Chitosan polyurethane composite hemostatic sponge and preparation method thereof

Abstract

The present invention relates to the technical field of medical consumables, and in particular to a chitosan polyurethane composite hemostatic sponge and a preparation method thereof. The present invention provides a preparation method of a chitosan polyurethane composite hemostatic sponge, wherein chitosan is mixed with polyurethane, reacted under the phase transition conditions of polyurethane to obtain an intermediate, and the intermediate is freeze-dried to obtain a composite hemostatic sponge, wherein the polyurethane is obtained by copolymerization of polyester monomer, polyol and isocyanate monomer, the deacetylation degree of the chitosan is 20-50%, and the phase transition conditions of the polyurethane are 0-10°C. The present invention can avoid the phase transition conditions of high temperature causing the polyurethane viscosity to decrease by introducing hydrophobic polyester and hydrophilic polyol into polyurethane, causing chitosan to settle in the polyurethane solution and cause uneven distribution, and when the polyurethane reaches the phase transition conditions, chitosan is embedded in the polyurethane molecular chain to form a mixture, which can ensure that the chitosan will not be washed away by the blood flow.

Description

Technical Field

[0001] The invention relates to the technical field of medical consumables, and in particular to a chitosan polyurethane composite hemostatic sponge and a preparation method thereof. Background Art

[0002] In order to accelerate wound healing, hemostatic materials are generally used to stop bleeding on the wound surface. Conventional packing materials, such as vaseline gauze and expanded sponges, achieve hemostasis by expanding, compressing and absorbing blood. However, there is adhesion when the packing material contacts the wound surface, which not only causes great pain to the patient but also causes secondary damage to the wound surface when the packing material is removed. Chitosan is a natural polysaccharide substance. Its positively charged amino groups can interact with negatively charged red blood cells. It has the function of enriching red blood cells in the blood and is widely used in hemostatic materials for wound hemostasis. At present, most chitosan needs to be compounded with other hemostatic materials to achieve hemostasis, and the hemostatic effect of chitosan alone is poor.

[0003] The prior art discloses a polyurethane sponge dressing with anti-adhesion and hemostatic functions and a preparation method thereof. The polyurethane sponge is used as an auxiliary material and paraffin oil loaded with nano-chitosan particles through vaseline, which has the function of preventing adhesion and improving the hemostatic effect. However, vaseline has poor adsorption performance for chitosan. During the hemostatic process, chitosan will flow with the blood, separate from the hemostatic material and enter the body to cause thrombosis. Summary of the invention

[0004] Therefore, the technical problem to be solved by the present invention is to overcome the poor connection performance between chitosan and carrier in the hemostatic material in the prior art, which causes chitosan to enter the body and cause thrombosis defects, thereby providing a chitosan polyurethane composite hemostatic sponge and a preparation method thereof.

[0005] On the one hand, the present invention provides a method for preparing a chitosan polyurethane composite hemostatic sponge, comprising the following steps: mixing chitosan and polyurethane, reacting under phase transition conditions of polyurethane to obtain an intermediate, and freeze-drying the intermediate to obtain a composite hemostatic sponge, wherein the polyurethane is obtained by copolymerizing a polyester monomer, a polyol and an isocyanate monomer, the deacetylation degree of the chitosan is 20-50%, and the phase transition conditions of the polyurethane are 0-10°C.

[0006] In some of the embodiments, the mass ratio of chitosan to polyurethane is (0.1-0.5):1.

[0007] In some embodiments, the chitosan is mixed with polyurethane and reacted under the phase transition conditions of polyurethane for a time of 0.5h-3h.

[0008] In some of the embodiments, before the chitosan and polyurethane react, the chitosan and polyurethane solution are mixed under stirring, the stirring speed is 100 rpm-200 rpm, and the stirring time is 20 min-60 min.

[0009] Preferably, the weight average molecular weight of the polyurethane is 100,000 Da to 1,000,000 Da.

[0010] Preferably, the solvent in the polyurethane solution is at least one of dioxane, dimethyl sulfoxide and N,N-dimethylformamide, and the concentration of polyurethane in the polyurethane solution is 40 g / L-100 g / L.

[0011] In some embodiments, the freeze-drying process further includes a step of annealing the intermediate after freezing the intermediate and before drying.

[0012] Preferably, the freezing temperature in the freeze-drying process is less than or equal to -30°C, and the freezing time is 3-6h. Preferably, the annealing temperature is 5-15°C, and the annealing time is 2-4h. Preferably, the drying temperature is -40°C to -20°C, and the drying time is 12-24h.

[0013] In some of the embodiments, the preparation method of chitosan includes dissolving a chitosan raw material and mixing it with an organic solvent to form a solution, adding anhydride to the solution for reaction, adjusting the pH value of the solution to 10-13, and performing solid-liquid separation to obtain chitosan with a deacetylation degree of 20-50%, wherein the ratio of the chitosan raw material to the anhydride is 2-8:1-3, and the unit is g:mL. Preferably, the ratio of the chitosan raw material to the anhydride is 15g-36g:6 mL-13 mL.

[0014] Preferably, the organic solvent includes at least one of methanol, isopropanol or pyridine.

[0015] Preferably, the acid anhydride comprises acetic anhydride.

[0016] In some of the embodiments, the method for preparing chitosan further comprises the step of swelling chitosan with a deacetylation degree of 20%-50% and then reacting with a first acid solution, wherein the first acid solution comprises an organic acid.

[0017] Preferably, the mass volume ratio of the chitosan with a deacetylation degree of 20-50% to the swelling agent is 0.1-0.2 g:0.5-1 mL.

[0018] Preferably, the organic acid includes at least one of acetic acid, lactic acid, glutamic acid, succinic acid and citric acid.

[0019] Preferably, the mass ratio of the organic acid to the reacetylated chitosan is 1:1.5-5, and the reacetylated chitosan is chitosan with a deacetylation degree of 20%-50%.

[0020] In the present invention, the term reacetylated chitosan refers to chitosan having a deacetylation degree of 20% to 50%.

[0021] Preferably, the swelling solvent for swelling chitosan with a deacetylation degree of 20%-50% is a C1-C6 alcohol solvent.

[0022] In some of the embodiments, the chitosan raw material has a deacetylation degree of 70%-95% and a weight average molecular weight of 80,000-300,000 Da.

[0023] Furthermore, the mass volume ratio of the chitosan raw material to the reagent for dissolving the chitosan raw material is 1g:25-100mL.

[0024] Furthermore, the volume ratio of the reagent for dissolving the chitosan raw material to the organic solvent is 1:1-2.

