A biodegradable absorbable hemostatic composition and uses thereof

Abstract

The application discloses a biodegradable absorbable hemostatic composition and application thereof, and belongs to the technical field of medical materials. The technical problems to be solved are that existing hemostatic materials have poor biocompatibility, can easily cause allergic reactions, have poor degradation and absorption performance, and have limited hemostatic effect. The technical solution points are that the hemostatic composition comprises, in terms of weight percentage, 0.03-10 parts of water-soluble polysaccharide and 90-99.97 parts of sodium carboxymethyl starch; the water-soluble polysaccharide is composed of sodium hyaluronate, sodium alginate, carboxymethyl chitosan and carboxymethyl cellulose with a mass ratio of 8-10:0-2:0-2:0-2; the molecular weight of the sodium carboxymethyl starch is 10 5 ‑10 6 , and the degree of substitution is 0.2-0.6%; the particle size of the hemostatic composition is 100-500 mu m, and the bulk density is 0.2-0.3 g / cm 3 .

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical materials, and provides a biodegradable and absorbable hemostatic composition and application thereof. BACKGROUND

[0002] For understanding the technical content of the present application:

[0003] After bleeding caused by trauma and surgery, if hemostasis is not performed in time, infection and trauma aggravation may be caused. At this time, hemostatic materials play an important role. For hemostatic materials, in addition to excellent hemostatic performance, good biocompatibility and degradability should also be possessed. Currently commonly used medical hemostatic materials include polysaccharide hemostatic materials such as cellulose, starch, etc., collagen hemostatic materials such as gelatin, etc., biological hemostatic materials such as thrombin, etc., and synthetic hemostatic materials such as polyethylene glycol, cyanoacrylate, etc. Different hemostatic materials have different hemostatic mechanisms. How to compound to achieve the best hemostatic effect is the research focus in the field.

[0004] Retrieved relevant non-patent literatures:

[0005] Journal name or book name: Journal of Surgical Research, document name: Study on the use of acellular porcine small intestinal submucosa powder for hemostasis of splenic partial resection wounds in rats, volume number: 30, publication date: December 2021. The document discloses that after defatting and decellularization treatment, the SIS acellular components are not left, and under a microscope, the SIS powder is in the form of a single layer of long and thin flakes. The water absorption rate of the SIS powder reaches saturation at 120s, which is 1.87 times that of the instant hemostatic powder, and the SIS powder is degradable in vivo, and has a wide application prospect.

[0006] Retrieved relevant patent literatures:

[0007] Publication country: China, publication number: CN117679552A, publication date: December 9, 2023. The document discloses a hemostatic sponge and a preparation method and application thereof. The preparation raw materials of the hemostatic sponge include a water-soluble polysaccharide solution and acellular small intestinal submucosa particles; the mass ratio of the acellular small intestinal submucosa particles to the water-soluble polysaccharide solution is (0.1-0.9):1. During use, the porous structure of the hemostatic sponge rapidly absorbs water in blood and tissue fluid, and then the polysaccharide component is dissolved into a viscous solution, which adheres to the wound surface for hemostasis; the growth factors in the acellular small intestinal submucosa particles promote wound healing, and the acellular small intestinal submucosa particles can maintain a triple helix structure, thereby causing platelets to coagulate, activate and release the particle components, accelerating the release of coagulation factors, and further promoting wound healing.

[0008] The prior art represented by the foregoing documents at least has the following unsolved technical problems or defects:

[0009] (1) SIS powder alone has limited effect, and the relevant evidence is that SIS is often used as a scaffold material to load other hemostatic materials, and its hemostatic effect and mechanism still need further study.

[0010] (2) The hemostatic effect of SIS particles and water-soluble polysaccharide solution is limited after compounding, and the relevant evidence is that although it has good adhesion (the viscous modulus is more than 40 GPa), the water absorption rate is insufficient (only about 30%), which limits the hemostatic and wound healing effect; at the same time, it is a sponge, and there is a certain inconvenience in use for uneven and irregular wounds. SUMMARY

[0011] The purpose of the present application is to provide:

[0012] A biodegradable and absorbable hemostatic composition and its application, and related technologies, to solve the technical problems or combinations of poor biocompatibility, easy to cause allergic reaction, poor degradation and absorption performance, and limited hemostatic effect of existing hemostatic materials.

[0013] Term explanation:

[0014] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise indicated, all patents, patent applications, publications, and other documents referenced herein are hereby incorporated by reference in their entirety. If there is a plurality of definitions for a term herein, those in this section prevail.

[0015] It should be understood that the above brief summary and the following detailed description are exemplary and are intended to explain, but not limit, the subject matter of the present application. In the present application, the singular also includes the plural unless otherwise specified. It should also be noted that "or" and "and / or" are used to mean "and / or" unless otherwise indicated. In addition, the terms "comprise", and other forms such as "comprises" and "comprising", are not limiting.

[0016] The definition of standard chemical terms can be found in the reference "Modern Medicine and Clinical Diagnosis and Treatment" edited by Guo Fang et al. Changchun: Jilin Science and Technology Press, 2021.07.

[0017] Unless otherwise specified, conventional methods within the scope of the art are used, such as wet granulation and other methods.

