A self-gelling rapid hemostatic spray and its preparation method and application

Abstract

The application discloses a self-gel rapid hemostatic spray, a preparation method and application thereof, and belongs to the technical field of hemostatic materials.The self-gel rapid hemostatic spray comprises a chitosan derivative, an ionic crosslinking agent and a solvent, wherein the mass ratio of the chitosan derivative and the ionic crosslinking agent is 20:1-1:20, and the ratio of the chitosan derivative to the solvent is 1-20 g:1 L.The self-gel rapid hemostatic spray is prepared by spraying the chitosan derivative and the ionic crosslinking agent, and the chitosan derivative and the ionic crosslinking agent can form non-covalent crosslinking rapidly after being sprayed and mixed, so that the preparation process is simple, the price is low, the self-gel rapid hemostatic spray is suitable for a wound, has good biological safety, and has excellent antibacterial performance, and the problems of poor adhesion of the existing hemostatic spray to a tissue and the incapability of forming physical plugging are solved, and the hemostatic effect of the hemostatic spray is further improved.

Description

Technical Field

[0001] This invention belongs to the medical field, specifically relating to a self-gelling rapid hemostatic spray, its preparation method, and its application. Background Technology

[0002] Traumatic bleeding leading to death is not uncommon. Hemostasis is a crucial part of pre-hospital medical care, and timely hemostasis measures play a vital role in reducing the disability and mortality rates of trauma patients.

[0003] Currently, traditional methods of hemostasis using gauze pressure and bandages have many drawbacks, such as uncertain hemostatic effects and the risk of limb ischemic necrosis, making them unsuitable as the first-line methods for emergency hemostasis. Existing new hemostatic materials mainly include hemostatic sponges, gels, and sprays. Hemostatic sponges are three-dimensional porous materials with strong liquid absorption capacity, which can concentrate clotting factors in a short time to achieve hemostasis.

[0004] Representative hemostatic sponges from abroad are based on zeolite, montmorillonite, or silicate mesoporous materials. and WoundStat TM Products and chitosan-based hemostatic agents However, hemostatic sponges still require pressure on the bleeding wound to achieve a physical sealing effect, and their effectiveness is limited for bleeding sites where pressure is not possible. Hydrogels are water-containing three-dimensional network polymers with good biocompatibility and can be effectively used for hemostasis in wounds where pressure is not possible. However, traditional hydrogel dressings have insufficient wound adhesion and a long gelation time, thus failing to achieve large-scale wound hemostasis in a short time. Furthermore, hydrogels also suffer from complex manufacturing processes, long cross-linking times, and initiator residues.

[0005] Hemostatic sprays can quickly and effectively cover irregular wounds, but newer hemostatic sprays such as Vistaseal... TM Fibrinogen derived from human plasma is scarce, has a complex extraction and purification process, is difficult to store, is expensive, and still has a clotting time of up to 240 seconds.

[0006] Therefore, there is an urgent need in this field for a biosafe, simple to prepare and easy-to-use rapid hemostatic material. Summary of the Invention

[0007] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0008] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0009] Therefore, the purpose of this invention is to overcome the shortcomings of the prior art and provide a self-gelling rapid hemostatic spray.

[0010] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a self-gelling rapid hemostatic spray, comprising,

[0011] Chitosan derivatives, ionic crosslinking agents, and solvents; among which,

[0012] The mass ratio of chitosan derivative to ionic crosslinking agent is 20:1 to 1:20;

[0013] The ratio of chitosan derivative to solvent is 1–50 g: 1 L.

[0014] As a preferred embodiment of the spray of the present invention, the solvent includes one or more of PBS buffer, Tris and its derivative buffer, physiological saline and tranexamic acid aqueous solution.

[0015] As a preferred embodiment of the spray agent of the present invention, the chitosan derivative includes one or more of quaternary ammonium chitosan and carboxymethyl chitosan.

[0016] In a preferred embodiment of the spray agent described in this invention, the chitosan derivative has a molecular weight of 50,000 to 400,000.

[0017] As a preferred embodiment of the spray agent of the present invention, the ionic crosslinking agent includes one or more of tannic acid, dopamine, phytic acid, citric acid, polyacrylic acid and polyvinyl alcohol.

[0018] In a preferred embodiment of the spray agent of the present invention, the mass ratio of the chitosan derivative to the ionic crosslinking agent is 10:1 to 1:10.