[0025] In some embodiments, the reagent for dissolving the chitosan raw material includes a second acid solution, the second acid solution includes at least one of formic acid, acetic acid, hydrochloric acid and sulfuric acid, and the concentration of the second acid solution is 1-3 vol%.

[0026] In some embodiments, the particle size of the chitosan modified by acid solution is 1-80 μm, preferably, the particle size of the chitosan modified by acid solution is 5-50 μm.

[0027] In some of the embodiments, the method for preparing the polyurethane comprises the following steps: S1, under the protection of an inert gas and in the presence of a catalyst, a polyester monomer and a polyol react to form a random copolyester; S2, under the protection of an inert gas and in the presence of an organic solvent, the random copolyester obtained in step S1 is polymerized with an isocyanate monomer to form a prepolymer; S3, in the presence of a solvent, the prepolymer produced in step S2 reacts with a chain extender, and solid-liquid separation is performed to obtain a polyurethane.

[0028] In some embodiments, the polyester monomer in step S1 includes D, L-lactide and caprolactone, and the polyol includes polyethylene glycol. Preferably, the caprolactone includes -Caprolactone.

[0029] Preferably, the random copolyester prepared in step S1 has an average molecular weight of 2000Da-4500Da and a glass transition temperature of -40°C to -60°C.

[0030] In some of the embodiments, when the random copolyester and the isocyanate monomer are polymerized to form a prepolymer in step S2, the reaction system also includes a catalyst.

[0031] Preferably, the mass of the catalyst accounts for 0.05‰-0.4‰ of the mass of the reaction material mixture.

[0032] Preferably, the catalyst in step S1 and / or step S2 includes at least one of stannous octoate, bismuth isooctanoate or bismuth neodecanoate.

[0033] In some embodiments, the isocyanate monomer in step S2 includes a diisocyanate monomer, and the organic solvent includes at least one of dimethyl sulfoxide and N,N-dimethylformamide.

[0034] In some embodiments, the molecular weight distribution of the prepolymer prepared in step S2 is 1.0≤Mw / Mn≤2.5.

[0035] In some embodiments, the chain extender in step S3 includes a hydroxyl-terminated isocyanate.

[0036] In some embodiments, the solvent in step S3 includes dioxane.

[0037] Preferably, the chain extender comprises a product obtained by heat treating 1,4-butanediol and isocyanate, washing and drying, the molar ratio of 1,4-butanediol to isocyanate is 10-25:1, the heat treatment temperature is 70-100°C, and the heat treatment time is 5-7h.

[0038] Preferably, the molar ratio of D,L-lactide to caprolactone in the polyester monomer is 1:0.5-2.

[0039] Preferably, the molar ratio of the polyester monomer to the polyol is 1-8:1.

[0040] Preferably, the mass ratio of isocyanate monomer to copolyester is 0.5-2:1.

[0041] Preferably, the isocyanate monomer includes at least one of dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, lysine diisocyanate, and 1,4-butanediisocyanate.

[0042] Preferably, the polyester monomer further comprises at least one of glycolide, trimethylene carbonate or p-dioxanone.

[0043] In some embodiments, the reaction temperature of step S1 is 110° C.-150° C., and the reaction time is 20 h-24 h.

[0044] In some of the embodiments, the specific steps of generating the prepolymer in step S2 include reacting the random copolyester obtained in step S1 with isocyanate monomer at 60° C.-100° C. for 4 h-10 h, adding a catalyst thereto, and continuing the reaction for 4 h-8 h.

[0045] In some embodiments, the reaction temperature of step S3 is 60° C.-100° C., and the reaction time is 10 h-20 h.

[0046] On the other hand, the present invention provides a composite hemostatic sponge prepared by the preparation method of the chitosan polyurethane composite hemostatic sponge.

[0047] The technical solution of the present invention has the following advantages:

[0048] 1. The present invention provides a method for preparing a chitosan polyurethane composite hemostatic sponge, comprising the following steps: mixing chitosan and polyurethane, reacting under the phase transition conditions of polyurethane to obtain an intermediate, and freeze-drying the intermediate to obtain a composite hemostatic sponge, wherein the polyurethane is obtained by copolymerizing a polyester monomer, a polyol and an isocyanate monomer, the deacetylation degree of the chitosan is 20-50%, and the phase transition conditions of the polyurethane are 0-10°C. The present invention introduces hydrophobic polyester and hydrophilic polyol into polyurethane to obtain polyurethane with a phase transition condition of 0-10 DEG C. On the one hand, due to the high temperature phase transition condition, the viscosity of polyurethane is reduced, so that chitosan is precipitated in the polyurethane solution, resulting in uneven distribution of chitosan. The present invention utilizes polyurethane with low temperature phase transition condition without affecting the viscosity of polyurethane, thereby improving the uniform distribution of chitosan in the polyurethane solution. On the other hand, when polyurethane reaches the phase transition condition, the polyester polyol soft satin is transformed from a crystalline state to an amorphous state, and the molecular chain is softer and even curled, which is conducive to the embedding of chitosan molecules. At the same time, -OH in chitosan and -NH in polyurethane are connected by hydrogen bonds, so that chitosan is finally embedded in the polyurethane molecular chain to form a firm and uniform mixture, which can ensure that chitosan will not be washed away by blood flow during the hemostasis process of chitosan polyurethane composite hemostatic sponge, so as to avoid the formation of thrombus, and no additional adhesive is needed to achieve the connection between polyurethane and chitosan.

[0049] At the same time, the present invention makes the chitosan polyurethane composite material into a sponge state through the freeze-drying step, which can not only provide expansion and compression at the wound, but also quickly absorb liquid. Furthermore, since the hemostatic effect of chitosan is mainly to interact with the positive charge formed by the protonation of amino groups and the positive charge of red blood cells, however, a higher degree of deacetylation is bound to increase the interaction between the hydroxyl group and the amino group in the chitosan, resulting in a reduction in the protonated amino group, thereby inhibiting the aggregation of blood and affecting the hemostatic effect. Therefore, the present invention can not only ensure a good hemostatic effect, but also improve the coagulation effect of the composite hemostatic sponge by using chitosan with a deacetylation degree of 20%-50%.

[0050] 2. The present invention provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, wherein the mass ratio of chitosan to polyurethane is (0.1-0.5):1. The preparation method provided by the present invention can reduce the amount of chitosan in the composite hemostatic sponge and still achieve a good hemostatic effect.

