Composite hemostatic patch as well as preparation method and application thereof

Abstract

The invention discloses a composite hemostasis patch and a preparation method and application thereof.The hemostasis patch comprises a backing layer, a hemostasis layer and a breathable protective layer, the hemostasis layer is a hydrophilic gel complex and is prepared from 20-50 parts of a cationic hemostasis high polymer material, 10-30 parts of anionic polysaccharide, 5-15 parts of a biocompatible cross-linking agent and 5-20 parts of a seepage absorption enhancing material, and the breathable protective layer is a breathable protective layer. The average pore size is 50-300 microns, and the porosity is greater than 85%. Through the electrostatic synergistic effect of cation and anion materials, rapid hemostasis within 32-45 seconds is achieved, the seepage absorption amount reaches 12.8-19.5 g / g, skin irritation is avoided, and wound healing can be effectively promoted through the porosity of 86-92%. The problems that a traditional hemostatic material is low in efficiency, poor in biocompatibility and insufficient in adaptability to complex wounds are solved, and the hemostatic material is suitable for scenes such as surgical operations and wound first aid and has important clinical application value.

Description

Technical Field

[0001] This invention relates to the field of medical hemostatic materials technology, and particularly to composite hemostatic patches, their preparation methods, and applications. Background Technology

[0002] Trauma hemostasis is a crucial aspect of clinical emergency care and surgery. In clinical surgery, trauma emergency care, and chronic wound management, rapidly and effectively controlling wound bleeding and exudation is a key step in preventing infection and promoting healing. Traditional hemostatic materials such as gauze and cotton pads mainly rely on physical pressure and absorption, which have limited hemostatic effect and are prone to adhering to newly formed granulation tissue, causing secondary damage during replacement.

[0003] In recent years, advanced hemostatic dressings based on polymer materials have been extensively studied. For example, some sponges or films made of materials such as chitosan and gelatin have certain hemostatic and healing-promoting functions. However, existing technologies still have some shortcomings: First, traditional hydrophilic materials are prone to blood leakage during massive arterial bleeding, and the hemostasis time generally exceeds 60 seconds; second, biocompatibility is insufficient, such as zeolite materials which may cause tissue burning sensation, and collagen products which pose an immune reaction risk; third, purely physical absorbent dressings are not fast enough to stop bleeding from arteries or veins and cannot adhere firmly to moist wounds; fourth, the pore size and porosity of the materials have not achieved optimal synergy with hemostasis, absorption, and breathability.

[0004] Therefore, it is of great significance to develop a composite hemostatic material that combines rapid hemostasis, high absorption efficiency, good biocompatibility, healing promotion, and ease of preparation. Summary of the Invention

[0005] In view of this, the present invention proposes a composite hemostatic patch, its preparation method and application, to solve the above problems.

[0006] The technical solution of the present invention is implemented as follows: the composite hemostatic patch includes a backing layer, a hemostatic layer and a breathable protective layer stacked in sequence. The hemostatic layer is a hydrophilic gel composite. The hydrophilic gel composite is made of raw materials including the following parts by weight: 20-50 parts of cationic hemostatic polymer, 10-30 parts of anionic polysaccharide, 5-15 parts of biocompatible crosslinking agent and 5-20 parts of exudate absorption enhancing material. The average pore size of the hydrophilic gel composite is 50-300 μm and the porosity is greater than 85%.

[0007] Furthermore, the cationic hemostatic polymer is at least one of chitosan derivatives and ε-polylysine; the anionic polysaccharide is at least one of sodium alginate, sodium hyaluronate, and sodium carboxymethyl cellulose.

[0008] Furthermore, the chitosan derivative is carboxymethyl chitosan, quaternary ammonium chitosan, or chitosan hydrochloride.

[0009] Furthermore, the biocompatible crosslinking agent is a complex of genipin, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), or oxidized dextran.

[0010] Furthermore, the permeation absorption enhancement material is porous silica microspheres, microcrystalline cellulose, or starch-grafted acrylate superabsorbent resin, with a particle size range of 10-150 μm.

[0011] More specifically, the starch-grafted acrylate superabsorbent resin is prepared by dispersing starch in deionized water and gelatinizing it in a water bath at 60-75°C for 20-40 minutes under inert gas protection to obtain a gelatinized starch solution; cooling the gelatinized starch solution to 40-55°C, adding acrylic acid and crosslinking agent N,N'-methylenebisacrylamide sequentially, stirring evenly, and then adding potassium persulfate or ammonium persulfate as an initiator, reacting at 40-55°C for 1-3 hours to obtain a reaction product; precipitating, washing, drying, pulverizing, and sieving the reaction product to obtain the starch-grafted acrylate superabsorbent resin; wherein the dry weight ratio of acrylic acid to starch is 4-8:1, and the mass of the crosslinking agent is 0.05-0.3% of the mass of acrylic acid.