[0019] Another objective of this invention is to overcome the shortcomings of the prior art and provide a method for preparing a self-gelling rapid hemostatic spray, comprising dissolving a chitosan derivative and an ionic crosslinking agent into a solvent respectively to obtain the self-gelling rapid hemostatic spray combination, which can be sprayed simultaneously or sequentially and mixed.

[0020] Another object of the present invention is to overcome the shortcomings of the prior art and provide the application of the spray in the preparation of hemostatic drugs.

[0021] Beneficial effects of this invention:

[0022] (1) This invention provides a rapid hemostatic material composed of a chitosan derivative and an ionic crosslinking agent spray, which aims to solve the problem of long hemostatic time of existing hemostatic sprays and further improve the hemostatic effect of hemostatic sprays; wherein, after the chitosan derivative and the ionic crosslinking agent are sprayed and mixed, non-covalent crosslinks are quickly formed, the preparation process is simple, the price is low, the wound adheres well, the biosafety is good, and the antibacterial properties are excellent.

[0023] (2) The method of the present invention uses chitosan derivatives and ionic crosslinking agent materials to prepare a novel rapid hemostatic spray material after simple mixing; compared with commercially available hemostatic materials, this hemostatic material has high hemostatic efficiency, is easy to carry, has good biosafety, and can be applied to rapid hemostasis of different bleeding tissues, and is expected to become a new generation of hemostatic materials. Attached Figure Description

[0024] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0025] Figure 1 This is a photograph of the chitosan derivative and ionic crosslinking agent spray material in Example 1 of the present invention.

[0026] Figure 2 This is a diagram illustrating the hemostatic material formed by simultaneously spraying the rapid hemostatic material prepared in Example 1 of the present invention onto a glass surface. Detailed Implementation

[0027] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0028] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0029] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0030] The raw materials used in the embodiments of this invention are all purchased through commercial channels and used directly without any special treatment.

[0031] The analysis method in this embodiment of the invention is as follows:

[0032] (1) Characterization of gelation time of hemostatic materials:

[0033] Spraying hemostatic material solutions of different concentrations onto a glass surface simultaneously can rapidly form hemostatic material, indicating that a three-dimensional gel network can be quickly formed after spraying.

[0034] (2) Characterization of platelet plasma recalcification time in anemia:

[0035] Rabbit blood was centrifuged at 8°C for 20 minutes (3000 rpm), and the supernatant was collected to obtain anemic platelet plasma.

[0036] Take 50 μL of anemic platelet plasma and 50 μL of calcium chloride solution (concentration of 0.025 mol / L), heat to 37°C, and drop onto the surface of a glass plate (the glass plate is preheated to 37°C). For the experimental group, spray the chitosan-based hemostatic spray prepared in the example onto the plasma. The spray volume is 50-100 μL (the two solutions are sprayed simultaneously, with a spray volume ratio of 1:1). Use a stainless steel hook to dip into the solution to observe whether filamentous fibrin forms. Record the time from the addition of calcium chloride solution to the formation of filamentous fibrin, which is the anemic platelet plasma coagulation and recalcification time.

[0037] (3) Characterization of hemostatic material in rat liver clotting time:

[0038] Rats (weighing approximately 300 grams) were anesthetized, and a 5 mm incision was made in the liver with a scalpel. The control group received no treatment, while the treatment group received a commercially available hemostatic agent, Vistaseal, sprayed at the wound site. TM In the experimental group, the chitosan-based hemostatic spray prepared in the example was sprayed on the wound. The spray volume was 50-100 microliters (the two solutions were sprayed simultaneously or sequentially and mixed in a 1:1 volume ratio). At the same time, the bleeding of the liver was observed.

[0039] Example 1

[0040] At room temperature, weigh 40 grams of quaternary ammonium salt chitosan with a molecular weight of approximately 200,000 and dissolve it in 1 liter of 1% tranexamic acid.

[0041] Dissolve 2 grams of tannic acid and 2 grams of phytic acid in 1 liter of 1% tranexamic acid;

[0042] Applying both solutions simultaneously creates a hemostatic material.

[0043] Figure 1 The hemostatic material prepared in Example 1 has a recalcification time of 96 seconds in anemic platelet plasma.

[0044] like Figure 2 As shown, when two solutions are sprayed onto a glass surface simultaneously, the material quickly gels, with a gelation time of approximately 10 seconds.