[0051] 3. A method for preparing a chitosan polyurethane composite hemostatic sponge provided by the present invention, wherein the method for preparing the chitosan polyurethane composite hemostatic sponge further comprises an annealing step after freezing the intermediate and before drying. The present invention adds an annealing step to the freeze-drying step of the chitosan polyurethane composite material, thereby increasing the crystal ratio during the pre-freezing process of the composite hemostatic sponge, forming a more stable crystalline structure, being beneficial to the uniformity of crystal distribution and pore size distribution in the chitosan polyurethane composite hemostatic sponge, and increasing the porosity and mechanical properties of the chitosan polyurethane composite hemostatic sponge.

[0052] 4. The present invention provides a method for preparing a chitosan polyurethane composite hemostatic sponge, the method for preparing chitosan comprising: dissolving a chitosan raw material and mixing it with an organic solvent to form a solution, adding anhydride to the solution for reaction, adjusting the solution pH to 10-13, and performing solid-liquid separation to obtain chitosan with a deacetylation degree of 20%-50%, wherein the ratio of the chitosan raw material to the anhydride is 10-40:5-15, and the unit is g:mL. The present invention uses chitosan as a raw material, removes residual protein and endotoxin from the chitosan by soaking in alkali solution to improve the safety of the chitosan, and better controls the deacetylation degree of the chitosan by controlling the molar ratio of the anhydride to the chitosan raw material.

[0053] 5. The present invention provides a method for preparing a chitosan polyurethane composite hemostatic sponge, wherein the reagent for dissolving the chitosan raw material is an acid solution, wherein the acid solution includes at least one of formic acid, acetic acid, hydrochloric acid or sulfuric acid, and the concentration of the acid solution is 1-3 vol%. The present invention can effectively avoid the gelation of chitosan by optimizing the concentration of the acid solution for dissolving the chitosan raw material.

[0054] 6. The present invention provides a method for preparing a chitosan polyurethane composite hemostatic sponge, wherein the chitosan is a product of chitosan modified by an organic acid. The method for preparing chitosan further comprises the step of acidifying chitosan with a deacetylation degree of 20-50%, and the specific method comprises swelling chitosan with a deacetylation degree of 20-50% and mixing it with an acid solution, wherein the acid solution is an organic acid. The present invention utilizes organic acid to modify chitosan, which can convert -NH 2 Protonation modifies it into a positively charged property, which can enhance the interaction with platelets and red blood cells during the hemostasis process, further improving the hemostasis and coagulation effects.

[0055] 7. The present invention provides a method for preparing a chitosan polyurethane composite hemostatic sponge, wherein the particle size of the chitosan modified by the acid solution is 1-80 μm, preferably, the particle size is 5-50 μm. The present invention controls the particle size of the modified chitosan particles, so that on the one hand, chitosan does not settle when mixed with polyurethane, and can be evenly distributed in the polyurethane solution, so that when the polyurethane undergoes a phase transition, the chitosan can be evenly connected with the polyurethane, and on the other hand, the chitosan within the particle size range acts as a nucleating agent for ice crystals during freeze drying, which is more conducive to the uniformity of the pore size of the chitosan polyurethane composite hemostatic sponge.

[0056] 8. The present invention provides a method for preparing a chitosan polyurethane composite hemostatic sponge, wherein the method for preparing the polyurethane comprises the following steps: S1, under the protection of an inert gas and in the presence of a catalyst, a polyester monomer and a polyol react to form a random copolyester; S2, under the protection of an inert gas and in the presence of an organic solvent and a catalyst, the random copolyester obtained in step S1 is polymerized with an isocyanate to form a prepolymer; S3, in the presence of a solvent, the prepolymer generated in step S2 reacts with a chain extender, and solid-liquid separation is performed to obtain a polyurethane. The present invention adopts a method for synthesizing the prepolymer in steps to achieve controlled polymerization, which is convenient for the purification and structural control of the product in each step, reduces the occurrence of side reactions such as ester exchange during the reaction, and achieves controlled polymerization.

[0057] 9. In the method for preparing a chitosan polyurethane composite hemostatic sponge provided by the present invention, the chain extender in step S3 is a hydroxyl-terminated isocyanate. The present invention uses a hydroxyl-terminated isocyanate with a uniform structure as a chain extender, which can improve the mechanical properties of polyurethane.

[0058] 10. The chitosan polyurethane composite hemostatic sponge provided by the present invention has the functions of absorbing liquid, expanding and compressing, and stopping bleeding, and is suitable for rapid hemostasis of wounds after surgery without causing the risk of thrombosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0060] Figure 1 This is a microscopic morphology of the composite hemostatic sponge prepared in Example 1 of the present invention;

[0061] Figure 2 This is another microscopic morphology of the composite hemostatic sponge prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0062] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0063] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0064] Preparation Example 1

[0065] This preparation example provides a chitosan modification method, and the specific steps and parameters are as follows:

[0066] (1) Dissolve 20g chitosan powder (70% deacetylation, weight average molecular weight 80000Da) in 500mL 2.5vol% acetic acid solution, add 750mL pure methanol solvent, stir to mix into a uniform solution, slowly add 8.22mL acetic anhydride, and react for 6 hours. Add 4M NaOH to the solution after the reaction until the pH of the solution is 10. After chitosan precipitates, continue to soak for 2 hours, filter to obtain the precipitate, soak the precipitate in ethanol for 2 hours to remove impurities, then repeatedly wash the precipitate with ethanol and vacuum dry.

[0067] The deacetylation degree of the prepared chitosan was determined to be 20% by acid-base titration.

[0068] (2) Take 10 g of chitosan with a deacetylation degree of 20% obtained in step (1), add 50 mL of 95% vol ethanol, stir and swell overnight, then add 1.42 mL of glacial acetic acid, continue the reaction for 2 h, wash the precipitate with ethanol 3 times, dry at 50°C to obtain a solid, grind the obtained solid with a ball mill to obtain acid-modified chitosan with a particle size of 5-15 μm, and set aside.

[0069] Preparation Example 2

[0070] This preparation example provides a chitosan modification method, and the specific steps and parameters are as follows:

[0071] (1) Dissolve 15 g of chitosan powder with a weight average molecular weight of 150,000 Da and a deacetylation degree of 95% in 500 mL of 1.0 vol% formic acid solution, add 900 mL of pyridine, stir and mix to form a uniform solution, slowly add 9.16 mL of acetic anhydride, react for 8 hours, add 4 M NaOH to the solution after the reaction to adjust the pH of the solution to 11, continue soaking for 2 hours after chitosan precipitates, filter out the precipitate, soak it in ethanol for 2 hours, wash the precipitate repeatedly, and vacuum dry it.

[0072] The deacetylation degree of the prepared chitosan was determined to be 30% by acid-base titration.

