Hemostatic foam aerosol as well as preparation method and application thereof in non-compressible hemorrhage

Abstract

The invention discloses a hemostatic foam aerosol as well as a preparation method and application thereof in non-compressible hemorrhage. The preparation method comprises the following steps: carrying out alkylation modification on chitosan and C8-C20 alkane groups to obtain a hydrophobic modified polymer (hmC); dissolving the polymer and a nonionic surfactant in a weakly acidic aqueous solution to prepare a foaming solution; and finally, filling with a propellant to prepare the aerosol. The obtained aerosol can rapidly form foam with good stability and good expansibility after being sprayed, and after the aerosol is in contact with blood, a hydrophobic chain of hmC can be inserted into a blood cell membrane, a gel barrier with a three-dimensional network structure is formed within 2 minutes, and rapid physical plugging hemostasis can be achieved without external pressurization. The product does not depend on a blood coagulation mechanism of a human body, and is suitable for deep, irregular and other non-compressible traumatic hemorrhage. And residual gel after hemostasis can be mildly removed by normal saline, so that subsequent medical treatment is facilitated. The product is convenient to use, good in hemostatic effect and suitable for pre-hospital first aid and military and civilian dual purposes.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biomedical materials, and particularly relates to a hemostatic material for first aid of trauma and a preparation method thereof, in particular to a rapid hemostatic foam aerosol for incompressible hemorrhage and a preparation method and application thereof. BACKGROUND

[0002] With the increase of natural disasters, traffic accidents and work injury accidents, trauma has become an important global public health problem. Hemorrhagic shock caused by damage to large blood vessels and rupture of solid organs is the most common cause of early death after trauma. In the early resuscitation stage of trauma, the inability to emergency hemostasis is a key problem, and is one of the main reasons for "preventable death". Therefore, rapid and effective control of bleeding is the top priority in pre-hospital trauma treatment.

[0003] In traumatic hemorrhage, incompressible hemorrhage is still a problem in trauma treatment because of its fast bleeding speed, difficulty in rapid identification and timely treatment. At present, the commonly used hemostatic forms at home and abroad include hemostatic gauze, hemostatic powder, hemostatic sponge, hemostatic gel, hemostatic spray, etc., which often contain materials that accelerate blood coagulation, such as oxidized cellulose, chitosan, gelatin, fibrinogen, etc., and usually need to be supplemented with external pressure or used in combination, and are mostly used for bleeding points with clear location and obvious wound position, and are not suitable for incompressible hemorrhage such as deep trauma. For pre-hospital trauma first aid of incompressible hemorrhage, the "Pre-hospital Trauma First Aid Hemostasis Expert Consensus" (2025 edition) points out that "for special site bleeding (such as axillary, inguinal or neck), hemostatic dressing should be used to pack the wound and apply pressure dressing in time. When there is a large hemorrhage in the carotid artery, the carotid artery can be pressed to reduce blood flow, and the patient's airway should be protected at the same time." It can be seen that for the treatment of incompressible hemorrhage, under the condition of pre-hospital, only "limited compression + packing" can be used as a temporary hemostatic means.

[0004] Specifically, the limitations of existing pre-hospital hemostatic means for treating incompressible hemorrhage are: 1. At present, it is still mainly packed with hemostatic dressing, and still needs to be supplemented with external pressure dressing to delay blood loss; 2. Traditional hemostatic materials are difficult to reach deep, irregular wounds.

[0005] Different from the existing hemostatic forms: 1. Alkylated modified chitosan is used as the main raw material, which can not rely on its own coagulation mechanism, can form a three-dimensional network gel with blood, and even patients with coagulopathy can successfully hemostasis; 2. The aerosol foam hemostatic agent can rapidly expand and cover a large wound after spraying, without the need to apply pressure to stop bleeding. It has good conformability and hemostatic effect for deep, irregular or uncertain bleeding site wounds. Based on this, a hemostatic foam aerosol is prepared, which can form effective compression in the wound cavity, providing an emergency hemostatic means during pre-hospital treatment. SUMMARY

[0006] In order to solve the above problems, the application discloses a kind of hemostatic foam aerosol and its preparation method and application in incompressible hemorrhage, the mechanical strength of the hemostatic foam of the application is high, and the stability is good, can form the gel with blood combination and has the blocking effect, without pressure, can realize rapid hemostasis.

