any two-point range value between 0.2 and 0.8 parts, such as 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, etc.; the methacrylated gelatin can be any point value or any two-point range value between 0.04 and 0.15 parts, such as 0.04 parts, 0.06 parts, 0.08 parts, 0.10 parts, 0.12 parts, 0.14 parts, 0.15 parts, etc.

[0011] The present invention has found through research that in the hydrogel matrix, the parts of chitosan, hydroxybutyl chitosan and methacrylated gelatin will not only affect the overall hydrophilicity and hydrophobicity of the hydrogel matrix, thereby affecting the subsequent drug loading effect and the slow release effect of drugs, but also affect the mechanical properties and water vapor permeability of the prepared hydrogel composite; when further selecting the parts of chitosan, hydroxybutyl chitosan and methacrylated gelatin in the above range in the hydrogel matrix, the comprehensive performance of the obtained hydrogel composite is better.

[0012] Preferably, the hydrogel matrix comprises the following components in parts by mass: 1 part of chitosan, 0.4-0.6 parts of hydroxybutyl chitosan, and 0.08-0.1 parts of methacrylated gelatin.

[0013] The research of the present invention finds that when further selecting the amounts of chitosan, hydroxybutyl chitosan and methacrylated gelatin in the hydrogel matrix to be within the above range values, the comprehensive performance of the obtained hydrogel composite is more excellent.

[0014] As a preferred embodiment of the hydrogel composite of the present invention, the chitosan satisfies at least one of the following:

[0015] a. The degree of deacetylation of the chitosan is 75 - 100%;

[0016] b. The weight-average molecular weight of the chitosan is 50,000 - 300,000.

[0017] It should be noted that chitosan can be self-made or can be a conventional commercially available product.

[0018] The test method for the degree of deacetylation of chitosan is as follows: Accurately weigh 0.3 g of chitosan dried to constant weight and place it in a 250 mL Erlenmeyer flask. Add 30 mL of standard 0.1 mol / L hydrochloric acid solution, stir at room temperature until dissolved, add 10 mL of distilled water for dilution, and add 3 drops of 1% I-KI reagent. Titrate with 0.1 mol / L sodium hydroxide standard solution until a light purple granular precipitate appears, which is the titration end point. Repeat three times and take the average value. Calculate the degree of deacetylation according to formula (1) and formula (2):

[0019] Formula (1): NH 2 % = [(C 1 V 1 - C 2 V 2 ) * 0.016 / G] * 100; where C 1 mol / L is the concentration of the hydrochloric acid standard solution, C 2 mol / L is the concentration of the sodium hydroxide standard solution, V 1 mL is the volume of the hydrochloric acid standard solution added, V 2 mL is the volume of the sodium hydroxide standard solution consumed, and G g is the sample mass;

[0020] Formula (2): Degree of deacetylation % = NH 2 % / 9.94% * 100.

[0021] The test method for the weight-average molecular weight of chitosan is obtained by testing with high performance gel permeation chromatography (GPC).

[0022] Exemplarily, the degree of deacetylation of the chitosan can be any point value or any two-point range value between 75-100%, such as 75%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, 100%, etc. The weight-average molecular weight of the chitosan can be any point value or any two-point range value between 50,000-300,000, such as 50,000, 60,000, 80,000, 100,000, 120,000, 140,000, 160,000, 180,000, 200,000, 220,000, 240,000, 260,000, 280,000, 300,000, etc.

[0023] The research of the present invention finds that the degree of deacetylation and the weight-average molecular weight of chitosan not only affect the water solubility of chitosan, but also affect the cross-linking effect, thus affecting the water vapor permeability, sustained release property of the hydrogel composite and its interaction with drugs; when further selecting the degree of deacetylation and the weight-average molecular weight of chitosan within the above ranges, the obtained hydrogel composite has better mechanical properties, better air permeability, and better sustained release property and wound healing promotion effect.

[0024] As a preferred embodiment of the hydrogel composite of the present invention, the chitosan satisfies at least one of the following:

[0025] c. The degree of deacetylation of the chitosan is 85-95%;

[0026] d. The weight-average molecular weight of the chitosan is 100,000-200,000.

