A gastrointestinal hemostatic granule and a preparation method thereof

Abstract

The present application provides a kind of digestive tract hemostatic granules and its preparation method, the component of the digestive tract hemostatic granules includes hemostatic agent and excipient;The hemostatic agent includes polyacrylic acid, polyethylene imine and polyoxyethylene;The mass ratio of polyacrylic acid, polyethylene imine and polyoxyethylene is 1:(1-2):(0.04-1).The hemostatic granule has excellent endoscopic catheter delivery performance, can quickly absorb a large amount of water in situ to form hydrogel after spraying on the bleeding wound, adhere to the tissue surface to form a physical barrier, realize instant hemostasis, at the same time, the hydrogel formed in situ has excellent adhesion stability and corrosion resistance, can ensure that the wound is still protected for 72 h after operation, reduce the risk of rebleeding.

Description

Technical Field

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

[0002] Gastrointestinal bleeding is a bleeding symptom caused by lesions in the esophagus, stomach, or duodenum. Severe cases can be life-threatening and are one of the common causes of death among gastroenterology patients. Gastrointestinal bleeding includes upper and lower gastrointestinal bleeding. Upper gastrointestinal bleeding includes esophageal bleeding, gastric bleeding, and duodenal bleeding, among which peptic ulcers account for 56.6%, gastric mucosal lesions for 13.6%, malignant tumors for 13.2%, and other causes for 16.6%, with peptic ulcers being the most common cause. Lower gastrointestinal bleeding includes bleeding caused by colon cancer, colon or rectal polyps, and anorectal diseases. In addition, iatrogenic upper gastrointestinal bleeding is increasing with the maturation of surgical procedures, such as bleeding caused by endoscopic mucosal resection, submucosal dissection, and polyp removal.

[0003] Traditional methods of hemostasis in gastrointestinal endoscopic surgery include electrocoagulation, ligation, arterial clamping, and submucosal injection of vasoconstrictors. However, due to the increase in patients with diabetes and those taking anticoagulants such as aspirin, and the advancement of endoscopic and related instrument technology, endoscopists are performing increasingly complex surgeries, and bleeding during and after minimally invasive procedures is becoming more common. Traditional hemostasis methods are no longer sufficient to meet clinical needs, necessitating the use of novel hemostatic materials to control large-area bleeding and prevent postoperative rebleeding.

[0004] Hemostatic powders offer a new treatment approach, requiring less learning time for medical staff, causing minimal trauma, reaching areas with complex anatomical structures, and being suitable for various types of gastrointestinal bleeding. Existing hemostatic powder products for gastrointestinal hemostasis include TC-325 from Cook Biotech (USA), EndoClot from Suzhou Andejia Biotechnology, and Nexpowder from Medtronic. These products have a high immediate hemostasis rate; however, they can cause catheter blockage when used with endoscopic catheters, have poor corrosion resistance, and insufficient adhesion stability to the gastrointestinal mucosa, easily leading to rebleeding.

[0005] Therefore, there is an urgent need to develop a digestive tract hemostatic granule that can be delivered via endoscopic catheter without causing blockage, can quickly adhere to the surface of mucosal tissue, and form a corrosion-resistant physical barrier. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide a digestive tract hemostatic granule and its preparation method. The digestive tract hemostatic granule provided by the present invention can be delivered through an endoscopic catheter without causing blockage, can stop bleeding immediately, is corrosion resistant, and significantly reduces the risk of postoperative rebleeding.

[0007] To achieve this objective, the present invention adopts the following technical solution:

[0008] In a first aspect, the present invention provides a digestive tract hemostatic granule, wherein the components of the digestive tract hemostatic granule include a hemostatic agent and an excipient; the hemostatic agent includes polyacrylic acid, polyethyleneimine and polyoxyethylene; the mass ratio of the polyacrylic acid, polyethyleneimine and polyoxyethylene is 1:(1-2):(0.04-1).

[0009] The specific point values ​​in (1-2) can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2, etc.

[0010] The specific point values ​​in (0.04-1) can be 0.04, 0.05, 0.06, 0.1, 0.2, 0.5, 0.8 or 1, etc.

[0011] The hemostatic granules for the digestive tract provided by this invention have a suitable particle size, and can be delivered through an endoscopic catheter without causing blockage. After being sprayed onto the bleeding wound of the digestive tract mucosa, they can quickly absorb a large amount of water and form an adhesive hydrogel through physical cross-linking effects such as strong electrostatic interaction and hydrogen bonding. This hydrogel adheres to the surface of the mucosal tissue, forming a physical barrier for immediate hemostasis. It has good adhesion stability and corrosion resistance, and can effectively protect the mucosal wound even 72 hours after the operation, avoiding erosion and damage from gastric juice, intestinal juice, bile, bacteria, etc., promoting mucosal repair and reducing the risk of postoperative rebleeding.

[0012] Polyacrylic acid (PAA) is an anionic polyelectrolyte with a large number of carboxyl groups, while polyethyleneimine (PEI) is a cationic polyelectrolyte with a large number of amino groups. PAA and PEI interact electrostatically, with their chain segments intertwining to form a polyelectrolyte complex. Polyoxyethylene (PEO) is a nonionic polymer that does not participate in electrostatic interactions, but it participates in constructing a three-dimensional gel network through hydrogen bonding and ionic coupling. Under strongly acidic conditions, PAA and PEI undergo protonation, leading to gel swelling and disintegration. However, due to the presence of ether-oxygen bonds in PEO, it can act as a hydrogen bond acceptor under strongly acidic conditions, crosslinking with the protonated PAA and PEI through hydrogen bonds, thereby improving the overall acid resistance of the gel.

[0013] The digestive tract hemostatic granules provided by this invention can quickly absorb water and form gels. The PAA-PEI-PEO gel forms strong electrostatic and hydrogen bond interactions with the tissue, and a topological network structure is formed between the long polymer chains, which has high adhesion stability and a maximum tissue burst pressure of up to 170 mmHg. The addition of polyoxyethylene to polyacrylic acid and polyethyleneimine greatly improves the toughness of the gel network, making the gel network less easily destroyed.

[0014] Preferably, the components of the digestive tract hemostatic granules, by weight, are 5-15 parts of hemostatic agent and 1-4 parts of excipient.

[0015] The hemostatic agent can be present in weight parts of 5, 5.2, 5.5, 5.7, 6, 6.3, 6.5, 6.8, 7, 8, 9, 10, 12, or 15 parts, etc.

[0016] The excipient can be expressed in parts by weight of 1, 1.1, 1.2, 1.5, 1.7, 2, 2.3, 2.5, 2.8, 3, 3.5, or 4 parts, etc.

[0017] Preferably, the weight-average molecular weight of the polyacrylic acid is 2,000-400,000 Da, for example, it can be 2,000 Da, 3,000 Da, 5,000 Da, 10,000 Da, 50,000 Da, 100,000 Da, 150,000 Da, 200,000 Da, 300,000 Da or 400,000 Da.

