CN118697931A - A kind of oral repair adhesive imitating mussel mucin and preparation method thereof - Google Patents

Abstract

The invention discloses an oral repair adhesive imitating mussel mucin and a preparation method thereof, and belongs to the technical field of bioadhesive materials. The preparation method comprises the following steps: hydroxyethyl cellulose is mixed with glycerol and heated to 45-50°C, and then a catechol derivative is added and mixed with it to form a reaction system; after adding an alkaline catalyst to the reaction system, a mixture is obtained at 60-70°C for a reaction time of 2-4h; the mixture is treated with an equal amount of hydrochloric acid with the alkaline catalyst, and then mixed with fatty acids and diols, and then concentrated hydrochloric acid is added and heated to reflux to obtain a catechol-hydroxyethyl cellulose derivative; the catechol-hydroxyethyl cellulose derivative is mixed with an aqueous acrylic acid curing agent in a mass ratio of 3:1 to obtain the oral repair adhesive. The present invention combines the catechol structure of the catechol derivative and the hydrophobic side chain of the fatty acid to the hydroxyethyl cellulose through covalent bonding, thereby achieving an improvement in the oral bonding performance of the hydroxyethyl cellulose.

Description

A kind of oral repair adhesive imitating mussel mucin and preparation method thereof

Technical Field

The invention belongs to the technical field of biological adhesive materials, and in particular relates to an oral repair adhesive imitating mussel mucin, which is developed according to the high-strength water-resistant adhesive property of mussel mucin and a preparation method thereof.

Background Art

Oral ulcer is a common ulcerative injury disease that occurs on the oral mucosa. It is characterized by repeated attacks, burning pain and various complications. The number of ulcers increases from a few to a lot, and the location changes from front to back. The ulcer surface is as large as a soybean or as small as a grain of rice, and a white ulcerated film is attached to the surface. In mild cases, it may occur once every few months. In severe cases, the interval gradually shortens, and the ulcer becomes more severe year by year. Even ulcers may occur one after another for several years or even decades without healing. Clinically, oral ulcers are often treated by local administration of drugs to the affected area. The commonly used drugs are mainly watermelon frost spray, oral ulcer gel, etc. Among them, the main function of oral ulcer gel is to protect the ulcer, and the drug ingredients promote ulcer healing and prevent ulcers from being contaminated by secondary pollution. However, the oral environment is relatively moist, and it is easy for the drug to fall off due to activities such as chewing and swallowing, which generally affects the treatment effect.

Mussel mucin originates from the foot gland of the marine organism blue mussel. It is a high-purity single protein that is easily absorbed by the human body. This protein is the only biomaterial with a positively charged macromolecular DOPA group. It has super strong viscosity and effectively promotes cell adhesion, crawling growth and wound healing. Studies have shown that the strong adhesion of mussel mucin is due to the cross-linking structure formed between DOPA in the protein structure and DOPA oxidized to DOPA quinone, and the catechol in the two structures, which allows mussels to adhere firmly to the reefs without fear of the impact of waves. However, the biggest problem with directly applying mussel mucin to adhesives is that the amount of naturally extracted mussel mucin is small and extremely expensive. The recombinant mussel mucin obtained by the recombinant protein expression system has unstable bonding properties due to the low DOPA content.

Therefore, preparing a waterproof repair adhesive that imitates mussel mucin and is suitable for use in a humid oral environment through a catechol structure has important application prospects for improving the oral bonding properties of hydroxyethyl cellulose adhesives.

Summary of the invention

According to the deficiencies of the prior art, the present invention uses a base as a catalyst to catalyze the ring opening of the epoxy group on the hydroxyethyl cellulose to obtain a carbon cation, and levodopa is used as a nucleophilic reagent to attack the carbon cation with the amino group in the structure, so that levodopa is bound to the hydroxyethyl cellulose through the bonding method of covalent bonds; and then alcohol is used as a bridging structure, so that the carboxyl group on the levodopa and the fatty acid are connected and fixed through the alcohol, on the one hand, the network structure formed by the cross-linking between the catechol exposed on the levodopa structure is improved, and the bonding performance of hydroxyethyl cellulose in the oral cavity is improved; on the other hand, the hydrophobic alkyl chain on the fatty acid is introduced into the levodopa covalently cross-linked with the epoxy group, and the solidification of hydroxyethyl cellulose is achieved through the agglomeration of hydrophobic action, so as to achieve the purpose of reducing the swelling rate of hydroxyethyl cellulose, and at the same time, the hydrophobic microenvironment prevents the oxidation of catechol, improves the water resistance of hydroxyethyl cellulose, and thus improves the oral bonding performance of hydroxyethyl cellulose. Specifically, the technical scheme of the present invention includes the following contents:

A method for preparing a mussel-mimicking oral repair adhesive, the preparation method comprising the following steps:

Hydroxyethyl cellulose and glycerin are mixed and heated to 45-50°C, and then catechol derivatives are added and mixed and stirred to form a reaction system;

After adding an alkaline catalyst to the reaction system, reacting at 60-70° C. for 2-4 hours to obtain a mixture;

The mixture is treated with an equal amount of hydrochloric acid as the alkaline catalyst, mixed with fatty acid and diol, and then 11.9-12 mol/L concentrated hydrochloric acid is added and heated under reflux to obtain a catechol-hydroxyethyl cellulose derivative;

The catechol-hydroxyethyl cellulose derivative and the aqueous acrylic curing agent are mixed and stirred in a mass ratio of 3:1 to obtain the oral restoration adhesive.

Furthermore, the catechol derivatives include levodopa, and the side carbon chains of the catechol derivatives need to be connected with carboxyl groups and amino groups. The amino groups, as electrophilic groups, initiate nucleophilic attacks on the carbon cations after ring opening on the hydroxyethyl cellulose and are covalently bonded to the hydroxyethyl cellulose; while the carboxyl groups can be covalently bonded to the fatty acids through a diol bridge having two hydroxyl groups by dehydration condensation.

Furthermore, the mass ratio of hydroxyethyl cellulose: glycerol: catechol derivative is 1:1:0.5-1.

Furthermore, the alkaline catalyst includes sodium hydroxide and potassium hydroxide, and the amount of the alkaline catalyst used is 0.1 to 0.15 of the mass of the hydroxyethyl cellulose.

Furthermore, the fatty acid includes a saturated fatty acid, and the saturated fatty acid includes stearic acid or palmitic acid. Unsaturated fatty acids may have a certain steric hindrance effect due to the carbon-carbon double bond in the structure, thereby reducing the success rate of connection with the catechol derivative.

Furthermore, the diol includes ethylene glycol or 1,5-pentanediol, and the hydroxyl groups of the diol are preferably diols with hydroxyl groups at both ends of the carbon chain, which can further increase the length of the hydrophobic chain.

Furthermore, the amount of the fatty acid used is 1 to 2 times the mass of the catechol derivative, and the amount of the diol used is 2 to 4 times the mass of the fatty acid.

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

(1) The present invention uses base-catalyzed ring opening of the epoxy group on hydroxyethyl cellulose to obtain a carbon cation, and then uses the catechol derivative levodopa with an amino structure as a nucleophilic reagent to initiate a nucleophilic attack on the carbon cation structure obtained after the ring opening of hydroxyethyl cellulose, forming a covalently bonded cross-linked network structure, so that levodopa is bound to the hydroxyethyl cellulose, and then treated with hydrochloric acid to remove the sodium ions bound to the catechol and carboxyl groups on the structure of levodopa due to base catalysis by strong acid to weak acid, thereby restoring the active effect of catechol and the acidity of the carboxyl group; and then using a diol with two hydroxyl groups as an alcohol bridge to form a covalent bond with the carboxyl group on the catechol derivative levodopa and the carboxyl group on the fatty acid through dehydration condensation, so that the fatty acid is connected to the catechol derivative levodopa through a covalently bonded bridge. On the mussel mucin-like structure of levodopa, the fatty acid forms a covalently cross-linked network structure with levodopa, and the fatty acid indirectly enters the hydroxyethyl cellulose structure through the connection with levodopa. On the one hand, the cross-linked network structure formed between the catechols exposed on the levodopa structure is used to improve the bonding performance of hydroxyethyl cellulose in the oral cavity. On the other hand, the hydrophobic side chains of the fatty acids are bonded to the hydroxyethyl cellulose through covalent cross-linking, and the solidification of the hydroxyethyl cellulose is achieved through the agglomeration effect of the hydrophobic effect, which not only achieves the purpose of reducing the swelling rate of hydroxyethyl cellulose, but also prevents the oxidation of catechols by the hydrophobic microenvironment, thereby improving the water resistance of hydroxyethyl cellulose. The synergistic effect of the cross-linked network structure formed by the catechols on levodopa and the hydrophobic side chains of fatty acids further improves the oral bonding performance of hydroxyethyl cellulose.