[0027] The research of the present invention finds that when further selecting the degree of deacetylation and the weight-average molecular weight of chitosan within the above ranges, the comprehensive performance of the obtained hydrogel composite is better.

[0028] As a preferred embodiment of the hydrogel composite of the present invention, the substitution degree of the hydroxybutyl chitosan is 1.0-1.25.

[0029] It should be noted that the substitution degree of hydroxybutyl chitosan is obtained by elemental analysis.

[0030] Exemplarily, the substitution degree of the hydroxybutyl chitosan can be any point value or any two-point range value between 1.0-1.25, such as 1.0, 1.02, 1.04, 1.06, 1.08, 1.10, 1.12, 1.14, 1.16, 1.18, 1.20, 1.22, 1.24, 1.25, etc.

[0031] The research of the present invention finds that the substitution degree of hydroxybutyl chitosan affects its own water solubility and the ability to form hydrogels, thus affecting the mechanical properties and air permeability of the hydrogel composite material, and also affecting its drug loading effect, and further affecting the sustained release property of drugs and the promotion effect on wound healing.

[0032] As a preferred embodiment of the hydrogel composite of the present invention, the degree of substitution of the methacrylated gelatin ≥ 80%.

[0033] It should be noted that the degree of substitution of the methacrylated gelatin is obtained by nuclear magnetic resonance spectroscopy.

[0034] Exemplarily, the degree of substitution of the methacrylated gelatin can be any point value or any two-point range value between ≥ 80%, for example, it can be 80 - 90%, or it can be 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, etc.

[0035] The present invention has found that the degree of substitution of the methacrylated gelatin not only affects its crosslinking performance, but also has an impact on the mechanical properties. When the degree of substitution of the methacrylated gelatin is further selected to be ≥ 80%, the comprehensive performance of the obtained product is more excellent.

[0036] As a preferred embodiment of the hydrogel composite of the present invention, the functional drug comprises the following components in parts by mass: 1 part of cannabidiol, 0.2 - 0.9 part of tobramycin, and 1 - 6 parts of acetylsalicylic acid.

[0037] Exemplarily, the tobramycin can be any point value or any two-point range value between 0.2 - 0.9 parts, for example, it can be 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.6 part, 0.7 part, 0.8 part, 0.9 part, etc.; the acetylsalicylic acid can be any point value or any two-point range value between 1 - 6 parts, for example, it can be 1 part, 2 part, 3 part, 4 part, 5 part, 6 part, etc.

[0038] Preferably, the functional drug comprises the following components in parts by mass: 1 part of cannabidiol, 0.4 - 0.6 part of tobramycin, and 2 - 4 parts of acetylsalicylic acid.

[0039] Cannabidiol has functions such as sterilization, analgesia, anti - inflammation, antioxidant, and anti - anxiety. Its downstream application scenarios are rich, and its main value lies in the medical field. Tobramycin is an aminoglycoside antibiotic that has good antibacterial effects against the vast majority of bacteria and can be used for infections caused by a variety of sensitive bacteria, with good anti - inflammatory effects. The research of this invention finds that the mass ratio between cannabidiol and tobramycin will affect the comprehensive performance of the hydrogel complex, especially the effects of antibacterial, anti - inflammation, hemostasis, and promoting wound healing. Acetylsalicylic acid, also known as aspirin, has various pharmacological effects such as antipyretic, analgesic, anti - inflammatory, antirheumatic, and anti - platelet aggregation. However, excessive use will also cause side effects such as allergic reactions, liver damage, and gastrointestinal symptoms. Gastrointestinal symptoms are the most common adverse reactions of aspirin, and the more common symptoms include nausea, vomiting, upper abdominal discomfort or pain, etc. The research of this invention finds that in the hydrogel system of this invention, cannabidiol, tobramycin, and acetylsalicylic acid have good compounding effects and excellent antibacterial, hemostatic, and anti - inflammatory effects, thus being able to rapidly promote wound healing; especially when the amounts of cannabidiol, tobramycin, and acetylsalicylic acid are within the ranges given in this invention, the comprehensive performance of the obtained hydrogel complex is more excellent.

