KR102656226B1 - Hemostatic material comprising calcium carboxymethyl cellulose powder and water-soluble chitosan compound powder and process for preparing the same - Google Patents

Abstract

Sheet-like substrate; and a hemostatic layer formed on at least one side of the sheet-like substrate and containing calcium carboxymethylcellulose powder. A hemostatic material and a method of manufacturing the same are provided.

Description

Hemostatic material comprising calcium carboxymethyl cellulose powder and water-soluble chitosan compound powder and process for preparing the same}

The present invention relates to a hemostatic material comprising calcium carboxymethyl cellulose powder and a water-soluble chitosan compound powder and a method for producing the same, and more specifically, to a hemostatic material with excellent blood absorption ability and improved blood coagulation characteristics and a method for producing the same. will be.

In a variety of environments, animals, including humans, can become injured. Bleeding often accompanies these wounds. In some cases, wounds and bleeding are not dangerous, and normal blood clotting will stop the bleeding without outside help. Unfortunately, in other cases, significant bleeding may occur.

In particular, excessive bleeding is one of the important causes that can instantly endanger a person's life and lead to death, and it has been reported that in the United States, more than 50,000 people die every year from excessive bleeding. The use of hemostatic agents is essential on the battlefield, in daily emergency situations, and in the operating room because effective initial bleeding control alone can greatly increase the chances of survival.

Humankind has long been devoted to developing hemostatic agents that can prevent bleeding early when it occurs, and various formulations have been developed to manage bleeding and skin damage caused by various causes.

In the case of general gauze or bandage, it is effective in hemostasis for minor bleeding, but there are limitations in its application to severe, life-threatening bleeding, and currently available hemostatic materials such as collagen wound dressing, dried fibrin, or thrombin wound dressing are not effective in hemostatic bleeding. Because mammalian raw materials are used, there are easy differences in physical properties between products, poor storage, risk of infection, and problems with hypersensitivity reactions.

Hemostatic agents using oxidized cellulose are based on vegetable materials, but their hemostatic performance is unsatisfactory.

In addition, inorganic hemostatic agents such as zeolite have been studied to promote blood clot formation, but the use of such activated zeolite in blood coagulation has been reported to have an undesirable heating effect. Inorganic hemostatic products with improved heat generation have also been developed, but their blood coagulation ability is still not good enough to be applied to excessive bleeding, and there are limitations in applying them quickly according to the shape of the bleeding area in urgent treatment situations.

Accordingly, there is still a need for the development of a hemostatic material that has an excellent hemostatic function that is more improved than the hemostatic agents previously studied and that can be easily disposed of in various sizes or shapes.

The problem to be solved by the present invention is to provide a hemostatic material with excellent blood absorption ability and fast blood coagulation time.

Another problem that the present invention seeks to solve is to provide a method for manufacturing the hemostatic material.

In order to solve this problem, according to one aspect of the present invention, hemostatic materials of the following embodiments are provided.

The first embodiment is,

Sheet-like substrate; and

It relates to a hemostatic material comprising a hemostatic layer formed on at least one side of the sheet-like substrate and containing calcium carboxymethylcellulose powder.

The second embodiment is according to claim 1,

It relates to a hemostatic material in which the hemostatic layer further includes water-soluble chitosan compound powder.

The third embodiment is, in the second embodiment,

It relates to a hemostatic material in which the weight ratio of calcium carboxymethylcellulose powder and water-soluble chitosan compound powder in the hemostatic layer is 99:1 to 1:99.

The fourth embodiment is, in any one of the first to third embodiments,

It relates to a hemostatic material in which the hemostatic layer further includes sodium carboxymethylcellulose.

The fifth embodiment is, in any one of the first to fourth embodiments,

It relates to a hemostatic material in which the weight ratio of Ca and Na (Ca:Na) in the calcium carboxymethylcellulose powder is 50:50 to 100:0.

The sixth embodiment is, in any one of the first to fifth embodiments,

The calcium carboxymethylcellulose powder relates to a hemostatic material having an average particle size of 5 to 500 ㎛.

The seventh embodiment is, in any one of the first to sixth embodiments,

It relates to a hemostatic material having a degree of substitution of calcium carboxymethylcellulose of 0.3 to 3.0.

The eighth embodiment is, in any one of the second to seventh embodiments,

The present invention relates to a hemostatic material in which the water-soluble chitosan compound powder has an average particle size of 100 to 1,000 ㎛.

The ninth embodiment is, in any one of the second to eighth embodiments,

The present invention relates to a hemostatic material in which the water-soluble chitosan compound has a degree of deacetylation of 60 to 100% and a weight average molecular weight of 5,000 to 500,000 g/mol.

The tenth embodiment is, in any one of the second to ninth embodiments,

It relates to a hemostatic material in which the water-soluble chitosan compound is one or more types of chitosan and chitosan derivatives.

The eleventh embodiment is, in any one of the first to tenth embodiments,

The sheet-like substrate relates to a hemostatic material including at least one selected from the group consisting of non-woven fabric, fabric, knitted fabric, sponge, and polymer film.

The twelfth embodiment is, in any one of the first to eleventh embodiments,

It relates to a hemostatic material in which the sheet-like substrate is a perforated spunlace nonwoven.

The thirteenth embodiment is, in any one of the first to twelfth embodiments,

It relates to a hemostatic material in which the sheet-like substrate has a liquid absorption degree of 4.0 g/100 cm ² or more based on 0.9% physiological saline solution.