[0018] Unless otherwise specified, the use of various commercially available products used herein uses standard techniques. For example, the manufacturer's instructions for using the kit can be used, or the implementation can be carried out according to the way known in the art or the description of the present application. In general, the above-mentioned techniques and methods can be carried out according to the description in the multiple outline and more specific literature cited and discussed in this specification, according to the conventional methods well known in the art.

[0019] The term "optionally" or "optionally" means that the event or circumstance subsequently described can or can not occur, and the description includes the occurrence of the event or circumstance and the non-occurrence of the event or circumstance.

[0020] The term "water-soluble polysaccharide" used herein is a kind of heteropolysaccharide, also known as glycosaminoglycan or acidic polysaccharide. They are composed of two or more different monosaccharide molecules, usually containing uronic acid and amino hexose or its derivatives.

[0021] The term "sodium carboxymethyl starch" used herein, also known as carboxymethyl starch, is an anionic starch ether, a kind of modified starch, which belongs to ether starch and is a water-soluble anionic polymer compound. It has strong water absorption and swelling property and can swell quickly in cold water.

[0022] The term "decellularized small intestinal submucosa (SIS)" used herein refers to: derived from pig, cow, sheep, dog, etc. small intestine, especially pig small intestine, taking appropriate length of intestinal segment, and then decellularizing to obtain. It is mainly composed of type I and type III collagen components (>90%), and contains other trace amounts of extracellular matrix components such as fibronectin, hyaluronic acid, and cytokines (including FGF-2, TGF-β), etc. It has good mechanical properties, tissue compatibility and low immunogenicity, and is a commonly used natural scaffold material for tissue engineering research.

[0023] The term "molecular weight" used herein refers to: relative molecular mass, in the present application, unless otherwise specified, it is weight average molecular weight.

[0024] The term "degree of substitution" used herein refers to: the degree of substitution of carboxymethyl on the hydroxyl group of each D-glucopyranose unit in the starch molecule, that is, the average number of -CH2COONa-CH2COONa functional groups contained in each D-glucopyranose unit.

[0025] The term "%" used herein refers to mass (weight) percentage.

[0026] In a first aspect, the present application provides: a biodegradable absorbable hemostatic composition, the hemostatic composition comprises, by weight fraction: water-soluble polysaccharide 0.03-10 parts and sodium carboxymethyl starch 90-99.7 parts; the water-soluble polysaccharide is composed of sodium hyaluronate, sodium alginate, carboxymethyl chitosan and carboxymethyl cellulose in a mass ratio of 8-10:0-2:0-2:0-2;

[0027] The molecular weight of the sodium carboxymethyl starch is 10 5 -106 , the degree of substitution is 0.2-0.6%;

[0028] The particle size of the hemostatic composition is 100-500 μm, and the bulk density is 0.2-0.3 g / cm 3 .

[0029] Among them, the technical features include: the composition of the biodegradable absorbable hemostatic composition, the composition of the water-soluble polysaccharide, the molecular weight and the degree of substitution of sodium carboxymethyl starch, and the particle size and the bulk density of the hemostatic composition.

[0030] Among them, the technical features of the composition of the biodegradable absorbable hemostatic composition are selected from: the hemostatic composition comprises, by weight fraction: water-soluble polysaccharide 0.03-10 parts, sodium carboxymethyl starch 90-99.97 parts.

[0031] Among them, the technical features of the composition of the biodegradable absorbable hemostatic composition are preferably: the hemostatic composition comprises, by weight fraction: water-soluble polysaccharide 0.03-5 parts, sodium carboxymethyl starch 95-99.97 parts.

[0032] Among them, the technical features of the composition of the biodegradable absorbable hemostatic composition are further preferably: the hemostatic composition comprises, by weight fraction: water-soluble polysaccharide 1 part, sodium carboxymethyl starch 99 parts.

[0033] Among them, the technical features of the composition of the water-soluble polysaccharide are selected from: sodium hyaluronate, sodium alginate, carboxymethyl chitosan and carboxymethyl cellulose with a mass ratio of 8-10:0-2:0-2:0-2.

