Chitosan hemostatic sponge and preparation method thereof

Abstract

This invention belongs to the field of biomedical materials technology, specifically relating to a chitosan hemostatic sponge and its preparation method. This patent addresses the problems of residual acetic acid and side reactions, low strength, and low absorbency caused by cross-linking methods during the preparation of chitosan hemostatic sponges. It innovatively proposes a method for physically cross-linking chitosan hemostatic sponges using hydrogen bonding-electrostatic synergistic superabsorbency based on alcohol-regulated substances. By introducing alcohols to regulate the electrostatic interaction between chitosan amino groups and acetic acid, while simultaneously adjusting the hydrogen bonding interaction between chitosan molecules, and introducing other polymer materials to construct a semi-interpenetrating network, the overall material properties are enhanced. The chitosan hemostatic material prepared by this process, although without the addition of cross-linking agents, still exhibits an insoluble sponge-like structure, good flexibility, and excellent absorbency and hemostatic effect.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a chitosan hemostatic sponge and its preparation method. Background Technology

[0002] Chitosan is a natural polysaccharide with excellent biocompatibility and hemostatic properties, widely used in medical dressings. Chitosan hemostatic sponges possess advantages such as biocompatibility and procoagulant properties, making them suitable for hemostasis in surgery and trauma, with broad application prospects in the medical field. Chitosan dissolves under acidic conditions, and acetic acid is commonly used to adjust the solution pH. However, conventional freeze-drying processes result in uneven distribution of acetic acid, and excessive residual acetic acid can cause severe hemolysis, leading to cytotoxicity and inflammatory reactions. Furthermore, the chemical cross-linking of chitosan sponges often uses chemical cross-linking agents such as glutaraldehyde and epoxy, which can easily trigger side reactions. Physical cross-linking of chitosan sponges can lead to insufficient cross-linking strength and low absorbency. Additionally, porous sponges prepared without chemical cross-linking agents can also be used as cell scaffolds. Summary of the Invention

[0003] To address the aforementioned technical problems, the technical solution adopted by this invention is: In a first aspect, the present invention provides a chitosan sponge, the raw materials for which are prepared include: chitosan, alcohol compounds, acetic acid and hydrophilic polymers.

[0004] In some embodiments of the present invention, the raw materials for preparation, by weight, include: 0.5-10 parts chitosan, 0.5-5 parts alcohols, 0.5-5 parts acetic acid, and 0.001-5 parts hydrophilic polymers.

[0005] In some embodiments of the present invention, the raw materials for preparation, by weight, include: 1-8 parts chitosan, 0.5-2 parts alcohols, 1-3 parts acetic acid and 0.01-5 parts hydrophilic polymers.

[0006] In some embodiments of the present invention, the alcohol compound includes at least one of ethanol, propylene glycol, hexanediol, glycerol, sorbitol, and xylitol.

[0007] In some embodiments of the present invention, the hydrophilic polymer includes at least one of carboxymethyl chitosan, cellulose, carboxymethyl cellulose, sodium alginate, polyacrylic acid, sodium polyacrylate, and carbomer.

[0008] In some embodiments of the present invention, the raw materials for preparation further include 80-100 parts by weight of water.

[0009] In some embodiments of the present invention, the molecular weight of the chitosan is 50-800 kDa.

[0010] A second aspect of the present invention provides a method for preparing the chitosan sponge described in the first aspect of the present invention, comprising the following steps: 1) According to the mass ratio, mix chitosan, water and hydrophilic polymer, and add acetic acid and mix until dissolved; 2) Add alcohol compounds to obtain a chitosan composite solution; 3) Freeze-dry to obtain chitosan sponge.

[0011] In some embodiments of the present invention, in step 2), the reaction time after adding the alcohol compound is 5 to 60 minutes.

[0012] In some embodiments of the present invention, the hemostatic product includes at least one of hemostatic sponge, hemostatic dressing, adhesive bandage, hemostatic powder, hemostatic microspheres, and hemostatic gel.

[0013] A third aspect of the present invention provides a hemostatic product comprising the chitosan sponge described in the first aspect of the present invention.

[0014] In some embodiments of the present invention, the hemostatic product includes pharmaceutically acceptable excipients.