[0040] In the second aspect of this invention, the invention provides a preparation method of the hydrogel complex, and the preparation method includes the following steps: successively mixing a hydrogel matrix solution, a sodium glycerophosphate pentahydrate solution, and a functional drug solution and then stirring to form a gel to obtain the hydrogel complex.

[0041] The preparation method of the hydrogel complex provided by this invention is simple in operation and is beneficial to practical production applications.

[0042] As a preferred embodiment of the preparation method of this invention, the mass percentage of the solute in the hydrogel matrix solution is 1 - 5%.

[0043] As a preferred embodiment of the preparation method of this invention, the mass percentage of the solute in the sodium glycerophosphate pentahydrate solution is 30 - 40%.

[0044] As a preferred embodiment of the preparation method of this invention, the concentration of the solute in the functional drug solution is 0.02 - 0.9 mol / L.

[0045] The research of this invention finds that when further selecting the mass percentage of the solute or the molar concentration of the solute in the above - mentioned solutions within the above - mentioned ranges respectively, it can better react to form the hydrogel complex.

[0046] As a preferred embodiment of the preparation method of the present invention, the volume ratio of the hydrogel matrix solution, the sodium glycerophosphate pentahydrate solution, and the functional drug solution is hydrogel matrix solution:sodium glycerophosphate pentahydrate solution:functionaldrug solution = 1:(0.1 - 0.4):(0.1 - 1.5).

[0047] The present invention researches and discovers that when further selecting the volume ratio between each solution within the above range, it can better cooperate with the preferred solute mass percentage range or the solute molar concentration range to achieve a good gelation reaction.

[0048] As a preferred embodiment of the preparation method of the present invention, the solvent of the hydrogel matrix solution is an acetic acid aqueous solution with a mass percentage of 1 - 5%.

[0049] As a preferred embodiment of the preparation method of the present invention, the solvent of the sodium glycerophosphate pentahydrate solution is deionized water.

[0050] As a preferred embodiment of the preparation method of the present invention, the solvent of the functional drug solution is an ethanol aqueous solution.

[0051] Preferably, in the ethanol aqueous solution, the mass percentage of ethanol is 30 - 70%.

[0052] As a preferred embodiment of the preparation method of the present invention, the temperature of stirring is 30 - 50 °C.

[0053] As a preferred embodiment of the preparation method of the present invention, after sequential mixing, stirring is carried out at a rotation speed of 300 - 500 rpm for 5 - 10 min after adding each solution to ensure thorough mixing.

[0054] In the third aspect of the present invention, the present invention provides the application of the hydrogel complex in the preparation of drugs for treating wounds.

[0055] The hydrogel complex provided by the present invention can not only effectively inhibit bacteria, but also has the effects of hemostasis, pain relief, and anti - inflammation. Therefore, it can be widely applied to the treatment of wounds.

[0056] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0057] The hydrogel composite provided by the present invention selects the compounding of chitosan, hydroxybutyl chitosan and methacrylated gelatin as the hydrogel matrix, so that the obtained hydrogel composite has good mechanical properties on the premise of having basic adhesion properties; specifically, it has excellent tensile strength and elongation at break; and, the compounding of chitosan, hydroxybutyl chitosan and methacrylated gelatin can also make the obtained hydrogel composite have excellent water vapor permeability, thereby further enhancing the antibacterial property of the product and accelerating the wound healing. At the same time, the present invention introduces sodium glycerophosphate pentahydrate. On the one hand, it can provide thermosensitivity for the hydrogel composite, and on the other hand, it can also help the hydrogel matrix to quickly crosslink into a network structure, so as to efficiently load drugs and achieve the sustained release effect of drugs. In addition, by selecting cannabidiol, tobramycin and acetylsalicylic acid as functional drugs, on the one hand, the compounding of the three can better achieve antibacterial, hemostatic, anti-inflammatory and promote cell growth, so as to achieve a more excellent effect of promoting wound healing; on the other hand, the three can have a strong hydrogen bond connection with the hydrogel matrix and sodium glycerophosphate pentahydrate, so as to achieve a stable and long-term sustained release effect and strengthen the promotion of wound healing. In addition, the preparation method of the hydrogel composite provided by the present invention is simple to operate and is beneficial to actual production. Brief Description of the Drawings

[0058] Figure 1 It is a photograph of the hydrogel composite prepared in Example 1 in the gelled state;

[0059] Figure 2 It is a photograph of the inverted state of the hydrogel composite prepared in Example 1. Detailed Description of the Invention

[0060] To better illustrate the purpose, technical solution and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0061] The reagents, methods and equipment used in the present invention, unless otherwise specified, are all conventional reagents, methods and equipment in the art.