[0018] Preferably, the weight-average molecular weight of the polyethyleneimine is 1800-70000 Da, for example, it can be 1800 Da, 2000 Da, 5000 Da, 10000 Da, 15000 Da, 20000 Da, 30000 Da, 50000 Da or 70000 Da.

[0019] When the weight-average molecular weights of polyacrylic acid and polyethyleneimine are outside the aforementioned ranges, the adhesiveness of the materials is difficult to adapt to form a hydrogel. The weight-average molecular weights of polyacrylic acid and polyethyleneimine affect the adhesiveness and adhesion stability of the hemostatic particles, further affecting their immediate hemostatic performance and corrosion resistance. The strength of adhesion stability further affects the rebleeding rate.

[0020] The adhesiveness of hemostatic agents primarily originates from PEI and PAA. This adhesion arises from the electrostatic and hydrogen bonding interactions between the numerous amine and carboxyl groups on the molecular chain and the carboxyl and amino groups on the mucosal tissue. Increasing the molecular weight of PEI and PAA within a specific range enhances their adhesiveness and gelling properties. The adhesive stability of hemostatic agents stems from the entire PEI-PAA-PEO gel network, with PEI-PAA being the primary factor in maintaining adhesion. The gel's toughness and acid resistance arise from the addition of PEO. Under strong acid conditions, PEO can reverse the protonation of PEI-PAA, forming hydrogen-bonded complexes and thus improving acid resistance. The maintenance of adhesion and the enhancement of acid resistance contribute to the improved adhesive stability of the PEI-PAA-PEO network.

[0021] Both PEI and PAA cannot have low molecular weights, otherwise a hydrogel cannot be formed. If their molecular weights are too high, raw material costs will increase significantly, freeze-drying time will be prolonged, and the powder will be too tough, resulting in poor processing performance, decreased yield, and a substantial increase in processing costs. Within a specific range, higher molecular weights of PEI and PAA improve acid resistance, make the gel network less susceptible to damage, provide longer protection for the gastrointestinal mucosa, and promote better mucosal wound repair, thus effectively reducing the mucosal rebleeding rate. However, it is ultimately the addition of PEO that significantly improves adhesion stability and acid resistance.

[0022] Preferably, the viscosity-average molecular weight of the polyoxyethylene is 100,000-2,000,000 Da, for example, it can be 100,000 Da, 200,000 Da, 500,000 Da, 700,000 Da, 1,000,000 Da, 1,300,000 Da, 1,500,000 Da, 1,800,000 Da or 2,000,000 Da, etc.

[0023] Polyoxyethylene exhibits good hemostatic effects within the aforementioned viscosity-average molecular weight range, and its water absorption increases with increasing viscosity-average molecular weight.

[0024] The water absorption of hemostatic agents mainly originates from PEO. Increasing the proportion, molecular weight, and mass fraction of PEO in the formulation within a specific range will increase water absorption and gel toughness. The higher the molecular weight of PEO, the stronger the water absorption and the better the hemostatic effect. However, excessively high PEO molecular weight leads to poor processing performance of lyophilized PAA-PEI-PEO, increased swelling rate, and decreased adhesion. Conversely, excessively low PEO molecular weight results in PAA-PEI-PEO that is too brittle, has poor toughness, and decreased water absorption, ultimately leading to a decline in hemostatic performance.

[0025] Preferably, the excipient comprises any one or a combination of at least two of fillers, binders, or lubricants.

[0026] The filler is used to maintain the shape of the hemostatic particles, the binder is used to promote adhesion between the powders, and the lubricant is used to improve the flowability of the hemostatic particles.

[0027] When it does not contain fillers, adhesives, or lubricants, it can enter the digestive tract without the need for a catheter.

[0028] More preferably, the excipient is a binder, without fillers and lubricants, which facilitates the preparation of granules.

[0029] Preferably, the excipient comprises, by weight, any one or a combination of at least two of the following: 0.75-3.65 parts of filler, 0.2-0.5 parts of binder, or 0.05-0.15 parts of lubricant.

[0030] The filler can be present in the following weight proportions: 0.75 parts, 1 part, 1.2 parts, 1.5 parts, 1.7 parts, 2 parts, 2.3 parts, 2.5 parts, 2.8 parts, 3 parts, or 3.65 parts.

[0031] The adhesive can be present in parts by weight of 0.2, 0.22, 0.25, 0.27, 0.3, 0.33, 0.35, 0.38, 0.4, 0.45, or 0.5 parts, etc.

[0032] The weight percentage of the lubricant can be 0.05 parts, 0.06 parts, 0.07 parts, 0.08 parts, 0.09 parts, 0.1 parts, 0.11 parts, 0.12 parts, 0.13 parts, 0.14 parts, or 0.15 parts, etc.

[0033] Preferably, the filler comprises any one or a combination of at least two of the following: microcrystalline cellulose, mannitol, hydroxypropyl cellulose phthalate, sucrose, low-substituted hydroxypropyl cellulose, polyacrylic acid resin, triethyl citrate, triacetin, sorbitol, gum arabic, calcium silicate, lactose, or dextrose.

[0034] The main function of the filler is to maintain the particle shape, make the particles fuller, and improve the delivery performance of the hemostatic particles through the endoscopic catheter (reduce the amount of particles retained in the catheter). Within the specified range, the type and dosage of the filler do not affect the performance of the hemostatic particles.

[0035] Preferably, the adhesive comprises any one or a combination of at least two of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, or vinyl acetate copolymer.

[0036] The main function of the adhesive is to bind all the powder together to form particles with a certain strength and density. Within the specified range, the type and dosage of the adhesive do not affect the performance of the hemostatic particles.

[0037] Preferably, the lubricant comprises any one or a combination of at least two of calcium stearate, magnesium stearate, zinc stearate, stearic acid, or talc.

[0038] The lubricant is mainly used to improve the delivery performance of hemostatic particles through endoscopic catheters, including increasing the delivery success rate and reducing the amount of particles retained in the catheter. The lubricant does not affect the performance of the hemostatic particles.

[0039] Preferably, the lubricant comprises calcium stearate and / or magnesium stearate.

[0040] Calcium stearate and magnesium stearate are safer as lubricants in medical materials and pharmaceutical granulation.

[0041] Preferably, the components of the digestive tract hemostatic granules also include a colorant.

[0042] The purpose of the colorant is to improve visibility, making it easier for doctors to observe when spraying particles during endoscopic surgery.

[0043] Preferably, the components of the digestive tract hemostatic granules further include 0.01-2.5 parts by weight of colorant.

[0044] The colorant can be expressed in parts by weight of 0.01, 0.02, 0.05, 0.07, 0.1, 0.13, 0.15, 0.18, 0.2, 0.3, 0.5, 1, 1.5, 2, or 2.5 parts.