[0073] (2) Take 10 g of the dried solid obtained in step (1), add 70 mL of 95% ethanol, stir and swell overnight, add 2.08 mL of lactic acid, and continue the reaction for 3 h. Wash the precipitate with ethanol three times and dry at 50°C. Grind the obtained solid with a ball mill to obtain acid-modified chitosan with a particle size of 20-30 μm, which is set aside.

[0074] Preparation Example 3

[0075] This preparation example provides a chitosan modification method, and the specific steps and parameters are as follows:

[0076] (1) Dissolve 30 g of chitosan powder with a weight average molecular weight of 300,000 Da and a deacetylation degree of 88% in 750 mL of 2.5 vol% hydrochloric acid solution, then add 1312.5 mL of isopropanol, stir and mix to form a uniform solution, slowly add 12.68 mL of acetic anhydride, and react for 7 hours. Add 4 M NaOH to the solution after the reaction to adjust the pH of the solution to 12. After the chitosan is precipitated, continue to soak for 2 hours, filter out the precipitate, soak it in ethanol for 2 hours, repeatedly wash the precipitate with ethanol, and vacuum dry it.

[0077] The deacetylation degree of the prepared chitosan was determined to be 40% by acid-base titration.

[0078] (2) Take 15 g of the dried solid obtained in step (1), add 150 mL of 95 vol% ethanol, stir and swell overnight, add 3.77 mL of succinic acid, and continue the reaction for 4 h. Wash the precipitate with ethanol three times and dry at 50°C. Grind the obtained solid with a ball mill to obtain acid-modified chitosan with a particle size of 30-40 μm, which is set aside.

[0079] Preparation Example 4

[0080] This preparation example provides a chitosan modification method, and the specific steps and parameters are as follows:

[0081] (1) Dissolve 36 g of chitosan powder with a weight average molecular weight of 200,000 Da and a deacetylation degree of 92% in 2700 mL of 1.5% acetic acid solution, add 4050 mL of methanol, stir to mix into a uniform solution, slowly add 6.9 mL of acetic anhydride, and react for 9 hours. Add 4 M NaOH to the solution after the reaction to adjust the pH of the solution to 13 to completely precipitate the chitosan. Wash the precipitate repeatedly with ethanol and dry in vacuum.

[0082] The deacetylation degree of the prepared chitosan was determined to be 50% by acid-base titration.

[0083] (2) Take 20 g of the dried solid obtained in step (1), add 80 mL of 95% ethanol, stir and swell overnight, add 5.34 mL of glutamic acid, and continue the reaction for 4 h. Wash the precipitate with ethanol three times and dry at 50°C. Grind the obtained solid with a ball mill to obtain acid-modified chitosan with a particle size of 20-30 μm, which is set aside.

[0084] Preparation Example 5

[0085] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as those in Preparation Example 1, except that the concentration of acetic acid in step (1) is 0.05 vol%.

[0086] Preparation Example 6

[0087] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as those in Preparation Example 1, except that the concentration of acetic acid in step (1) is 3.5 vol%.

[0088] Preparation Example 7

[0089] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as those in Preparation Example 1, except that step (2) is not included, that is, the deacetylated chitosan is not acidified.

[0090] Preparation Example 8

[0091] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as those in Preparation Example 1, except that in step (2), the obtained solid is ground with a ball mill to obtain acid-modified chitosan with a particle size range of 5-50 μm.

[0092] Preparation Example 9

[0093] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as those in Preparation Example 1, except that in step (2), the obtained solid is ground with a ball mill to obtain acid-modified chitosan with a particle size range of 1-80 μm.

[0094] Preparation Example 10

[0095] This preparation example provides a method for preparing polyurethane, and the specific steps and parameters are as follows:

[0096] (1) 18g polyethylene glycol (molecular weight 600Da), 5g D,L-lactide, 3g -Caprolactone, 5g of 4-dioxanone, and 0.005g of stannous octoate were added to the reaction flask and mixed evenly. Vacuum was evacuated to ensure that the flask was oxygen-free and water-free. Under nitrogen protection, the reaction flask was heated to 130°C and reacted for 21 hours. The obtained product was repeatedly washed and purified with dichloromethane and acetone for many times to obtain a random copolyester with an average molecular weight of 2170Da and a glass transition temperature of -45°C. It was vacuum dried and set aside.

[0097] (2) 3.8 g of dried random copolyester and 2.6 g of dicyclohexylmethane diisocyanate (HMDI) were added to a reaction flask, and dimethyl sulfoxide was added to the reaction flask to dissolve it. The flask was evacuated to remove oxygen and water, and nitrogen was introduced. The reaction flask was heated to 80°C under nitrogen protection and stirred to allow the reaction to continue for 8 hours. 0.003 g of stannous octoate was added to the reaction flask, and the reaction was continued to stir for 6 hours to complete the synthesis of the polyurethane single-component prepolymer. The obtained product was repeatedly washed with n-hexane and then vacuum dried at 60°C. The obtained prepolymer had a molecular weight distribution coefficient of 2.2.

[0098] (3) Take 10 g of 1,4-diol and 1.8 g of dicyclohexylmethane diisocyanate (HMDI) and react them at 90 °C for 6 hours. The product is washed with acetone and filtered three times to obtain a BDO-terminated chain extender.

[0099] (4) The polyurethane single-component prepolymer and the chain extender were dissolved in a dioxane solvent at a molar ratio of 2:3, and reacted at 70° C. for 15 hours. The product was washed and dried to obtain a polyurethane solid with a weight average molecular weight of 190,000 Da.

[0100] Preparation Example 11

[0101] This preparation example provides a method for preparing polyurethane, and the specific steps and parameters are as follows:

[0102] (1) 42g of 800Da polyethylene glycol, 16g of D,L-lactide, 13g -Caprolactone, 15g trimethylene carbonate, and 0.005g stannous octoate were added to the reaction flask and mixed evenly. Vacuum the flask to ensure that it is oxygen-free and water-free. Under nitrogen protection, the reaction flask was heated to 110°C and reacted for 24 hours. The obtained product was repeatedly washed and purified with dichloromethane and acetone for many times to obtain a random copolyester with an average molecular weight of 3200Da and a glass transition temperature of -50°C. It was vacuum dried and set aside.

[0103] (2) Add 10g of dried random copolyester and 6.5g of hexamethylene diisocyanate (HDI) to a reaction flask, and add dimethyl sulfoxide to dissolve. Vacuum to remove oxygen and water, and introduce nitrogen. Then, heat the reaction flask to 100°C under nitrogen protection and stir to allow the reaction to continue for 4 hours. Add 0.006g of stannous octoate to the reaction flask, continue stirring at 100°C and maintain the reaction for 8 hours to complete the synthesis of the polyurethane single-component prepolymer. The resulting product is repeatedly washed with n-hexane and then vacuum dried at 60°C to obtain a prepolymer with a molecular weight distribution coefficient of 1.9.