[0034] The technical feature water-soluble polysaccharide is preferably composed of sodium hyaluronate, sodium hyaluronate and sodium alginate with a mass ratio of 8-10:0.1-2, specifically, the mass ratio of sodium hyaluronate and sodium alginate includes but is not limited to 10:0.1, 9:0.1, 8:0.1, 10:0.5, 9:0.5, 8:0.5, 10:1, 9:1, 8:1, 5:1, 4.5:1 and 4:1; or sodium hyaluronate and carboxymethyl chitosan with a mass ratio of 8-10:0.1-2, specifically, the mass ratio of sodium hyaluronate and carboxymethyl chitosan includes but is not limited to 10:0.1, 9:0.1, 8:0.1, 10:0.5, 9:0.5, 8:0.5, 10:1, 9:1, 8:1, 5:1, 4.5:1 and 4:1; or sodium hyaluronate and carboxymethyl cellulose with a mass ratio of 8-10:0.1-2, specifically, the mass ratio of sodium hyaluronate and carboxymethyl cellulose includes but is not limited to 10:0.1, 9:0.1, 8:0.1, 10:0.5, 9:0.5, 8:0.5, 10:1, 9:1, 8:1, 5:1, 4.5:1 and 4:1; or sodium hyaluronate, sodium alginate and carboxymethyl chitosan with a mass ratio of 8-10:0.1-2:0.1-2, specifically, the mass ratio of sodium hyaluronate, sodium alginate and carboxymethyl chitosan includes but is not limited to 10:2:2, 10:1:2, 10:0.1:2, 10:2:1, 10:2:0.1, 10:1:1, 10:1:0.1, 10:0.1:1, 10:0.1:0.1, 9:2:2, 9:1:2, 9:0.1:2, 9:2:1, 9:2:0.1, 9:1:1, 9:1:0.1, 9:0.1:1, 9:0.1:0.1, 8:2:2, 8:1:2, 8:0.1:2, 8:2:1, 8:2:0.1, 8:1:1, 8:1:0.1, 8:0.1:1 and 8:0.1:0.1; or sodium hyaluronate, sodium alginate and carboxymethyl cellulose with a mass ratio of 8-10:0.1-2:0.1-2, specifically, the mass ratio of sodium hyaluronate, sodium alginate and carboxymethyl cellulose includes but is not limited to 10:2:2, 10:1:2, 10:0.1:2, 10:2:1, 10:2:0.1, 10:1:1, 10:1:0.1, 10:0.1:1, 10:0.1:0.1, 9:2:2, 9:1:2, 9:0.1:2, 9:2:1, 9:2:0.1, 9:1:1, 9:1:0.1, 9:0.1:1, 9:0.1:0.1, 8:2:2, 8:1:2, 8:0.1:2, 8:2:1, 8:2:0.1, 8:1:1, 8:1:0.1, 8:0.1:1 and 8:0.1:0.1.1-2 sodium hyaluronate, carboxymethyl chitosan and carboxymethyl cellulose, in particular, the mass ratio of sodium hyaluronate, carboxymethyl chitosan and carboxymethyl cellulose includes but is not limited to: 10:2:2, 10:1:2, 10:0.1:2, 10:2:1, 10:2:0.1, 10:1:1, 10:1:0.1, 10:0.1:1, 10:0.1:0.1, 9:2:2, 9:1:2, 9:0.1:2, 9:2:1, 9:2:0.1, 9:1:1, 9:1:0.1, 9:0.1:1, 9:0.1:0.1, 8:2:2, 8:1:2, 8:0.1:2, 8:2:1, 8:2:0.1, 8:1:1, 8:1:0.1, 8:0.1:1 and 8:0.1:0.1; or the mass ratio of sodium hyaluronate, sodium alginate, carboxymethyl chitosan and carboxymethyl cellulose is 8-10:0.1-2:0.1-2:0.1-2, in particular, the mass ratio of sodium hyaluronate, sodium alginate, carboxymethyl chitosan and carboxymethyl cellulose includes but is not limited to: 10:2:2:2, 10:1:2:2, 10:2:1:2, 10:2:2:1, 10:1:1:2, 10:1:2:1, 10:1:2:2, 10:1:1:1, 10:0.1:1:1, 10:1:0.1:1, 10:1:1:0.1, 10:0.1:0.1:1, 10:0.1:1:0.1, 10:1:0.1:0.1, 10:0.1:0.1:0.1, 9:2:2:2, 9:1:2:2, 9:2:1:2, 9:2:2:1, 9:1:1:2, 9:1:2:1, 9:1:2:2, 9:1:1:1, 9:0.1:1:1, 9:1:0.1:1, 9:1:1:0.1, 9:0.1:0.1:1, 9:0.1:1:0.1, 9:1:0.1:0.1, 9:0.1:0.1:0.1, 8:2:2:2, 8:1:2:2, 8:2:1:2, 8:2:2:1, 8:1:1:2, 8:1:2:1, 8:1:2:2, 8:1:1:1, 8:0.1:1:1, 8:1:0.1:1, 8:1:1:0.1, 8:0.1:0.1:1, 8:0.1:1:0.1, 8:1:0.1:0.1 and 8:0.1:0.1:0.1.

[0035] The technical feature of the water-soluble polysaccharide composition is further preferably sodium hyaluronate; or sodium hyaluronate, sodium alginate and carboxymethyl chitosan in a mass ratio of 8-10:1-2:1-2, specifically, the mass ratio of sodium hyaluronate, sodium alginate and carboxymethyl chitosan includes but is not limited to 10:2:2, 10:1:2, 10:2:1, 10:1:1, 10:1:0.1, 9:2:2, 9:1:2, 9:2:1, 9:1:1, 8:2:2, 8:1:2, 8:2:1 and 8:1:1; or sodium hyaluronate, carboxymethyl chitosan and carboxymethyl cellulose in a mass ratio of 8-10:1-2:1-2, specifically, the mass ratio of sodium hyaluronate, carboxymethyl chitosan and carboxymethyl cellulose includes but is not limited to 10:2:2, 10:1:2, 10:2:1, 10:1:1, 9:2:2, 9:1:2, 9:2:1, 9:1:1, 8:2:2, 8:1:2, 8:2:1 and 8:1:1.