The fourteenth embodiment is, in any one of the first to thirteenth embodiments,

It relates to a hemostatic material in which the weight of the hemostatic layer is 20 to 200 g/m ² per unit area of the sheet-like substrate.

The fifteenth embodiment is, in any one of the first to fourteenth embodiments,

The hemostatic layer relates to a hemostatic material formed as a pattern layer on at least one side of the sheet-like substrate.

The sixteenth embodiment is, in the fifteenth embodiment,

The pattern layer is selected from the group consisting of dot, circle, polygon, doughnut, stripe, step, concavo-convex, and grid. It relates to a hemostatic material that is one selected type or a combination of two or more types.

The seventeenth embodiment is, in any one of the first to sixteenth embodiments,

The hemostatic material has a blood clotting index (BCI) of 40% or less,

The blood coagulation index is defined by the following equation 1, where the blood coagulation characteristic evaluation absorbance in equation 1 is the blood and anticoagulant (sodium citrate, 3.8w) in a hemostatic material measuring 1 cm × 1 cm (width × height). /v%) in a volume ratio of 9:1 was added dropwise, 5 μl of 0.2M CaCl ₂ aqueous solution was added and coagulated in an incubator at 37°C for 1 minute, and then the blood that did not participate in the coagulation was again washed in 6.25% distilled water. Elute in ㎖, collect 200㎕ of the eluate and measure the absorbance [AB] at a wavelength of 540 nm, measure the absorbance [AW] of 200㎕ of distilled water at a wavelength of 540 nm, and then measure the effect of the distilled water contained in the blood eluate on the absorbance. Calculated by equation 2 below to exclude,

The absorbance [AI] of used blood in Equation 1 is obtained by mixing 50 ㎕ of used blood with 6.25 ㎖ of distilled water, collecting 200 ㎕ of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and measuring 200 ㎕ of distilled water at 540 nm. It relates to a hemostatic material in which the absorbance [AW] is measured at a wavelength and then calculated by Equation 3 below to exclude the influence of absorbance of distilled water contained in the blood eluate.

[Equation 1]

Blood coagulation index ( BCI , % ) = blood coagulation characteristic evaluation absorbance [AS] × 100/absorbance of used blood [AI]

[Equation 2]

Evaluation of blood coagulation characteristics Absorbance [AS] = Absorbance of blood eluate [AB] - Absorbance of distilled water [AW]

[Equation 3]

Absorbance of used blood [AI] = Absorbance of blood [AB] - Absorbance of distilled water [AW].

The eighteenth embodiment is, in any one of the first to seventeenth embodiments,

The hemostatic material has a blood clotting index (BCI) of 60% or less,

The blood coagulation index is defined by the following equation 1, where the blood coagulation characteristic evaluation absorbance in equation 1 is the blood and anticoagulant (sodium citrate, 3.8w) in a hemostatic material measuring 1 cm × 1 cm (width × height). /v%) in a volume ratio of 9:1 was added dropwise, 10 μl of 0.2M CaCl ₂ aqueous solution was added and coagulated in an incubator at 37°C for 1 minute, and the blood that did not participate in the coagulation was again washed in 12.5% distilled water. Elute in ㎖, collect 200㎕ of the eluate and measure the absorbance [AB] at a wavelength of 540 nm, measure the absorbance [AW] of 200㎕ of distilled water at a wavelength of 540 nm, and then measure the effect of the distilled water contained in the blood eluate on the absorbance. Calculated by equation 2 below to exclude,

The absorbance [AI] of used blood in Equation 1 is obtained by mixing 100 ㎕ of used blood with 12.5 ㎖ of distilled water, collecting 200 ㎕ of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and measuring 200 ㎕ of distilled water at 540 nm. It relates to a hemostatic material in which the absorbance [AW] is measured at a wavelength and then calculated by Equation 3 below to exclude the influence of absorbance of distilled water contained in the blood eluate.

[Equation 1]

Blood coagulation index ( BCI , % ) = blood coagulation characteristic evaluation absorbance [AS] × 100/absorbance of used blood [AI]

[Equation 2]

Evaluation of blood coagulation characteristics Absorbance [AS] = Absorbance of blood eluate [AB] - Absorbance of distilled water [AW]

[Equation 3]

Absorbance of used blood [AI] = Absorbance of blood [AB] - Absorbance of distilled water [AW].

According to another aspect of the present invention, a method for producing a hemostatic material of the following embodiments is provided.

The 19th embodiment is,

Preparing a sheet-like substrate;

Applying a composition for forming a hemostatic layer containing calcium carboxymethylcellulose powder on at least one side of the sheet-like substrate; and

It relates to a method of manufacturing a hemostatic material including the step of drying the sheet-like substrate.

The 20th embodiment, in the 19th embodiment,

Before applying the composition for forming a hemostatic layer, it further includes adding a water-containing solvent to at least one surface of the sheet-like substrate, or

It relates to a method of manufacturing a hemostatic material further comprising exposing the applied sheet-like substrate to water vapor after applying the composition for forming a hemostatic layer.

The 21st embodiment is the 19th or 20th embodiment,

It relates to a method of manufacturing a hemostatic material further comprising water-soluble chitosan compound powder in the composition for forming a hemostatic layer.

The 22nd embodiment is the 20th or 21st embodiment,

It relates to a method of producing a hemostatic material in which the hydrous solvent is water or a mixture of water and an organic solvent.