(2) The covalently cross-linked network structure constructed by the present invention introduces hydrophobic side chains into hydroxyethyl cellulose, thereby reducing the water absorption and swelling effect of hydroxyethyl cellulose and obtaining a good swelling rate.

DETAILED DESCRIPTION

The technical solution of the present invention will be clearly and completely described below through the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

Unless otherwise specified, the raw materials and reagents used in the present invention are commercially available or can be prepared by known methods.

Embodiment 1:

A method for preparing a mussel-mimicking oral repair adhesive specifically comprises the following steps:

100 g of hydroxyethyl cellulose and 100 g of glycerol were weighed and mixed and placed in a flask. After heating to 45° C., 50 g of levodopa was added and mixed and stirred until the levodopa was completely dissolved, 10 g of sodium hydroxide was added and stirred, the temperature of the entire reaction system was controlled at 60° C. and refluxed for 2 hours, 10 g of hydrochloric acid was added and mixed and stirred, and then an excess of deionized water was added and stirred, and the aqueous phase layer was removed after standing for stratification. The retained organic phase layer was mixed with 50 g of stearic acid and 100 g of ethylene glycol, and 10 g of concentrated hydrochloric acid with a concentration of 12 mol/L was slowly added dropwise, and the mixture was refluxed at 60° C. for 2 hours to obtain a catechol-hydroxyethyl cellulose derivative; 60 g of the catechol-hydroxyethyl cellulose derivative was weighed and mixed with 20 g of an aqueous acrylic curing agent to obtain an oral restoration adhesive.

Embodiment 2:

A method for preparing a mussel-mimicking oral repair adhesive specifically comprises the following steps:

100 g of hydroxyethyl cellulose and 100 g of glycerol were weighed and mixed and placed in a flask. After heating to 46° C., 60 g of levodopa was added and mixed and stirred until the levodopa was completely dissolved. 12 g of sodium hydroxide was added and stirred. The temperature of the entire reaction system was controlled at 64° C. and refluxed for 2 h. 12 g of hydrochloric acid was added and mixed and stirred. Then, an excess of deionized water was added and stirred, and the aqueous phase layer was removed by standing for stratification. The retained organic phase layer was mixed with 72 g of stearic acid and 180 g of ethylene glycol, and 13.2 g of concentrated hydrochloric acid with a concentration of 12 mol/L was slowly added dropwise. The mixture was refluxed at 65° C. for 2 h to obtain a catechol-hydroxyethyl cellulose derivative. 60 g of the catechol-hydroxyethyl cellulose derivative was weighed and mixed with 20 g of the water-based acrylic curing agent in Preparation Example 2 to obtain an oral repair adhesive.

Embodiment 3:

A method for preparing a mussel-mimicking oral repair adhesive specifically comprises the following steps:

100 g of hydroxyethyl cellulose and 100 g of glycerol were weighed and mixed and placed in a flask. After heating to 48° C., 80 g of levodopa was added and mixed and stirred until the levodopa was completely dissolved. 14 g of potassium hydroxide was added and stirred. The temperature of the entire reaction system was controlled at 66° C. and refluxed for 3 hours. 14 g of hydrochloric acid was added and mixed and stirred. Then, an excess of deionized water was added and stirred, and the aqueous phase layer was removed after standing for stratification. The retained organic phase layer was mixed with 128 g of palmitic acid and 448 g of 1,5-pentanediol, and 20.8 g of concentrated hydrochloric acid with a concentration of 12 mol/L was slowly added dropwise. The mixture was refluxed at 75° C. for 3 hours to obtain a catechol-hydroxyethyl cellulose derivative. 60 g of the catechol-hydroxyethyl cellulose derivative was weighed and mixed with 20 g of the aqueous acrylic curing agent in Preparation Example 3 to obtain an oral restoration adhesive.

