A medical chitosan-based foam dressing and its preparation method

Abstract

This invention discloses a medical chitosan-based foam dressing and its preparation method, relating to the field of medical dressing technology. The method for preparing the medical chitosan-based foam dressing includes the following steps: (1) reacting hydroxybutyl chitosan with vanillic acid to obtain modified chitosan; (2) adding the modified chitosan to a weak acid aqueous solution, stirring and mixing, adding a modifier and zinc salt, adjusting the pH to 5-6, heating and stirring, adding a foam stabilizer and a foaming agent, cooling, stirring at high speed, and freeze-drying to obtain the medical chitosan-based foam dressing; the medical chitosan-based foam dressing prepared by this invention has excellent water absorption, compressive strength and antibacterial properties.

Description

Technical Field

[0001] This invention relates to the field of medical dressing technology, specifically to a medical chitosan-based foam dressing and its preparation method. Background Technology

[0002] Medical chitosan foam dressings are a novel type of wound dressing made primarily from chitosan. Chitosan molecules contain amino and hydroxyl groups, exhibiting good biocompatibility, biodegradability, and procoagulant properties, thus showing promising application prospects in burns, pressure ulcers, chronic ulcers, and postoperative wound care. Hydroxybutyl chitosan is a modified chitosan material obtained by introducing hydroxybutyl groups into the chitosan molecular chain. The introduction of hydroxybutyl segments weakens the intermolecular hydrogen bonding of chitosan, improves its water solubility, and facilitates the formation of a more uniform foam structure. However, hydroxybutyl chitosan foam dressings are prone to insufficient mechanical strength, decreased structural stability, and poor flexibility under wet conditions; simultaneously, their antibacterial activity is weak and lacks durability, making it difficult to meet the clinical needs of wounds with high exudation, susceptibility to infection, and long-term care.

[0003] Chinese invention patent CN109224114A discloses a foam dressing, its preparation method, and its application. The foam dressing is mainly prepared from the following raw materials: chitosan, hyaluronic acid, biosaccharide gum, and clove extract. In this invention, chitosan and clove extract work synergistically to inhibit bacterial growth and reproduction. Combined with hyaluronic acid and biosaccharide gum, it provides a sterile, moist microenvironment conducive to wound healing, exhibiting excellent hemostatic, anti-inflammatory, healing-promoting, and antibacterial effects. However, its mechanical properties need further improvement. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the purpose of this invention is to provide a medical chitosan-based foam dressing and its preparation method.

[0005] A method for preparing a medical chitosan-based foam dressing includes the following steps: (1) Hydroxybutyl chitosan was reacted with vanillic acid to obtain modified chitosan; (2) Add the modified chitosan to a weak acid aqueous solution, stir and mix well, add the modifier and zinc salt, adjust the pH to 5-6, heat and stir, add the foam stabilizer and foaming agent, cool, stir at high speed, freeze dry to obtain medical chitosan-based foam dressing. The structural formula of the modifier is as follows: .

[0006] In step (1), the mass ratio of hydroxybutyl chitosan to vanillic acid is 1:(0.2-0.3).

[0007] In step (1), the reaction temperature is 50-60℃ and the time is 10-12h.

[0008] In step (2), the mass ratio of the modified chitosan, modifier, zinc salt, foam stabilizer and foaming agent is 1:(0.08-0.12):(0.02-0.04):(0.06-0.12):(0.04-0.08).

[0009] In step (2), the zinc salt is zinc acetate dihydrate.

[0010] In step (2), the foam stabilizer is gelatin.

[0011] In step (2), the foaming agent is poloxamer.

[0012] In step (2), the high-speed stirring speed is 4000-5000 rpm and the time is 3-8 min.

[0013] The modifier is prepared by reacting lipoic acid with dopamine hydrochloride.

[0014] A medical chitosan-based foam dressing is prepared by the above method.

[0015] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include: The medical chitosan-based foam dressing prepared by this invention has excellent water absorption, compressive strength and antibacterial properties. Attached Figure Description

[0016] Figure 1 The image shows the 1H NMR spectrum of the modifier prepared in Example 1.