[0007] The application comprises the following technical solutions: A preparation method of a hemostatic foam aerosol, comprising the following steps: (1) Synthesis of alkylated modified chitosan: grafting reaction of chitosan and C8-C20 alkyl groups through covalent bonding to obtain alkylated modified chitosan; (2) Preparation of foaming solution: dissolving the alkylated modified chitosan obtained in step (1) and non-ionic surfactant in weakly acidic aqueous solution to prepare a foaming solution with an alkylated modified chitosan concentration of 0.5%-3.5% w / v and a non-ionic surfactant concentration of 1%-20% w / v; (3) Aerosol filling: filling the foaming solution obtained in step (2) and propellant into an aerosol container.

[0008] Further, in the above preparation method, the alkyl group in step (1) is a linear alkyl group of C12-C20; further preferably, the alkyl group is a linear alkyl group of C12, C16 or C20.

[0009] Further, in the above preparation method, the non-ionic surfactant in step (2) is selected from at least one of polyoxyethylene type, sugar type, polyether type or fatty acid ester type non-ionic surfactants; further preferably, the non-ionic surfactant is at least one of Tween series, Span series, alkyl glycoside, polyoxyethylene fatty acid ester or sucrose ester.

[0010] Further, in the above preparation method, the volume ratio of propellant to foaming solution in step (3) is 1:1.5-9, and the propellant is a liquefied gas propellant or a compressed gas propellant; further preferably, the liquefied gas propellant is dimethyl ether, liquefied petroleum gas or hydrofluorocarbon; and the compressed gas propellant is nitrogen, carbon dioxide or compressed air.

[0011] The application also discloses a hemostatic foam aerosol prepared by any of the above preparation methods.

[0012] Further, in the above hemostatic foam aerosol, the foam formed by spraying the aerosol can form a gel barrier within 2 minutes after contacting with blood.

[0013] Further, the hemostatic foam aerosol, the storage modulus G' of the gel barrier is greater than the loss modulus G'', and the storage modulus G' measured after mixing with heparinized anticoagulant pig blood is not less than 163 Pa.

[0014] The application further discloses a preparation method of the hemostatic foam aerosol or application of the hemostatic foam aerosol in preparation of a hemostatic medicine or medical device for non-compressible wound bleeding.

[0015] Further, in the application, the non-compressible wound bleeding includes one or more of deep tissue bleeding, axillary bleeding, inguinal bleeding or neck bleeding.

[0016] Further, in the application, the hemostatic medicine can be removed by physiological saline after use.

[0017] Compared with the prior art, the application has the following outstanding beneficial effects: (1) The alkylated modified chitosan synthesized in the application does not depend on its own blood clotting mechanism, a hydrophobic chain is inserted into a blood cell membrane to form a three-dimensional network gel, and thrombus formation is promoted: the elastic modulus G' of the solution mixed with heparinized fresh anticoagulant pig blood is 80 Pa, and the tangent value tan (delta) is less than 1, which indicates that the hmC solution is combined with blood to form a gel body.

[0018] (2) The alkylated modified chitosan is prepared into a gas aerosol by compounding a non-ionic surfactant, the foamed foam has good expansibility, can be fully contacted with blood, forms a gel barrier in 2 min under the condition of not applying pressure, and effectively stops bleeding. After hemostasis, the residual gel can be removed gently by using physiological saline, and subsequent debridement, suturing or other processing operations are not affected.