[0015] In some embodiments of the present invention, the pharmaceutically acceptable excipients include at least one of the following: solvents, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and anti-flocculators, filter aids, release inhibitors, and carriers.

[0016] The pharmaceutically acceptable excipients mentioned above are generally recognized for use in this purpose and as inactive ingredients in the pharmaceutical preparation. Compilations of pharmaceutically acceptable excipients can be found in reference books such as the *Handbook of Pharmaceutical Excipients* (2nd edition, edited by A. Wade and PJ Weller; published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994) and the *Pharmacopoeia of the People's Republic of China - List of Pharmaceutical Excipients*.

[0017] This invention also provides the following three applications: 1) Alcohols are used to prepare superabsorbent insoluble chitosan sponges by regulating the hydrogen bonds and electrostatic interactions between chitosan molecules; 2) Application of adding hydrophilic polymers to improve the mechanical properties and liquid absorption properties of chitosan hemostatic materials.

[0018] 3) The application of the chitosan sponge described in the first aspect of the present invention in the preparation of cell scaffolds.

[0019] This invention introduces alcohols into a chitosan-acetic acid solution system to prepare a water-insoluble, flexible, and biocompatible porous chitosan sponge scaffold material without the use of chemical crosslinking agents. The alcohol molecules regulate the electrostatic interaction between chitosan amino groups and acetic acid through competitive protonation, weakening the electrostatic repulsion between chitosan molecular chains and promoting molecular chain aggregation. The hydroxyl groups of the alcohol molecules can form hydrogen bonds with acetic acid molecules, reducing the degree of dissociation of acetic acid and thus reducing the protonation degree of chitosan amino groups. This invention solves the problems of residual toxic crosslinking agents in traditional cell scaffold preparation processes, which affect the biocompatibility of the material, and the potential for excessive rigidity in the covalent network formed by chemical crosslinking, limiting the material's flexibility and dynamic response.

[0020] The beneficial effects of this invention are: This patent addresses the problems of residual acetic acid and side reactions, low strength, and low absorbency caused by cross-linking methods in the preparation of chitosan hemostatic sponges. It innovatively proposes a method based on alcohol-regulated hydrogen bonding-electrostatic synergistic superabsorbency physical cross-linking of chitosan hemostatic sponges. By introducing alcohols to regulate the electrostatic interaction between chitosan amino groups and acetic acid, while simultaneously adjusting the hydrogen bonding interaction between chitosan molecules, and introducing other polymer materials to construct a semi-interpenetrating network, the overall material properties are enhanced. The chitosan hemostatic material prepared by this process, although without the addition of cross-linking agents, still exhibits an insoluble sponge-like structure with good flexibility, excellent absorbency, and hemostatic effect, showing promising application prospects in hemostasis and cell scaffold fields. Attached Figure Description

[0021] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein: Figure 1 The rapidly swelling chitosan hemostatic sponge prepared in Example 1.

[0022] Figure 2 Scanning electron microscope images of chitosan hemostatic sponges prepared with chitosan of different molecular weights; (A) 100 kDa; (B) 300 kDa; (C) 500 kDa, corresponding to Examples 1-3.

[0023] Figure 3Chitosan hemostatic sponges prepared from different hydrophilic polymer composites were tested for hemostasis in rat livers; (A) sodium alginate; (B) carbomer; (C) carboxymethyl chitosan, corresponding to Examples 4-6. Detailed Implementation

[0024] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0025] Example 1 A raw material for a rapidly swelling, hemostatic chitosan sponge is composed of the following components: Table 1. Raw material composition of rapidly swelling and hemostatic chitosan sponge

[0026] The specific preparation method is as follows: 1. Disperse 5g of chitosan evenly in 89g of deionized water, add 3g of hydrophilic high molecular weight carboxymethyl chitosan, then add 2g of acetic acid, and stir at room temperature until dissolved; 2. Further add 1g of propylene glycol to the above solution and stir at room temperature for 30 minutes to form a chitosan composite solution.

[0027] 3. Finally, the above chitosan composite solution is freeze-dried to obtain a rapidly swelling and hemostatic chitosan sponge.

[0028] Example 2 The raw material for a rapid swelling and hemostatic chitosan hemostatic sponge is composed of the following components: Table 2. Raw material composition of rapidly swelling and hemostatic chitosan sponge

[0029] The specific preparation method is the same as in Example 1, and the relevant raw material ratios are replaced according to the contents of Table 2.