[0036] The technical feature of the water-soluble polysaccharide composition is further preferably sodium hyaluronate; or sodium hyaluronate, sodium alginate and carboxymethyl chitosan in a mass ratio of 8-10:1-2:1-2, specifically, the mass ratio of sodium hyaluronate, sodium alginate and carboxymethyl chitosan includes but is not limited to 10:2:2, 10:1:2, 10:2:1, 10:1:1, 10:1:0.1, 9:2:2, 9:1:2, 9:2:1, 9:1:1, 8:2:2, 8:1:2, 8:2:1 and 8:1:1; or sodium hyaluronate, carboxymethyl chitosan and carboxymethyl cellulose in a mass ratio of 8-10:1-2:1-2, specifically, the mass ratio of sodium hyaluronate, carboxymethyl chitosan and carboxymethyl cellulose includes but is not limited to 10:2:2, 10:1:2, 10:2:1, 10:1:1, 9:2:2, 9:1:2, 9:2:1, 9:1:1, 8:2:2, 8:1:2, 8:2:1 and 8:1:1.

[0037] The technical feature of the decellularized small intestinal submucosa particles is selected from any one of decellularized pig small intestinal submucosa particles, decellularized cow small intestinal submucosa particles, decellularized sheep small intestinal submucosa particles and decellularized dog small intestinal submucosa particles.

[0038] The technical feature of the decellularized small intestinal submucosa particles is preferably any one of decellularized pig small intestinal submucosa particles, decellularized cow small intestinal submucosa particles, decellularized sheep small intestinal submucosa particles and decellularized dog small intestinal submucosa particles with a particle size of 30-50 μm (including but not limited to 30 μm, 35 μm, 40 μm, 45 μm and 50 μm).

[0039] The technical feature of the decellularized small intestinal submucosa particles is further preferably decellularized pig small intestinal submucosa particles with a particle size of 30-40 μm (including but not limited to 30 μm, 35 μm and 40 μm).

[0040] The technical feature of the decellularized small intestinal submucosa particles is further preferably decellularized pig small intestinal submucosa particles with a particle size of 35 μm.

[0041] The technical feature of the carboxymethyl starch sodium is selected from carboxymethyl starch sodium with a molecular weight of 10 5 -10 6 and a degree of substitution of 0.2-0.6%.

[0042] The technical feature of the carboxymethyl starch sodium is preferably: the carboxymethyl starch sodium has a molecular weight of 1 x 10 5 -5 x 10 5 , and a degree of substitution of 0.2-0.5%.

[0043] The technical feature of the carboxymethyl starch sodium is further preferably: the carboxymethyl starch sodium has a molecular weight of 5 x 10 5 , and a degree of substitution of 0.2-0.3%.

[0044] The technical feature of the carboxymethyl starch sodium is further preferably: the carboxymethyl starch sodium has a molecular weight of 5 x 10 5 , and a degree of substitution of 0.2%.

[0045] Based on further solving or simultaneously solving multiple technical problems of the technical problem of the present application, in the technical solution provided by the first aspect of the present application, the preferred solution comprises:

[0046] The first preferred solution: the water-soluble polysaccharide is sodium hyaluronate, sodium carboxymethyl chitosan and sodium alginate in a mass ratio of 8-10:1-2:1-2 or sodium hyaluronate, sodium carboxymethyl chitosan and carboxymethyl cellulose in a mass ratio of 8-10:1-2:1-2. This technical solution further solves the technical problem of "increasing the water absorption rate to more than 79%, increasing the viscous modulus to more than 42 Pa, simultaneously reducing the hemostatic time to within 16 s, and reducing the complete healing time to within 9 days" on the basis of solving the technical problem of "increasing the water absorption rate to more than 18%, increasing the viscous modulus to more than 40 Pa, simultaneously reducing the hemostatic time to within 42 s, and reducing the complete healing time to within 14 days".

[0047] The second preferred solution: the carboxymethyl starch sodium has a molecular weight of 1 x 10 5 -5 x 10 5 ; and a degree of substitution of 0.2-0.5%. This technical solution further solves the technical problem of "increasing the water absorption rate to more than 80%, increasing the viscous modulus to more than 42 Pa, simultaneously reducing the hemostatic time to within 15 s, and reducing the complete healing time to within 8.5 days" on the basis of solving the technical problem of "increasing the water absorption rate to more than 18%, increasing the viscous modulus to more than 40 Pa, simultaneously reducing the hemostatic time to within 42 s, and reducing the complete healing time to within 14 days".

[0048] The third preferred solution: the particle size of the hemostatic composition is 100-250 μm, and the bulk density is 0.3 g / cm 3The technical scheme solves the technical problems of increasing the water absorption rate to more than 18%, increasing the viscous modulus to more than 40 Pa, and simultaneously reducing the hemostatic time to within 42 s and the complete healing time to within 14 days.