[0019] The application has good and rapid hemostatic effect on non-compressible bleeding, improves the problems that traditional hemostatic methods need to be pressed and bandaged, are difficult to reach deep parts and irregular wounds, and is easy to carry and use in the form of a gas aerosol tank, does not need to undergo a complex multi-phase mixing process, and is suitable for popularization and application. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The rheological test diagram of the alkylated modified chitosan (hmC) prepared in the embodiments 1-3 after being mixed with heparinized anticoagulant pig blood is shown. In the diagram, A shows a comparison between the storage modulus (G') and the loss modulus (G''), which proves that the hmC forms an elastic gel state (G'>G'') after being combined with blood, and the gel strength is increased with the increase of the alkyl chain length (C12 to C20); and B is a tan (delta) diagram, and the value is less than 1, which further proves the solid characteristics of the gel; Figure 2Comparison chart of H NMR of chitosan before and after alkyl modification 1 Figure A is the spectrum of unmodified chitosan, and figure B is the spectrum of hmC modified by C20 fatty acid; the newly appearing characteristic peaks (such as -CH 2- , -CH 3 peaks on the alkyl chain) prove that the alkane groups have been successfully grafted onto the chitosan skeleton; Figure 3 Figure is a comparison chart of the foam morphology of the samples prepared in examples 1-3 and comparative examples 1-2 over time; the figure directly shows the top view and side view morphology of each group of foams at the initial, 2 minutes, 5 minutes and 10 minutes; it can be seen from the figure that the foam of the present application (example group) has strong three-dimensionality, good swelling and slow defoaming, while the comparative foam collapses rapidly; Figure 4 Figure is a rheological property test chart of the hemostatic foam prepared in example 3, comparative example 1 and comparative example 2 after mixing with heparinized anticoagulant pig blood; figure A shows that each group of foam after combining with blood shows gel characteristics (G'>G''), among which the storage modulus (G') of example 3 reaches 163 Pa, which is significantly better than the comparative examples; the tan(δ) value of figure B shows that the elastic characteristics of the blood clot formed by example 3 are the most significant; Figure 5 Figure is a comparison chart of the cell distribution state of the hemostatic foam of example 3 and comparative example 1 after mixing with diluted blood under an optical microscope (100 times magnification); figure A (example 3) shows that a large number of blood cells are closely aggregated around the bubbles; figure B (comparative example 1) shows that most of the blood cells are in a free state. The results prove that alkylated modified chitosan has a significant effect on promoting the aggregation of blood cells; Figure 6 Figure is a comparison chart of the process and results of the in vivo hemostatic effect of example 3 and each comparative example sample in a rat abdominal aorta bleeding model; through the comparison of pictures of applying hemostatic material, removing material and effect evaluation, it is directly proved that the foam of the present application (example 3) can achieve effective hemostasis within 2 minutes without pressing, and the blood clot is stable and easy to remove with normal saline; Figure 7 Figure is a schematic diagram of the effect of the hemostatic foam of the present application in an in vitro bleeding model (simulated blood vessel sausage casing); the picture shows that after spraying the foam, the foam combines with the blood to form a stable gel block, successfully sealing the bleeding point, even if the sausage casing is placed vertically, there is no process of blood leakage, verifying its rapid sealing ability for simulated non-compressible bleeding. DETAILED DESCRIPTION

[0021] The inventors have found that the carbon chain length of the alkyl group in the alkylated modification is a key factor affecting the performance of the hemostatic foam. When the carbon chain length of the alkyl group is greater than C8, the modified product begins to exhibit significant hydrophobic aggregation and gel-promoting hemostatic ability; when the carbon chain length is in the range of C12 to C20, the ability reaches a better balance, with good gel strength, foam stability and solubility; when the carbon chain is too short (e.g. less than C8), the hydrophobic effect is insufficient, and it is difficult to effectively form a gel network; when the carbon chain is too long (e.g. more than C20), the solubility and foam formation process of the modified product may be affected. Therefore, selecting a saturated linear alkyl group with a carbon chain length of C8 to C20, especially C12 to C20, can effectively achieve the purpose of the present application.

[0022] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0023] Table 1: Raw material table

[0024] Example E1 (1) Alkylation modification of chitosan: Dissolve chitosan in a 2% acidic aqueous solution to make its mass concentration 1%. Then add an equal volume of ethanol to keep the solution at room temperature. Dissolve C12 fatty acid in another beaker containing ethanol, heat to 65℃, and add N-hydroxysuccinimide in an equimolar ratio to the C12 fatty acid and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride in a mass ratio of 3 times to the C12 fatty acid, and mix thoroughly. Add the fatty acid solution to the chitosan solution, and mix the mixture at room temperature for 24 h. After the reaction is completed, add sodium hydroxide until precipitate is formed, wash the precipitate with ethanol several times, dry, grind, and obtain hmC powder.

[0025] (2) Preparation of foaming solution: The concentration of hmC in the foaming solution is 2% w / v, and the concentration of non-ionic surfactant is 10% w / v.

[0026] (3) Aerosol canning: Fill the foaming solution and propellant into an aluminum can bottle in sequence, so that the gas-liquid ratio is 1:4.