[0045] As the colorant content increases, the color development effect gradually improves.

[0046] Preferably, the colorant includes any one of brilliant blue, sorghum red, curcumin, or bilberry red.

[0047] Preferably, the gelation time of the hemostatic granules is less than 5 seconds, for example, it can be 1 second, 2 seconds, 3 seconds or 4 seconds.

[0048] Preferably, the water absorption ratio of the hemostatic granules is greater than 5 times, for example, it can be 1 times, 2 times, 3 times, 4 times, etc.

[0049] Preferably, the maximum tissue burst pressure of the hemostatic granules is greater than 120 mmHg, for example, it can be 125 mmHg, 130 mmHg, 140 mmHg, 150 mmHg, 160 mmHg, 170 mmHg or 180 mmHg, etc.

[0050] Preferably, the degradation rate of the hemostatic particles in PBS buffer, intestinal fluid or gastric fluid is less than 30%, for example, it can be 1%, 2%, 5%, 8%, 10%, 15%, 20%, 25% or 29%, etc.

[0051] Preferably, the shedding time of the hemostatic granules is not less than 72 hours, for example, it can be 72 hours, 74 hours, 76 hours, 78 hours, 80 hours or 90 hours.

[0052] Secondly, the present invention provides a method for preparing a hemostatic agent, the method comprising:

[0053] A mixture of aqueous polyacrylic acid, aqueous polyethyleneimine and aqueous polyoxyethylene forms a hydrogel, which is then freeze-dried to obtain a hemostatic agent (Method 1).

[0054] Alternatively, an aqueous solution of polyacrylic acid and an aqueous solution of polyethyleneimine can be mixed to form a hydrogel, which is then freeze-dried and mixed with polyethylene oxide to obtain a hemostatic agent (Method 2).

[0055] Alternatively, the aqueous solutions of polyethyleneimine and polyoxyethylene are mixed with the aqueous solution of polyacrylic acid to form two hydrogels, which are then freeze-dried and mixed to obtain a hemostatic agent (Method 3).

[0056] When polyethylene oxide (PEO) is directly mixed with PAA-PEI lyophilized gel in a non-aqueous form, there is no pre-crosslinking process, and it directly participates in the gelation of the subsequent hemostasis process. When PEO is pre-crosslinked in an aqueous solution, the PEO molecular chains run throughout the entire gel, resulting in better hemostatic properties compared to the non-aqueous form. Furthermore, hemostatic particles prepared by directly mixing PEO in an aqueous solution with aqueous polyacrylic acid and polyethyleneimine solutions exhibit better hemostatic properties than those prepared by first mixing PEO with an aqueous polyacrylic acid solution and then mixing it with PAA-PEI lyophilized gel.

[0057] Preferably, the mass fraction of the polyacrylic acid aqueous solution is 5-20 wt%, for example, it can be 5 wt%, 5.2 wt%, 5.5 wt%, 5.7 wt%, 6 wt%, 6.3 wt%, 6.5 wt%, 6.8 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, or 20 wt%.

[0058] Preferably, the mass fraction of the polyethyleneimine aqueous solution is 5-20 wt%, for example, it can be 5 wt%, 5.2 wt%, 5.5 wt%, 5.7 wt%, 6 wt%, 6.3 wt%, 6.5 wt%, 6.8 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, or 20 wt%.

[0059] Preferably, the mass fraction of the polyoxyethylene aqueous solution is 1-5 wt%, for example, it can be 1 wt%, 1.2 wt%, 1.5 wt%, 1.7 wt%, 2 wt%, 2.3 wt%, 2.5 wt%, 2.8 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, or 5 wt%.

[0060] The polyoxyethylene aqueous solution exhibits good hemostatic effect when the mass fraction is within the above-mentioned range.

[0061] Preferably, the volume ratio of the polyacrylic acid aqueous solution to the polyethyleneimine aqueous solution is 1:(0.5-1).

[0062] The specific point values ​​in (0.5-1) can be 0.5, 0.6, 0.7, 0.8, 0.9 or 1, etc.

[0063] Preferably, the volume ratio of the polyacrylic acid aqueous solution to the polyethyleneimine aqueous solution is 1:1.

[0064] Preferably, the volume ratio of the polyacrylic acid aqueous solution to the polyoxyethylene aqueous solution is 1:(0.1-1).

[0065] The specific point values ​​in (0.1-1) can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1, etc.

[0066] The proportion of polyoxyethylene added affects the adhesiveness and adhesion stability of hemostatic particles, which in turn affects immediate hemostatic performance and corrosion resistance. The strength of adhesion stability further affects the rebleeding rate.

[0067] Adding appropriate amounts of PEO can improve adhesion stability (mainly by improving acid resistance) without significantly affecting adhesion. However, excessive PEO addition can lead to a significant decrease in adhesion and adhesion stability.

[0068] Preferably, in method 1, the volume ratio of the polyacrylic acid aqueous solution to the polyoxyethylene aqueous solution is 1:(0.1-0.8).

[0069] The specific point values ​​in (0.1-0.8) can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8, etc.

[0070] Preferably, in method 3, the volume ratio of the polyacrylic acid aqueous solution to the polyoxyethylene aqueous solution is 1:(0.5-1).

[0071] The specific point values ​​in (0.5-1) can be 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95 or 0.1, etc.

[0072] Preferably, the hydrogel formed by mixing the polyacrylic acid aqueous solution and the polyethyleneimine aqueous solution, after freeze-drying, has a mass ratio of (0.5-1.5):(0.5-1.5) to polyoxyethylene.

[0073] The specific point values ​​in the first (0.5-1.5) can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5, etc.

[0074] The specific point values ​​in the second (0.5-1.5) can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5, etc.

[0075] Preferably, the hydrogel formed by mixing the aqueous solutions of polyacrylic acid and polyethyleneimine has a mass ratio of 1:1 with polyoxyethylene after freeze-drying.

[0076] Preferably, the two hydrogels formed by mixing the polyethyleneimine aqueous solution and the polyoxyethylene aqueous solution with the polyacrylic acid aqueous solution are mixed in a mass ratio of (0.5-1.5):(0.5-1.5) after freeze-drying.

[0077] The specific point values ​​in the first (0.5-1.5) can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5, etc.

[0078] The specific point values ​​in the second (0.5-1.5) can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5, etc.

[0079] Preferably, the two hydrogels formed by mixing the polyethyleneimine aqueous solution and the polyoxyethylene aqueous solution with the polyacrylic acid aqueous solution are mixed in a mass ratio of 1:1 after freeze-drying.

[0080] Preferably, the method for preparing the hemostatic agent in method 1 includes:

[0081] An aqueous solution of polyoxyethylene and an aqueous solution of polyethyleneimine are added sequentially to an aqueous solution of polyacrylic acid, mixed to form a hydrogel, and then freeze-dried to obtain a hemostatic agent (Method 4).