Embodiment 4:

A method for preparing a mussel-mimicking oral repair adhesive specifically comprises the following steps:

100 g of hydroxyethyl cellulose and 100 g of glycerol were weighed and mixed and placed in a flask. After heating to 50° C., 100 g of levodopa was added and mixed and stirred until the levodopa was completely dissolved, and 15 g of potassium hydroxide was added for stirring. The temperature of the entire reaction system was controlled at 70° C. and refluxed for 4 hours. Then, 15 g of hydrochloric acid was added for mixing and stirring. Then, an excess of deionized water was added, stirred, and allowed to stand for stratification to remove the aqueous phase. The retained organic phase was mixed with 200 g of palmitic acid and 100 g of 1,5-pentanediol, and 30 g of concentrated hydrochloric acid with a concentration of 12 mol/L was slowly added dropwise. The mixture was refluxed at 80° C. for 3 hours to obtain a catechol-hydroxyethyl cellulose derivative. 60 g of the catechol-hydroxyethyl cellulose derivative was weighed and mixed with 20 g of the aqueous acrylic curing agent in Preparation Example 4 to obtain an oral repair adhesive.

Comparative Example 1:

The difference from Example 1 is that no water-based acrylic curing agent is added, and the rest remains unchanged.

The oral repair adhesives prepared in Examples 1 to 4 and Comparative Example 1 were tested for glass tower shear performance. The test results are shown in the following table:

Sources Compressive strength(MPa) Bond strength (MPa) Example 1 51.42 4.09 Example 2 55.20 4.25 Example 3 58.79 4.62 Example 4 60.03 4.97 Comparative Example 1 34.11 2.57

The oral repair adhesives prepared in Examples 1 to 4 and Comparative Example 1 were immersed in PBS buffer for 7 days, and the swelling rates were measured. The results are shown in the following table:

Sources Swelling rate (%) Example 1 10.14% Example 2 9.27% Example 3 8.47% Example 4 8.26% Comparative Example 1 20.06%

The above-described embodiments are described in detail in comparison with the technical solutions and beneficial effects of the present invention. It should be understood that the above is only a specific embodiment of the present invention and is not intended to limit the present invention. Without departing from the spirit and scope of the present invention, the present invention may also have various changes and improvements, including the optimization of reaction conditions and the adjustment of reaction ratio, and these changes and improvements all fall within the scope of the present invention claimed.

Claims (8)

1. A method for preparing a mussel-like oral repair adhesive, characterized in that the preparation method comprises the following steps: Hydroxyethyl cellulose and glycerin are mixed and heated to 45-50°C, and then catechol derivatives are added and mixed and stirred to form a reaction system; After adding an alkaline catalyst to the reaction system, reacting at 60-70° C. for 2-4 hours to obtain a mixture; The mixture is treated with an equal amount of hydrochloric acid as the alkaline catalyst, mixed with fatty acid and diol, and then concentrated hydrochloric acid is added and heated under reflux to obtain a catechol-hydroxyethyl cellulose derivative; The catechol-hydroxyethyl cellulose derivative and the aqueous acrylic curing agent are mixed and stirred in a mass ratio of 3:1 to obtain the oral restoration adhesive. 2. The method for preparing a mussel mucin-mimicking oral repair adhesive according to claim 1, wherein the catechol derivative comprises levodopa. 3. The method for preparing a mussel mucin-mimicking oral repair adhesive according to claim 1, characterized in that the mass ratio of hydroxyethyl cellulose: glycerol: catechol derivative is 1:1:0.5-1. 4. The method for preparing a mussel-mimicking oral repair adhesive according to claim 1, characterized in that the alkaline catalyst comprises sodium hydroxide or potassium hydroxide, and the amount of the alkaline catalyst is 0.1 to 0.15 of the mass of the hydroxyethyl cellulose. 5. The method for preparing a mussel mucin-mimicking oral repair adhesive according to claim 1, characterized in that the fatty acid comprises a saturated fatty acid, and the saturated fatty acid comprises stearic acid or palmitic acid. 6 . The method for preparing a mussel mucin-mimicking oral repair adhesive according to claim 1 , wherein the diol comprises ethylene glycol or 1,5-pentanediol. 7. The method for preparing a mussel mucin-mimicking oral repair adhesive according to claim 1, characterized in that the amount of the fatty acid used is 1 to 2 times the mass of the catechol derivative, and the amount of the diol used is 2 to 4 times the mass of the fatty acid. 8. An oral repair adhesive prepared by the method for preparing an oral repair adhesive imitating mussel mucin according to any one of claims 1 to 7.