Method for the preparation of a hydrogel dressing and its use in diabetic foot

Abstract

The present application relates to the technical field of cellulose hydrogel, and discloses a preparation method of a hydrogel dressing and application thereof in diabetic foot, wherein microcrystalline cellulose, diisocyanate compound and amino acid compound are reacted to obtain modified cellulose, which is then crosslinked with hyperbranched quaternary ammonium salt through hydrogen bonding and ionic bonding to obtain the hydrogel dressing; the hydrogel dressing has higher tensile strength and water absorption rate, and the hyperbranched quaternary ammonium salt in the hydrogel dressing contains a large number of quaternary ammonium salt antibacterial groups, which has a strong killing effect on bacteria and microorganisms such as staphylococcus aureus and escherichia coli, thereby significantly improving the antibacterial performance of the dressing. The prepared hydrogel dressing has good practical application in diabetic foot dressing and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of cellulose hydrogel, in particular to a preparation method of hydrogel dressing and application in diabetic foot. BACKGROUND

[0002] Hydrogel is mainly made of cellulose, polyvinyl alcohol, polyacrylamide and other materials, and has the advantages of good biocompatibility, good hydrophilic and skin-friendly property, high liquid absorption rate, etc. It is widely used in biological medical fields such as dressing application, drug release, tissue engineering, etc. Improving the hydrophilicity, antibacterial property and other properties of hydrogel is beneficial to expand its practical application in antibacterial hemostatic dressing, diabetic foot dressing and other aspects. The literature "Observation on the curative effect of 40 cases of diabetic foot ulcer treated by hydrophilic dressing" discloses that the hydrophilic dressing can create a humid environment on the wound surface, reduce the adhesion between the dressing and the wound surface, avoid damage to the newly generated tissue on the wound surface during dressing change, and accelerate the healing of the wound surface. It has good practical application in the treatment of diabetic foot ulcers.

[0003] Traditional cellulose-based hydrogel has the problems of low water absorption and liquid absorption rate, poor mechanical strength, no antibacterial property, etc. The introduction of multiple cross-linking networks such as chemical bond cross-linking, ionic bond cross-linking and hydrogen bond cross-linking into the hydrogel matrix can improve the mechanical strength, water absorption rate and other properties of the hydrogel material. The present application aims to improve the water absorption and liquid absorption rate, antibacterial property and mechanical strength of cellulose hydrogel, and expand its practical application in diabetic foot dressing. SUMMARY

[0004] (I) The technical problem solved by the present application is to provide a hydrogel dressing with good hydrophilicity and excellent antibacterial property.

[0005] (II) Technical solution: A preparation method of a hydrogel dressing:

[0006] Step A: Add microcrystalline cellulose, diisocyanate compound, amino acid compound and triethylamine into toluene, stir at 20-30℃ for 12-18h, filter, then wash the product with ethanol, soak the product in sodium hydroxide solution, filter the product, then dialyze the product in a dialysis bag with distilled water for 3 days, and dry to obtain modified cellulose. The reaction formula is:

[0007]

[0008] Step B: Add modified cellulose and hyperbranched quaternary ammonium salt into distilled water, stir at 20-35℃ for 4-10h, filter after stirring, dialyze the product in a dialysis bag with distilled water for 3 days, and dry to obtain a hydrogel dressing.

[0009] Further, the mass ratio of the cellulose, the diisocyanate compound, the amino acid compound and the triethylamine in step A is 100:(18-25):(9-15):(1.4-2). The diisocyanate compound is isophorone diisocyanate or hexamethylene diisocyanate.

[0010] Further, the amino acid compound is glycine, beta-alanine, aspartic acid or glutamic acid.

[0011] Further, the mass ratio of the modified cellulose and the hyperbranched quaternary ammonium salt in step B is 100:(5-25).

[0012] Further, the preparation method of the hyperbranched quaternary ammonium salt is as follows:

[0013] Step (1), adding tri(2-aminoethyl)amine and the diisocyanate compound in a molar ratio of 1:(1.5-1.7) into N,N-dimethylformamide, and reacting at 60-75 DEG C for 3-5 h, then distilling under reduced pressure, washing with ethanol and drying to obtain the hyperbranched polymer. The diisocyanate compound is isophorone diisocyanate or hexamethylene diisocyanate.