[0062] Chitosan 1: The degree of deacetylation is 95%, the weight average molecular weight is 100,000, and it is self-made. The preparation method includes the following steps: Take 5 g of chitosan and hydrolyze it in 50 mL of 10 mol / L sodium hydroxide aqueous solution. The hydrolysis temperature is 110 °C, and the hydrolysis time is 1.8 h. After hydrolysis, filter, wash, and dry to obtain a product with a degree of deacetylation of 95%; dissolve the dried product in 145 mL of 0.34 mol / L acetic acid solution and heat it to 60 °C, then add 7.5 mL of hydrogen peroxide solution and react for 130 min. After the reaction, cool to room temperature, and dropwise add sodium hydroxide solution with stirring until the pH value is 8.5, then filter, collect the filter residue and wash and dry; obtain chitosan 1.

[0063] Chitosan 2: The degree of deacetylation is 85%, the weight-average molecular weight is 200,000, self-made. The difference in the preparation method from Chitosan 1 lies in adjusting the hydrolysis temperature and time to achieve 85% degree of deacetylation, and adjusting the reaction time of adding hydrogen peroxide to achieve a weight-average molecular weight of 200,000.

[0064] Chitosan 3: The degree of deacetylation is 75%, the weight-average molecular weight is 80,000, self-made. The difference in the preparation method from Chitosan 1 lies in adjusting the hydrolysis temperature and time to achieve 75% degree of deacetylation, and adjusting the reaction time of adding hydrogen peroxide to achieve a weight-average molecular weight of 80,000.

[0065] Chitosan 4: The degree of deacetylation is 98%, the weight-average molecular weight is 300,000, self-made. The difference in the preparation method from Chitosan 1 lies in adjusting the hydrolysis temperature and time to achieve 98% degree of deacetylation, and adjusting the reaction time of adding hydrogen peroxide to achieve a weight-average molecular weight of 300,000.

[0066] Hydroxybutyl chitosan 1: The degree of substitution is 1.05, self-made. The preparation method includes the following steps: Weigh 1 g of chitosan and disperse it in 10 mL of 50% NaOH solution for alkalization treatment. Stir at room temperature for 24 h under nitrogen protection, then filter. Collect the filter residue and add 10 mL of isopropanol aqueous solution (in the isopropanol aqueous solution, the volume ratio of isopropanol to water is 15:5) and stir for 24 h until the alkalized chitosan is completely dispersed in the isopropanol system. Then measure 12 mL of 1,2-epoxybutane and drop it into the reaction vessel, and react at room temperature for 1 h. After the reaction is completed, add 10% HCl solution dropwise to the reaction solution to adjust the pH of the system to neutral. Wait until the mixed solution becomes clear and transparent, filter and collect the filtrate, and carry out alcohol precipitation overnight. Then centrifuge, collect the solid precipitate and dry it to obtain hydroxybutyl chitosan 1.

[0067] Hydroxybutyl chitosan 2: The degree of substitution is 1.20, self-made. The difference in the preparation method from hydroxybutyl chitosan 1 lies in achieving a degree of substitution of 1.20 by adjusting the volume ratio of isopropanol to water in the isopropanol aqueous solution, the dosage of 1,2-epoxybutane, and the reaction temperature and time.

[0068] Hydroxybutyl chitosan 3: The degree of substitution is 0.9, self-made. The difference in the preparation method from hydroxybutyl chitosan 1 lies in achieving a degree of substitution of 0.9 by adjusting the volume ratio of isopropanol to water in the isopropanol aqueous solution, the dosage of 1,2-epoxybutane, and the reaction temperature and time.