[0017] Figure 2 The high-resolution mass spectrum of the modifier prepared in Example 1 is shown.

[0018] Figure 3 The Fourier transform infrared spectrum of the modifier prepared in Example 1.

[0019] Figure 4 Fourier transform infrared spectra of hydroxybutyl chitosan and modified chitosan prepared in Example 3.

[0020] Figure 5 Scanning electron microscope image of the medical chitosan-based foam dressing prepared in Example 3. Detailed Implementation

[0021] Example 1 Preparation of Modifier Under nitrogen protection, 150 ml of N,N-dimethylformamide (DMF), 0.1 mol of lipoic acid, 0.11 mol of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 0.12 mol of N-hydroxysuccinimide were added sequentially to a reaction flask and stirred for 20 min. Then, 0.11 mol of dopamine hydrochloride and 0.2 mol of triethylamine were added sequentially. The reaction was carried out at room temperature in the dark for 24 h. 400 ml of deionized water was added and stirred until homogeneous. The pH was adjusted to 4.5 with 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (3 × 200 ml), and the ethyl acetate phases were combined. The mixture was washed with saturated brine (2 × 100 ml), dried over 50 g of anhydrous magnesium sulfate, filtered, and the filtrate was rotary evaporated at 50 °C to constant weight. The filtrate was added to 100 ml of diethyl ether, stirred to precipitate, filtered, washed with 50 ml of diethyl ether, and dried under vacuum at 50 °C for 10 h to obtain the modifier. The reaction equation is shown below:

[0022] Its proton nuclear magnetic resonance spectrum is as follows Figure 1 As shown, the proton NMR data are as follows: 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.06 (s, 1H), 7.74 (s, 1H), 7.52 (t, J = 4.9 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 6.65 – 6.57 (m, 1H), 6.51 – 6.48 (m, 1H), 3.35 – 3.22 (m, 3H), 3.18 – 3.03 (m, 2H), 2.80–2.67 (m, 2H), 2.23 – 2.13 (m, 3H), 1.90 – 1.83 (m, 1H), 1.75 – 1.32 (m, 6H); its high-resolution mass spectrum is shown below. Figure 2 As shown, HRMS (m / z): 342.1193 [M+H] + .

[0023] Figure 3 The Fourier transform infrared spectrum of the modifier is shown in the figure. It can be seen from the figure that in the 3500-3300 cm⁻¹ range... -1 The broad absorption peaks appearing within the range are due to the stretching vibrations of the phenolic hydroxyl group (OH) and the amide (NH); at 2926 cm⁻¹ -1 and 2854cm -1 The peak appearing nearby is the methylene CH stretching vibration peak; at 1648 cm⁻¹ -1 The peak appearing nearby is the C=O stretching vibration peak of amide, at 1546 cm⁻¹. -1The nearby peak is a vibrational peak of the amide II band, indicating that an amide bond has formed between lipoic acid and dopamine; 1450 cm⁻¹ -1 The nearby peak is a vibrational peak of the aromatic ring skeleton; 1282 cm⁻¹ -1 The peak appearing nearby is the stretching vibration peak of the phenolic hydroxyl group (CO), and it is located at 500-700 cm⁻¹. -1 The corresponding CS / SS vibrational peaks are within the specified range. The appearance of these characteristic peaks proves that the modifier was successfully prepared.