[0014] Step (2), adding the hyperbranched polymer and the bromoalkane in a mass ratio of 100:(35-47) into N,N-dimethylformamide, and reacting at 100-120 DEG C for 36-48 h, then distilling under reduced pressure, washing with dichloromethane and drying to obtain the hyperbranched quaternary ammonium salt. The reaction route is as follows:

[0015]

[0016] Further, the bromoalkane is 1-bromodecane, 1-bromoundecane, 1-bromododecane, 1-bromotridecane, 1-bromotetradecane, 1-bromopentadecane or 1-bromohexadecane.

[0017] (Three) beneficial technical effects: the diisocyanate compound is used as a bridging agent, and is reacted with microcrystalline cellulose and amino acid respectively to obtain modified cellulose containing carboxyl and urea groups. The hyperbranched quaternary ammonium salt polymer is obtained by using tri(2-aminoethyl)amine, diisocyanate compound and bromoalkane as reactants. Then the modified cellulose and the hyperbranched quaternary ammonium salt are blended and crosslinked to obtain the hydrogel dressing.

[0018] The modified cellulose of the present application contains a large number of carboxyl and urea hydrophilic groups, and the hyperbranched quaternary ammonium salt also contains urea hydrophilic groups, which is beneficial to improve the hydrophilicity of the cellulose hydrogel matrix, thereby improving the water absorption rate of the hydrogel dressing.

[0019] The urea groups of the modified cellulose and the urea groups of the hyperbranched quaternary ammonium salt form hydrogen bond cross-linking, the sodium carboxylate anions of the modified cellulose and the quaternary ammonium salt cations of the hyperbranched quaternary ammonium salt form ionic bond cross-linking, thereby forming a high-stability double-network cross-linking structure in the hydrogel matrix, significantly improving the tensile strength and mechanical properties of the hydrogel dressing, and the hyperbranched quaternary ammonium salt contains hyperbranched dendritic molecular chains, forming a three-dimensional cross-linked microporous structure with the modified cellulose, which is beneficial to improve the water absorption and liquid absorption rate.

[0020] The hyperbranched quaternary ammonium salt in the hydrogel dressing of the present application contains a large number of quaternary ammonium salt antibacterial groups, which has a strong killing effect on bacteria such as Staphylococcus aureus and Escherichia coli, significantly improving the antibacterial performance of the dressing. The prepared hydrogel dressing has good practical application in antibacterial and anti-inflammatory dressings, diabetic foot dressings and the like. DETAILED DESCRIPTION

[0021] The technical solutions in the present application will be clearly and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments.

[0022] The microcrystalline cellulose in the specific embodiment is purchased from Shandong Xinguanglong Biological Material Co., Ltd.

[0023] Example 1

[0024] (1), 10 mmol (amino-NH2 content 30 mmol) tris (2-aminoethyl) amine, 15 mmol hexamethylene diisocyanate were added into 30 mL N,N-dimethylformamide, and reacted at 75℃ for 3 h, distilled under reduced pressure, washed with ethanol, and dried to obtain a hyperbranched polymer.

[0025] (2), 2 g of the hyperbranched polymer, 0.94 g of 1-bromohexadecane were added into 30 mL N,N-dimethylformamide, and reacted at 110℃ for 48 h, distilled under reduced pressure, washed with dichloromethane, and dried to obtain a hyperbranched quaternary ammonium salt.

[0026] (3), 8 g of microcrystalline cellulose, 1.44 g of hexamethylene diisocyanate, 0.72 g of β-aminopropionic acid, and 1.12 g of triethylamine were added into 120 mL of toluene, and stirred and reacted at 20℃ for 18 h, then filtered and washed with ethanol, the product was soaked in a 5% sodium hydroxide aqueous solution for 1 h, then filtered and the product was dialyzed in a dialysis bag with distilled water for 3 days, and dried to obtain modified cellulose.

[0027] (4), 10 g of the modified cellulose, 0.5 g of the hyperbranched quaternary ammonium salt were added into 400 mL of distilled water, and stirred and cross-linked at 25℃ for 4 h, then filtered after stirring, the product was dialyzed in a dialysis bag with distilled water for 3 days, and dried to obtain a hydrogel dressing.

[0028] Example 2:

[0029] (1) To 40 mL of N,N-dimethylformamide, 10 mmol of tris(2-aminoethyl)amine, 16 mmol of hexamethylene diisocyanate were added, and reacted at 60°C for 5 h, distilled under reduced pressure, washed with ethanol, and dried to obtain a hyperbranched polymer.