[0069] Hydroxybutyl chitosan 4: The degree of substitution is 1.3, self-made. The difference in the preparation method from hydroxybutyl chitosan 1 lies in achieving a degree of substitution of 1.30 by adjusting the volume ratio of isopropanol to water in the isopropanol aqueous solution, the dosage of 1,2-epoxybutane, and the reaction temperature and time.

[0070] Methacryloyl gelatin 1: degree of substitution 85%, Xi'an Qiyue Biotechnology Co., Ltd.

[0071] Methacryloyl gelatin 2: degree of substitution 75%, Xi'an Qiyue Biotechnology Co., Ltd.

[0072] Example 1

[0073] An embodiment of the present invention provides a hydrogel composite, and a method for preparing the hydrogel composite comprises the following steps:

[0074] (1) Preparation of hydrogel matrix solution: 1 part chitosan 1, 0.4 parts hydroxybutyl chitosan 1, and 0.08 parts methacryloyl gelatin 1 were weighed and dissolved in 1% by weight acetic acid aqueous solution to prepare a hydrogel matrix solution with a solute weight percentage of 2%;

[0075] (2) Preparation of sodium glycerophosphate pentahydrate solution: dissolving sodium glycerophosphate pentahydrate in a deionized water solution to prepare a sodium glycerophosphate pentahydrate solution having a solute mass percentage of 35%;

[0076] (3) Preparation of functional drug solution: 1 part of cannabidiol, 0.4 parts of tobramycin and 2 parts of acetylsalicylic acid were dissolved in 50% ethanol aqueous solution to prepare a functional solution with a temperature of 40-45° C. and a solute concentration of 0.24 mol / L;

[0077] (4) Preparation of hydrogel complex: 1 mL of hydrogel matrix solution was placed in a container, the temperature of the container was controlled at 40-45°C, 0.2 mL of sodium glycerophosphate pentahydrate solution was added, and the mixture was stirred at 400 rpm for 5 min, followed by addition of 0.24 mL of functional drug solution, stirring at 400 rpm for 5 min, and then standing at room temperature for 1 min to form a hydrogel, thereby obtaining a hydrogel complex.

[0078] The schematic diagram of the gel formation of the prepared hydrogel composite is as follows: Figure 1 As shown, the inverted state after gelation is as follows Figure 2 shown.

[0079] Example 2

[0080] An embodiment of the present invention provides a hydrogel composite, and a method for preparing the hydrogel composite comprises the following steps:

[0081] (1) Preparation of hydrogel matrix solution: 1 part chitosan 1, 0.6 parts hydroxybutyl chitosan 1, and 0.1 parts methacryloyl gelatin 1 were weighed and dissolved in a 1% by weight acetic acid aqueous solution to prepare a hydrogel matrix solution with a solute weight percentage of 5%;

[0082] (2) Preparation of sodium glycerophosphate pentahydrate solution: Dissolve sodium glycerophosphate pentahydrate in deionized water to prepare a sodium glycerophosphate pentahydrate solution with a mass percentage of the solute of 40%;

[0083] (3) Preparation of functional drug solution: Dissolve 1 part of cannabidiol, 0.4 part of tobramycin, and 2 parts of acetylsalicylic acid in a 50% ethanol aqueous solution to prepare a functional solution with a temperature of 40 - 45 °C and a solute concentration of 0.48 mol / L;

[0084] (4) Preparation of hydrogel composite: Place 1 mL of hydrogel matrix solution in a container, control the temperature of the container at 40 - 45 °C, add 0.2 mL of sodium glycerophosphate pentahydrate solution, stir at a rotation speed of 400 rpm for 5 min, then add 0.48 mL of functional drug solution, stir at a rotation speed of 400 rpm for 5 min, and then let it stand at room temperature for 1 min to form a hydrogel, obtaining the hydrogel composite.