[0045] The experimental group sprayed the hemostatic spray prepared in Example 1, and the liver stopped bleeding within 120 seconds.

[0046] This demonstrates that the hemostatic spray prepared in Example 1 has rapid and efficient hemostatic ability.

[0047] The control group received no treatment and failed to clot after 240 seconds, meaning the clotting time was greater than 240 seconds. The control group was sprayed with the commercially available hemostatic product, Vestal. TM The liver stopped bleeding after 240 seconds.

[0048] The experimental group, after being sprayed with the hemostatic spray prepared in Example 1, experienced a complete cessation of bleeding within 120 seconds. Compared to commercially available hemostatic products, the hemostatic powder prepared in Example 1 demonstrated superior hemostatic efficacy.

[0049] Example 2

[0050] At room temperature, weigh 5 grams of carboxymethyl chitosan with a molecular weight of approximately 100,000 and 5 grams of carboxymethyl chitosan with a molecular weight of approximately 400,000 and dissolve them in 1 liter of PBS buffer. Dissolve 2 grams of tannic acid and 2 grams of citric acid in 1 liter of PBS buffer. Spray the two solutions together sequentially to obtain the hemostatic material.

[0051] The experimental group sprayed the hemostatic spray prepared in Example 2, and the bleeding stopped within 132 seconds.

[0052] Example 3

[0053] At room temperature, weigh 10 grams of carboxymethyl chitosan with a molecular weight of approximately 200,000 and dissolve it in 1 liter of physiological saline. Also dissolve 5 grams of citric acid and 5 grams of dopamine in 1 liter of physiological saline. Spray both solutions simultaneously to obtain the hemostatic material.

[0054] The experimental group sprayed the hemostatic spray prepared in Example 3, and the bleeding stopped within 162 seconds.

[0055] Example 4

[0056] At room temperature, weigh 20 grams of quaternary ammonium salt chitosan with a molecular weight of approximately 400,000 and dissolve it in 1 liter of water. Also dissolve 20 grams of polyacrylic acid and 15 grams of phytic acid in 1 liter of water. Spray the two solutions together sequentially to obtain the hemostatic material.

[0057] The experimental group was sprayed with the hemostatic spray prepared in Example 4, and the bleeding stopped within 144 seconds.

[0058] Example 5

[0059] At room temperature, weigh 4 grams of quaternary ammonium salt chitosan with a molecular weight of approximately 200,000 and dissolve it in 1 liter of physiological saline. Dissolve 16 grams of tannic acid and 24 grams of citric acid in 1 liter of physiological saline. Spray both solutions simultaneously to obtain the hemostatic material.

[0060] The experimental group sprayed the hemostatic spray prepared in Example 5, and the bleeding stopped within 147 seconds.

[0061] Comparative Example 1

[0062] At room temperature, weigh 20 grams of carboxymethyl chitosan with a molecular weight of approximately 300,000 and dissolve it in 1 liter of water. Also dissolve 0.5 grams of tannic acid and 0.5 grams of phytic acid in 1 liter of water. Spray both solutions simultaneously to obtain a hemostatic material.

[0063] The hemostatic spray prepared in Comparative Example 1 stopped bleeding after 204 seconds.

[0064] Comparative Example 2

[0065] At room temperature, weigh 1 gram of quaternary ammonium salt chitosan with a molecular weight of approximately 300,000 and dissolve it in 1 liter of water. Also dissolve 10 grams of tannic acid and 10 grams of phytic acid in 1 liter of water. Spray both solutions simultaneously to obtain a hemostatic material.

[0066] The hemostatic spray prepared in Comparative Example 2 stopped bleeding after 228 seconds.

[0067] Comparative Example 3

[0068] At room temperature, weigh 40 grams of quaternary ammonium salt chitosan with a molecular weight of approximately 200,000 and dissolve it in 1 liter of 1% tranexamic acid. Also dissolve 0.8 grams of tannic acid and 0.8 grams of phytic acid in 1 liter of 1% tranexamic acid. Spray both solutions simultaneously to obtain the hemostatic material.

[0069] The hemostatic spray prepared in Comparative Example 3 stopped bleeding after 240 seconds.