[0012] Furthermore, the backing layer is a medical nonwoven fabric with a thickness of 0.08-0.15 mm, and the medical nonwoven fabric is hydrophilically treated with a surface contact angle ≤30°; the breathable protective layer is a modified polyurethane membrane, and the surface of the polyurethane membrane is provided with microporous pores with a pore size of 1-5 μm and an air permeability of 500-800 g / (m³). 2 •24h).

[0013] This invention also provides a method for preparing a composite hemostatic patch, comprising the following steps:

[0014] S1. Dissolve the cationic hemostatic polymer in an aqueous acetic acid solution with a volume concentration of 0.5-2% to obtain solution A; disperse the anionic polysaccharide and the exudate absorption enhancement material in deionized water to obtain dispersion B;

[0015] S2. Under stirring conditions, solution A and dispersion B are mixed, and a biocompatible crosslinking agent is added. After the reaction is complete, a prepolymer slurry is obtained.

[0016] S3. The prepolymer slurry is coated onto the backing layer, and after being frozen at low temperature, it is freeze-dried to form the hemostatic layer;

[0017] S4. The breathable protective layer is applied to the surface of the dried hemostatic layer, and after cutting and sterilization, the composite hemostatic patch is obtained.

[0018] Further, in step S1, the mass-to-volume ratio of the cationic hemostatic polymer material and the acetic acid aqueous solution is 1g:(20-100)mL; the total weight of the anionic polysaccharide and the exudate absorption enhancement material, to the volume of the deionized water used, is 1g:(10-50)mL; in step S2, the mixing temperature is 4-15℃, and the reaction time is 30-90 minutes; in step S3, the low-temperature freezing temperature is -20℃ to -50℃, and the freezing time is 2-6 hours; the freeze-drying cold trap temperature is below -50℃, and the drying time is 24-48 hours.

[0019] The present invention also provides the application of the composite hemostatic patch for hemostasis of surgical wounds and trauma emergency wounds.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] In this invention, the cationic material in the hemostatic layer neutralizes and aggregates with negatively charged components in the blood, such as red blood cells and platelets. The anionic polysaccharide forms a stable network under the action of a cross-linking agent, which can quickly absorb water in the blood and concentrate clotting factors, achieving a dual synergy of physical and chemical hemostasis. It is especially suitable for bleeding wounds. When combined with exudate absorption-enhancing materials, it gives the hemostatic patch extremely high absorption capacity and water-locking ability, which can quickly absorb wound exudate, keep the wound moderately moist, and avoid maceration.

[0022] The raw materials selected for this invention are all biocompatible natural or synthetic polymers, and their degradation products are safe. The porous structure facilitates oxygen exchange and cell migration, while the moist environment promotes epithelial growth and accelerates wound healing. The hydrophilic backing layer is easy to apply, and the modified polyurethane protective layer is breathable and antibacterial. The gel formed after the hemostatic layer absorbs water does not stick to the wound surface, making replacement painless and reducing damage to newly formed tissue.

[0023] This invention optimizes the raw material ratio, solvent ratio, mixing reaction conditions, and freeze-drying process to stably prepare three-dimensional porous structures with specified pore sizes and porosities, ensuring batch-to-batch consistency and excellent overall performance. Detailed Implementation

[0024] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0025] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0026] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0027] Example 1

[0028] 1. Raw material ratio (parts by weight)

[0029] 20 parts of cationic hemostatic polymer: carboxymethyl chitosan;

[0030] 10 parts of anionic polysaccharide: sodium alginate;

[0031] 5 parts of biocompatible cross-linking agent: Genipin;

[0032] Five parts of permeation absorption enhancement material: porous silica microspheres (10-150μm);

[0033] Backing layer: Medical non-woven fabric (thickness 0.08mm, contact angle 25°);

[0034] Breathable protective layer: Modified polyurethane membrane (pore size 1μm, air permeability 500g / (m²)) 2 ·24h).

[0035] Example 2

[0036] 1. Raw material ratio (parts by weight)

[0037] 50 parts of cationic hemostatic polymer: carboxymethyl chitosan;

[0038] 30 parts of anionic polysaccharide: sodium alginate;

[0039] 15 parts of biocompatible cross-linking agent: Genipin;

[0040] 20 parts of permeation absorption enhancement material: microcrystalline cellulose (150μm);

[0041] Backing layer: Medical non-woven fabric (thickness 0.15mm, contact angle 28°);

[0042] Breathable protective layer: Modified polyurethane membrane (pore size 5μm, air permeability 800g / (m²)) 2 ·24h).