[0085] Examples 3 - 15

[0086] The examples of the present invention provide a hydrogel composite. The difference between the hydrogel composite and that of Example 1 lies in Table 1. Except for Table 1, the rest is the same as that of Example 1; the parts in Table 1 are by mass. Specifically, the differences between Examples 3 - 12 and Example 1 lie in changing the raw materials and the parts of the raw materials used in the preparation of the hydrogel matrix solution in step (1), and the differences between Examples 13 - 15 and Example 1 lie in changing the parts of the functional drug in step (3);

[0087] Table 1

[0088]

[0089]

[0090] Comparative Examples 1 - 9

[0091] The comparative examples of the present invention provide a hydrogel composite. The difference between the hydrogel composite and that of Example 1 lies in Table 2. Except for Table 2, the rest is the same as that of Example 1; the parts in Table 2 are by mass. Specifically, the differences between Comparative Examples 1 - 4 and Example 1 lie in changing the raw materials used in the preparation of the hydrogel matrix solution in step (1), and the differences between Comparative Examples 5 - 9 and Example 1 lie in changing the raw materials of the functional drug in step (3);

[0092] Table 2

[0093]

[0094] Effect Examples

[0095] The performance of the hydrogel composites prepared in Examples 1-15 and Comparative Examples 1-9 of the verification of the effects of the present invention includes the following aspects:

[0096] 1. Mechanical property test

[0097] The hydrogel composites in the examples and comparative examples were prepared into dumbbell shapes with a total length of 30 mm, a width of 10 mm, dumbbell parts on both sides, a sample part in the middle, a sample length of 20 mm, a sample width (i.e., the shortest distance in the middle of the dumbbell) of 10 mm, and a sample thickness of 1 mm. With a set tensile rate of 25 mm / min, a WDW-50 microcomputer-controlled electronic universal testing machine was used to measure the tension (N) and elongation (mm) at the time of sample fracture. Each sample was repeated 5 times and the average value was taken to calculate the tensile strength and elongation at break of the hydrogel dressing;

[0098] Among them, the tensile strength (σ) of the hydrogel is the ratio of the maximum tensile stress of the gel to the cross-sectional area of the sample, that is, where: σ is the tensile strength in MPa, F max is the maximum tensile stress in N, and A is the cross-sectional area of the sample (sample width × sample thickness) in mm 2 ; the elongation at break (ε) is the ratio of the deformed length of the sample at the time of tensile fracture to the initial length, that is, where ε (%) is the elongation at break, L 0 and L max are the initial and fracture lengths of the sample in mm respectively;

[0099] The results obtained are shown in Table 3.

[0100] 2. Water vapor permeability

[0101] With reference to the American Society for Testing and Materials (ASTM) standard test method E96-00 for material properties, the water vapor permeability of the prepared hydrogel composites was tested. Specifically:

[0102] First, 4 mL of distilled water was added to a vial with an open diameter of 14 mm. Then, the gel composite was cut into a 17-mm round piece, covered on the bottle mouth (just completely cover the vial), and the joint was sealed with petroleum jelly and sealing film and weighed. A desiccator was taken and saturated ammonium sulfate solution was added. The vial was placed in the desiccator, the lid was covered, and it was placed in a constant temperature drying oven at 37 °C for 24 h and then weighed again;

[0103] The results obtained are shown in Table 3.

[0104] 3. Drug release performance

[0105] Take 0.5 g of the hydrogel composites prepared in the examples and comparative examples respectively in a conical flask, add 50 mL of phosphate buffer solution (0.01 mol / L, containing 0.2% SDS) with pH = 6.8, and conduct the test under constant temperature oscillation at 37 °C and 100 rpm. At the preset time points (specifically 0.5 h, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, 25 h, 30 h), take 2 mL of the sample, and simultaneously supplement 2 mL of freshly prepared phosphate buffer solution. Subsequently, use high-performance liquid chromatography to detect the contents of cannabidiol, tobramycin, and acetylsalicylic acid in the sample and record them, so as to calculate the cumulative drug release rate. The cumulative drug release rate = (initial drug content - real-time drug content) / initial drug content × 100%. Record the cumulative drug release rate measured at 25 h in Table 1.

[0106] 4. Biocompatibility test

[0107] The test was carried out with reference to GB / T 16886.5-2003. Among them, the biotoxicity score: no cytotoxicity (0), slight cytotoxicity (1), moderate cytotoxicity (2), severe cytotoxicity (3); the test results are shown in Table 3.