[0082] Alternatively, polyethyleneimine aqueous solution and polyoxyethylene aqueous solution are added sequentially, mixed to form a hydrogel, and then freeze-dried to obtain a hemostatic agent (method 5).

[0083] Alternatively, an aqueous solution of polyacrylic acid and an aqueous solution of polyethyleneimine can be mixed, and then an aqueous solution of polyoxyethylene can be added to form a hydrogel. After lyophilization, a hemostatic agent can be obtained (Method 6).

[0084] Method 4: Although there are hydrogen bonds between PAA and PEO, they are very weak. Pre-mixing PAA and PEO solutions can break the chain entanglement of PEO to a certain extent, playing a role in "dilution" and pre-dispersion. Then, PEI solution is added, which is equivalent to adding a crosslinking agent to the pre-mixed PAA-PEO system. PEI can quickly interact with PAA-PEO through strong electrostatic, hydrogen bond and ionic dipole interactions to form a uniform gel composite network.

[0085] Method 5: Due to the strong hydrogen bonds and ionic dipole interactions between PEI and PEO, the addition of PAA will cause local gel formation, leading to phase separation and affecting the freeze-drying of the sample.

[0086] Method 6: Since the PEI solution and PAA solution will quickly form a gel after contact, PEO will not be able to penetrate and disperse into the PEI-PAA gel network, affecting the uniformity of the sample.

[0087] In this invention, methods 4, 5, and 6 can all produce hemostatic agents, with method 4 being the preferred method.

[0088] Preferably, the freeze-drying time is 24-48 h, for example, it can be 24 h, 25 h, 26 h, 27 h, 28 h, 29 h, 30 h, 35 h, 40 h, 45 h or 48 h.

[0089] The higher the mass fraction of the polyacrylic acid aqueous solution, polyethyleneimine aqueous solution, and polyoxyethylene aqueous solution, the longer the freeze-drying time.

[0090] Thirdly, the present invention provides a method for preparing the digestive tract hemostatic granules as described in the first aspect, the method comprising: mixing a hemostatic agent, an excipient and an organic solution, granulating, and obtaining the digestive tract hemostatic granules.

[0091] Preferably, the method includes: mixing an organic solution containing a binder with a hemostatic agent and a filler to form wet granules, drying them to obtain dry granules, and then mixing them with a lubricant to obtain the digestive tract hemostatic granules.

[0092] Preferably, the hemostatic agent further includes a pulverizing step before mixing.

[0093] Preferably, the solvent of the organic solution includes any one or a combination of at least two of glycerol, acetone, isopropanol, formic acid, glacial acetic acid, or methanol.

[0094] Preferably, the adhesive has a mass percentage content of 1-20 wt% in the organic solution, for example, it can be 1 wt%, 1.2 wt%, 1.5 wt%, 1.7 wt%, 2 wt%, 2.3 wt%, 2.5 wt%, 2.8 wt%, 3 wt%, 5 wt%, 8 wt%, 10 wt%, 15 wt%, or 20 wt%.

[0095] Preferably, the organic solution also includes a colorant.

[0096] Preferably, the colorant has a mass percentage content of 0-0.5 wt% in the organic solution, for example, it can be 0 wt%, 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.05 wt%, 0.08 wt%, 0.1 wt%, 0.12 wt%, 0.15 wt%, 0.17 wt%, 0.2 wt%, 0.25 wt%, 0.3 wt%, 0.4 wt%, or 0.5 wt%, etc.

[0097] Preferably, the drying temperature is 40-60℃, for example, 40℃, 42℃, 45℃, 47℃, 50℃, 53℃, 55℃, 58℃ or 60℃; the drying time is 20-40 min, for example, 20 min, 22 min, 25 min, 27 min, 30 min, 33 min, 35 min, 38 min or 40 min, etc.

[0098] Within the above parameter range, wet particles can be dried completely; otherwise, they cannot be dried thoroughly or the integrity of the particles will be damaged.

[0099] Preferably, the drying process further includes a sieving step.

[0100] Preferably, the particle size of the dry particles is 50-400 μm, for example, it can be 50 μm, 52 μm, 55 μm, 57 μm, 60 μm, 63 μm, 65 μm, 68 μm, 70 μm, 100 μm, 150 μm, 200 μm, 300 μm or 400 μm, etc.

[0101] When the particle size of dry particles is outside the above range, the delivery performance through the endoscopic catheter will deteriorate.

[0102] Preferably, the process of mixing with the lubricant further includes a sterilization step.

[0103] Preferably, the sterilization method includes irradiation sterilization and / or ethylene oxide sterilization.

[0104] Preferably, the irradiation sterilization includes electron beam sterilization and gamma-ray sterilization.

[0105] Compared to irradiation sterilization, ethylene oxide sterilization has less impact on the performance of hemostatic granules. Compared to electron beam sterilization, gamma-ray sterilization has less impact on the performance of hemostatic granules.

[0106] Compared with the prior art, the present invention has the following beneficial effects:

[0107] The digestive tract hemostatic granules provided by this invention have a suitable particle size, and can be delivered through an endoscopic catheter without causing blockage. After being sprayed onto the bleeding wound of the digestive tract mucosa, they can quickly absorb a large amount of water and form an adhesive hydrogel through physical cross-linking effects such as strong electrostatic interaction and hydrogen bonding. This hydrogel adheres to the surface of the mucosal tissue, forming a physical barrier for immediate hemostasis. Even 72 hours after the operation, it can still effectively protect the mucosal wound, preventing it from being eroded and damaged by gastric juice, intestinal juice, bile, bacteria, etc., promoting mucosal repair, and reducing the risk of postoperative rebleeding. Attached Figure Description

[0108] Figure 1An optical microscope image of the digestive tract hemostatic granules provided in Example 1. Detailed Implementation

[0109] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0110] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0111] The sources of materials used in the following specific embodiments are as follows:

[0112] Polyvinylpyrrolidone is sourced from Shanghai Titan Technology Co., Ltd.; microcrystalline cellulose is sourced from Merck Biotech, Inc.; hydroxypropyl cellulose phthalate is sourced from Merck Biotech, Inc.

[0113] Example 1

[0114] This embodiment provides a digestive tract hemostatic granule, the preparation method of which is as follows:

[0115] (1) Preparation of hemostatic agent: 10 wt% aqueous solution of polyacrylic acid (PAA weight average molecular weight 240,000 Da), 10 wt% aqueous solution of polyethyleneimine (PEI weight average molecular weight 50,000 Da) and 2.5 wt% aqueous solution of polyoxyethylene (PEO viscosity average molecular weight 400,000 Da) were mixed and shaken at a volume ratio of 1:1:0.4 (PAA was added first, then PEO, then PEI), and a hydrogel (PAA-PEI-PEO) was rapidly formed. After freezing in liquid nitrogen for 20 min, it was freeze-dried in a freeze dryer for 36 h, and then thoroughly ground into a fine powder for later use.