[0043] Example 3

[0044] 1. Raw material ratio (parts by weight)

[0045] 30 parts of cationic hemostatic polymer: carboxymethyl chitosan;

[0046] 20 parts of anionic polysaccharide: sodium alginate;

[0047] 10 parts of biocompatible cross-linking agent: Genipin;

[0048] 15 parts of permeation absorption enhancement material: starch-grafted acrylate superabsorbent resin (100μm).

[0049] Backing layer: Medical non-woven fabric (thickness 0.10mm, contact angle 25°);

[0050] Breathable protective layer: Modified polyurethane membrane (pore size 3μm, air permeability 700g / (m²)) 2 ·24h).

[0051] 2. Preparation of starch-grafted acrylate superabsorbent resin:

[0052] Specifically, starch is dispersed in deionized water and gelatinized in a 70°C water bath for 30 minutes under inert gas protection to obtain a gelatinized starch solution. The gelatinized starch solution is then cooled to 50°C, and acrylic acid and crosslinking agent N,N'-methylenebisacrylamide are added sequentially. After stirring evenly, potassium persulfate or ammonium persulfate initiator is added, and the mixture is reacted at 50°C for 2 hours to obtain a reaction product. The reaction product is then precipitated, washed, dried, pulverized, and sieved to obtain the starch-grafted acrylate superabsorbent resin. The dry weight ratio of acrylic acid to starch is 6:1, and the mass of the crosslinking agent is 0.2% of the mass of acrylic acid.

[0053] The above Examples 1-3 were prepared using the following methods:

[0054] S1. Dissolve the cationic hemostatic polymer in a 1% (v / v) acetic acid aqueous solution, with a mass-to-volume ratio of 1g:50mL, to obtain solution A; disperse the anionic polysaccharide and exudate absorption enhancing material in deionized water, with a total weight ratio of the anionic polysaccharide and exudate absorption enhancing material to the volume of the deionized water used being 1g:30mL, to obtain dispersion B;

[0055] S2. Under stirring conditions, solution A and dispersion B are mixed and reacted at 10°C for 60 minutes, and a biocompatible crosslinking agent is added. After the reaction is complete, a prepolymer slurry is obtained.

[0056] S3. The prepolymer slurry is coated onto the backing layer, frozen at -30°C for 4 hours, and then dried at a cold trap temperature of -50°C and a vacuum degree of 20Pa for 36 hours to form the hemostatic layer.

[0057] S4. The breathable protective layer is applied to the surface of the dried hemostatic layer, and after cutting and sterilization, the composite hemostatic patch is obtained.

[0058] Comparative Example 1

[0059] The difference between this comparative example and Example 3 is that the hemostatic layer material does not contain anionic polysaccharides, but only uses cationic hemostatic polymers and biocompatible cross-linking agents.

[0060] Comparative Example 2

[0061] The difference between this comparative example and Example 3 is that commercially available sodium polyacrylate superabsorbent polymer (SAP) particles are used instead of the starch-grafted acrylate superabsorbent polymer prepared according to the specific method of this invention.

[0062] Comparative Example 3

[0063] The difference between this comparative example and Example 3 is that the hemostatic layer material does not contain exudate absorption enhancement material.

[0064] I. Performance Testing

[0065] The present invention conducts performance tests on the composite hemostatic patches prepared in Examples 1-3 and Comparative Examples 1-3. The specific test methods and results are as follows:

[0066] 1. Hemostatic performance test (rabbit ear artery hemorrhage model)

[0067] Laboratory animals: Healthy New Zealand white rabbits (weighing 2.0-2.5 kg, half male and half female), used after 3 days of acclimatization feeding;

[0068] Operating steps:

[0069] (1) White rabbits were anesthetized by intravenous injection of sodium pentobarbital (3%, 50mg / kg) in the ear margin. After fixation, the hair within 2cm of the ear tip was cut off to expose the central auricular artery.

[0070] (2) Cut the artery horizontally with surgical scissors (1mm incision length). After the blood flows out naturally for 3 seconds, immediately cover the wound with the hemostatic patch to be tested and press lightly with sterile gauze (0.5kg pressure).

[0071] (3) Record the time from when the bandage is applied to when there is no obvious bleeding from the wound for 30 seconds. Five rabbits were tested in each group, and the average value was taken.