[0108] 5. Performance of promoting wound healing

[0109] 1) Take 125 SPF-grade rats (BALB / c, female, 6 weeks old, body weight 25 ± 4 g). After one week of adaptive feeding, depilate the rats one day before making the wound model. Anesthetize the mice with an animal anesthesia machine and fix them on the operating table. First, use a hair clipper to remove most of the hair on the back of the mice, and then wet a cotton swab and dip it in depilatory cream to wipe the clipped hair area. Let it stand for a few minutes, and then wipe off the excess depilatory cream with a cotton ball. Then, dip a clean cotton ball in 0.9% physiological saline and wipe the skin at the depilated area to wash away the remaining depilatory cream on the skin to prevent skin burns. After wiping, dry the skin at the depilated area with a clean cotton ball;

[0110] 2) Establish a full-thickness skin wound model on the back of the mice: Anesthetize the depilated mice with an animal anesthesia machine and fix them on the operating table. After disinfecting the skin with alcohol, use sterile surgical instruments to create a circular full-thickness skin excision wound with an area of 1 × 1 cm on the back. Randomly divide them into 25 groups, with 5 mice in each group on average, corresponding to Examples 1-15, Comparative Examples 1-9, and the blank group numbers respectively;

[0111] 3) In the blank group, drop 100 μL of sterile PBS on the skin wound surface, and then fix the wound edge with a medical sterile transparent fixing tape; in the other groups, adhere the hydrogel composite to the wound surface, and fix the wound edge with a medical sterile transparent fixing tape. Finally, raise the mice in cages according to the requirements of small animal welfare.

[0112] 4) On the 1st, 4th, 7th, and 14th days, mice were anesthetized with isoflurane, and the wounds were photographed to calculate the area. When calculating the wound healing rate, the back wounds need to be photographed at each time point, and the area was calculated using ImageJ software, and the wound healing rate was calculated according to the formula: wound healing rate = (original wound area - current measured area) / original wound area * 100%;

[0113] The results obtained are shown in Table 3.

[0114] Table 3

[0115]

[0116]

[0117] As can be seen from Table 3, when the technical solution provided by the present invention is adopted, the obtained hydrogel composite has good mechanical properties, water vapor permeability, slow-release performance, and the ability to promote wound healing. Moreover, the obtained hydrogel composite also has good biocompatibility and excellent adhesion performance. The peeling force obtained by testing according to the standard of "GB / T2791-1995_T Peeling Strength Test Method for Adhesives Flexible Material to Flexible Material" is above 28.7 kg·m / S 2 above; specifically, the tensile strength of the obtained hydrogel composite is above 30.4 MPa, the elongation at break is above 129%, the water vapor permeability is above 0.35 g / cm 2 / 24h, the cumulative drug release rate at 25 h is below 46%, the wound healing rate on the 4th day is above 42%, and the wound healing rate on the 14th day is above 90%.

[0118] As can be seen from Example 1 and Comparative Examples 1-3, the components in the hydrogel matrix of the present invention are indispensable. When any one of the components is not added in Comparative Examples 1-3, the obtained product not only shows a significant decrease in mechanical properties, but also shows an obvious downward trend in the water vapor permeability, and the slow-release effect of the loaded drug also becomes worse, resulting in a decrease in the overall effect when applied to wound healing subsequently; as can be seen from Example 1 and Comparative Example 4, when similar components are used to replace the components in the present invention, the effects of the present invention cannot be achieved; as can be seen from Example 1 and Examples 2-12, the parameters of chitosan, hydroxybutyl chitosan, and methacrylated gelatin provided by the present invention and the amounts of the three added will also have a certain impact on the comprehensive performance of the product. When further selecting the parameters of chitosan, hydroxybutyl chitosan, and methacrylated gelatin and the amounts of the three within the preferred range of the present invention, the tensile strength of the obtained hydrogel composite is above 30.4 MPa, the elongation at break is above 138%, and the water vapor permeability is above 0.41 g / cm 2Above 24 h, the cumulative drug release rate at 25 h is below 36%, the wound healing rate on the 4th day is above 53%, and the wound healing rates on the 14th day are all 100%.