The 23rd embodiment is, in any one of the 19th to 22nd embodiments,

It relates to a method of manufacturing a hemostatic material further comprising a softener in the composition for forming a hemostatic layer.

The hemostatic material according to an embodiment of the present invention includes a calcium carboxymethyl cellulose material in which calcium divalent ions are bonded to the carboxyl group of carboxymethyl cellulose, thereby inducing crosslinking between carboxymethyl cellulose molecular chains, thereby reducing the gel blocking phenomenon and increasing the liquid absorption rate. This is significantly improved, and hemostatic performance can be further improved by promoting blood coagulation by releasing calcium ions upon contact with blood or body fluids.

In addition, the hemostatic material according to an embodiment of the present invention is manufactured in powder form compared to the calcium carboxymethyl cellulose material manufactured in the form of a conventional fiber, sheet, or foam, so the manufacturing process is very simple, and the specific surface area is small. It is wide, greatly improving the hemostatic effect, and can be easily cut and applied to the shape of the treatment area when used.

In addition, the hemostatic material according to an embodiment of the present invention simultaneously has the excellent hemostatic function of the water-soluble chitosan compound, the excellent liquid absorption and liquid retention performance of calcium carboxymethyl cellulose, the thickening effect due to moisture absorption, and the function of promoting coagulation by releasing calcium ions. By providing it, problems such as the somewhat slow absorption rate when using conventional chitosan alone, the low hemostatic performance of poorly water-soluble chitosan, the decrease in hemostatic function when using sodium carboxymethyl cellulose alone, and the decrease in shape stability due to gelation are solved, and excellent liquid absorption properties and Hemostasis functions can exhibit mutual synergistic effects.

The hemostatic material according to an embodiment of the present invention can be used as a variety of medical materials, such as anti-adhesion materials and wound dressings, in addition to hemostatic agents.

The following drawings attached to this specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the detailed description of the invention described later. Therefore, the present invention includes the matters described in such drawings. It should not be interpreted as limited to only .
Figure 1A is a photograph of the exterior of the hemostatic material prepared in Example 1, and Figure 1B is a photograph of the exterior of the hemostatic material manufactured in Example 8.
Figure 2 is a photograph showing the blood coagulation results 1 minute after the hemostatic materials prepared in Examples 1 to 4 and Comparative Example 1 were evaluated according to the blood coagulation characteristic evaluation 1 (blood volume 50 μl/cm ² ) method.
Figure 3 is a graph showing the blood coagulation index of the hemostatic materials prepared in Examples 1 to 4 and Comparative Example 1 according to the blood coagulation characteristic evaluation 1 (blood volume 50 μl/cm ² ) method.
Figures 4a and 4b are SEM photographs at 100x and 3,000x magnifications observing the blood coagulation shape of the hemostatic material prepared in Example 1.
Figures 4c and 4d are SEM photographs at 100x and 3,000x magnifications observing the blood coagulation shape of the hemostatic material prepared in Example 2.
Figures 4e and 4f are SEM photographs at 100x and 3,000x magnifications observing the blood coagulation shape of the hemostatic material prepared in Example 3.
Figures 4g and 4h are SEM photographs at 100x and 3,000x magnifications observing the blood coagulation shape of the hemostatic material prepared in Example 4.
Figures 4i and 4j are SEM photographs at 100x and 3,000x magnifications observing the blood coagulation shape of the hemostatic material prepared in Comparative Example 1.
Figure 5 shows blood coagulation characteristic evaluation 2 (blood volume 100 ㎕/ This is a graph showing the blood coagulation index evaluated according to the cm ² ) method.
Figure 6 is a graph showing the blood coagulation index of the hemostatic materials prepared in Examples 3 and 5 to 7 evaluated according to the blood coagulation characteristic evaluation 2 (blood volume 100 μl/cm ² ) method.
Figure 7 is a graph showing the blood coagulation index of the hemostatic materials prepared in Examples 3 and 8 evaluated according to the blood coagulation characteristic evaluation 2 (blood volume 100 μl/cm ² ) method.

Hereinafter, the present invention will be described in detail. Prior to this, the terms or words used in this specification and claims should not be construed as limited to their usual or dictionary meanings, and the inventor should appropriately define the concept of terms in order to explain his or her invention in the best way. It must be interpreted as meaning and concept consistent with the technical idea of the present invention based on the principle of definability.

Accordingly, the configuration shown in the embodiments described in this specification is only one of the most preferred embodiments of the present invention and does not completely represent the technical spirit of the present invention, so various equivalents can be substituted for them at the time of filing the present application. It should be understood that there may be variations.

The hemostatic material according to one aspect of the present invention includes a sheet-like substrate; and is formed on at least one side of the sheet-like substrate and includes calcium carboxymethylcellulose powder.

Additionally, the sheet-like substrate may be in the form of non-woven fabric, fabric, knitted fabric, sponge, polymer film, or a mixture of two or more of these. That is, two of these may be stacked on top of each other, or one base material layer may be formed in a form where two or more different types of sheet-like base materials are adjacent to each other.

Specifically, the sheet-like substrate may preferably be a knitted fabric or non-woven fabric, more preferably a non-woven fabric, and more specifically, a perforated spunlace nonwoven. When the sheet-like substrate is made of non-woven fabric, the manufacturing process is simple, pore characteristics can be easily controlled, and liquid absorption characteristics can be further improved.