[0072] 2. Water absorption rate test

[0073] Simulated exudate preparation: physiological saline and 1% bovine serum albumin (simulating wound exudate components), pH=7.4;

[0074] Operating steps:

[0075] (1) Take the hemostatic layer of the patch to be tested (cut into 2cm×2cm, remove the backing layer and protective layer), and accurately weigh the initial mass (W0).

[0076] (2) Immerse the sample completely in simulated permeate at a constant temperature of 37°C and let it stand for 24 hours;

[0077] (3) Take out the sample, use sterile filter paper to absorb the seepage on the surface, and accurately weigh the mass after saturation and water absorption (W1).

[0078] (4) The amount of permeate absorbed (g / g) = (W1-W0) / W0. Three parallel samples were tested in each group, and the average value was taken.

[0079]

[0080] 3. Porosity testing

[0081] Operating steps:

[0082] (1) Take a hemostatic layer sample, freeze it with liquid nitrogen and then fracture it to expose the cross section, and then spray it with gold (coating thickness 5nm).

[0083] (2) Observe the cross-sectional morphology using SEM (accelerating voltage 10kV, magnification 500x), and randomly select 5 different fields of view to take images;

[0084] (3) Use ImageJ software to calculate the proportion of pore area in each field of view to the total field of view area. Porosity = average of the proportions of the 5 fields of view.

[0085] 4. Skin irritation test (rat skin sensitization test)

[0086] Experimental animals: SPF grade SD rats (weight 180-220g), with hair removed from their backs (hair removal area 5cm×5cm), and used after 24 hours of recovery;

[0087] Operating steps:

[0088] (1) Cut the hemostatic patch to be tested into 2cm×2cm, apply it to the hairless area of ​​the rat, and fix it with medical tape. The blank control group was covered with sterile gauze.

[0089] (2) Remove the sample after 24 hours and observe the skin reaction (redness, swelling, erythema, papules, ulcers) at 1 hour, 24 hours and 48 hours after removal.

[0090] (3) Graded according to the grading standard: Grade 0 (no reaction), Grade 1 (mild erythema), Grade 2 (obvious erythema, mild edema), Grade 3 (severe erythema, edema, papules), Grade 4 (ulcer).

[0091] 5. Wound healing time test (rat dorsal full-thickness skin defect model);

[0092] Experimental animals: SPF grade SD rats (weighing 200-250g), with a 1cm×1cm full-thickness skin defect (deep to the fascia layer) prepared after hair removal on the back.

[0093] Operating steps:

[0094] (1) The hemostatic patch to be tested was placed on the wound and fixed with sterile gauze. The blank control group was only bandaged with gauze.

[0095] (2) Observe the wound healing status (amount of exudate, scab formation, degree of epithelialization) every day, and take photos every 3 days.

[0096] (3) Record the time when the wound is completely epithelialized (no exposed wound, scab falls off). Six rats were tested in each group, and the average value was taken.

[0097]

[0098] Conclusion: The composite hemostatic patches of Examples 1-3 of the present invention exhibit excellent performance in terms of hemostasis speed, exudate absorption, structural stability, biocompatibility, and wound healing promotion. Among them, Example 3 has the best performance and can meet the high-strength requirements of surgical procedures, trauma emergency care, and other scenarios.

[0099] Compared with Comparative Example 1, the lack of electrostatic synergistic effect of anionic polysaccharides weakens the ability of blood cells to aggregate, makes it difficult for coagulation factors to accumulate rapidly, and results in a loose gel network formed by a single cationic material with insufficient water absorption capacity and water retention stability. Anionic-cationic electrostatic cross-linking is the core of gel network stability, and its absence makes the structure prone to breakage. Due to slow hemostasis and insufficient exudate absorption, the wound microenvironment deteriorates, and the repair efficiency is reduced.

[0100] Compared with Comparative Example 2, it is shown that ordinary SAP lacks the hydrophilic groups and cross-linking structure of starch grafting, and its water absorption rate and saturation capacity are lower than those of the self-made resin. Ordinary SAP has poor biocompatibility, and some rats showed mild erythema on their skin (which subsided within 48 hours), while the self-made starch grafted resin is a natural polymer derivative and is non-irritating. Insufficient absorption efficiency leads to moist adhesion of the wound surface, and mild irritation affects the repair process.

[0101] Compared with Comparative Example 3, no exudate absorption enhancement material was used, and the wound relied solely on the gel matrix itself for water absorption. Lacking a dedicated exudate absorption unit, it could not cope with a large amount of bleeding wounds. Exudate remained on the wound surface, hindering the interaction between clotting factors and blood cells, and prolonging the time for thrombosis. Exudate adhesion led to an increased risk of wound infection, slowed epithelialization, and prolonged healing time.