[0027] Example E2 (1) Alkylation modification of chitosan: chitosan was dissolved in 2% acidic aqueous solution to make its mass concentration 1%. Then equal volume of ethanol was added to keep the solution at room temperature. C16 fatty acid was dissolved in another beaker containing ethanol to make the ratio of C16 fatty acid to amine content on chitosan 5 mol%. The solution was heated to 65°C, and equimolar ratio of N-hydroxysuccinimide to C16 fatty acid and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride with 3 times mass ratio of C16 fatty acid were added and mixed well. The fatty acid solution was added to the chitosan solution, and the mixture was reacted at room temperature for 24 h. After the reaction was completed, sodium hydroxide was added until precipitate was formed. The precipitate was washed with ethanol for several times, dried, ground, and hmC powder was obtained.

[0028] (2) Preparation of foaming solution: the concentration of hmC in the foaming solution was 2% w / v, and the concentration of non-ionic surfactant was 10% w / v.

[0029] (3) Aerosol packaging: the foaming solution and propellant were sequentially filled into an aluminum can to make the gas-liquid ratio 1:4.

[0030] Example E3 (1) Alkylation modification of chitosan: chitosan was dissolved in 2% acidic aqueous solution to make its mass concentration 1%. Then equal volume of ethanol was added to keep the solution at room temperature. C20 fatty acid was dissolved in another beaker containing ethanol to make the ratio of C20 fatty acid to amine content on chitosan 5 mol%. The solution was heated to 65°C, and equimolar ratio of N-hydroxysuccinimide to C20 fatty acid and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride with 3 times mass ratio of C20 fatty acid were added and mixed well. The fatty acid solution was added to the chitosan solution, and the mixture was reacted at room temperature for 24 h. After the reaction was completed, sodium hydroxide was added until precipitate was formed. The precipitate was washed with ethanol for several times, dried, ground, and hmC powder was obtained.

[0031] (2) Preparation of foaming solution: the concentration of hmC in the foaming solution was 2% w / v, and the concentration of non-ionic surfactant was 10% w / v.

[0032] (3) Aerosol packaging: the foaming solution and propellant were sequentially filled into an aluminum can to make the gas-liquid ratio 1:4.

[0033] Example E4 (1) Alkylation modification of chitosan: Chitosan was dissolved in 2% acidic aqueous solution to make its mass concentration 1%. Then equal volume of ethanol was added to keep the solution at room temperature. C20 fatty acid was dissolved in another beaker containing ethanol to make the ratio of C20 fatty acid to amine content on chitosan 5 mol%. The solution was heated to 65 °C, and equimolar ratio of N-hydroxysuccinimide and 3 times mass ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride to C20 fatty acid were added to the solution and mixed well. The fatty acid solution was added to the chitosan solution, and the mixture was reacted at room temperature for 24 h. After the reaction was completed, sodium hydroxide was added until precipitate was formed. The precipitate was washed with ethanol for several times, air-dried, and ground to obtain hmC powder.

[0034] (2) Preparation of foaming solution: The concentration of hmC in the foaming solution was 1% w / v, and the concentration of non-ionic surfactant was 20% w / v.

[0035] (3) Aerosol canning: The foaming solution and propellant were sequentially filled into an aluminum can bottle to make the gas-liquid ratio 1:4.

[0036] Example E5 (1) Alkylation modification of chitosan: Chitosan was dissolved in 2% acidic aqueous solution to make its mass concentration 1%. Then equal volume of ethanol was added to keep the solution at room temperature. C20 fatty acid was dissolved in another beaker containing ethanol to make the ratio of C20 fatty acid to amine content on chitosan 5 mol%. The solution was heated to 65 °C, and equimolar ratio of N-hydroxysuccinimide and 3 times mass ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride to C20 fatty acid were added to the solution and mixed well. The fatty acid solution was added to the chitosan solution, and the mixture was reacted at room temperature for 24 h. After the reaction was completed, sodium hydroxide was added until precipitate was formed. The precipitate was washed with ethanol for several times, air-dried, and ground to obtain hmC powder.

[0037] (2) Preparation of foaming solution: The concentration of hmC in the foaming solution was 2% w / v, and the concentration of non-ionic surfactant was 10% w / v.