[0024] Example 2: Preparation of Medical Chitosan-Based Foam Dressing (1) Mix 5g of hydroxybutyl chitosan with 300ml of deionized water and stir to dissolve to obtain hydroxybutyl chitosan solution; add 50ml of 50wt% ethanol aqueous solution, 1g of vanillic acid, 1.5g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.7g of N-hydroxysuccinimide to the reaction flask and stir for 30min. Add the hydroxybutyl chitosan solution and stir at room temperature for 15h. During the reaction, use 1wt% hydrochloric acid solution / sodium hydroxide solution to adjust and maintain pH at 6; put the reaction solution into a dialysis bag (3500Da) and dialyze with deionized water for 48h. Replace the deionized water every 6h. After pre-freezing at -56℃ for 4h, freeze-dry at -56℃ and vacuum degree of 30Pa for 24h to obtain modified chitosan; (2) Add 5g of modified chitosan to 200ml of 0.5wt% acetic acid aqueous solution, stir at 500rpm for 1h at room temperature, add 10ml of anhydrous ethanol containing 0.4g of modifier (prepared in Example 1) and 0.1g of zinc acetate dihydrate, adjust the pH to 5 with 5wt% sodium bicarbonate solution, heat to 50℃ and stir for 4h, add 30g of 1wt% gelatin aqueous solution and 0.2g of poloxamer, stir for 20min, cool to room temperature, stir at 4000rpm for 8min, pour into a container with dimensions of 10cm×10cm×5cm, pre-freeze at -56℃ for 4h, and then freeze-dry at -56℃ and vacuum degree of 30Pa for 24h to obtain medical chitosan-based foam dressing.

[0025] Example 3: Preparation of Medical Chitosan-Based Foam Dressing (1) Mix 5g of hydroxybutyl chitosan with 300ml of deionized water and stir to dissolve to obtain hydroxybutyl chitosan solution; add 50ml of 50wt% ethanol aqueous solution, 1.2g of vanillic acid, 1.8g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.8g of N-hydroxysuccinimide to the reaction flask and stir for 30min. Add the hydroxybutyl chitosan solution and stir at room temperature for 16h. During the reaction, use 1wt% hydrochloric acid solution / sodium hydroxide solution to adjust and maintain pH at 6; put the reaction solution into a dialysis bag (3500Da) and dialyze with deionized water for 48h. Change the deionized water every 6h. After pre-freezing at -56℃ for 4h, freeze-dry at -56℃ and vacuum degree of 30Pa for 24h to obtain modified chitosan; Figure 4 The figures show the Fourier transform infrared (FTIR) spectra of hydroxybutyl chitosan and modified chitosan. As can be seen from the figures, hydroxybutyl chitosan and modified chitosan exhibit wavelengths in the range of 3420-3370 cm⁻¹. -1 The broad absorption peak is an overlapping absorption peak of the OH and NH stretching vibrations in the structure of hydroxybutyl chitosan and modified chitosan; 2924 cm⁻¹ -1 and 2875cm -1 The nearby absorption peak corresponds to the aliphatic CH stretching vibration peak; compared with hydroxybutyl chitosan, modified chitosan has a peak at 1650 cm⁻¹. -1 The enhanced absorption peak indicates that the carboxyl group of vanillic acid reacted with the amino group of hydroxybutyl chitosan to form an amide bond; 1602-1510 cm⁻¹ -1 The nearby absorption peak corresponds to the vibrational peak of the aromatic ring skeleton; 1154 cm⁻¹ -1 -1030cm -1 The absorption peaks observed are due to the stretching vibrations of COC and CO in the hydroxybutyl chitosan polysaccharide backbone. These characteristic peaks collectively indicate the successful preparation of modified chitosan.

[0026] (2) Add 5g of modified chitosan to 200ml of 0.5wt% acetic acid aqueous solution, stir at 500rpm for 1h at room temperature, add 10ml of anhydrous ethanol containing 0.5g of modifier (prepared in Example 1) and 0.15g of zinc acetate dihydrate, adjust the pH to 5.5 with 5wt% sodium bicarbonate solution, heat to 55℃ and stir for 3h, add 50g of 1wt% gelatin aqueous solution and 0.3g of poloxamer, stir for 20min, cool to room temperature, stir at 4500rpm for 5min, pour into a container with dimensions of 10cm×10cm×5cm, pre-freeze at -56℃ for 4h, and then freeze-dry at -56℃ and vacuum degree of 30Pa for 24h to obtain medical chitosan-based foam dressing.