[0030] (2) To 25 mL of N,N-dimethylformamide, 2 g of the hyperbranched polymer, 0.7 g of 1-bromodecane were added, and reacted at 100°C for 48 h, distilled under reduced pressure, washed with dichloromethane, and dried to obtain a hyperbranched quaternary ammonium salt.

[0031] (3) To 120 mL of toluene, 8 g of microcrystalline cellulose, 1.65 g of hexamethylene diisocyanate, 0.87 g of glutamic acid, 1.29 g of triethylamine were added, and reacted at 20°C for 18 h with stirring, filtered, and washed with ethanol. The product was immersed in a 5% by mass aqueous sodium hydroxide solution, stirred for 1 h, filtered, and the product was dialyzed in a dialysis bag using distilled water for 3 days, and dried to obtain a modified cellulose.

[0032] (4) To 500 mL of distilled water, 10 g of the modified cellulose, 1.2 g of the hyperbranched quaternary ammonium salt were added, and crosslinked at 20°C for 10 h with stirring. After stirring, it was filtered, and the product was dialyzed in a dialysis bag using distilled water for 3 days, and dried to obtain a hydrogel dressing.

[0033] Example 3:

[0034] (1) To 40 mL of N,N-dimethylformamide, 10 mmol of tris(2-aminoethyl)amine, 17 mmol of isophorone diisocyanate were added, and reacted at 65°C for 5 h, distilled under reduced pressure, washed with ethanol, and dried to obtain a hyperbranched polymer.

[0035] (2) To 30 mL of N,N-dimethylformamide, 2 g of the hyperbranched polymer, 0.79 g of 1-bromododecane were added, and reacted at 120°C for 36 h, distilled under reduced pressure, washed with dichloromethane, and dried to obtain a hyperbranched quaternary ammonium salt.

[0036] (3) To 130 mL of toluene, 8 g of microcrystalline cellulose, 1.83 g of isophorone diisocyanate, 1.03 g of aspartic acid, 1.42 g of triethylamine were added, and reacted at 30°C for 12 h with stirring, filtered, and washed with ethanol. The product was immersed in a 5% by mass aqueous sodium hydroxide solution, stirred for 1 h, filtered, and the product was dialyzed in a dialysis bag using distilled water for 3 days, and dried to obtain a modified cellulose.

[0037] (4) To 600 mL distilled water, 10 g modified cellulose, 1.8 g hyperbranched quaternary ammonium salt were added, and crosslinked at 35 °C for 6 h with stirring. After stirring, the product was filtered, and the product was dialyzed in a dialysis bag with distilled water for 3 days, dried to obtain a hydrogel dressing.

[0038] Example 4:

[0039] (1) To 30 mL N,N-dimethylformamide, 10 mmol tris (2-aminoethyl) amine, 15 mmol isophorone diisocyanate were added, and reacted at 75 °C for 3 h, distilled under reduced pressure, washed with ethanol, and dried to obtain a hyperbranched polymer.

[0040] (2) To 30 mL N,N-dimethylformamide, 2 g hyperbranched polymer, 0.87 g 1-bromotetradecane were added, and reacted at 100 °C for 48 h, distilled under reduced pressure, washed with dichloromethane, and dried to obtain a hyperbranched quaternary ammonium salt.

[0041] (3) To 140 mL toluene, 8 g microcrystalline cellulose, 2 g isophorone diisocyanate, 1.2 g glycine, 1.6 g triethylamine were added, and reacted at 30 °C for 12 h with stirring. After filtration, the product was washed with ethanol, and the product was immersed in a 5% mass fraction sodium hydroxide aqueous solution and stirred for 1 h. After filtration, the product was dialyzed in a dialysis bag with distilled water for 3 days, and dried to obtain a modified cellulose.

[0042] (4) To 800 mL distilled water, 10 g modified cellulose, 2.5 g hyperbranched quaternary ammonium salt were added, and crosslinked at 25 °C for 10 h with stirring. After stirring, the product was filtered, and the product was dialyzed in a dialysis bag with distilled water for 3 days, dried to obtain a hydrogel dressing.

[0043] Comparative Example 1:

[0044] (1) To 400 mL distilled water, 10 g modified cellulose (prepared according to the method of Example 1), 0.5 g hyperbranched polymer (prepared according to the method of Example 1) were added, and crosslinked at 25 °C for 4 h with stirring. After stirring, the product was filtered, and the product was dialyzed in a dialysis bag with distilled water for 3 days, dried to obtain a hydrogel dressing.