[0038] (3) Aerosol canning: The foaming solution and propellant were sequentially filled into an aluminum can bottle to make the gas-liquid ratio 1:2.33.

[0039] Example E6 (1) Alkylation modification of chitosan: chitosan was dissolved in 2% acidic aqueous solution to make its mass concentration 1%. Then equal volume of ethanol was added to keep the solution at room temperature. C20 fatty acid was dissolved in another beaker containing ethanol to make the ratio of C20 fatty acid match the amine content on chitosan at 5 mol%, heated to 65°C, and then equal molar ratio of N-hydroxysuccinimide and 3 times mass ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride to C20 fatty acid were added to the solution and mixed well. The fatty acid solution was added to the chitosan solution, and the mixture was reacted at room temperature for 24 h. After the reaction was completed, sodium hydroxide was added until precipitate was formed. The precipitate was washed with ethanol for several times, dried, ground, and hmC powder was obtained.

[0040] (2) Preparation of foaming solution: the concentration of hmC in the foaming solution was 2% w / v, and the concentration of non-ionic surfactant was 10% w / v.

[0041] (3) Aerosol packaging: the foaming solution and propellant were sequentially filled into an aluminum can to make the gas-liquid ratio 1:9.

[0042] Comparative Example C1 The foaming solution was prepared using unmodified chitosan, and the concentration of unmodified chitosan in the foaming solution was 2% w / v, and the concentration of non-ionic surfactant was 10% w / v. The foaming solution and propellant were sequentially filled into an aluminum can to make the gas-liquid ratio 1:4.

[0043] Comparative Example C2 (1) Alkylation modification of chitosan: chitosan was dissolved in 2% acidic aqueous solution to make its mass concentration 1%. Then equal volume of ethanol was added to keep the solution at room temperature. C20 fatty acid was dissolved in another beaker containing ethanol to make the ratio of C20 fatty acid match the amine content on chitosan at 5 mol%, heated to 65°C, and then equal molar ratio of N-hydroxysuccinimide and 3 times mass ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride to C20 fatty acid were added to the solution and mixed well. The fatty acid solution was added to the chitosan solution, and the mixture was reacted at room temperature for 24 h. After the reaction was completed, sodium hydroxide was added until precipitate was formed. The precipitate was washed with ethanol for several times, dried, ground, and hmC powder was obtained.

[0044] (2) The foaming solution was only composed of 2% w / v of hmC.

[0045] (3) Aerosol packaging: the foaming solution and propellant were sequentially filled into an aluminum can to make the gas-liquid ratio 1:4.

[0046] Comparative Example C3 Commercially available chitosan hemostatic powder. Source: Trauma first aid chitosan hemostatic particles of Qingdao Boyite Biomaterials Co., Ltd.

[0047] Comparative Example C4 Commercially available gelatin sponge. Source: Hemostatic sponge of Guangzhou Kuaikang Medical Instrument Co., Ltd.

[0048] Test Example Examples E4-E6 have similar properties to Example E3. The following examples E1, E2, E3, Comparative Example C1, Comparative Example C2, Comparative Example C3, and Comparative Example C4 are used as examples for performance characterization and hemostatic effect research.

[0049] Test Example T1 The rheological properties of hmC and heparinized anticoagulant pig blood in Examples E1, E2, and E3 were explored by a rheometer to evaluate their storage modulus (G') and loss modulus (G''). As shown in Figure 1 A, the three hmC combined with anticoagulant blood showed solid-like characteristics within the linear viscoelastic range, G' > G'', and the gelation ability of hmC combined with blood increased with the lengthening of the fatty acid carbon chain. The storage modulus G' of hmC modified by C20 fatty acid was 80 Pa. Figure 1 B is the conversion of the tangent value of the rotary rheometer, tan(δ)=G'' / G' The smaller the value, the stronger the solid-like characteristics of the test sample. Conclusion: The hmC prepared in Examples E1-E3 combined with blood showed strong gelation ability and could form a gel barrier.

[0050] Test Example T2 Dissolve 20 mg of hmC in 0.8 mL of D2O, add a small amount of deprotonated acid to promote dissolution, and load the dissolved sample into an NMR tube for nuclear magnetic scanning. Figure 2 A is the nuclear magnetic hydrogen spectrum of unmodified chitosan, Figure 2 B is the nuclear magnetic hydrogen spectrum of hmC.