[0104] (3) 15 g of 1,4-diol and 2.0 g of hexamethylene diisocyanate (HDI) were reacted at 100 °C for 5 hours. The product was washed with acetone and filtered three times to obtain a BDO-terminated chain extender.

[0105] (4) The polyurethane single-component prepolymer and the chain extender were dissolved in a dioxane solvent at a molar ratio of 2:3, and reacted at 60° C. for 20 hours. The product was washed and dried to obtain a polyurethane solid with a weight average molecular weight of 400,000 Da.

[0106] Preparation Example 12

[0107] This preparation example provides a method for preparing polyurethane, and the specific steps and parameters are as follows:

[0108] (1) 30 g of polyethylene glycol with a molecular weight of 1000 Da, 3.0 g of D,L-lactide, 2.8 g -Caprolactone, 1.0g of lysine diisocyanate (LDI), and 0.005g of bismuth isooctanoate were added to the reaction flask and mixed evenly. Vacuum the flask to ensure that it is oxygen-free and water-free. Under nitrogen protection, the reaction flask was heated to 150°C and reacted for 20 hours. The obtained product was repeatedly washed and purified with dichloromethane and acetone for many times to obtain a random copolyester with an average molecular weight of 3700 Da and a glass transition temperature of -54°C. It was vacuum dried and set aside.

[0109] (2) 12 g of dried random copolyester and 14 g of lysine diisocyanate (LDI) were added to a reaction bottle, and dimethyl sulfoxide was added to the reaction bottle to dissolve. Vacuum the reaction bottle to remove oxygen and water, and nitrogen was introduced. The reaction bottle was heated to 60°C under nitrogen protection, and the reaction was continued for 10 hours with stirring. 0.008 g of bismuth isooctanoate was added to the reaction bottle, and the reaction was continued for 4 hours with stirring to complete the synthesis of the polyurethane single-component prepolymer. The obtained product was repeatedly washed with n-hexane and then vacuum dried at 60°C to obtain a prepolymer with a molecular weight distribution coefficient of 2.2.

[0110] (3) 20 g of 1,4-diol and 2.2 g of lysine diisocyanate (LDI) were reacted at 70°C for 7 hours. The product was washed with acetone and filtered three times to obtain a BDO-terminated chain extender K3.

[0111] (4) The prepolymer and the chain extender were dissolved in a dioxane solvent at a molar ratio of 2:3, and the reaction was carried out at 100°C for 10 hours. The product was washed and dried to obtain a polyurethane solid with a weight average molecular weight of 680,000 Da.

[0112] Preparation Example 13

[0113] This preparation example provides a method for preparing polyurethane, and the specific steps and parameters are as follows:

[0114] (1) 40 g of 3000 Da polyethylene glycol, 3 g of D,L-lactide, 1.5 g -Caprolactone, 1.6g of lactide, and 0.05g of bismuth neodecanoate were added to the reaction flask and mixed evenly. Vacuum the flask to ensure that it is oxygen-free and water-free. Under nitrogen protection, the reaction flask was heated to 130°C and reacted for 20 hours. The obtained product was repeatedly washed and purified with dichloromethane and acetone for many times to obtain a random copolyester with an average molecular weight of 4400 Da and a glass transition temperature of -58°C. It was vacuum dried and set aside.

[0115] (2) Add 3g of dry random copolyester and 2g of 1,4-butylene diisocyanate (BDI) to the reaction bottle, and add dimethyl sulfoxide to dissolve. Vacuum to remove oxygen and water, and introduce nitrogen. Add 0.008g of bismuth neodecanoate to the reaction bottle, and then heat the reaction bottle to 100°C under nitrogen protection. Stir and continue the reaction for 8 hours to complete the synthesis of the polyurethane single-component prepolymer. The obtained product is repeatedly washed with n-hexane and vacuum dried at 60°C to obtain a prepolymer with a molecular weight distribution coefficient of 1.6;

[0116] (3) 30 g of 1,4-diol and 3.3 g of 1,4-butanediisocyanate (BDI) were reacted at 100°C for 6 hours. The product was washed with acetone and filtered three times to obtain a BDO-terminated chain extender.

[0117] (4) The prepolymer and the chain extender were dissolved in a dioxane solvent at a molar ratio of 2:3, and the reaction was carried out at 80°C for 20 hours. The product was washed and dried to obtain a polyurethane solid with a weight average molecular weight of 880,000 Da.

[0118] Example 1

[0119] This embodiment provides a method for preparing a chitosan polyurethane composite hemostatic sponge, and the specific steps and parameters are as follows:

[0120] (1) 16 g of the polyurethane solid obtained in Preparation Example 10 was dissolved in 400 mL of a dioxane solution to form a polyurethane dioxane solution, to which 1.6 g of the acid-modified chitosan obtained in Preparation Example 1 was added, and the mixture was stirred at 150 rpm for 30 minutes to obtain a mixed solution.

[0121] (2) The mixed solution obtained in step (1) of this embodiment is poured into a mold, reacted at 0°C for 0.5h, and then frozen at -30°C at normal pressure for 6h, followed by annealing at 5°C for 2h, and then vacuum drying at -20°C for 24h. Finally, the freeze-dried product is packaged and sterilized by cobalt 60 irradiation to obtain a chitosan polyurethane composite hemostatic sponge.

[0122] according to Figure 1 and Figure 2 As shown, it is the electron microscope pictures of the chitosan polyurethane composite hemostatic sponge prepared in this example at different magnifications. Figure 1 and Figure 2 It can be seen that the chitosan particles are embedded in the pore edges of the polyurethane sponge and are distributed relatively evenly.

[0123] Example 2

[0124] This embodiment provides a method for preparing a chitosan polyurethane composite hemostatic sponge, and the specific steps and parameters are as follows:

[0125] (1) 20 g of the polyurethane solid obtained in Preparation Example 11 was dissolved in 330 mL of dimethyl sulfoxide (DMSO) to form a dimethyl sulfoxide solution of polyurethane, to which 4 g of the acid-modified chitosan obtained in Preparation Example 2 was added, and the mixture was stirred at 100 rpm for 40 minutes to obtain a polyurethane mixed solution.

[0126] (2) The mixed solution obtained in step (1) of this embodiment is poured into a mold, reacted at 5°C for 1.5 hours, then frozen at -35°C at normal pressure for 4.5 hours, then annealed at 8°C for 3 hours, and then vacuum dried at -30°C for 18 hours. Finally, the obtained freeze-dried product is packaged and sterilized by cobalt 60 irradiation to obtain a chitosan polyurethane composite hemostatic sponge.