[0049] The fourth preferred scheme: the hemostatic composition further comprises: decellularized small intestinal submucosa particles; the hemostatic composition comprises, in terms of weight fraction: 0.03-10 parts of water-soluble polysaccharide, 90-99.97 parts of sodium carboxymethyl starch, and 1-10 parts of decellularized small intestinal submucosa particles. The technical scheme solves the technical problems of increasing the water absorption rate to more than 80%, increasing the viscous modulus to more than 46 Pa, and simultaneously reducing the hemostatic time to within 16 s and the complete healing time to within 8.5 days on the basis of solving the technical problems of increasing the water absorption rate to more than 18%, increasing the viscous modulus to more than 40 Pa, and simultaneously reducing the hemostatic time to within 42 s and the complete healing time to within 14 days.

[0050] The fifth preferred scheme: the biodegradable absorbable hemostatic composition is prepared by the following method:

[0051] (1) Dissolve each component of the water-soluble polysaccharide in water to form a water-soluble polysaccharide solution;

[0052] (2) Mix the decellularized small intestinal submucosa particles and the sodium carboxymethyl starch to obtain a mixture, and spray the mixture into the water-soluble polysaccharide solution to perform wet granulation to obtain wet granules;

[0053] (3) Perform granulation, drying, and sterilization on the wet granules to obtain the biodegradable absorbable hemostatic composition.

[0054] Among them, the technical features include: water-soluble polysaccharide solution, wet granulation.

[0055] Among them, the technical feature of the water-soluble polysaccharide solution concentration is selected from: 0.5-3 wt%.

[0056] Among them, the technical feature of the water-soluble polysaccharide solution concentration is preferably: 0.5-2 wt%.

[0057] Among them, the technical feature of the water-soluble polysaccharide solution concentration is further preferably: 0.5-1 wt%.

[0058] Among them, the technical feature of the water-soluble polysaccharide solution concentration is still further preferably: 1 wt%.

[0059] Among them, the technical feature of the wet granulation process condition is selected from: the temperature of the mixture is 30-35℃; and the rotation speed of the peristaltic pump is 5-10 r / min.

[0060] The technical feature of the wet granulation process condition is preferably that the temperature of the mixed material is 32-35 DEG C, and the rotation speed of the peristaltic pump is 5-8r / min.

[0061] The technical feature of the wet granulation process condition is preferably that the temperature of the mixed material is 32-35 DEG C, and the rotation speed of the peristaltic pump is 5-8r / min.

[0062] The technical feature of the wet granulation process condition is preferably that the temperature of the mixed material is 32-35 DEG C, and the rotation speed of the peristaltic pump is 5-8r / min.

[0063] The technical feature of the wet granulation process condition is preferably that the temperature of the mixed material is 32-35 DEG C, and the rotation speed of the peristaltic pump is 5-8r / min.

[0064] In the second aspect, the application provides the use of the biodegradable absorbable hemostatic composition in the preparation of a medical hemostatic product.

[0065] The application has the following beneficial effects:

[0066] Compared with the prior art, the application has better technical effects in water absorption, adhesion, hemostatic time, complete healing time and the like.

[0067] According to experimental tests, the application increases the water absorption from less than 18% of the prior art to more than 79%.

[0068] According to experimental tests, the application increases the adhesion modulus from 40Pa of the prior art to more than 42Pa.

[0069] According to experimental tests, the application reduces the hemostatic time from more than 30s of the prior art to less than 16s.

[0070] According to experimental tests, the application reduces the complete healing time from more than 10 days of the prior art to less than 8.5 days. BRIEF DESCRIPTION OF DRAWINGS

[0071] Figure 1 The appearance photo of the hemostatic granules prepared in the embodiment 1 of the application;

[0072] Figure 2 The SEM appearance photo of the hemostatic granules prepared in the embodiment 1 of the application. DETAILED DESCRIPTION

[0073] In order to make the purposes, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are some of the embodiments of the present application but not all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0074] The present application will be further described below in the manner of specific examples. The various instruments, devices, equipment, reagents, products and the like used in the embodiments of the present application are obtained through conventional commercial channels unless otherwise specified.

[0075] The raw materials used in the embodiments of the present application are as follows:

[0076] Sodium hyaluronate is purchased from Huaxi Biotechnology Co., Ltd.;

[0077] Carboxymethyl chitosan is purchased from Chongqing Daqinghaid Technology Co., Ltd.;

[0078] Sodium alginate is purchased from Xi'an Jinxing Pharmaceutical Auxiliary Material Co., Ltd.;

[0079] Carboxymethyl cellulose is purchased from Xi'an Jinxing Pharmaceutical Auxiliary Material Co., Ltd.;

[0080] Sodium carboxymethyl starch is purchased from Anhui Shanhe Pharmaceutical Auxiliary Material Co., Ltd.

[0081] Preparation of decellularized porcine small intestinal submucosa (SIS) particles: According to the method described in the literature "Experimental Study on the Effect of Decellularization on Cell Residue and Growth Factor Content in Small Intestinal Submucosa" (Chen Wei, Li Cihui, Wu Shu, Xie Huiqi, Luo Jingcong (2010) Chinese Journal of Reparative and Reconstructive Surgery v.24(01):94-99), fresh commercial porcine jejunum within 4 hours is washed and disinfected, and then mechanically stripped, defatted, decellularized, degreased and vacuum freeze-dried to obtain SIS particles. Then, the particles are ground into microparticles with a particle size of 30-50 μm at-80°C using a grinding pulverizer to obtain SIS particles.