Additionally, when the sheet-like substrate is hydrophilic or porous, there is an advantage in that the liquid absorption characteristics are further improved upon contact with blood. Specifically, the liquid absorption degree of the sheet-like substrate may be 4.0 g/100 cm ² or more, specifically 4.5 g/100 cm ² or more, and more specifically 5.0 g/100 cm ² or more, based on 0.9% physiological saline solution. If the liquid absorption degree of the sheet-type substrate satisfies this range, the absorption of blood components may increase, increasing the possibility of contact between the hemostatic material and components that act on the blood coagulation mechanism, and the moisture in the blood selectively moves quickly to the substrate. Blood viscosity increases, which can accelerate coagulation.

The material of the sheet-like substrate is synthetic materials such as polyurethane, polyester, nylon, polypropylene, polyethylene, polylactic acid, polyglycolic acid, polydioxanone, polycaprolactone, polyvinyl alcohol, etc., or natural materials such as cotton and viscose rayon. Alternatively, regenerated fibers, etc. may be used, but are not limited thereto.

In this specification, powder refers to powder or powder that is a general term for finely broken grains, and can be classified into three-dimensional, powder, fine powder, and ultrafine powder depending on its size, for example, 1 to 1,000 ㎛, Alternatively, it may have an average particle diameter of 10 to 1,000 ㎛, or 100 to 1,000 ㎛.

The hemostatic layer may be located on one or both sides of the sheet-like substrate, and the hemostatic layer includes calcium carboxymethyl cellulose powder.

According to one embodiment of the present invention, the hemostatic layer includes calcium carboxymethyl cellulose powder alone, a mixture of calcium carboxymethyl cellulose powder and sodium carboxymethyl cellulose powder, or calcium carboxymethyl cellulose powder and water-soluble chitosan compound powder. It may include a mixture of, or a mixture of calcium carboxymethyl cellulose powder, sodium carboxymethyl cellulose powder, and water-soluble chitosan compound powder.

In the present specification, the calcium carboxymethyl cellulose means that a calcium divalent ion is bound to the carboxyl group of carboxymethyl cellulose.

The term carboxymethyl cellulose means that the hydroxyl group of glucose constituting cellulose is replaced with a carboxymethyl group. This carboxymethyl cellulose has a thickening effect of increasing viscosity by gelling when in contact with moisture, so it is used in various fields such as glue, food, cosmetics, pharmaceutical additives, and petroleum excavation. In particular, it is widely used as a medical material due to its excellent biocompatibility.

In addition, the calcium carboxymethyl cellulose powder was analyzed by, for example, ICP-OES (Inductively Coupled Plasma Optical Emission Spectrometry), based on the total weight of calcium carboxymethyl cellulose, and was found to be 0.5 to 16% by weight, or 1.0 to 10% by weight, Alternatively, it may have a calcium content of 2 to 8% by weight. When the calcium content satisfies this range, hemostatic performance is further enhanced when in contact with blood, and the absorption rate can be improved.

In addition, as a result of analysis by ICP-OES (Inductively Coupled Plasma Optical Emission Spectrometry), the weight ratio of Ca and Na (Ca:Na) in the calcium carboxymethyl cellulose powder was 50:50 to 100:0, or 60:40 to 60:40. It may be 95:5, or 70:30 to 90:10. If the ratio of sodium ions is high, the gel blocking phenomenon increases and the blood absorption rate is slow, whereas if the ratio of calcium ions is high, the divalent calcium ions combine with the carboxyl group of carboxymethyl cellulose, thereby inducing crosslinking between carboxymethyl cellulose, resulting in gel blocking. This phenomenon can be reduced and the liquid absorption speed can become very fast. Additionally, upon contact with blood, calcium ions are released, which is expected to serve as a catalyst to further promote blood coagulation. In particular, when the weight ratio of Ca and Na (Ca:Na) in the calcium carboxymethylcellulose powder is 70:30 to 90:10, the effect of introducing calcium ions is increased by the water used in the process of attaching the hemostatic material to the substrate. As the sodium carboxymethyl cellulose component is partially dissolved, the hemostatic material can be easily attached to the substrate without a separate binder component.

In addition, in addition to controlling the weight ratio of Ca and Na (Ca:Na) in the calcium carboxymethyl cellulose powder, the weight ratio of calcium carboxymethyl cellulose powder and sodium carboxymethyl cellulose powder is, for example, 50:50 to 100:0. Even by mixing and using within the range, the above-described advantageous effects obtained by coexistence of calcium and sodium in carboxymethyl cellulose itself can be equally achieved.

According to one embodiment of the present invention, the degree of substitution of the calcium carboxymethyl cellulose may be, for example, 0.3 to 3.0, preferably 0.4 to 1.5, and more preferably 0.5 to 1.2. When the degree of substitution satisfies this range, a larger amount of calcium ions can be introduced, thereby improving the dissociation of calcium ions, which can promote blood coagulation when in contact with water or body fluids. In addition, carboxymethyl cellulose from which calcium ions are dissociated is partially dissolved, thereby increasing the viscosity of blood. Here, the degree of substitution refers to the degree to which the hydroxy group of glucose, which makes up cellulose, is substituted with a carboxymethyl group. When an average of one hydroxy group out of three hydroxy groups in cellulose is replaced with a carboxymethyl group, the degree of substitution is 1. do.