[0127] Example 3

[0128] This embodiment provides a method for preparing a chitosan polyurethane composite hemostatic sponge, and the specific steps and parameters are as follows:

[0129] (1) 30 g of the polyurethane solid obtained in Preparation Example 12 was dissolved in 380 mL of N,N-dimethylformamide (DMF) to form a dimethylformamide solution of polyurethane, to which 10 g of the chitosan succinate particles obtained in Preparation Example 3 were added, and the mixture was stirred at 200 rpm for 20 minutes to obtain a polyurethane mixed solution.

[0130] (2) Pour the mixed solution obtained in step (4) into a mold, react at 10°C for 3 hours, freeze at -40°C for 3 hours, anneal at 15°C for 4 hours, and then vacuum dry at -40°C for 12 hours. Finally, package the freeze-dried product and sterilize it by cobalt 60 irradiation to obtain a chitosan polyurethane composite hemostatic sponge.

[0131] Example 4

[0132] This embodiment provides a method for preparing a chitosan polyurethane composite hemostatic sponge, and the specific steps and parameters are as follows:

[0133] (1) 20 g of the polyurethane solid obtained in Preparation Example 13 was dissolved in 200 mL of 1,4-dioxane to form a polyurethane dioxane solution, to which 10 g of the acid-modified chitosan obtained in Preparation Example 4 was added, and the mixture was stirred at 150 rpm for 60 minutes to obtain a polyurethane mixed solution.

[0134] (2) Pour the mixture obtained in step (4) 3 into a mold, react at 5°C for 1 hour, freeze at -40°C for 3 hours, anneal at 15°C for 4 hours, and then vacuum dry at -40°C for 12 hours. Finally, package the freeze-dried product and sterilize it by cobalt 60 irradiation to obtain a chitosan polyurethane composite hemostatic sponge.

[0135] Example 5

[0136] This embodiment provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that in step (1), the mass ratio of chitosan to polyurethane is 0.5:1.

[0137] Example 6

[0138] This embodiment provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that in step (1), the mass ratio of chitosan to polyurethane is 0.05:1.

[0139] Example 7

[0140] This embodiment provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that in step (1), the mass ratio of chitosan to polyurethane is 0.6:1.

[0141] Example 8

[0142] This embodiment provides a method for preparing a chitosan polyurethane composite hemostatic sponge, wherein the specific steps and parameters are the same as those in embodiment 1, except that in step (2), no annealing step is provided between freezing and drying, that is, (2) the mixed solution obtained in step (1) of this embodiment is poured into a mold, reacted at 5°C for 1.5 hours, then frozen at normal pressure at -35°C for 4.5 hours, and then vacuum dried at -30°C for 18 hours. Finally, the obtained freeze-dried product is packaged and sterilized by cobalt 60 irradiation to obtain a chitosan polyurethane composite hemostatic sponge.

[0143] Example 9

[0144] This example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that the acid-modified chitosan prepared in Preparation Example 5 is used to replace the acid-modified chitosan prepared in Preparation Example 1 in step (1).

[0145] Example 10

[0146] This example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that the acid-modified chitosan prepared in Preparation Example 6 is used to replace the acid-modified chitosan prepared in Preparation Example 1 in step (1).

[0147] Embodiment 11

[0148] This example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that the acid-modified chitosan prepared in Preparation Example 7 is used to replace the acid-modified chitosan prepared in Preparation Example 1 in step (1).

[0149] Example 12

[0150] This example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that the acid-modified chitosan prepared in Preparation Example 8 is used to replace the acid-modified chitosan prepared in Preparation Example 1 in step (1).

[0151] Embodiment 13

[0152] This example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that the acid-modified chitosan prepared in Preparation Example 9 is used to replace the acid-modified chitosan prepared in Preparation Example 1 in step (1).

[0153] Comparative Example 1

[0154] This comparative example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that an acid-modified chitosan with a deacetylation degree of 10% of the same mass is used to replace the acid-modified chitosan in step (1).

[0155] Comparative Example 2

[0156] This comparative example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that an acid-modified chitosan with a deacetylation degree of 60% of the same mass is used to replace the acid-modified chitosan in step (1).

[0157] Comparative Example 3

[0158] This comparative example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that an equal mass of commercially available polyurethane (TECOPHILIC™ SP-80A-150, which does not contain polyester) is used to replace the polyurethane in step (1).

[0159] Comparative Example 4

[0160] The present comparative example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that the reaction temperature in step (2) is 15°C, that is, in step (5), the mixed solution obtained in step (4) is poured into a mold, reacted at 15°C for 0.5h, and then frozen at -30°C for 6h, followed by annealing at 15°C for 2h, and then vacuum drying at -20°C for 24h. Finally, the freeze-dried product is packaged and sterilized by cobalt 60 irradiation to obtain a chitosan polyurethane composite hemostatic sponge.

[0161] Comparative Example 5

[0162] This comparative example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1, except that step (2) does not contain a freeze-drying step. That is, in step (2), the mixed solution obtained in step (1) of this example is poured into a mold, placed at 0°C for 0.5h, and then vacuum-dried at 40°C for 24h. The obtained product is packaged and sterilized by cobalt 60 irradiation to obtain a chitosan polyurethane composite hemostatic sponge.

[0163] Experimental Example 1

[0164] The porosity, water absorption rate, compression strength, in vitro coagulation index and degradation performance of the chitosan polyurethane composite hemostatic sponges prepared in Examples 1-13 and Comparative Examples 1-5 and commercially available hemostatic products were tested, among which the degradable ear and nose hemostatic sponge Nasopore produced by Stryker Corporation was selected as commercial product 1. The test results are shown in Table 1.

[0165] The porosity and water absorption rate were tested using the MAY-ME104E sponge porosity and water absorption rate analyzer of Miaozhun Technology; the compression strength was tested using the CTM2050 universal material testing machine of Shanghai Xieqiang Company; the in vitro coagulation index (BCI) determination method is as follows:

[0166] Fresh sodium citrate anticoagulated rabbit whole blood (100uL) and CaCl 2 (0.2M, 10uL) was added to the surface of the sample (0.02g), incubated at 37°C for 5min, deionized water (25mL) was added, and incubated in a constant temperature oscillator at 37°C for 5min. The absorbance of the supernatant at 540nm was measured using a UV-Vis spectrophotometer UV8000 (Shanghai Yuanxi Instrument Co., Ltd.) 540nmsample ), the sample-free group was used as a reference (the absorbance value was recorded as A 540nmcontrol ).