[0082] Example 1

[0083] A biodegradable absorbable hemostatic composition is prepared by the following method:

[0084] (1) Dissolve 3.0 g of mixed water-soluble polysaccharides in 300 ml of purified water, uniformly stir to completely dissolve, and obtain a water-soluble polysaccharide solution with a concentration of 1 wt%; wherein the mixed water-soluble polysaccharides are sodium hyaluronate, carboxymethyl chitosan and sodium alginate with a mass ratio of 8:1:1.

[0085] (2) SIS particles 27 g (particle size 50 μm) and sodium carboxymethyl starch (molecular weight 5 x 10 5 , degree of substitution 0.2%) 270 g were mixed in a mass ratio of 1:10 and added to a fluidized bed granulator. The blower frequency was set to 25 Hz, the total gas pressure to 0.44 MPa, the gas seal pressure to 0.14 MPa, and the spray gun pressure to 0.2 MPa. After heating for 20 min, the material temperature was about 32°C, and the liquid (water-soluble polysaccharide solution) was started to be added. The peristaltic pump was set to a speed of 5 r / min. After granulation and drying, the particles were sieved with 150 mesh and 60 mesh screens to obtain particles with a particle size of 100-250 μm and a bulk density of 0.3 g / cm 3 ;

[0086] (3) The particles prepared in step (2) were filled into a push device and then placed in an aluminum foil bag for sealing and irradiation sterilization to obtain hemostatic granules 1.

[0087] Example 2: Composition of polysaccharides

[0088] On the basis of Example 1, the composition of polysaccharides was investigated. The amount of polysaccharides was the same as that of hemostatic granules 1, and the only difference was the composition and mass ratio, as shown in Table 1.

[0089] Table 1 Composition of polysaccharides in hemostatic granules

[0090]

[0091] The preparation method of hemostatic granules was the same as that of Example 1.

[0092] Test Example 1

[0093] The basic properties of hemostatic granules 1-7 were tested, and the detection indexes and specific methods are as follows:

[0094] (1) Water absorption rate: Distilled water was used to wet the filter paper in a Buchner funnel (diameter 40 mm). After the funnel stopped dripping, the wet filter paper was weighed as m1. About 0.2 g (accurate to 0.001 g) of sample was accurately weighed and evenly sprinkled on the filter paper in the Buchner funnel. Then 20 ml of water was poured in. After the funnel stopped dripping, the wet filter paper and sample were weighed as m2. The water absorption rate was calculated according to the following formula:

[0095] Water absorption rate = (m2 - m1) / m.

[0096] (2) Adhesion: After the hemostatic granules were completely absorbed, the adhesion modulus G'' of the absorbed hemostatic granules was detected by a TA rheometer. The equipment parameters were temperature 37°C, deformation 1%, and frequency 0.9 Hz.

[0097] The water absorption and adhesion results of the hemostatic granules 1-7 are shown in Table 2.

[0098] Table 2 Water absorption and adhesion results of each hemostatic granule

[0099]

[0100] Example 2: Animal hemostatic healing test

[0101] The above hemostatic granules were used for wound repair in rabbits (2.5 kg) as follows. After sterilizing a 5x5 cm area on the back of the rabbit where the back hair was removed, a 1x1 cm wound was made on the back of the rabbit with a surgical knife. 1 g of each of the above hemostatic granules was applied to the surface of the wound, and the hemostatic effect was observed and the hemostatic time was recorded. The healing of the wound was observed every 12 hours until the wound of the rabbit was completely healed, and the infection and healing time of the wound of the rabbit were recorded and statistically analyzed. The results are shown in Table 3.

[0102] Table 3 Hemostatic effect of each hemostatic granule

[0103]

[0104] As can be seen from Tables 2 and 3, compared with the hemostatic granule 8 without polysaccharide, the addition of adhesive polysaccharide can effectively combine SIS granules and sodium carboxymethyl starch, forming porous and uniformly mixed microparticles, increasing the water absorption rate and the adhesion of the product, so that the product can effectively adhere to the wound surface and improve the hemostatic efficiency. However, the water absorption performance or adhesion modulus of the hemostatic granules with different polysaccharide compositions differs to varying degrees. Among them, the hemostatic granules 1-3 containing sodium hyaluronate have higher water absorption rate and adhesion modulus, shorter hemostatic time and complete healing time, and the best hemostatic effect.

[0105] Example 3: Molecular weight and degree of substitution of sodium carboxymethyl starch

[0106] On the basis of Example 1, the molecular weight and degree of substitution of sodium carboxymethyl starch were investigated. The molecular weight and degree of substitution of sodium carboxymethyl starch are shown in Table 4.

[0107] Table 4 Molecular weight and degree of substitution of sodium carboxymethyl starch

[0108]

[0109] The hemostatic granules were prepared according to the method of Example 1.

[0110] Example 3

[0111] The water absorption, adhesion and hemostatic effect of the above hemostatic granules were evaluated according to the methods of Examples 1 and 2, and the results are shown in Table 5.