[0045] Comparative Example 2:

[0046] (1) To 30 mL N,N-dimethylformamide, 15 mmol (amino-NH2 content 30 mmol) 2,2'-diamino-N-methyldiethylamine (chemical structure formula is ), 15 mmol hexamethylene diisocyanate were added, and reacted at 75 °C for 3 h, distilled under reduced pressure, washed with ethanol, and dried to obtain a linear polymer.

[0047] (2) To 30 mL of N,N-dimethylformamide, 2 g of linear polymer, 0.94 g of 1-bromohexadecane were added and reacted at 110°C for 48 h, distilled under reduced pressure, washed with dichloromethane, and dried to obtain a quaternary ammonium salt polymer.

[0048] (3) To 400 mL of distilled water, 10 g of modified cellulose (prepared according to the method of Example 1), 0.5 g of quaternary ammonium salt polymer were added, and cross-linked at 25°C for 4 h with stirring, filtered after stirring, and the product was dialyzed in a dialysis bag using distilled water for 3 days, and dried to obtain a hydrogel dressing.

[0049] Comparative Example 3:

[0050] (1) To 400 mL of distilled water, 10 g of microcrystalline cellulose, 0.5 g of hyperbranched quaternary ammonium salt (prepared according to the method of Example 1) were added, and cross-linked at 25°C for 4 h with stirring, and dried after stirring to obtain a hydrogel dressing.

[0051] Comparative Example 4:

[0052] (1) To 120 mL of toluene, 8 g of microcrystalline cellulose, 1.44 g of hexamethylene diisocyanate, 0.72 g of n-propylamine, 1.12 g of triethylamine were added and reacted at 20°C for 18 h with stirring, washed with ethanol after filtration, and the product was immersed in a 5% by mass aqueous sodium hydroxide solution and stirred for 1 h, filtered, and the product was dialyzed in a dialysis bag using distilled water for 3 days, and dried to obtain modified cellulose.

[0053] (2) To 400 mL of distilled water, 10 g of modified cellulose, 0.5 g of hyperbranched quaternary ammonium salt (prepared according to the method of Example 1) were added, and cross-linked at 25°C for 4 h with stirring, filtered after stirring, and the product was dialyzed in a dialysis bag using distilled water for 3 days, and dried to obtain a hydrogel dressing.

[0054] The hydrogel dressing was prepared into a test sample with a size of 80 x 10 mm x 1 mm, and the tensile properties were tested by a universal material testing machine, the test temperature was room temperature, the tensile rate was 5 mm / min, and the gap was 15 mm. Each group of samples was tested 5 times, and the average value was taken.

[0055] The hydrogel dressing was prepared into a test sample with a size of 50 x 50 mm x 20 mm, dried, weighed, immersed in distilled water at room temperature for 24 h, the hydrogel was taken out, the surface water was absorbed with filter paper, weighed, and the water absorption rate was calculated. Water absorption rate = (mass after water absorption - mass before water absorption) ÷ mass before water absorption. Each group of samples was tested 3 times, and the average value was taken.

[0056] Staphylococcus aureus and Escherichia coli were respectively activated at 37°C for 24 h, diluted with a PBS buffer solution to 10 6The bacteria solution of 1.0 x 108cfu / mL was taken, 0.1 mL of the bacteria solution was uniformly coated on beef extract protein peptone medium, and the hydrogel dressing (a round film with a diameter of 6 mm) was attached to the medium. Then, the medium was cultured in a constant temperature and humidity incubator at 37°C for 24 h, and then the diameter of the inhibition zone was measured. Each group of samples was tested 3 times, and the average value was taken. The test results are shown in Table 1.

[0057] Table 1: Test results

[0058]

[0059] Through testing, the hydrogel dressings of Examples 1-4 have higher tensile strength, water absorption rate and antibacterial rate, because the modified cellulose in the hydrogel dressing contains a large number of carboxyl and urea groups hydrophilic groups, and the super-branched quaternary ammonium salt added at the same time also contains urea hydrophilic groups, which is conducive to improving the hydrophilicity of the cellulose hydrogel matrix, thereby improving the water absorption rate of the hydrogel dressing. At the same time, the urea groups of the modified cellulose and the urea groups of the super-branched quaternary ammonium salt form hydrogen bond crosslinking, and the sodium carboxylate anions of the modified cellulose and the quaternary ammonium salt cations of the super-branched quaternary ammonium salt form ionic bond crosslinking, thereby forming a high-stability double-network crosslinking structure in the hydrogel matrix, significantly improving the tensile strength and mechanical properties of the hydrogel dressing. In addition, the super-branched quaternary ammonium salt contains super-branched dendritic molecular chains, which form a three-dimensional crosslinking microporous structure with the modified cellulose, which is conducive to improving the water absorption rate. The hydrogel dressing contains a large number of quaternary ammonium salt antibacterial groups, which have a strong killing effect on bacteria such as Staphylococcus aureus and Escherichia coli, thereby improving the antibacterial performance of the dressing.