[0116] (2) Add 10 g of the hemostatic agent prepared in step (1), 0.8 g of microcrystalline cellulose, 0.3 g of mannitol, 0.2 g of hydroxypropyl cellulose phthalate, and 0.4 g of sucrose to 4 g of an ethanol solution containing 10 wt% polyvinylpyrrolidone and 1 wt% brilliant blue. Stir until the mixture can be formed into a ball when squeezed by hand but can be easily broken apart when pressed with fingers, forming a soft material. Then, pass the soft material through a 24-mesh sieve to make wet granules. Dry at 50℃ for 30 min, and then sieve through 45-mesh and 300-mesh sieves to obtain dry granules with a particle size of 50-400 μm. Add 0.1 g of calcium stearate and mix evenly. Sterilize with ethylene oxide to obtain the digestive tract hemostatic granules. The optical microscope image is shown below. Figure 1 As shown.

[0117] Example 2

[0118] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), "add PAA first, then PEO, then PEI" is replaced with "add PEI first, then add PEO, then add PAA", while the other raw materials and steps remain unchanged.

[0119] Because of the strong hydrogen bonds and ionic dipole interactions between PEI and PEO, the addition of PAA will cause local gel formation and phase separation, making it impossible to completely freeze-dry the sample.

[0120] Example 3

[0121] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), "add PAA first, then PEO, then PEI" is replaced with "add PEI first, then add PAA, then add PEO", while the other raw materials and steps remain unchanged.

[0122] Because the PEI solution and PAA solution form a gel quickly upon contact, PEO cannot penetrate and disperse into the PEI-PAA gel network, resulting in uneven freeze-dried samples.

[0123] Example 4

[0124] This embodiment provides a digestive tract hemostatic granule, the preparation method of which is as follows:

[0125] (1) Preparation of hemostatic agent: 10 wt% aqueous solution of polyacrylic acid (PAA weight average molecular weight 240,000 Da) and 10 wt% aqueous solution of polyethyleneimine (PEI weight average molecular weight 50,000 Da) were mixed and shaken at a volume ratio of 1:1 to rapidly form a hydrogel (PAA-PEI). After freezing in liquid nitrogen for 20 min, it was freeze-dried in a freeze dryer for 36 h. Then it was mixed with an equal mass of polyoxyethylene (PEO viscosity average molecular weight 400,000 Da) and ground into a fine powder for later use.

[0126] (2) Add 10 g of the hemostatic agent prepared in step (1), 0.8 g of microcrystalline cellulose, 0.3 g of mannitol, 0.2 g of hydroxypropyl cellulose phthalate, and 0.4 g of sucrose to 4 g of an ethanol solution containing 10 wt% polyvinylpyrrolidone and 1 wt% brilliant blue. Stir until the mixture can be formed into a ball when squeezed by hand but can be easily broken apart when pressed with fingers, forming a soft material. Then, pass the soft material through a 24-mesh sieve to make wet granules. Dry at 50℃ for 30 min, and then sieve through 45-mesh and 300-mesh sieves to obtain dry granules with a particle size of 50-400 μm. Add 0.1 g of calcium stearate and mix well. Sterilize with ethylene oxide to obtain the digestive tract hemostatic granules.

[0127] Example 5

[0128] This embodiment provides a digestive tract hemostatic granule, the preparation method of which is as follows:

[0129] (1) Preparation of hemostatic agents: 10 wt% aqueous solution of polyacrylic acid (PAA weight average molecular weight 240,000 Da) and 10 wt% aqueous solution of polyethyleneimine (PEI weight average molecular weight 50,000 Da) were mixed and shaken at a volume ratio of 1:1 to rapidly form a hydrogel (PAA-PEI); 2.5 wt% aqueous solution of polyacrylic acid (PAA weight average molecular weight 250,000 Da) and 10 wt% aqueous solution of polyoxyethylene (PEO viscosity average molecular weight 400,000 Da) were mixed and shaken at a volume ratio of 1:1 to rapidly form a hydrogel (PAA-PEO). The two hydrogels were frozen in liquid nitrogen for 20 min, then freeze-dried for 36 h, and then mixed by equal mass and ground into a fine powder for later use.

[0130] (2) Add 10 g of the hemostatic agent prepared in step (1), 0.8 g of microcrystalline cellulose, 0.3 g of mannitol, 0.2 g of hydroxypropyl cellulose phthalate, and 0.4 g of sucrose to 4 g of an ethanol solution containing 10 wt% polyvinylpyrrolidone and 1 wt% brilliant blue. Stir until the mixture can be formed into a ball when squeezed by hand but can be easily broken apart when pressed with fingers, forming a soft material. Then, pass the soft material through a 24-mesh sieve to make wet granules. Dry at 50℃ for 30 min, and then sieve through 45-mesh and 300-mesh sieves to obtain dry granules with a particle size of 50-400 μm. Add 0.1 g of calcium stearate and mix well. Sterilize with ethylene oxide to obtain the digestive tract hemostatic granules.

[0131] Example 6

[0132] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity average molecular weight 400000 Da)” is replaced with an equal volume of “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity average molecular weight 2000000 Da)”, while the other raw materials and steps remain unchanged.

[0133] Example 7

[0134] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity average molecular weight 400000 Da)” is replaced with an equal volume of “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity average molecular weight 100000 Da)”, while the other raw materials and steps remain unchanged.

[0135] Example 8

[0136] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 400000 Da)” is replaced with an equal volume of “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 50000 Da)”, while the other raw materials and steps remain unchanged.

[0137] Example 9

[0138] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity average molecular weight 400000 Da)” is replaced with an equal volume of “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity average molecular weight 2500000 Da)”, while the other raw materials and steps remain unchanged.

[0139] Example 10

[0140] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 400000 Da)” is replaced with an equal volume of “1 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 400000 Da)”, while the other raw materials and steps remain unchanged.

[0141] Example 11

[0142] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 400000 Da)” is replaced with an equal volume of “5 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 400000 Da)”, while the other raw materials and steps remain unchanged.

[0143] Example 12

[0144] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity average molecular weight 400000 Da)” is replaced with an equal volume of “0.5 wt% polyoxyethylene aqueous solution (PEO viscosity average molecular weight 400000 Da)”, while the other raw materials and steps remain unchanged.

[0145] Example 13

[0146] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 400000 Da)” is replaced with an equal volume of “6 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 400000 Da)”, while the other raw materials and steps remain unchanged.

[0147] Example 14

[0148] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “volume ratio 1:1:0.2” is replaced with “volume ratio 1:1:1”, while the other raw materials and steps remain unchanged.