[0070] Comparative Example 4

[0071] At room temperature, weigh 10 grams of quaternary ammonium salt chitosan with a molecular weight of approximately 200,000 and dissolve it in 1 liter of 1% tranexamic acid. Also dissolve 130 grams of tannic acid and 120 grams of phytic acid in 1 liter of 1% tranexamic acid. Spray both solutions simultaneously to obtain the hemostatic material.

[0072] The hemostatic spray prepared in Comparative Example 4 stopped bleeding after 240 seconds.

[0073] Comparative Example 5

[0074] At room temperature, 44 grams of quaternary ammonium salt chitosan with a molecular weight of approximately 200,000 are dissolved in 1 liter of 1% tranexamic acid and sprayed to obtain a hemostatic material.

[0075] The hemostatic spray prepared in Comparative Example 5 failed to coagulate after 240 seconds, meaning the coagulation time was greater than 240 seconds.

[0076] Comparative Example 6

[0077] At room temperature, weigh 40 grams of quaternary ammonium salt chitosan with a molecular weight of approximately 200,000 and dissolve it in 1 liter of 1% tranexamic acid. Dissolve 4 grams of gelatin in 1 liter of 1% tranexamic acid. Spray both solutions simultaneously to obtain a hemostatic material.

[0078] The hemostatic spray prepared in Comparative Example 6 stopped bleeding after 240 seconds and still could not clot after 240 seconds, meaning the clotting time was greater than 240 seconds.

[0079] The chitosan and its derivatives of this invention are a class of polycationic polysaccharides with good hemostatic properties, good biocompatibility, no immunogenicity and no skin irritation, and therefore are widely used in wound repair materials.

[0080] The main content of this invention is to utilize chitosan derivatives and ionic crosslinking agents to rapidly form non-covalent crosslinks after spray mixing. This results in a high-efficiency hemostatic material with simple preparation process, low price, good wound adhesion, good biocompatibility, and excellent antibacterial properties.

[0081] Chitosan derivatives and ionic crosslinking agents are mixed in a certain proportion to form the rapid hemostatic spray material provided by this invention. After contacting the wound, the chitosan derivatives and ionic crosslinking agents rapidly form a three-dimensional hydrogel material through non-covalent interactions such as electrostatic interaction and hydrogen bonding, thereby providing rapid physical sealing and hemostasis to the wound.

[0082] Meanwhile, the ionic crosslinking agent complexes iron ions in the blood to form a second three-dimensional crosslinking network, which can increase the strength of the hydrogel network and further improve the physical sealing efficiency of the hydrogel.

[0083] On the other hand, the positively charged chitosan derivatives and the negatively charged platelets aggregate through electrostatic interactions, promoting hemostasis. Furthermore, this hemostatic spray exhibits excellent adhesion and conformability, effectively addressing blood occlusion under pressure, overcoming the shortcomings of traditional hemostatic sprays or gels such as inadequate physical sealing and long hemostasis times.

[0084] In summary, this invention utilizes a water-soluble chitosan derivative and an ionic crosslinking agent to obtain a hemostatic spray with excellent hemostatic effect. The ionic crosslinking agent can complex with iron ions in the blood to form a three-dimensional network structure; furthermore, the ionic crosslinking agent can also form a second three-dimensional network structure with the chitosan derivative through electrostatic interactions and hydrogen bonds. The preparation process is simple, and the dual network structure endows the hemostatic material with excellent mechanical properties, enabling rapid and effective physical sealing of bleeding sites. In addition, the ionic crosslinking agent used in this patent reacts with amino groups on the skin surface through hydrogen bonds and electrostatic interactions, thus the hemostatic material also has very good tissue adhesion, allowing for physical sealing of sites with bleeding pressure without detachment.

[0085] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the present invention.

Claims

1. A method for preparing a self-gelling rapid hemostatic spray, characterized in that: include, Chitosan derivatives and ionic crosslinking agents are dissolved in solvents to obtain the self-gelling rapid hemostatic spray combination, which can be sprayed simultaneously or sequentially and mixed. in, The mass ratio of chitosan derivative to ionic crosslinking agent is 10:1; The ratio of chitosan derivative to solvent is 40 grams to 1 liter; Wherein, the chitosan derivative is quaternary ammonium salt chitosan, and the ionic crosslinking agent is a mixture of tannic acid and phytic acid in a mass ratio of 1:1; The solvent is an aqueous solution of tranexamic acid, and the chitosan derivative has a molecular weight of 200,000.

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