The calcium carboxymethylcellulose powder may have an average particle diameter of 5 to 500㎛, specifically 10 to 200㎛, and more specifically 50 to 100㎛. When the average particle size of the calcium carboxymethyl cellulose powder satisfies this range, the blood absorption rate is fast, the specific surface area of the calcium carboxymethyl cellulose powder is increased, and blood coagulation can be promoted, and the calcium carboxymethyl cellulose powder is incorporated into the substrate. It can reduce the phenomenon of deterioration of hemostatic performance due to excessive use, and also prevent the problem of the blood coagulation effect being reduced due to the specific surface area being reduced as the average particle size becomes too large.

Chitosan compound is a deacetylated form of chitin, a major component of shrimp, crab, lobster, and cuttlefish, and is commercially available in various forms.

These chitosan compounds can provide a positively charged surface with strong permeability and a high specific surface area, which can create a highly reactive surface for the interaction of red blood cells and platelets. The red blood cell membrane has a negative charge, which is attracted to the positively charged surface of the chitosan compound, and the cell membrane of the attracted red blood cell comes into contact with the chitosan compound and fuses, allowing a clot to form very quickly. For this reason, chitosan compounds exhibit very good blood coagulation properties and can also bind to bacteria, endotoxins, and microorganisms, thereby exerting the effect of killing bacterial, microbial, and/or viral agents.

The hemostatic material according to an embodiment of the present invention may further include water-soluble chitosan compound powder in the hemostatic layer.

As used herein, a water-soluble chitosan compound means a chitosan compound that is soluble in neutral water, that is, a chitosan compound that is soluble in water without adding a separate acid for dissolution. In contrast, the water-insoluble chitosan compound means that it does not dissolve in neutral water, but dissolves when the pH is lowered by adding a separate acid, for example, to pH 6.5 or less.

In one embodiment of the present invention, by including water-soluble chitosan compound powder as the chitosan compound powder, it has excellent liquid absorption and liquid retention performance of calcium carboxymethylcellulose, thickening effect due to moisture absorption, and serves as a catalyst to promote blood coagulation by calcium ions. , by having a blood coagulation effect due to the cationic nature of the water-soluble chitosan compound, the hemostatic function can exhibit a synergistic effect. Water-soluble chitosan compounds can provide a positively charged surface (-NH ³⁺ ) with strong permeability and a high specific surface area, and this positively charged surface can form a highly reactive surface for the interaction of red blood cells and platelets. . The red blood cell membrane is negatively charged, which is attracted to the positively charged surface of the chitosan compound, and the cell membrane of the attracted red blood cell comes into contact with the chitosan compound and fuses, allowing a clot to form very quickly. It is difficult for water-soluble chitosan compounds to provide the positive charge surface even when in contact with blood or body fluids, but water-soluble chitosan compounds tend to be positively charged when in contact with blood or body fluids, making them more desirable as hemostatic materials.

The water-soluble chitosan compound may be one or more of chitosan and chitosan derivatives. According to one embodiment of the present invention, the degree of deacetylation of the water-soluble chitosan compound may be, for example, 60 to 100%, or 80 to 100%, and the weight average molecular weight of the water-soluble chitosan compound may be, for example, 5,000. to 500,000 g/mol, or 10,000 to 300,000 g/mol. Specifically, when the degree of deacetylation and weight average molecular weight satisfy these ranges, the water solubility of the chitosan compound can be improved, and the hemostatic function and wound covering effect can be further improved.

In addition, the water-soluble chitosan compound powder may have an average particle diameter of, for example, 100 to 1,000 μm, specifically 100 to 500 μm, and more specifically 200 to 400 μm. When the average particle size of the water-soluble chitosan compound powder satisfies this range, the blood absorption rate is fast, and the phenomenon of reducing the blood coagulation effect due to excessive water-soluble chitosan compound powder entering the inside of the substrate can be reduced. In addition, when the average particle diameter of the water-soluble chitosan compound powder satisfies this range, the average particle diameter of the water-soluble chitosan compound is too small and the specific surface area becomes too large, so the water-soluble chitosan compound is dissolved too quickly and blood components are transferred to the hemostatic layer. The problem of decreased absorption or decreased blood coagulation effect as the average particle size of the water-soluble chitosan compound is too large and the specific surface area decreases can be solved.

The weight ratio of the calcium carboxymethyl cellulose powder and the water-soluble chitosan compound powder in the hemostatic layer is 99:1 to 1:99, or 90:10 to 10:90, or 80:20 to 20:80, or 70:30 to 70:30. It could be 30:70. When the weight ratio satisfies this range, the shape stability is excellent, the liquid absorption speed is fast, the thickening effect is improved, and the hemostatic effect can be excellent.

The weight per unit area of the hemostatic layer may be 20 to 200 g/m ² , preferably 30 to 180 g/m ² , and more preferably 80 to 150 g/m ² .

When the weight per unit area of the hemostatic layer satisfies this range, blood coagulation characteristics can be improved, the problem of the hemostatic material becoming stiff due to a thicker hemostatic layer can be solved, and the hemostatic material that can come into contact with the hemostatic material can be solved. Since the amount of blood is limited, the problem of low blood coagulation efficiency relative to the amount of hemostatic substances can be prevented.

According to one embodiment of the present invention, when the hemostatic layer is formed on at least one side of the sheet-shaped substrate, the hemostatic layer may be formed on the entire surface of the sheet-shaped substrate, or may be formed on only a portion of the sheet-shaped substrate. Even when the hemostatic layer is formed entirely on one side of the sheet-like substrate or only on a part of it, it can be formed as a pattern layer in various three-dimensional shapes with different thicknesses.