[0060] The super-branched polymer of Comparative Example 1 does not contain quaternary ammonium salt groups, and cannot form ionic bond crosslinking with the sodium carboxylate anions of the modified cellulose, so it does not form a high-stability double-network crosslinking structure and a three-dimensional crosslinking microporous structure, resulting in lower tensile strength and water absorption rate of the hydrogel dressing, and poor antibacterial performance.

[0061] The quaternary ammonium salt polymer of Comparative Example 2 has a linear structure and does not have super-branched dendritic molecular chains, so the enhancement effect is not good, and the water absorption rate of the hydrogel is low.

[0062] The cellulose of Comparative Example 3 does not contain urea groups and sodium carboxylate structures, and cannot form a double-network crosslinking structure with the super-branched quaternary ammonium salt, resulting in lower tensile strength and water absorption rate of the hydrogel dressing.

[0063] In Comparative Example 4, n-propylamine is used instead of β-aminopropionic acid, and the modified cellulose does not contain sodium carboxylate structures, so the hydrophilicity is poor, and it also cannot form ionic bond crosslinking with the super-branched quaternary ammonium salt, resulting in lower tensile strength and water absorption rate of the hydrogel dressing.

[0064] The above merely describes the preferred embodiments of the present application, and it should be pointed out that, for those skilled in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as falling within the protection scope of the present application.

Claims

1. A method for preparing a hydrogel dressing, characterized in that, The preparation method includes the following steps: Step A: Add microcrystalline cellulose, diisocyanate compound, amino acid compound, and triethylamine to toluene, stir to react, filter and wash with ethanol, soak the product in sodium hydroxide solution, filter and dialyze with distilled water, dry to obtain modified cellulose; Step B: Add modified cellulose and hyperbranched quaternary ammonium salt to distilled water, stir to crosslink, filter after stirring, dialyze with distilled water, and dry to obtain hydrogel dressing; The preparation method of hyperbranched quaternary ammonium salt is as follows: Step (1): Add tris(2-aminoethyl)amine and diisocyanate compound in a molar ratio of 1:(1.5-1.7) to N,N-dimethylformamide, react at 60-75℃ for 3-5 h, distill under reduced pressure, wash, and dry to obtain hyperbranched polymer. Step (2): Add hyperbranched polymer and bromoalkane in a mass ratio of 100:(35-47) to N,N-dimethylformamide, react at 100-120℃ for 36-48h, distill under reduced pressure, wash, and dry to obtain hyperbranched quaternary ammonium salt.

2. The method for preparing the hydrogel dressing according to claim 1, characterized in that, The reaction in step A is carried out at 20-30℃ for 12-18 hours.

3. The method for preparing the hydrogel dressing according to claim 1, characterized in that, In step A, the mass ratio of microcrystalline cellulose, diisocyanate compound, amino acid compound, and triethylamine is 100:(18-25):(9-15):(1.4-2).

4. The method for preparing the hydrogel dressing according to claim 3, characterized in that, The amino acid compound is glycine, β-aminopropionic acid, aspartic acid, or glutamic acid.

5. The method for preparing the hydrogel dressing according to claim 1, characterized in that, In step B, the mass ratio of modified cellulose to hyperbranched quaternary ammonium salt is 100:(5-25).

6. The method for preparing the hydrogel dressing according to claim 1, characterized in that, In step B, the crosslinking is carried out at 20-35℃ for 4-10 hours.

7. The method for preparing the hydrogel dressing according to claim 1, characterized in that, The bromoalkane is 1-bromodecane, 1-bromoundecane, 1-bromododecane, 1-bromotridecane, 1-bromotetradecane, 1-bromopentadecanane, or 1-bromohexadecane.

8. The method for preparing the hydrogel dressing according to claim 1, characterized in that, The diisocyanate compound in step (1) is isophorone diisocyanate or hexamethylene diisocyanate.

9. The application of a hydrogel dressing obtained by the preparation method according to any one of claims 1-8 in diabetic foot dressings.

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