[0102] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A composite hemostatic patch, characterized in that, The product comprises the following raw materials: a backing layer, a hemostatic layer, and a breathable protective layer stacked sequentially. The hemostatic layer is a hydrophilic gel composite, which is made from the following raw materials in parts by weight: 20-50 parts of cationic hemostatic polymer, 10-30 parts of anionic polysaccharide, 5-15 parts of biocompatible crosslinking agent, and 5-20 parts of exudate absorption enhancing material. The average pore size of the hydrophilic gel composite is 50-300 μm, and the porosity is greater than 85%.

2. The composite hemostatic patch as described in claim 1, characterized in that, The cationic hemostatic polymer is at least one of chitosan derivatives and ε-polylysine; the anionic polysaccharide is at least one of sodium alginate, sodium hyaluronate, and sodium carboxymethyl cellulose.

3. The composite hemostatic patch as described in claim 1, characterized in that, The chitosan derivative is carboxymethyl chitosan, quaternary ammonium chitosan, or chitosan hydrochloride.

4. The composite hemostatic patch as described in claim 1, characterized in that, The biocompatible crosslinking agent is a complex of genipin, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, or oxidized dextran.

5. The composite hemostatic patch as described in claim 1, characterized in that, The permeation absorption enhancement material is porous silica microspheres, microcrystalline cellulose, or starch-grafted acrylate superabsorbent resin, with a particle size range of 10-150 μm.

6. The composite hemostatic patch as described in claim 5, characterized in that, The starch-grafted acrylate superabsorbent resin is specifically prepared by dispersing starch in deionized water and gelatinizing it in a water bath at 60-75°C for 20-40 minutes under inert gas protection to obtain a gelatinized starch solution. The gelatinized starch solution is then cooled to 40-55°C, and acrylic acid and crosslinking agent N,N'-methylenebisacrylamide are added sequentially. After stirring until homogeneous, potassium persulfate or ammonium persulfate is added as an initiator. The reaction is carried out at 40-55°C for 1-3 hours to obtain a reaction product. The reaction product is then precipitated, washed, dried, pulverized, and sieved to obtain the starch-grafted acrylate superabsorbent resin. The dry weight ratio of acrylic acid to starch is 4-8:1, and the mass of the crosslinking agent is 0.05-0.3% of the mass of acrylic acid.

7. The composite hemostatic patch as described in claim 1, characterized in that, The backing layer is a medical nonwoven fabric with a thickness of 0.08-0.15 mm. This medical nonwoven fabric undergoes hydrophilic treatment, and its surface contact angle is ≤30°. The breathable protective layer is a modified polyurethane membrane. The surface of the polyurethane membrane has microporous pores with a pore size of 1-5 μm and an air permeability of 500-800 g / (m³). 2 •24h).

8. The method for preparing the composite hemostatic patch according to any one of claims 1-7, characterized in that, Includes the following steps: S1. Dissolve the cationic hemostatic polymer in an aqueous acetic acid solution with a volume concentration of 0.5-2% to obtain solution A; Anionic polysaccharide and permeation absorption enhancement material were dispersed in deionized water to obtain dispersion B; S2. Under stirring conditions, solution A and dispersion B are mixed, and a biocompatible crosslinking agent is added. After the reaction is complete, a prepolymer slurry is obtained. S3. The prepolymer slurry is coated onto the backing layer, and after being frozen at low temperature, it is freeze-dried to form the hemostatic layer; S4. The breathable protective layer is applied to the surface of the dried hemostatic layer, and after cutting and sterilization, the composite hemostatic patch is obtained.

9. The method for preparing the composite hemostatic patch as described in claim 8, characterized in that, In step S1, the mass-to-volume ratio of the cationic hemostatic polymer and the acetic acid aqueous solution is 1g:(20-100)mL; the total weight of the anionic polysaccharide and the exudate absorption enhancement material, in proportion to the volume of the deionized water used, is 1g:(10-50)mL; in step S2, the mixing temperature is 4-15℃, and the reaction time is 30-90 minutes; in step S3, the low-temperature freezing temperature is -20℃ to -50℃, and the freezing time is 2-6 hours; the freeze-drying cold trap temperature is below -50℃, and the drying time is 24-48 hours.

10. An application of the composite hemostatic patch as described in any one of claims 1-7, characterized in that, The composite hemostatic patch is used for hemostasis of surgical wounds and traumatic emergency wounds.

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