These pattern layers include dots, circles, polygons, doughnuts, stripes, steps, concavo-convex, and grid. It may be one type or a combination of two or more types selected from, and may also be an amorphous pattern without a variety of regular patterns.

According to one embodiment of the present invention, when applying a pattern layer in which a large amount of a hemostatic layer is combined with a small amount of hemostatic layer, calcium ions are quickly released from the powder into calcium carboxymethyl cellulose when it comes into contact with body fluid or blood, thereby further demonstrating the hemostatic effect. Additionally, if the hemostatic layer further contains water-soluble chitosan compound powder, the hemostatic function and blood absorption rate can be improved.

A more preferable example of such a complex pattern layer may be a stepped or uneven pattern.

The hemostatic material according to an embodiment of the present invention may have a blood clotting index (BCI) of 40% or less, specifically 30% or less, and more specifically 20% or less.

At this time, the blood coagulation index is defined by the following equation 1, where the blood coagulation characteristic evaluation absorbance in equation 1 is blood and anticoagulant (sodium citrate, sodium citrate, 3.8 w/v%) at a volume ratio of 9:1 was added dropwise, 5 μl of 0.2M CaCl ₂ aqueous solution was added and coagulated in an incubator at 37°C for 1 minute, and then the blood that did not participate in the coagulation was again incubated. Elute in 6.25 ml of distilled water, collect 200 ㎕ of the eluate and measure the absorbance [AB] at a wavelength of 540 nm, measure the absorbance [AW] of 200 ㎕ of distilled water at a wavelength of 540 nm, and measure the absorbance of the distilled water contained in the blood eluate. In order to exclude the influence, it is calculated by Equation 2 below.

In addition, the absorbance [AI] of the used blood in Equation 1 is obtained by mixing 50 ㎕ of used blood with 6.25 ㎖ of distilled water, collecting 200 ㎕ of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and mixing 200 ㎕ of distilled water at 540 ㎕. After measuring the absorbance [AW] at a wavelength of nm, it is calculated using Equation 3 below to exclude the influence of the absorbance of distilled water contained in the blood eluate.

[Equation 1]

Blood coagulation index (BCI, %) = blood coagulation characteristic evaluation absorbance [AS] *100/absorbance of used blood [AI]

[Equation 2]

Evaluation of blood coagulation characteristics Absorbance [AS] = Absorbance of blood eluate [AB] - Absorbance of distilled water [AW]

[Equation 3]

Absorbance of used blood [AI] = Absorbance of blood [AB] - Absorbance of distilled water [AW].

In addition, the hemostatic material according to an embodiment of the present invention is used when evaluating blood coagulation characteristics in situations where more bleeding occurs than the blood coagulation index evaluation conditions described above, that is, when evaluating blood and anticoagulant (sodium citrate, 3.8w) /v%) at a volume ratio of 9:1, when 100 ㎕ is used instead of 50 ㎕, 60% or less, specifically 55% or less, more specifically 50% or less, even more specifically 40% It may have a blood clotting index (BCI) of less than %.

At this time, the blood coagulation index is defined by the following equation 1, where the blood coagulation characteristic evaluation absorbance in equation 1 is blood and anticoagulant (sodium citrate, sodium citrate, 3.8 w/v%) at a volume ratio of 9:1 was added dropwise, 10 μl of 0.2M CaCl ₂ aqueous solution was added and allowed to coagulate in an incubator at 37°C for 1 minute, and then the blood that did not participate in the coagulation was incubated again. Elute in 12.5 ml of distilled water, collect 200 ㎕ of the eluate and measure the absorbance [AB] at a wavelength of 540 nm, measure the absorbance [AW] of 200 ㎕ of distilled water at a wavelength of 540 nm, and measure the absorbance of the distilled water contained in the blood eluate. Calculated by equation 2 below to exclude the influence,

The absorbance [AI] of used blood in Equation 1 is obtained by mixing 100 ㎕ of used blood with 12.5 ㎖ of distilled water, collecting 200 ㎕ of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and measuring 200 ㎕ of distilled water at 540 nm. After measuring the absorbance [AW] at the wavelength, it is calculated using Equation 3 below to exclude the influence of the absorbance of distilled water contained in the blood eluate.

[Equation 1]

Blood coagulation index ( BCI , % ) = blood coagulation characteristic evaluation absorbance [AS] × 100/absorbance of used blood [AI]

[Equation 2]

Evaluation of blood coagulation characteristics Absorbance [AS] = Absorbance of blood eluate [AB] - Absorbance of distilled water [AW]

[Equation 3]

Absorbance of used blood [AI] = Absorbance of blood [AB] - Absorbance of distilled water [AW].

In addition, the hemostatic layer in the hemostatic material according to an embodiment of the present invention may further include additives, and these additives may be freely selected depending on the required properties, examples of which include physiologically active substances, softeners, and hemostatic agents. Examples include substances, antibacterial substances, cells, enzymes, antigens, pigments, etc.

According to one embodiment of the present invention, an appropriate amount of softener such as glycerol or Tween® can be mixed to increase the flexibility or adhesiveness of the hemostatic material.

Alternatively, antibacterial substances such as silver, silver compounds, triclosan, biguanide compounds, methylene blue, etc. can be added to block penetration of microorganisms such as bacteria into the skin.