[0030] Example 3 The raw material for a rapid swelling and hemostatic chitosan hemostatic sponge is composed of the following components: Table 3. Raw material composition of rapidly swelling and hemostatic chitosan sponge

[0031] The specific preparation method is the same as in Example 1, and the relevant raw material ratios are replaced according to Table 3.

[0032] Example 4 The raw material for a rapid swelling and hemostatic chitosan hemostatic sponge is composed of the following components: Table 4. Raw material composition of rapidly swelling and hemostatic chitosan sponge

[0033] The specific preparation method is the same as in Example 1, and the relevant raw material ratios are replaced according to Table 4.

[0034] Example 5 The raw material for a rapid swelling and hemostatic chitosan hemostatic sponge is composed of the following components: Table 5. Raw material composition of rapidly swelling and hemostatic chitosan sponge

[0035] The specific preparation method is the same as in Example 1, and the relevant raw material ratios are replaced according to the contents of Table 5.

[0036] Example 6 The raw material for a rapid swelling and hemostatic chitosan hemostatic sponge is composed of the following components: Table 6. Raw material composition of rapidly swelling and hemostatic chitosan sponge

[0037] The specific preparation method is the same as in Example 1, and the relevant raw material ratios are replaced according to Table 6.

[0038] Example 7 The raw material for a rapid swelling and hemostatic chitosan hemostatic sponge is composed of the following components: Table 7. Raw material composition of rapidly swelling chitosan hemostatic sponge

[0039] The specific preparation method is the same as in Example 1, and the relevant raw material ratios are replaced according to Table 7.

[0040] Example 8 The raw material for a rapid swelling and hemostatic chitosan hemostatic sponge is composed of the following components: Table 8. Raw material composition of rapidly swelling chitosan hemostatic sponge

[0041] The specific preparation method is the same as in Example 1, and the relevant raw material ratios are replaced according to Table 8.

[0042] Comparative Example 1 The raw material for a chitosan hemostatic sponge is composed of the following components: Table 9 Raw material composition of chitosan hemostatic sponge

[0043] The specific preparation method is as follows: 1. Disperse 5g of chitosan evenly in 90g of deionized water, add 3g of hydrophilic high molecular weight carboxymethyl chitosan, then add 2g of acetic acid, and stir at room temperature until dissolved; 2. The above solution was freeze-dried to obtain a chitosan hemostatic sponge.

[0044] Comparative Example 2 The raw material for a chitosan hemostatic sponge is composed of the following components: Table 10 Raw material composition of chitosan hemostatic sponge

[0045] The specific preparation method is as follows: 1. Disperse 5g of chitosan evenly in 92g of deionized water, add 2g of acetic acid, and stir at room temperature until dissolved; 2. Further add 1g of propylene glycol to the above solution and stir at room temperature for 30 minutes to form a chitosan composite solution.

[0046] 3. The above solution was freeze-dried to obtain a chitosan hemostatic sponge.

[0047] Test case 1. Experimental Methods 1) Animal model construction: Healthy SD rats weighing 190-250g were selected for the rat liver wound bleeding model. After anesthesia with sodium pentobarbital injected intraperitoneally, the rats were fixed in a supine position. The abdomen was routinely prepared and disinfected. The skin and abdominal muscles were incised layer by layer along the midline of the abdomen to fully expose the left lobe of the liver. The liver lobe was gently pulled out. Avoiding the area of ​​large blood vessels on the surface of the liver, a 1cm incision with a depth of 3mm was made on the liver with a special scalpel. After 30 seconds, hemostatic material was applied to the incision to stop the bleeding.

[0048] 2) Absorption rate: Cut three 5mm×20mm×3mm hemostatic sponge samples and accurately weigh them, recording the weight as m1. Immerse them in water at (37±1)℃ until completely wetted, gently removing air with your fingers, being careful not to break them. When the sponge shows no obvious change in shape, it has absorbed enough water. Gently remove the product from the water by holding one corner with tweezers and let it hang in the air for (30±1) seconds to drain the water. Weigh it again, recording the weight as m2. Calculate the absorption rate using the formula A = (m2-m1) / m1, and report the result as the average of the three measurements.