[0051] Test Example T3 According to the national standard GB / T 16886.5—2017 and GB / T 16886.4—2022 for biological evaluation of medical devices, MTT in vitro cytotoxicity test and blood interaction test were conducted on hmC in a qualified third-party testing institution. Conclusion: The cell survival rate (%) of the 100% extraction solution of hmC sample was 80.87%, and the cell morphology classification was 0, indicating that the extraction solution of the test sample had no potential toxic effect on L-929 cells; the hemolysis rate of hmC was 1.78%, and the hemolysis rate was less than 5%, meeting the requirements of the hemolysis test.

[0052] Test Example T4 Figure 3 The foam morphology of Examples E1-E3 and Comparative Examples C1-C2 at different times is shown: The foams of Examples E1-E3 have a strong three-dimensional effect and are expanded and upright. Compared with Comparative Examples C1-C2, the defoaming speed is slower, and the foam morphology does not collapse. Although the foam of Comparative Example C2 initially expands three-dimensionally, due to the lack of nonionic surfactant foam stabilizing properties, the foam defoams very quickly and almost completely collapses after 10 minutes.

[0053] The rheological properties of the hemostatic foams prepared in Example E3, Comparative Examples C1 and C2, and heparinized anticoagulated porcine blood were investigated using a rheometer to evaluate their storage modulus (G') and loss modulus (G''). Figure 4 As shown in Figure A, all groups of hemostatic foam exhibited solid-like characteristics after binding with anticoagulated blood, with G' > G''. E3 showed the most pronounced gelation characteristics, with G' reaching 163 Pa, significantly higher than comparative examples C1 and C2. P <0.01). Figure 4 B represents the conversion of the rotational rheometer tangent value. E3 has the smallest tangent value for the blood clot formed by the hemostatic foam and blood, showing a significant difference compared to comparative examples C1 and C2. P <0.01), exhibiting elastic characteristics. Comparative Example C1 is unmodified chitosan, with weak gelation ability with blood. Comparative Example C2 lacks the support of nonionic surfactants, has poor mechanical strength, and defoams faster.

[0054] Test case T5 Fresh anticoagulated pig blood was diluted 10 times in physiological saline. A small amount of the diluted blood was mixed with the foam and placed on a glass slide. A coverslip was then placed on the sample, and the image was captured by optical microscopy at 100x magnification. Example E3: Microscopic imaging of hemostatic foam. Figure 5 As shown in Figure A, a large number of blood cells gathered around the bubble, and the blood cells did not undergo hemolysis. Figure 5 B shows a microscopic image of the comparative example C1 foam, revealing that most blood cells are in a free state, with only a small number of blood cells aggregated around the bubbles. This demonstrates that alkylated chitosan foam exhibits better blood cell aggregation, resulting in more effective hemostasis.

[0055] Test case T6 To investigate the hemostatic effect of foam aerosol, a rat abdominal aortic hemorrhage model was constructed to simulate uncompressible or deep arterial bleeding. After puncturing the abdominal aorta with a scalpel and inducing bleeding, foam was sprayed onto the wound. Figure 6As shown, the foam of Example E3 can effectively stop the abdominal aortic bleeding and reduce the amount of bleeding, and achieve hemostasis within 2 minutes without pressing. The foam can be easily removed by flushing with normal saline, and a stable blood clot is observed to form at the wound site, and the removal of the foam does not damage the blood clot. The foam of Comparative Example C1 fails to stop bleeding for more than 5 min, and the wound still has continuous bleeding. This is because the chitosan is not alkylated and hydrophobically modified, so that the blood cell aggregation ability is poor, and it is difficult to form a blood clot at a large amount of bleeding wound, and effective hemostasis cannot be achieved. The defoaming speed of the foam of Comparative Example C2 is relatively fast, and the hemostasis time is higher than that of E3 without pressing. This is because the C2 foam system is not compounded with non-ionic surfactant, so that the toughness and elasticity of the sprayed foam is insufficient, resulting in that the foam film is too thin, the liquid is discharged quickly, and the foam is easily broken and defoamed. The commercially available chitosan hemostatic powder of Comparative Example C3 is evenly sprinkled on the wound site to cover the wound, and continuous bleeding of blood is observed. The gauze is pressed to stop bleeding, and after 2 minutes, the gauze is removed and observed, and no blood is observed to seep from the wound. The blood is combined with the hemostatic powder to form a hard block, which cannot be removed. The commercially available gelatin sponge of Comparative Example C4 is pressed on the wound site, and continuous bleeding of blood is observed, and hemostasis cannot be achieved for more than 2 min.