[0027] Figure 5The image shows a scanning electron microscope image of a medical chitosan-based foam dressing. As can be seen from the image, the foam dressing has formed a continuous porous structure. The pores are nearly circular and irregular polygonal in shape. The pore walls are interconnected to form a continuous supporting skeleton. The surface is relatively rough, indicating that the foam dressing has formed a relatively complete porous network structure.

[0028] Example 4: Preparation of Medical Chitosan-Based Foam Dressing (1) Mix 5g of hydroxybutyl chitosan with 300ml of deionized water and stir to dissolve to obtain hydroxybutyl chitosan solution; add 50ml of 50wt% ethanol aqueous solution, 1.5g of vanillic acid, 2g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1g of N-hydroxysuccinimide to the reaction flask and stir for 30min. Add the hydroxybutyl chitosan solution and stir at room temperature for 18h. During the reaction, use 1wt% hydrochloric acid solution / sodium hydroxide solution to adjust and maintain pH at 6; put the reaction solution into a dialysis bag (3500Da) and dialyze with deionized water for 48h. Replace the deionized water every 6h. After pre-freezing at -56℃ for 4h, freeze-dry at -56℃ and vacuum degree of 30Pa for 24h to obtain modified chitosan; (2) Add 5g of modified chitosan to 200ml of 0.5wt% acetic acid aqueous solution, stir at 500rpm for 1h at room temperature, add 10ml of anhydrous ethanol containing 0.6g of modifier (prepared in Example 1) and 0.2g of zinc acetate dihydrate, adjust the pH to 6 with 5wt% sodium bicarbonate solution, heat to 60℃ and stir for 2h, add 60g of 1wt% gelatin aqueous solution and 0.4g of poloxamer, stir for 20min, cool to room temperature, stir at 5000rpm for 3min, pour into a container with dimensions of 10cm×10cm×5cm, pre-freeze at -56℃ for 4h, and then freeze-dry at -56℃ and vacuum degree of 30Pa for 24h to obtain medical chitosan-based foam dressing.

[0029] Comparative Example 1 Preparation of medical chitosan-based foam dressing Add 5g of hydroxybutyl chitosan to 200ml of 0.5wt% acetic acid aqueous solution and stir at 500rpm for 1h at room temperature. Add 10ml of anhydrous ethanol containing 0.5g of modifier (prepared in Example 1) and 0.15g of zinc acetate dihydrate. Adjust the pH to 5.5 using 5wt% sodium bicarbonate solution. Heat to 55℃ and stir for 3h. Add 50g of 1wt% gelatin aqueous solution and 0.3g of poloxamer and stir for 20min. Cool to room temperature and stir at 4500rpm for 5min. Pour into a container with dimensions of 10cm×10cm×5cm. Pre-freeze at -56℃ for 4h and then freeze-dry under vacuum at -56℃ and a vacuum degree of 30Pa for 24h to obtain medical chitosan-based foam dressing.

[0030] Comparative Example 2 The preparation method of medical chitosan-based foam dressing is basically the same as that in Example 3, except that vanillic acid in step (1) is replaced with an equal weight of 3-methoxybenzoic acid.

[0031] Comparative Example 3 The preparation method of medical chitosan-based foam dressing is basically the same as that in Example 3, except that vanillic acid in step (1) is replaced with an equal weight of thioctic acid.

[0032] Comparative Example 4 The preparation method of medical chitosan-based foam dressing is basically the same as that in Example 3, except that the amount of modifier added in step (2) is replaced with 0.2g.

[0033] Comparative Example 5 The preparation method of medical chitosan-based foam dressing is basically the same as that in Example 3, except that the modifier in step (2) is replaced with an equal weight of a mixture of dopamine hydrochloride and thioctic acid in a mass ratio of 1:1.

[0034] Comparative Example 6 The preparation method of the medical chitosan-based foam dressing is basically the same as that in Example 3, except that the modifier in step (2) is replaced with an equal weight of the modifier prepared by the following method: The preparation method of the modifier is basically the same as that in Example 1, except that lipoic acid is replaced with an equimolar amount of 4-(methyl disulfide)butyric acid.