[0112] Table 5 Water absorption, adhesion and hemostatic effect of each hemostatic granule

[0113]

[0114] As can be seen from Table 5, too high molecular weight and too small degree of substitution, or too low molecular weight and too large degree of substitution, will result in different degrees of reduction in water absorption and adhesive modulus, and further result in prolonged hemostatic time and healing time, and poor hemostatic and healing-promoting effect.

[0115] Test Example 4

[0116] Take 1 g of hemostatic granule 1, hemostatic granule 9, hemostatic granule 10, hemostatic granule 11 and hemostatic granule 12, connect the push device to the endoscope tube, simulate the abdominal pressure to spray the petri dish containing 15 ml of distilled water, record the spraying state, and record the time for each hemostatic granule to completely absorb the water, and the results are shown in Table 6.

[0117] Table 6 Water absorption of hemostatic granules

[0118]

[0119] Compared with hemostatic granule 1, hemostatic granule 10 and hemostatic granule 11, hemostatic granule 9 has large molecular weight, low degree of substitution, poor hydrophilicity, slow water absorption speed, and after complete water absorption, it may be excessively swollen, the volume increases, causing compression, the viscosity increases, and the coagulation factor aggregation is delayed; hemostatic granule 12 has small molecular weight, high degree of substitution, strong hydrophilicity, and is easy to form a water film on the surface, affecting the water absorption speed.

[0120] Example 4: Dosage ratio of sodium carboxymethyl starch, water-soluble polysaccharide and SIS granule

[0121] On the basis of Example 1, the dosage of water-soluble polysaccharide, SIS granule and sodium carboxymethyl starch was investigated, and the specific raw material composition is shown in Table 7.

[0122] Table 7 Dosage of water-soluble polysaccharide, SIS granule and sodium carboxymethyl starch

[0123]

[0124] Among them, the water-soluble polysaccharide of hemostatic granule 13 is sodium hyaluronate; the water-soluble polysaccharide of hemostatic granule 14 and 15 is the same as that of hemostatic granule 1.

[0125] The preparation method of the hemostatic granule is the same as that of Example 1.

[0126] Test Example 5

[0127] The water absorption, adhesion and hemostatic effect of the above hemostatic granules were evaluated according to the methods of Test Examples 1 and 2, and the results are shown in Table 8.

[0128] Table 8 Water absorption, adhesion and hemostatic effect of each hemostatic granule

[0129]

[0130] As can be seen from Table 8, the water-soluble polysaccharide, SIS granule and sodium carboxymethyl starch have high water absorption and adhesion modulus, and good hemostatic and healing-promoting effects within a certain ratio.

[0131] Example 5: Particle size range and bulk density of hemostatic granules

[0132] On the basis of Example 1, the particle size range and bulk density of the hemostatic granules were investigated, wherein the particle size range was obtained by sieving with different mesh sieves, and the bulk density was achieved by controlling the spray gun pressure during preparation. See Table 9 for details.

[0133] Table 9 Particle size range and bulk density of hemostatic granules

[0134]

[0135] The hemostatic granules were prepared according to the method of Example 1.

[0136] Test Example 6

[0137] The water absorption, adhesion and hemostatic effect of the above hemostatic granules were evaluated according to the methods of Test Examples 1 and 2, and the results are shown in Table 10.

[0138] Table 10 Water absorption, adhesion and hemostatic effect of each hemostatic granule

[0139]

[0140] As can be seen from Table 10, the particle size and bulk density of the hemostatic granules also have a great influence on their water absorption and adhesion. Only within a certain particle size and bulk density range, the hemostatic granules have better water absorption and adhesion, and thus achieve better hemostatic and healing-promoting effects.

[0141] Test Example 7

[0142] The hemostatic granules 1, 16-19 were connected to the endoscope tube through the pushing device, and the bleeding site was sprayed to simulate the abdominal pressure, and the spraying state was recorded.

[0143] The results showed that when the particle size was less than 100 μm and the bulk density was less than 0.2 g / cm 3 , the product was easily dispersed during spraying, resulting in product drifting and not reaching the wound surface, affecting the surgical field. When the particle size was greater than 850 μm and the bulk density was greater than 0.3 g / cm 3 , the product could not be atomized and uniformly dispersed on the wound surface.

[0144] Comparative Example 1

[0145] Composite microporous polysaccharide hemostatic powder, purchased from Shandong Saikesais Biological Technology Co., Ltd.

[0146] Comparative Example 2

[0147] A hemostatic sponge was prepared according to the components and preparation method of Example 1 of application number CN202311683472.7.

[0148] Comparative Example 3

[0149] A biodegradable absorbable hemostatic granule, which is only different from Example 1 in that it does not contain sodium carboxymethyl starch, and the preparation method is as follows:

[0150] (1) Dissolve 3.0 g of mixed water-soluble polysaccharide in 300 mL of purified water, uniformly stir to completely dissolve, and prepare a 1wt% water-soluble polysaccharide solution; wherein the mixed water-soluble polysaccharide is sodium hyaluronate, carboxymethyl chitosan and sodium alginate in a mass ratio of 8:1:1.