In addition, the physiologically active substance refers to a substance that has a significant impact on the function of the living body even in trace amounts, and may include vitamins, hormones, enzymes, neurotransmitters, etc., but is not limited to these, but is not limited to the nature of the wound or Depending on the patient's medical condition, human serum albumen, bovine thrombin, human thrombin (h thrombin), rh thrombin, factor VIIa, factor XIII, recombinant factor XIII (r factor XIII), thromboxane A2, prostaglandin-2a, epithelial cell growth. factor, platelet-derived growth factor, von Wilbrand factor, tumor necrosis factor (TNF), TNF-alpha, transforming growth factor (TGF), TGF-alpha, TGF-beta, insulin-like growth factor, fibroblast growth factor, keratinocyte Growth factors, nerve growth factors, penicillin, ampicillin, methicillin, amoxicillin, clavamox, clavulanic acid, amoxicillin, aztreonam, imipenem, streptomycin, kanamycin, tobramycin, gentamicin, vancomycin, clindamycin, erythromycin , polymyxin, bacitracin, amphotericin, nystatin, rifampicin, tetracycline, doxycycline, chloramphenicol, and combinations thereof. The hemostatic substances may include collagen, gelatin, alginate, oxidized cellulose, chitin and chitin derivatives, chitosan derivatives, calcium chloride, etc.

In addition, the hemostatic material according to an embodiment of the present invention has excellent physical properties, so it can be used as a filling hemostatic agent for holes and perforations in the body, and as a hemostatic material during surgical operations.

According to another aspect of the present invention, preparing a sheet-like substrate; Applying a composition for forming a hemostatic layer containing calcium carboxymethylcellulose powder on at least one side of the sheet-like substrate; A method for producing a hemostatic material is provided, including the step of drying the sheet-like substrate.

According to one embodiment of the present invention, the calcium carboxymethyl cellulose powder contains at least one selected from sodium carboxymethyl cellulose powder or carboxymethyl cellulose powder, water, a non-solvent of the sodium carboxymethyl cellulose powder, and a calcium compound. It can be prepared by a method including the step of mixing in a solution.

Non-solvents of the sodium carboxymethyl cellulose powder may include methanol, ethanol, isopropyl alcohol, acetone, methylene chloride, ethyl acetate, chloroform, etc. For example, the non-solvent may be alcohol. The solvent used to treat calcium ions is water; The reason for using a mixed solvent of sodium carboxymethyl cellulose powder and non-solvent of sodium carboxymethyl cellulose powder is that while increasing the efficiency of introducing calcium ions in the aqueous solution, the sodium carboxymethyl cellulose powder or carboxymethyl cellulose powder is reduced due to the excess water used in the treatment process. This is to prevent the powder from losing its shape due to dissolution or gelation.

the water; A mixed solution containing a non-solvent of sodium carboxymethyl cellulose powder may be prepared by mixing the non-solvent and water in a volume ratio of, for example, 70:30 to 95:5, or 75:25 to 90:10. You can.

At this time, the calcium compound may be one or more selected from the group consisting of calcium chloride, calcium carbonate, calcium citrate, calcium gluconate, calcium gluvionate, calcium hydroxide, and calcium oxalate, but is not limited thereto.

Thereafter, the water; and non-solvent of sodium carboxymethyl cellulose powder; Calcium carboxymethyl cellulose powder can be obtained by adding sodium carboxymethyl cellulose powder or carboxymethyl cellulose powder to a solution containing a calcium compound and stirring it using a stirrer, etc. At this time, heating can be performed to increase reaction efficiency.

The content of the calcium compound in the calcium compound solution may be 0.25 molar ratio or more, 0.5 molar ratio or more, or 1 molar ratio or more compared to sodium carboxymethyl cellulose powder or carboxymethyl cellulose powder. When the amount of the calcium compound satisfies this range, calcium carboxymethyl cellulose powder containing an appropriate amount of calcium ions can be produced.

Afterwards, the obtained calcium carboxymethyl cellulose powder was mixed with water; and a non-solvent of calcium carboxymethyl cellulose, washed with water, further washed again with a non-solvent of calcium carboxymethyl cellulose powder, and then dried.

The non-solvent of the calcium carboxymethyl cellulose powder may be alcohol. The alcohol may be used as one type or a mixture of two or more types such as methanol, ethanol, propanol, etc., but is not limited thereto.

According to one embodiment of the present invention, as described above, the composition for forming a hemostatic layer may further include water-soluble chitosan compound powder.

Specifically, according to one embodiment of the present invention, the composition for forming a hemostatic layer includes calcium carboxymethyl cellulose powder alone, a mixture of calcium carboxymethyl cellulose powder and sodium carboxymethyl cellulose powder, or calcium carboxymethyl cellulose. It may include a mixture of powder and water-soluble chitosan compound powder, or a mixture of calcium carboxymethyl cellulose powder, sodium carboxymethyl cellulose powder, and water-soluble chitosan compound powder. Details regarding the calcium carboxymethyl cellulose powder and water-soluble chitosan compound powder are the same as described above.

In addition, the composition for forming a hemostatic layer may further include additives depending on the characteristics required for the hemostatic material, examples of which include biologically active substances, softeners, hemostatic substances, antibacterial substances, cells, enzymes, antigens, pigments, etc. You can.