[0167] Calculate BCI according to the following formula:

[0168] BCI (%) = A 540nmsample / A 540nmcontrol ×100%;

[0169] The degradation performance test method is as follows:

[0170] 1 / 15 mol / L potassium dihydrogen phosphate and 1 / 15 mol / L sodium dihydrogen phosphate were mixed in a volume ratio of 18.2:81.8 to prepare a phosphate buffer solution with a pH of 7.4±0.3. No other ingredients were added to the solution, and it was sterilized at high temperature before use.

[0171] 1) Accurately weigh the sample to be tested, put it into a sterilized reagent bottle, add (25±0.5) mL of test solution, cover the sample in the bottle with phosphate buffer, seal it and place it in a constant temperature water bath, and keep it constant at (37±1)℃ for the preset time. 2) After degradation to the set time point (14 days), take out the container containing the sample. First dry the filter to constant weight under vacuum conditions at 37℃, then filter out the sample fragments with the filter, rinse the filtrate with a small amount of deionized water 3 times, dry it under vacuum conditions at 37℃ and weigh it. 3) Count the mass difference before and after sample degradation and calculate the mass loss percentage. Mass loss percentage %=(sample weight before degradation - sample weight after degradation) / sample weight before degradation × 100%.

[0172] Table 1 Hemostatic sponge performance test results

[0173]

[0174] The test results show that, compared with Comparative Examples 1-5, the water absorption rate of the chitosan polyurethane composite hemostatic sponges prepared in Examples 1-4 is all above 1800%, the porosity is all above 93%, and the depression strength is all above 2.0N, which is equivalent to the pure polyurethane hemostatic sponges available on the market. It can be seen that the products prepared by the present invention have good physical and mechanical properties. This will be more conducive to the product to quickly absorb blood, enrich red blood cells and platelets to achieve the purpose of rapid hemostasis, and the good strength also ensures that the product will not break during the hemostasis process.

[0175] For further information, see Figure 1 and Figure 2As shown, it can be known that chitosan particles can be embedded in the pore edges of the polyurethane sponge. Therefore, in the process of hemostasis, chitosan is bound by the microporous structure of the polyurethane and will not fall off. Furthermore, the coagulation index test method used in this experimental example once again verifies the bonding performance of chitosan and polyurethane on the composite hemostatic sponge through water washing and oscillation steps. The coagulation index of the composite hemostatic sponge of Examples 1-13 of the present invention is lower than that of the control example, which once again proves that the chitosan and polyurethane of the composite hemostatic sponge can be tightly bonded and will not be washed away by the liquid, and can play a coagulation effect in the experimental example.

[0176] At the same time, the coagulation index (BCI) of the chitosan polyurethane composite hemostatic sponges prepared in Examples 1-13 of the present invention is significantly lower than that of Comparative Examples 1-5 and the commercial product 1, indicating that chitosan has played a better coagulation effect after modification, while the commercial products only have a dominant role in blood absorption, and the coagulation effect is very small or even non-existent. Among them, the product of Comparative Example 4 is prepared under non-phase transition conditions, and its coagulation index is significantly higher than that of the chitosan polyurethane composite hemostatic sponges prepared in Examples 1-13 of the present invention, indicating that the mixing conditions of the present invention have a great influence on the product performance. After 14 days of degradation in phosphate buffer solution, the chitosan polyurethane composite hemostatic sponges prepared in Examples 1-13 of the present invention have a mass loss of more than 70%, which is similar to that of the commercial product 1, and has reached the requirements for the in vitro degradation test endpoint in YY / T 0473-2004 "In vitro degradation test of polylactide copolymers and blends for surgical implants". Comparative Example 3 is a commercially available thermoplastic polyurethane without a random copolyester structure, and its degradation rate is significantly lower than that of the example product.

[0177] Experimental Example 2

[0178] The hemostatic effects of the chitosan polyurethane composite hemostatic sponges prepared in Examples 1-13 and Comparative Examples 1-5 and commercially available products were measured (commercially available product 1 is the degradable ear and nose hemostatic sponge Nasopore produced by Stryker Corporation, and commercially available product 2 is the vaseline gauze produced by Zhende Medical Supplies Co., Ltd.), and the measuring method is as follows:

[0179] New Zealand white rabbits, male, 5 months old, weighing 2-3.5 kg, were used for animal experiments for the first time. During the experiment, the rabbits were anesthetized and fixed on the operating table. The nose was disinfected with iodine. Under nasal endoscopy, the ethmoid turbinate was partially removed with tissue forceps at a distance of about 1.5 cm from the anterior nostril on the outer wall of the rabbit's nasal cavity. The ethmoid turbinate was bitten off with tissue forceps, about 3×4 mm 2 After the rabbit nasal bleeding model was prepared, the bleeding wound was immediately filled with hemostatic sponge or commercially available products. The filling material was cut into 0.5 cm 3Roll it tightly and stuff it into the nasal cavity until it is full; after one side is stuffed, create the same bleeding model in the other nasal cavity.

[0180] Postoperative feeding: Animals were kept in single cages in a conventional manner after surgery, and the cages were cleaned daily. The drinking water, mental state, and activity status of the experimental animals were recorded.

[0181] The hemostasis effect was observed under nasal endoscopy every 5 minutes for the first 10 minutes and every 2 minutes thereafter; the bleeding stopped when there was no blood around the sponge and no active bleeding. 72 hours after surgery, the packing material was removed and the wound healing degree and redness and swelling were observed under nasal endoscopy.

[0182] The test sample was fixed on the wound surface, and the average hemostasis time of the wound was recorded; the test sample was removed 72 hours after surgery, and the redness and swelling of the wound were observed under nasal endoscopy to determine the degree of wound healing. The results are shown in Table 2. The number of rabbits treated in each treatment group was 10.

[0183] Table 2 Determination of hemostatic effect of hemostatic sponge

[0184]

[0185] It can be seen from the above test results that compared with the chitosan polyurethane composite hemostatic sponges prepared in comparative examples 1-5, commercially available product 1 and commercially available product 2, the chitosan polyurethane composite hemostatic sponges prepared in embodiments 1-13 of the present invention can contact the wound surface well, achieve rapid hemostasis, reduce the effect of inflammatory response, further accelerate the healing of the wound, and the degree of redness and swelling of the wound surface is only slight.