[0035] Comparative Example 7 The preparation method of the medical chitosan-based foam dressing is basically the same as that in Example 3, except that the modifier in step (2) is replaced with an equal weight of the modifier prepared by the following method: The preparation method of the modifier is basically the same as that in Example 1, except that the dopamine hydrochloride is replaced with an equimolar amount of 4-amino-1,2-catechol hydrochloride.

[0036] Comparative Example 8 The preparation method of medical chitosan-based foam dressing is basically the same as that in Example 3, except that the amount of poloxamer added in step (2) is replaced with 0.15g.

[0037] The hydroxybutyl chitosan used in this application is of type HBC30, with a degree of substitution of 0.5 and a molecular weight of 30 kDa, and is produced by Zhejiang Jinke Pharmaceutical Co., Ltd.; the gelatin is a food additive gelatin, type 180, and is produced by Shandong Jiruit Gelatin Co., Ltd.; the poloxamer is of type poloxamer 188.

[0038] The medical chitosan-based foam dressings prepared in the examples and comparative examples were tested for water absorption, antibacterial properties, and compression performance. The test results are shown in Table 1.

[0039] Water absorption test: Dissolve 8.298g sodium chloride and 0.368g calcium chloride dihydrate in 800ml deionized water, and dilute to 1L in a volumetric flask to obtain saline solution. Cut medical chitosan-based foam dressing into 1cm×1cm×1cm samples, and accurately weigh their mass m. d Then, the sample was soaked in saline solution at room temperature for 24 hours. After removing the sample, it was drained for 30 seconds, and then the surface free liquid was removed by gently touching it with filter paper. The weight was then measured to obtain m. w The absorption rate is calculated using the following formula: ; Compression strength test: Medical chitosan-based foam dressing was cut into 10mm×10mm×10mm samples and soaked in PBS buffer (0.1M, pH=7.4) solution for 4h. After the samples were removed, they were drained for 30s and then the surface free liquid was removed by gently touching with filter paper. The samples were compressed at a compression rate of 5mm / min using a WDW-05 universal testing machine at a temperature of 25℃ and a relative humidity of 45%. The stress on the samples when they were compressed to a height of 5mm was recorded.

[0040] Antibacterial performance test: Medical chitosan-based foam dressings were cut into uniform circular shapes (9mm in diameter and 3mm in thickness), placed in capped glass bottles, and sterilized by irradiating both sides with 254nm UV light for 30 minutes each in a clean bench. 2ml of 5×10 5 Staphylococcus aureus (ATCC 25923) at CFU / mL was cultured at 37°C for 6 hours. The bacterial suspension was diluted with 2 ml of PBS buffer (0.1 M, pH 7.4) and the cells were vortexed to resuspend the cells. 100 μL of the diluted bacterial suspension was then diluted again with 4.9 ml of PBS buffer (0.1 M, pH 7.4) to obtain a second-diluted bacterial suspension. This second-diluted bacterial suspension was evenly spread on a culture medium and cultured at 37°C for another 24 hours. The colony count was then counted, and the inhibition rate was calculated using the following formula: ×100%; Wherein, N0 is the number of colonies in the blank group (excluding foam dressing samples); N1 is the number of colonies in the foam dressing sample group after culture.

[0041] Table 1 Performance Test Data

[0042] As can be seen from the data in Table 1, the medical chitosan-based foam dressing prepared by the present invention has excellent water absorption, compressive strength and antibacterial properties.