[0149] Example 15

[0150] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “volume ratio 1:1:0.2” is replaced with “volume ratio 1:1:1.5”, while the other raw materials and steps remain unchanged.

[0151] Example 16

[0152] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “10 wt% polyacrylic acid aqueous solution (PAA weight average molecular weight 250000 Da)” is replaced with an equal volume of “10 wt% polyacrylic acid aqueous solution (PAA weight average molecular weight 2000 Da)”, while the other raw materials and steps remain unchanged.

[0153] Example 17

[0154] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “10 wt% polyacrylic acid aqueous solution (PAA weight average molecular weight 250000 Da)” is replaced with an equal volume of “10 wt% polyacrylic acid aqueous solution (PAA weight average molecular weight 400000 Da)”, while the other raw materials and steps remain unchanged.

[0155] Example 18

[0156] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “10 wt% polyethyleneimine aqueous solution (PEI weight average molecular weight 50000 Da)” is replaced with an equal volume of “10 wt% polyethyleneimine aqueous solution (PEI weight average molecular weight 1800 Da)”, while the other raw materials and steps remain unchanged.

[0157] Example 19

[0158] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (1), “10 wt% polyethyleneimine aqueous solution (PEI weight average molecular weight 50000 Da)” is replaced with an equal volume of “10 wt% polyethyleneimine aqueous solution (PEI weight average molecular weight 70000 Da)”, while the other raw materials and steps remain unchanged.

[0159] Example 20

[0160] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (2), "0.1 g calcium stearate" is not added, while the other raw materials and steps remain unchanged.

[0161] Example 21

[0162] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (2), "passing through 45 mesh and 300 mesh sieves to obtain dry granules with a particle size of 50-400 μm" is replaced with "passing through 35 mesh and 45 mesh sieves to obtain dry granules with a particle size of 400-500 μm", while the other raw materials and steps remain unchanged.

[0163] Example 22

[0164] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (2), "passing through 45 mesh and 300 mesh sieves to obtain dry granules with a particle size of 50-400 μm" is replaced with "passing through 300 mesh and 800 mesh sieves to obtain dry granules with a particle size of 22-50 μm", while the other raw materials and steps remain unchanged.

[0165] Example 23

[0166] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (2), "sterilized by ethylene oxide" is replaced by "sterilized by electron beam irradiation", while the other raw materials and steps remain unchanged.

[0167] Example 24

[0168] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (2), "sterilized by ethylene oxide" is replaced by "sterilized by γ-ray irradiation", while the other raw materials and steps remain unchanged.

[0169] Example 25

[0170] This embodiment provides a digestive tract hemostatic granule, which differs from Embodiment 1 only in that: in step (2), "0.8 g microcrystalline cellulose, 0.3 g mannitol, 0.2 g hydroxypropyl cellulose phthalate and 0.4 g sucrose" are not added, and the other raw materials and steps remain unchanged.

[0171] Comparative Example 1

[0172] This comparative example provides a digestive tract hemostatic granule, which differs from Example 1 only in that: in step (1), 2.5 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 400,000 Da) was not added, and 10 wt% polyacrylic acid aqueous solution (PAA weight-average molecular weight 240,000 Da) and 10 wt% polyethyleneimine aqueous solution (PEI weight-average molecular weight 50,000 Da) were directly mixed and shaken at a volume ratio of 1:1 to rapidly form a hydrogel (PAA-PEI). After freezing in liquid nitrogen for 20 min, it was freeze-dried in a freeze dryer for 36 h, and then thoroughly ground into a fine powder for later use. All other raw materials and steps remained unchanged.

[0173] Comparative Example 2

[0174] This comparative example provides a commercially available hemostatic granule (Suzhou Andejia Biotechnology Co., Ltd. Endclot). TM The adhesive hemostatic particles (AHP) in the intraoperative hemostatic device have a main hemostatic component of medical-grade polyoxyethylene with a viscosity-average molecular weight of 1 million.

[0175] Comparative Example 3

[0176] This comparative example provides a digestive tract hemostatic granule, which differs from Example 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity-average molecular weight 400000 Da)” is replaced with an equal volume of “2.5 wt% chitosan aqueous solution (chitosan viscosity-average molecular weight 400000 Da)”, while the other raw materials and steps remain unchanged.

[0177] Comparative Example 4

[0178] This comparative example provides a digestive tract hemostatic granule, which differs from Example 1 only in that: in step (1), “2.5 wt% polyoxyethylene aqueous solution (PEO viscosity average molecular weight 400000 Da)” is replaced with “zeolite (particle size 5 μm)” of the same mass as polyoxyethylene, and the other raw materials and steps remain unchanged.

[0179] Test Example 1

[0180] Weigh 0.3 g of the hemostatic granules provided in Examples 1, 4-15, 23-24, and Comparative Examples 1-4, respectively, and record it as m1. Add 10 mL of PBS solution to each group, record the gelation time, and weigh the hydrogel, recording it as m2. Each group has 3 parallel samples, and the final data is the average value. The water absorption ratio is calculated as (m2-m1) / m1.

[0181] The test results are shown in Table 1. The hemostatic granules provided by this invention can quickly absorb a large amount of water to form a hydrogel, ensuring immediate hemostatic performance in practical applications. The gelation time is less than 5 seconds, and the water absorption ratio is greater than 6 times. The test results of Example 1 and Comparative Example 1 show that PAA-PEI has good gelation properties but poor water absorption. The addition of PEO greatly improves its water absorption performance without affecting gelation properties. As can be seen from the test results of Examples 1, 4, and 5, the hemostatic granules prepared by Method 1 have the same gelation time as those prepared by Methods 2 and 3, but a larger water absorption ratio. As can be seen from Examples 6-9, at the same mass fraction, the higher the molecular weight of PEO, the better the water absorption performance, but the gelation time will increase. As can be seen from Examples 10-13, the higher the mass fraction of PEO aqueous solution in the preparation of the hemostatic agent, the stronger the water absorption performance, but the gelation performance decreases. As can be seen from Examples 14-15, the higher the proportion of PEO added, the higher the water absorption ratio, but the gelation time will increase. As shown in Examples 1, 23, and 24, different sterilization processes have no effect on gelation properties. Ethylene oxide sterilization has the least impact on the water absorption of hemostatic particles, followed by γ-irradiation sterilization, while electron beam sterilization has the greatest impact on the water absorption of hemostatic particles.