[0186] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A method for preparing a chitosan polyurethane composite hemostatic sponge, characterized in that: The following steps are included: Chitosan and polyurethane are mixed, reacted under the phase transition conditions of polyurethane to obtain an intermediate, and the intermediate is freeze-dried to obtain a composite hemostatic sponge. The polyurethane is prepared by copolymerizing polyester monomers, polyols and isocyanate monomers. The deacetylation degree of the chitosan is 20-50%, The phase transition condition of the polyurethane is 0-10°C.

2. The method for preparing the chitosan polyurethane composite hemostatic sponge according to claim 1, characterized in that: The mass ratio of chitosan to polyurethane is (0.1-0.5):1; and / or, The chitosan is mixed with polyurethane and reacted for 0.5h-3h under the phase transition conditions of polyurethane; and / or, Before the chitosan and polyurethane react, the chitosan and polyurethane solution are mixed under stirring at a speed of 100 rpm to 200 rpm for a time of 20 min to 60 min; and / or, The freeze-drying process further includes a step of annealing the intermediate after freezing the intermediate and before drying.

3. The method for preparing the chitosan polyurethane composite hemostatic sponge according to claim 2, characterized in that: The preparation method of chitosan comprises the steps of dissolving a chitosan raw material and mixing it with an organic solvent to form a solution, adding an acid anhydride to the solution for reaction, adjusting the pH value of the solution to 10-13, and performing solid-liquid separation to obtain chitosan with a deacetylation degree of 20-50%, wherein the ratio of the chitosan raw material to the acid anhydride is 2-8:1-3, and the unit is g:mL; and / or, The solvent in the polyurethane solution includes at least one of dioxane, dimethyl sulfoxide and N,N-dimethylformamide; and / or, The concentration of polyurethane in the polyurethane solution is 40 g / L-100 g / L; and / or, During the freeze-drying process, the freezing temperature is less than or equal to -30°C, and the freezing time is 3-6 hours. The annealing temperature is 5℃-15℃, and the annealing time is 2h-4h. The drying temperature is -40℃~-20℃, and the drying time is 12h-24h.

4. The method for preparing the chitosan polyurethane composite hemostatic sponge according to claim 3, characterized in that: The method for preparing chitosan further comprises the steps of swelling chitosan with a deacetylation degree of 20% to 50%, and then reacting with a first acid solution to obtain acid solution-modified chitosan, wherein the first acid solution comprises an organic acid; and / or, The chitosan raw material has a deacetylation degree of 70%-95% and a weight average molecular weight of 80000Da-300000Da; and / or, The mass volume ratio of the chitosan raw material to the reagent for dissolving the chitosan raw material is 1 g: 25-100 mL; and / or, The volume ratio of the reagent for dissolving the chitosan raw material to the organic solvent is 1:1-2; and / or, The reagent for dissolving the chitosan raw material is a second acid solution, wherein the second acid solution comprises at least one of formic acid, acetic acid, hydrochloric acid and sulfuric acid, and the concentration of the second acid solution is 1-3 vol%; and / or, The organic solvent comprises at least one of methanol, isopropanol or pyridine; and / or, The acid anhydride includes acetic anhydride.

5. The method for preparing the chitosan polyurethane composite hemostatic sponge according to claim 4, characterized in that: The swelling solvent for swelling chitosan with a deacetylation degree of 20-50% comprises a C1-C6 alcohol solvent; and / or, The mass volume ratio of the chitosan with a deacetylation degree of 20-50% to the swelling agent is 0.1-0.2 g: 0.5-1 mL; and / or, The organic acid comprises at least one of acetic acid, lactic acid, glutamic acid, succinic acid and citric acid; and / or, The particle size of chitosan modified by acid solution is 1-80 μm.

6. The method for preparing the chitosan polyurethane composite hemostatic sponge according to any one of claims 1 to 5, characterized in that: The preparation method of polyurethane comprises the following steps: S1, under the protection of inert gas and in the presence of a catalyst, polyester monomer and polyol react to form a random copolyester; S2, under the protection of an inert gas and in the presence of an organic solvent, polymerizing the random copolyester obtained in step S1 with an isocyanate monomer to form a prepolymer; S3, in the presence of a solvent, the prepolymer produced in step S2 reacts with a chain extender, and solid-liquid separation is performed to obtain a polyurethane.

7. The method for preparing the chitosan polyurethane composite hemostatic sponge according to claim 6, characterized in that: In step S1, the polyester monomers include D,L-lactide and caprolactone, The polyol comprises polyethylene glycol; and / or, In the step S2, when the random copolyester and the isocyanate monomer are polymerized to form a prepolymer, the reaction system also includes a catalyst; and / or, The isocyanate monomer in step S2 includes a diisocyanate monomer, The organic solvent includes at least one of dimethyl sulfoxide and N,N-dimethylformamide; and / or, The chain extender in step S3 comprises a hydroxyl-terminated isocyanate; and / or, The solvent in step S3 includes dioxane.

8. The method for preparing the chitosan polyurethane composite hemostatic sponge according to claim 7, characterized in that: The random copolyester prepared in step S1 has an average molecular weight of 2000Da-4500Da and a glass transition temperature of -40 to -60°C; and / or, The catalyst in step S1 and / or step S2 comprises at least one of stannous octoate, bismuth isooctanoate or bismuth neodecanoate; and / or, The chain extender comprises a product obtained by heat treating 1,4-butanediol and isocyanate, washing and drying, wherein the molar ratio of 1,4-butanediol to isocyanate is 10-25:1, the heat treatment temperature is 70°C-100°C, and the heat treatment time is 5 h-7 h; and / or, The molar ratio of D, L-lactide to caprolactone in the polyester monomer is 1:0.5-2; and / or, The molar ratio of polyester monomer to polyol is 1-8:1; and / or, The mass ratio of isocyanate monomer to copolyester is 0.5-2:1; and / or, The isocyanate monomer includes at least one of dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, lysine diisocyanate, and 1,4-butanediisocyanate; and / or, The polyester monomer further comprises at least one of glycolide, trimethylene carbonate or p-dioxanone.

9. The method for preparing the chitosan polyurethane composite hemostatic sponge according to claim 8, characterized in that: The reaction temperature of step S1 is 110°C-150°C, and the reaction time is 20 h-24 h; and / or, The specific steps of generating the prepolymer in step S2 include reacting the random copolyester obtained in step S1 with an isocyanate monomer at 60° C.-100° C. for 4 h-10 h, adding a catalyst thereto, and continuing the reaction for 4 h-8 h; and / or, The reaction temperature of step S3 is 60° C.-100° C., and the reaction time is 10 h-20 h.

10. A chitosan polyurethane composite hemostatic sponge, characterized in that: The chitosan polyurethane composite hemostatic sponge is prepared by the preparation method of any one of claims 1 to 9.

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