[0043] This invention utilizes the synergistic effect of modified chitosan, a modifier containing disulfide ring and catechol structures, and zinc ions to give medical chitosan-based foam dressings excellent water absorption, compressive strength, and antibacterial properties. The hydrophilic groups (such as hydroxyl groups and unreacted amino groups) in the modified chitosan form a hydrophilic composite matrix network through hydrogen bonding, thereby improving the liquid absorption rate and wet structural stability of the foam dressing. The phenolic hydroxyl groups and catechol structures enhance the inter-chain bonding through hydrogen bonding and form dynamic cross-linking points through coordination with zinc ions, thus improving the mechanical properties of the foam dressing. The disulfide ring structure, as a flexible sulfur-containing structural unit, participates in intermolecular interactions, dissipating external forces, buffering stress concentration, and promoting network structure reconstruction during the compression process of the foam dressing, thereby improving the toughness and compressive strength of the foam pore walls. The residual amino groups in the modified chitosan can disrupt bacterial cell membranes; zinc ions can bind to active groups in bacterial membrane proteins and enzyme molecules, inhibiting enzyme activity and disrupting cell membrane integrity, synergistically enhancing the antibacterial effect of the foam dressing with the amino structure of chitosan. In addition, gelatin, as a foam stabilizer and flexibility enhancer, improves the system viscosity and foam strength; poloxamer reduces interfacial tension, promotes uniform air dispersion during high-speed stirring, and forms an interconnected porous structure after freeze-drying, providing numerous capillary channels and storage space. This gives the medical chitosan-based foam dressing excellent water absorption, compressive strength, and antibacterial properties.

[0044] Comparative Example 1 used unmodified hydroxybutyl chitosan, resulting in a lack of rigid support for the benzene ring structure and reduced hydrogen bonding and coordination, thus degrading performance; Comparative Example 2 used modified chitosan lacking phenolic hydroxyl groups, which, combined with Zn... 2+ Reduced coordination leads to a decrease in the compressive modulus and antibacterial rate of foam dressings. Comparative Example 3 uses lipoic acid to modify chitosan; although the disulfide ring structure increases, the lack of aromatic phenolic hydroxyl structures reduces antibacterial and antioxidant capabilities, as well as coordination with zinc ions, thus decreasing the performance of the foam dressing. In Comparative Example 4, the reduced amount of modifier lowers the foam crosslinking density, resulting in decreased compressive strength and antibacterial activity. Comparative Example 5 uses a physical mixture of dopamine and lipoic acid, which cannot form a stable amide-type modifier, leading to a decrease in liquid absorption and compressive modulus. Comparative Example 6 alters the disulfide bond structure, reducing the participation of sulfur-containing structural units in intermolecular forces and thus reducing support. In Comparative Example 7, the amino group in the modifier is directly linked to the aromatic ring, resulting in a rigid molecule lacking flexible spacer chains, which is detrimental to its interaction with Zn. 2+ The phenolic hydroxyl groups of modified chitosan fully form a uniform coordination cross-linking network, leading to a decrease in performance. In Comparative Example 8, the reduced amount of poloxamer resulted in decreased foam uniformity and connectivity, leading to a lower liquid absorption rate.

[0045] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.

Claims

1. A method for preparing a medical chitosan-based foam dressing, characterized in that, Includes the following steps: (1) Hydroxybutyl chitosan was reacted with vanillic acid to obtain modified chitosan; (2) Add the modified chitosan to a weak acid aqueous solution, stir and mix well, add the modifier and zinc salt, adjust the pH to 5-6, heat and stir, add the foam stabilizer and foaming agent, cool, stir at high speed, freeze dry to obtain medical chitosan-based foam dressing. The structural formula of the modifier is as follows: ； In step (1), the mass ratio of hydroxybutyl chitosan to vanillic acid is 1:(0.2-0.3), the reaction temperature is 50-60℃, and the reaction time is 10-12h; In step (2), the mass ratio of the modified chitosan, modifier, zinc salt, foam stabilizer and foaming agent is 1:(0.08-0.12):(0.02-0.04):(0.06-0.12):(0.04-0.08), the zinc salt is zinc acetate dihydrate, the foam stabilizer is gelatin, and the foaming agent is poloxamer.

2. The method for preparing a medical chitosan-based foam dressing according to claim 1, characterized in that, In step (2), the high-speed stirring speed is 4000-5000 rpm and the time is 3-8 min.

3. The method for preparing a medical chitosan-based foam dressing according to claim 1, characterized in that, The modifier is prepared by reacting lipoic acid with dopamine hydrochloride.

4. A medical chitosan-based foam dressing, characterized in that, It is prepared by the method according to any one of claims 1 to 3.

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