[0182] Table 1

[0183]

[0184] Test Example 2

[0185] Take pig large intestines (using the same pig large intestine of consistent size and specifications from the same batch of experiments, regardless of age) soaked in PBS solution at 37°C. Wrap the large intestine around the cut end of a syringe and secure it with a rubber band. Connect a three-way valve, with a digital differential pressure gauge and an injection device connected to the other two sides of the valve, filling the entire device with PBS solution. Create a 3 mm defect in the center of the pig large intestine using a scalpel, then spray 0.1 g of the hemostatic particles provided in Examples 1, 4-5, 14-19, 23-24, and Comparative Examples 1-4 to seal the defect. After 5 minutes, inject PBS solution into the sealing device at a rate of 2 mL / min using a syringe pump. The pressure at which the PBS solution flows out of the large intestine defect is considered the maximum tissue burst pressure, which reflects the adhesiveness of the hemostatic particles. Each sample was tested three times, and the final test results were averaged.

[0186] The test results are shown in Table 2. Normal systolic blood pressure in the human body is 90-140 mmHg, diastolic blood pressure is 60-90 mmHg, and mean arterial pressure is 70-105 mmHg. The maximum tissue burst pressure of the hemostatic particles provided by this invention is greater than 120 mmHg, reaching a maximum of 170 mmHg, which is 1.6 times the maximum mean arterial pressure and 1.5 times the burst pressure of commercially available PEO hemostatic particles. This indicates that the hemostatic particles provided by this invention have a strong adhesive effect on mucosal tissue. This is due to the large number of carboxyl, amino, and ether oxygen bonds between PAA-PEI-PEO hydrogels and between PAA-PEI-PEO hydrogels and tissues, forming a topological network structure between long polymer chains through strong electrostatic interactions and hydrogen bonding interactions. The addition of PEO greatly improves the toughness of the hydrogel network, preventing it from being easily destroyed. Chitosan or inorganic materials, compared to PEO, have a slightly less effective effect on improving the toughness of the hydrogel. Examples 1 and 4-5 show that the preparation method of the hemostatic granules affects the adhesion; the hemostatic granules prepared according to method 1 have the strongest adhesion. Examples 14-15 show that the higher the proportion of PEO added, the worse the adhesion. Examples 16-19 show that the higher the molecular weight of PAA and PEI, the stronger the adhesion. Examples 1, 23, and 24 show that different sterilization processes affect the adhesion of the hemostatic granules; irradiation sterilization has a greater impact on the adhesion of the hemostatic granules.

[0187] Table 2

[0188]

[0189] Test Example 3

[0190] Weigh 0.3 g of the hemostatic granules provided in Examples 1, 4-19, 23-24, and Comparative Examples 1-4, respectively, and record as m1. After gelling with PBS solution, soak the samples in 10 mL of PBS solution, artificial intestinal fluid, and artificial gastric fluid, respectively. Replace the soaking solution with fresh solution every 24 h. After 72 h, freeze-dry the samples and weigh them, recording as m2. Calculate the degradation rate: Degradation rate (%) = (m1-m2) / m1. Set up 3 parallel samples for each group, and take the average value of the final data.

[0191] The test results are shown in Table 3. The hemostatic particles provided by this invention exhibit excellent corrosion resistance. The adhesive hydrogel formed by spraying them onto mucosal tissue can protect the mucosa from erosion and damage by digestive juices and microorganisms for 72 hours, with a degradation rate of less than 30%. Comparative Examples 1-4 show that commercially available PEO hemostatic particles have a high degradation rate in PBS solution, artificial intestinal fluid, and artificial gastric fluid. However, the gel formed by adding PEO to PAA-PEI significantly reduces the degradation rate in all soaking solutions, demonstrating a significant improvement in corrosion resistance compared to chitosan or inorganic materials. We hypothesize that the mechanism of action is as follows: under gastric acid conditions, the electrostatic interaction between PAA and PEI is weakened, while the ether oxygen bond (-O-) on the PEO chain can act as a hydrogen bond acceptor, forming a new, dense hydrogen bond cross-linking network with protonated PAA (-COOH) and PEI (-NH3+). This dynamically generated hydrogen bond under acidic conditions effectively compensates for and stabilizes the potentially damaged gel network, thus achieving excellent acid resistance. Examples 1 and 4-5 show that the preparation method of the hemostatic granules affects corrosion resistance; the hemostatic granules prepared according to method 1 have the best corrosion resistance. Examples 6-13 show that the lower the mass fraction and molecular weight of PEO, the worse the corrosion resistance. Examples 14-15 show that the higher the proportion of PEO added, the worse the corrosion resistance. Examples 16-19 show that the higher the molecular weight of PAA and PEI, the better the corrosion resistance. Examples 1, 23, and 24 show that different sterilization processes affect corrosion resistance; ethylene oxide sterilization has the least impact on the corrosion resistance of the hemostatic granules.

[0192] Table 3

[0193]

[0194] Test Example 4

[0195] Weigh 0.3 g of the hemostatic granules provided in Examples 1, 4-5, 14-19, 23-24, and Comparative Examples 1-4 respectively, and record it as m1. Spray it onto the wet porcine gastric tissue. After gelation, soak it in artificial gastric fluid and place it on a shaker. Observe the adhesion of the hydrogel to the tissue after 72 h. Remove the still-adhering gel, freeze-dry it, weigh the residual gel, and record it as m2. Calculate the gel retention rate: gel retention rate (%) = m2 / m1.

[0196] The longer the gel adheres to the mucosa, the longer its protective effect on the mucosa, thus preventing rebleeding. The test results are shown in Table 4. The hemostatic granules provided in Examples 1, 4-5, 14-19, and 23-24, soaked in artificial gastric fluid, retained a large amount of gel on the porcine gastric mucosa for 72 hours, with a gel retention rate greater than 70%, demonstrating high adhesion stability. In contrast, the commercially available PEO hemostatic granules, PAA-PEI granules, and chitosan or inorganic material-doped PAA-PEI granules in Comparative Example 2 showed complete gel detachment within 72 hours, indicating poor adhesion stability.

[0197] Table 4

[0198]

[0199] Test Example 5

[0200] The delivery performance of hemostatic granules was tested using a 15 psi delivery pump and air as the gas, through a PTFE or PP delivery catheter with an inner diameter of 2.2 mm, an outer diameter of 2.6 mm, and a length of 2.2 m.

[0201] Weigh 5 g of the hemostatic granules provided in Examples 1, 4-5, 20-22, 25, and Comparative Example 2, respectively, and record it as m1. After spraying through a catheter, weigh the collected product mass and record it as m2. Observe whether blockage occurs during delivery and whether there are granule residues in the catheter. Calculate the delivery residue amount: Delivery residue amount (%) = (m1-m2) / m1. Set up 5 parallel samples in each group, and take the average value of the final data.

[0202] The test results are shown in Table 5. The gastrointestinal hemostatic granules provided by this invention have excellent delivery performance, ensuring no particulate matter residue in the catheter, and preventing blockage during endoscopic catheter delivery, with a delivery success rate of 100%. Comparative Example 2 shows that commercially available PEO hemostatic granules have poor catheter delivery performance. Example 20 shows that not adding lubricant reduces catheter delivery performance. Examples 21-22 show that hemostatic granules larger than 400 μm or smaller than 50 μm can cause catheter blockage. Example 25 shows that not adding filler reduces delivery performance.