[0151] (2) Add 27 g of SIS particles (particle size 50 μm) to the fluidized bed granulator, set the fan frequency to 25 Hz, the total gas pressure to 0.44 MPa, the gas tightness pressure to 0.14 MPa, and the spray gun pressure to 0.2 MPa. After heating for 20 min, the material temperature is about 32℃, start liquid feeding (spray water-soluble polysaccharide solution), set the peristaltic pump liquid feeding speed to 5 r / min, granulate, dry, and sieve with 150 mesh and 60 mesh screens to obtain granules with a particle size of 100-250 μm and a bulk density of 0.3 g / cm 3 ;

[0152] (3) The granules prepared in step (2) are filled into a push device and then placed in an aluminum foil bag for sealing and irradiation sterilization, and hemostatic granules 20 are obtained.

[0153] Detection Example 8

[0154] The water absorption, adhesion and hemostatic effect of the above hemostatic granules were evaluated according to the methods of detection examples 1 and 2, and the results are shown in Table 11.

[0155] Table 11 Water absorption, adhesion and hemostatic effect of various hemostatic materials

[0156]

[0157] As can be seen from Table 11, the prepared hemostatic granules 1 are far superior to the existing commercially available composite microporous polysaccharide hemostatic powder and the hemostatic sponge disclosed in application No. CN202311683472.7 in various aspects. Moreover, compared with the hemostatic granules 1, the hemostatic granules 20 do not add sodium carboxymethyl starch, although the viscosity changes little, but the water absorption rate decreases significantly, thereby causing the hemostatic time and healing time to be significantly prolonged.

[0158] Test Example 9

[0159] During the animal hemostatic healing test of the above-mentioned hemostatic granules 1 and hemostatic sponge, the skin tissues of the rabbits using the hemostatic granules 1 and hemostatic sponge were taken at 3 days, 7 days and after complete healing, respectively, and the blue reaction of starch and iodine was used to determine whether the sodium carboxymethyl starch was completely degraded; at the same time, HE pathological observation was carried out to determine whether the SIS was completely degraded, and the results are shown in Table 12.

[0160] Table 12 Degradation of raw materials of hemostatic granules 1 and hemostatic sponge

[0161]

[0162] As can be seen from Table 12, the sodium carboxymethyl starch in the prepared hemostatic granules of the present application has a very small amount of residue at 3 days, and is completely degraded at 7 days, and the SIS particle size becomes smaller and is completely degraded during healing, which is more close to the wound healing period, but the hemostatic sponge of Comparative Example 2 still has a small amount of SIS particles remaining after healing, and the degradation rate is slower.

[0163] In addition, the prepared hemostatic granules of the present application are powdery granules (the appearance photos and micro-SEM morphologies are shown in Figs. 1 and 2, respectively), which can more easily reach the narrow cavity in the body for hemostasis through the endoscope extension tube, and do not need to consider disintegration during entering the endoscope, and can be uniformly sprayed on uneven and irregular wounds, which has more advantages than sponge. Figure 1 and Figure 2

[0164] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.​

Claims

1. A biodegradable absorbable hemostatic composition characterized in that, The hemostatic composition comprises, by weight fraction, 0.03-10 parts of water-soluble polysaccharide and 90-99.7 parts of sodium carboxymethyl starch; the water-soluble polysaccharide is composed of sodium hyaluronate, sodium alginate, carboxymethyl chitosan and carboxymethyl cellulose in a mass ratio of 8-10:0-2:0-2:0-2; The sodium carboxymethyl starch has a molecular weight of 10 5 -10 6 , a degree of substitution of 0.2-0.6%; The hemostatic composition has a particle size of 100-500 μm and a bulk density of 0.2-0.3 g / cm 3 .

2. The hemostatic composition according to claim 1, wherein The water-soluble polysaccharide is sodium hyaluronate; or sodium hyaluronate, carboxymethyl chitosan and sodium alginate in a mass ratio of 8-10:1-2:1-2; sodium hyaluronate, carboxymethyl chitosan and carboxymethyl cellulose in a mass ratio of 8-10:1-2:1-2.

3. The hemostatic composition according to claim 1, wherein The hemostatic composition further comprises: decellularized small intestinal submucosa particles; the hemostatic composition comprises, by weight fraction, 0.03-10 parts of water-soluble polysaccharide, 90-99.97 parts of sodium carboxymethyl starch and 1-10 parts of decellularized small intestinal submucosa particles.

4. The hemostatic composition according to claim 3, wherein The decellularized small intestinal submucosa particles are selected from any one of decellularized pig small intestinal submucosa particles, decellularized cow small intestinal submucosa particles, decellularized sheep small intestinal submucosa particles and decellularized dog small intestinal submucosa particles.

5. The hemostatic composition according to claim 3, wherein The decellularized small intestinal submucosa particles have a particle size of 30-50 μm.

6. The hemostatic composition according to claim 1, wherein The sodium carboxymethyl starch has a molecular weight of 1 x 10 5 -5 x 10 5 ; and a degree of substitution of 0.2-0.5%.

7. The hemostatic composition according to claim 1, wherein The hemostatic composition has a particle size of 100-250 μm and a bulk density of 0.3 g / cm 3 .

8. Use of the hemostatic composition according to any one of claims 1-7 in the preparation of a medical hemostatic product.

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