[0119] It can be seen from Example 1 and Comparative Example 9 that when cannabidiol, tobramycin and acetylsalicylic acid are introduced into the hydrogel matrix of the present invention, the effect of promoting wound healing of the product can be significantly improved; it can be seen from Example 1 and Comparative Examples 5-7 that cannabidiol, tobramycin and acetylsalicylic acid have excellent synergistic effects in the hydrogel system of the present invention. When the total amount of the drugs remains unchanged, no matter which substance is reduced, the ability of the obtained product to promote wound healing will be significantly reduced; it can be seen from Example 1 and Comparative Example 8 that when other substances with similar effects are used to replace the components of the present invention, the effects of the present invention cannot be achieved; it can be seen from Example 1 and Examples 13-15 that the proportions among cannabidiol, tobramycin and acetylsalicylic acid will also affect the ability of the product to promote wound healing. When the proportions of the three are further selected within the preferred range of the present invention, the obtained wound healing rate is above 54% on the 4th day and can reach 100% on the 14th day.

[0120] Finally, it should be noted that the above embodiments are used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A hydrogel composite, characterized in that: The hydrogel composite comprises the following raw materials: Hydrogel matrix, sodium glycerophosphate pentahydrate, and functional drug; The hydrogel matrix comprises the following components in parts by mass: 1 part of chitosan, 0.2-0.8 parts of hydroxybutyl chitosan and 0.04-0.15 parts of methacryloyl gelatin; The deacetylation degree of the chitosan is 75-100%, and the weight average molecular weight of the chitosan is 50,000-300,000; The degree of substitution of the hydroxybutyl chitosan is 1.0-1.25; The degree of substitution of the methacryloyl gelatin is ≥80%; The functional medicine comprises the following components in parts by mass: 1 part of cannabidiol, 0.2-0.9 parts of tobramycin and 1-6 parts of acetylsalicylic acid.

2. The hydrogel composite according to claim 1, characterized in that The hydrogel matrix comprises the following components in parts by mass: 1 part of chitosan, 0.4-0.6 parts of hydroxybutyl chitosan and 0.08-0.1 parts of methacryloyl gelatin.

3. The hydrogel composite according to claim 1, characterized in that The chitosan satisfies at least one of the following: a. The degree of deacetylation of the chitosan is 85-95%; b. The weight average molecular weight of the chitosan is 100,000-200,000.

4. The hydrogel composite according to claim 1, characterized in that The functional medicine comprises the following components in parts by mass: 1 part of cannabidiol, 0.4-0.6 parts of tobramycin and 2-4 parts of acetylsalicylic acid.

5. The method for preparing the hydrogel composite according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: The hydrogel matrix solution, the sodium glycerophosphate pentahydrate solution and the functional drug solution are sequentially mixed and stirred into gel to obtain a hydrogel composite.

6. The preparation method according to claim 5, characterized in that: Satisfy at least one of the following: c. The mass percentage of the solute in the hydrogel matrix solution is 1-5%; d. The mass percentage of the solute in the sodium glycerophosphate pentahydrate solution is 30-40%; e. The concentration of the solute in the functional drug solution is 0.02-0.9 mol / L.

7. The preparation method according to claim 5, characterized in that: The volume ratio of the hydrogel matrix solution, sodium glycerophosphate pentahydrate solution and functional drug solution is hydrogel matrix solution: sodium glycerophosphate pentahydrate solution: functional drug solution = 1: (0.1-0.4): (0.1-1.5).

8. The preparation method according to claim 5, characterized in that: Satisfy at least one of the following: f. The solvent of the hydrogel matrix solution is 1-5% by mass of an acetic acid aqueous solution; g. The solvent of the sodium glycerophosphate pentahydrate solution is deionized water; h. The solvent of the functional drug solution is ethanol aqueous solution.

9. The preparation method according to claim 5, characterized in that: The stirring temperature is 30-50°C.

10. Use of the hydrogel complex according to any one of claims 1 to 4 in preparing a drug for treating trauma.

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