[0203] Table 5

[0204]

[0205] Test Example 6

[0206] New Zealand rabbits (male to female ratio 1:1) were anesthetized with amobarbital solution and placed supine on the operating table. Hemorrhage was induced 5 cm from the ear tip using a 23-G needle to construct an ear artery hemorrhage model. The stomach was exposed through an abdominal incision, the left gastric artery was located, and hemorrhage was induced in the left gastric artery using a 23-G needle to construct a gastric artery hemorrhage model.

[0207] After inducing bleeding, the hemostatic granules provided in Examples 1, 4-19, 23-24, or Comparative Examples 1-4 were quickly sprayed onto the wound surface. The hemostasis was observed. If there was still oozing, more granules were applied until there was no more oozing on the surface of the hemostatic material. The hemostasis time was recorded. If there was still oozing after two consecutive applications, the hemostasis failed. Six parallel tests were conducted in each group, and the final data were the average value.

[0208] The test results are shown in Table 6. The digestive tract hemostatic granules provided by this invention have excellent immediate hemostatic performance and a short hemostatic time. As shown in Comparative Examples 1-4, the gel formed by adding PEO to PAA-PEI can significantly accelerate hemostasis compared to chitosan or inorganic materials. As shown in Examples 1 and 4-5, the preparation method of the hemostatic agent affects the immediate hemostatic performance, and the hemostatic granules prepared in Example 1 have the best immediate hemostatic performance. As shown in Examples 6-9, the higher the molecular weight of PEO, the better its water absorption and the better its immediate hemostatic performance. As shown in Examples 10-13, the higher the mass fraction of PEO solution, the stronger its water absorption, but the lower its adhesion. The gel adhering to the mucosa is easily washed away, resulting in a decrease in the final immediate hemostatic performance. As shown in Examples 14-15, the proportion of PEO added affects the immediate hemostatic performance. Too high a proportion of PEO leads to decreased adhesion, poorer sealing hemostasis ability, and increased immediate hemostatic time. Examples 16-19 show that the higher the molecular weight of PAA and PEI, the better the immediate hemostatic effect. Examples 1 and 23-24 show that the sterilization method affects the immediate hemostatic effect, and hemostatic particles sterilized with ethylene oxide have the best hemostatic performance.

[0209] Table 6

[0210]

[0211] This invention illustrates a digestive tract hemostatic granule and its preparation method through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of this invention.

[0212] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0213] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A gastric hemostatic granule, characterized in that, By weight, the gastric hemostatic granules comprise 5-15 parts of a hemostatic agent and 1-4 parts of an excipient; the hemostatic agent comprises polyacrylic acid, polyethyleneimine, and polyethylene oxide; the mass ratio of the polyacrylic acid, polyethyleneimine, and polyethylene oxide is 1:(1-2):(0.04-1); the weight-average molecular weight of the polyacrylic acid is 2000-400000 Da; the weight-average molecular weight of the polyethyleneimine is 1800-70000 Da; and the viscosity-average molecular weight of the polyethylene oxide is 400000-2000000 Da. The hemostatic agent is prepared by a method comprising the following steps: sequentially adding an aqueous solution of polyoxyethylene and an aqueous solution of polyethyleneimine to an aqueous solution of polyacrylic acid, mixing to form a hydrogel, and lyophilizing to obtain the hemostatic agent; the mass fraction of the aqueous solution of polyoxyethylene is 1-5 wt%. The gastric hemostatic granules have a water absorption ratio of more than 5 times, a maximum tissue burst pressure of more than 120 mmHg, a degradation rate of less than 30% after soaking in artificial gastric fluid for 72 hours, and a gel retention rate of more than 70% on porcine gastric mucosa after soaking in artificial gastric fluid for 72 hours.

2. The gastric hemostatic granules according to claim 1, characterized in that, The excipients include any one or a combination of at least two of fillers, binders or lubricants; The filler is used to maintain the shape of the hemostatic particles, the binder is used to promote adhesion between the powders, and the lubricant is used to improve the flowability of the hemostatic particles.

3. The gastric hemostatic granules according to claim 1, characterized in that, The excipient comprises, by weight, any one or a combination of at least two of the following: 0.75-3.65 parts of filler, 0.2-0.5 parts of binder, or 0.05-0.15 parts of lubricant.

4. The gastric hemostatic granules according to claim 2, characterized in that, The filler includes any one or a combination of at least two of the following: microcrystalline cellulose, mannitol, hydroxypropyl cellulose phthalate, sucrose, low-substituted hydroxypropyl cellulose, polyacrylic acid resin, triethyl citrate, triacetin, sorbitol, gum arabic, calcium silicate, lactose, or dextrose. The adhesive comprises any one or a combination of at least two of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, or vinyl acetate copolymer; The lubricant includes any one or a combination of at least two of calcium stearate, magnesium stearate, zinc stearate, stearic acid, or talc.

5. The gastric hemostatic granules according to claim 1, characterized in that, The components of the gastric hemostatic granules also include coloring agents; The colorant includes any one of brilliant blue, sorghum red, curcumin, or bilberry red.

6. The gastric hemostatic granules according to claim 1, characterized in that, The mass fraction of the polyacrylic acid aqueous solution is 5-20 wt%. The mass fraction of the polyethyleneimine aqueous solution is 5-20 wt%.

7. The gastric hemostatic granules according to claim 1, characterized in that, The volume ratio of the polyacrylic acid aqueous solution to the polyethyleneimine aqueous solution is 1:(0.5-1).

8. The gastric hemostatic granules according to claim 1, characterized in that, The volume ratio of the polyacrylic acid aqueous solution to the polyoxyethylene aqueous solution is 1:(0.1-1).

9. The method for preparing gastric hemostatic granules according to any one of claims 1-8, characterized in that, The method includes: The hemostatic agent, excipient, and organic solution are mixed and granulated to obtain the gastric hemostatic granules.

10. The method according to claim 9, characterized in that, The method includes: An organic solution containing a binder is mixed with a hemostatic agent and a filler to form wet granules, which are then dried to obtain dry granules. These dry granules are then mixed with a lubricant to obtain the gastric hemostatic granules.

11. The method according to claim 10, characterized in that, The hemostatic agent further includes a pulverizing step before mixing; The solvent of the organic solution includes any one or a combination of at least two of ethanol, glycerol, acetone, isopropanol, formic acid, glacial acetic acid, or methanol. The adhesive has a mass percentage of 1-20 wt% in the organic solution. The organic solution also includes the addition of a colorant; The colorant has a mass percentage content of 0-0.5 wt% in the organic solution. The drying temperature is 40-60℃, and the time is 20-40 min; The drying process also includes a sieving step; The particle size of the dry particles is 50-400 μm.

Images