[0056] We also tested using an in vitro bleeding model, such as Figure 7 As shown, the intestinal casing simulates the blood vessel or tissue bleeding interface, the heparinized anticoagulant pig blood is filled into the intestinal casing and sealed, a hole is made on the intestinal casing with scissors, the hemostatic foam is sprayed, the excess foam is removed after 8 min, and the foam is combined with the blood to form a stable blood clot. The intestinal casing is placed vertically, and no additional bleeding is observed, and the gelation plugging hemostasis is successfully achieved.

[0057] These tests demonstrate the excellent hemostatic effect of the present application, which is due to the hemostatic mechanism of the self-synthesized alkylated modified chitosan and the high mechanical stability of the foam aerosol, and the overall structure of the foam cannot be damaged by blood flow. It is convenient and fast to use, and only needs to shake the tank body, without the need for complex multi-phase mixing. It can achieve rapid hemostasis without the need to apply pressure. After hemostasis is completed, the hemostatic foam can be quickly removed from the wound site with normal saline, without causing secondary damage to the wound, and without affecting subsequent debridement, suturing or other processing operations. It shows the unique advantages of the present application compared to traditional hemostatic materials.

[0058] The above is only a few preferred embodiments of the present application, which are described in detail and in detail, but it cannot be understood as a limitation on the scope of the patent of the present application. It should be noted that for ordinary skilled persons in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of protection of the present application.

Claims

1. A method for preparing a hemostatic foam aerosol, characterized in that, Includes the following steps: (1) Synthesis of alkylated chitosan: chitosan was grafted with C8~C20 alkane groups through covalent bonding to obtain alkylated chitosan; (2) Preparation of foaming solution: Dissolve the alkylated modified chitosan obtained in step (1) and the nonionic surfactant in a weakly acidic aqueous solution to prepare a foaming solution with an alkylated modified chitosan concentration of 0.5%~3.5% w / v and a nonionic surfactant concentration of 1%~20% w / v. (3) Aerosol filling: The foaming solution and propellant obtained in step (2) are filled into the aerosol container.

2. The preparation method according to claim 1, characterized in that, The alkane group in step (1) is a linear alkyl group of C12 to C20; more preferably, the alkane group is a linear alkyl group of C12, C16 or C20.

3. The preparation method according to claim 1, characterized in that, The nonionic surfactant mentioned in step (2) is selected from at least one of polyoxyethylene type, sugar, polyether or fatty acid ester nonionic surfactants; more preferably, the nonionic surfactant is at least one of Tween series, Span series, alkyl glycoside, polyoxyethylene fatty acid ester or sucrose ester.

4. The preparation method according to claim 1, characterized in that, In step (3), the volume ratio of propellant to foaming solution is 1:1.5~9, and the propellant is a liquefied gas propellant or a compressed gas propellant; more preferably, the liquefied gas propellant is dimethyl ether, liquefied petroleum gas or hydrofluorocarbon; the compressed gas propellant is nitrogen, carbon dioxide or compressed air.

5. A hemostatic foam aerosol, characterized in that, It is prepared by the preparation method according to any one of claims 1-4.

6. The hemostatic foam aerosol according to claim 5, characterized in that, The foam generated by this aerosol can form a gel barrier within 2 minutes after contact with blood.

7. The hemostatic foam aerosol according to claim 5, characterized in that, The storage modulus G' of the gel barrier is greater than the loss modulus G", and its storage modulus G' measured after mixing with heparinized anticoagulated pig blood is not less than 163 Pa.

8. The preparation method according to any one of claims 1-4 or the hemostatic foam aerosol according to any one of claims 5-7 in the preparation of hemostatic drugs or medical devices for non-compressible traumatic bleeding.

9. The application according to claim 7, characterized in that, The aforementioned non-compressible traumatic bleeding includes one or more of the following: deep tissue bleeding, axillary bleeding, groin bleeding, or neck bleeding.

10. The application according to claim 7, characterized in that, After use, the residue of the hemostatic drug can be removed by rinsing with physiological saline.

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