[0049] 3) Hemostasis time: In the above-mentioned rat liver wound bleeding model, 30 seconds after the formation of the liver tissue wound, sterile gauze was quickly placed under the wound, and a 5mm×20mm×3mm chitosan hemostatic sponge was immediately pressed and adhered to the wound while a stopwatch was started. The timing was stopped when there was no more fresh blood seeping from the surface of the sponge and a stable blood clot formed on the wound.

[0050] 4) Blood Loss: Accurately weigh and record the dry weight of the sterile gauze (m1), the dry weight of the sealed container (m2), and the dry weight of the 5mm×20mm×3mm chitosan hemostatic sponge (m3). Immediately 30 seconds after the liver tissue wound forms, place the weighed sterile gauze under the wound and quickly press the chitosan hemostatic sponge onto the wound. From the start of wound formation until successful hemostasis, collect all blood-stained gauze and sponges and immediately place them in the pre-weighed sealed container. Accurately weigh the total mass and record it as m4. Blood loss (g) = m4 - m1 - m2 - m3.

[0051] 2. Experimental Results 1) Characterization results Taking the chitosan hemostatic sponge prepared in Example 1 as an example, its appearance was photographed, and the results are as follows: Figure 1 As shown.

[0052] Taking Examples 1-3 as examples, the scanning electron microscopy results of chitosan hemostatic sponges prepared with chitosan of different molecular weights are as follows: Figure 2 As shown.

[0053] 2) Performance Results The product performance of Examples 1-8 and Comparative Examples 1-2 is shown in Table 11 below.

[0054] Table 11 Properties of Chitosan Hemostatic Sponge

[0055] As can be seen from Table 11, compared with the chitosan hemostatic sponge prepared without the addition of alcohols and other hydrophilic polymers in the comparative example, the chitosan hemostatic sponge prepared using the alcohol regulation technology of the present invention has a higher liquid absorption rate and a significantly shorter hemostasis time.

[0056] Figure 3 This study demonstrates the preparation of chitosan hemostatic sponges using different hydrophilic polymer composites for liver hemostasis experiments: sodium alginate (A), carbomer (B), and carboxymethyl chitosan (C). The aforementioned hydrophilic polymers exhibit good hemostatic effects.

[0057] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments, and various changes can be made within the scope of knowledge possessed by those skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. A chitosan sponge, the raw materials for its preparation include: Chitosan, alcohols, acetic acid, and hydrophilic polymers.

2. The application according to claim 1, characterized in that: The raw materials for preparation, by weight, include: 0.5-10 parts chitosan, 0.5-5 parts alcohols, 0.5-5 parts acetic acid, and 0.001-5 parts hydrophilic polymers.

3. The application according to claim 2, characterized in that: The alcohol compounds include at least one of ethanol, propylene glycol, hexanediol, glycerol, sorbitol, and xylitol.

4. The application according to claim 2, characterized in that: The hydrophilic polymer includes at least one of carboxymethyl chitosan, cellulose, carboxymethyl cellulose, sodium alginate, polyacrylic acid, sodium polyacrylate, and carbomer.

5. The chitosan sponge according to claim 2, characterized in that: The raw materials for preparation also include 80-100 parts by weight of water.

6. A method for preparing chitosan sponge according to any one of claims 1 to 5, comprising the following steps: 1) According to the mass ratio, mix chitosan, water and hydrophilic polymer, and add acetic acid and mix until dissolved; 2) Add alcohol compounds to obtain a chitosan composite solution; 3) Freeze-dry to obtain chitosan sponge.

7. The preparation method according to claim 6, characterized in that: In step 2), the reaction time after adding the alcohol compound is 5-60 minutes.

8. The use of the chitosan sponge according to any one of claims 1 to 5 in the preparation of hemostatic products; The hemostatic products include at least one of the following: hemostatic sponge, hemostatic dressing, adhesive bandage, hemostatic powder, hemostatic microspheres, and hemostatic gel.

9. A hemostatic product, characterized in that: The hemostatic product includes the chitosan sponge as described in any one of claims 1 to 5.

10. The hemostatic product according to claim 9, characterized in that: The hemostatic product includes pharmaceutically acceptable excipients.

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