According to one embodiment of the present invention, before applying the composition for forming a hemostatic layer, the step of adding a water-containing solvent to at least one surface of the sheet-like substrate may be further included, or applying the composition for forming a hemostatic layer After the step, the step of exposing the applied sheet-like substrate to water vapor may be further included. Or, before the step of applying the composition for forming a hemostatic layer, it further includes the step of adding a water-containing solvent to at least one surface of the sheet-like substrate, and at the same time, after the step of applying the composition for forming a hemostatic layer, the applied sheet-like substrate It may also include both exposure steps to water vapor.

After wetting at least one side of the sheet-like substrate with a water-containing solvent, for example, a water/ethanol mixed solvent at a volume ratio of 30/30, the composition for forming a hemostasis layer is applied to the water-soluble or water-swellable composition for forming a hemostasis layer in the water-soluble solvent. By partially dissolving it in the included water and then going through a drying process, it can be easily attached to the substrate without a separate binding ingredient. At this time, in order to improve the flexibility of the final hemostatic material, glycerol may be added to the water-containing solvent in a small amount (for example, 1 to 10 volume ratio compared to the water-containing solvent). In addition, in order to improve the convenience and flexibility of the process, the composition for forming a hemostatic layer is applied to the substrate and then sprayed with a water-containing solvent, for example, water containing a small amount of softener to partially dissolve the composition for forming a hemostatic layer and then dried. It can be easily attached to the substrate even without a binding component.

At this time, the water-containing solvent may be water or a mixture of water and an organic solvent. The organic solvent used at this time includes non-solvents of the composition for forming a hemostatic layer, for example, alcohol such as methanol, ethanol, and propanol. In the case of a mixture of water and organic solvent, the volume ratio of water and organic solvent is 100/0. to 10/90, specifically 100/0 to 20/80, and specifically 100/0 to 30/70. When this volume ratio is satisfied, the composition for forming a hemostatic layer can be partially dissolved and easily attached to the substrate. In the case of organic solvents, it is desirable to have a lower boiling point than water.

According to one embodiment of the present invention, an additional gamma ray irradiation step may be performed after manufacturing the hemostatic material.

This gamma ray irradiation step has the effect of sterilizing hemostatic materials applied directly to the skin without using heat or chemicals. In particular, treatment by gamma irradiation can also be performed even when the hemostatic material is sealed as a final product. For example, the gamma ray irradiation may be performed at a dose of 5 to 30 kGy.

Hereinafter, the present invention will be described in detail through examples to aid understanding. However, the embodiments according to the present invention may be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Example 1 Preparation of hemostatic material containing Ca-CMC powder

<Step 1> Preparation of calcium carboxymethyl cellulose powder

CaCl ₂ was dissolved in 2,500 mL of a mixed solution of ethanol (94.5%) and distilled water at a volume ratio of 80:20 to prepare a 0.41 mol/L solution, and sodium carboxymethyl cellulose powder (Na-CMC) was added thereto. , degree of substitution 0.6) was added and treated with a stirrer at 60°C for about 60 minutes to prepare calcium carboxymethyl cellulose (Ca-CMC) powder.

The calcium carboxymethyl cellulose powder prepared in this way was washed with water for 20 minutes using a mixed solution of ethanol and distilled water (80:20 by volume), and then filtered through a vacuum filtration device with a mixed solution of ethanol and distilled water (80:20 by volume) at 60°C. Washed twice. To remove moisture, it was washed twice with 99.5% methanol through a reduced pressure filtration device. The washed calcium carboxymethyl cellulose powder was sufficiently dried at 50°C in a vacuum oven. At this time, the average particle size of the obtained calcium carboxymethyl cellulose powder was 81 ㎛, and when measured by ICP-OES, the weight fraction of Ca was 4.7% and the weight fraction of Na was 0.9%.

<Step 2> Preparation of hemostatic material containing Ca-CMC powder (90 g/m ² )

Mix 99.5% methanol and distilled water at a volume ratio of 80:20 and stir vigorously with a stirrer to prepare a dispersion medium. Add the calcium carboxymethyl cellulose powder prepared in step 1 above, knead sufficiently, and then mix manually. A plain type cotton spunlace non-woven fabric with a basis weight of 40 g/m ² was placed on a hand sheet former as a strainer to remove the dispersion medium, forming a hemostatic layer of calcium carboxymethyl cellulose powder on one side of the non-woven fabric. , Afterwards, it was dried at 50°C in a convection oven to prepare a hemostatic material. At this time, the content of the hemostatic layer in the hemostatic material was 90 g/m ² per unit area of the nonwoven fabric, and the basis weight of the hemostatic material was 130 g/m ² . A photograph of the appearance of the prepared hemostatic material is shown in Figure 1a.

Example 2 Preparation of hemostatic material containing Ca-CMC powder/water-soluble chitosan powder (weight ratio 70/30)

Instead of using calcium carboxymethyl cellulose powder alone, the calcium carboxymethyl cellulose powder prepared in step 1 of Example 1 and water-soluble chitosan powder (average diameter 235 ㎛, degree of deacetylation 80%, weight average molecular weight 183,000 g/mol) were mixed at 70 °C. A hemostatic material in which a hemostatic layer of calcium carboxymethyl cellulose powder and water-soluble chitosan powder was formed on one side of the nonwoven fabric was manufactured in the same manner as in Example 1, except that it was used at a weight ratio of :30. At this time, the content of the hemostatic layer in the hemostatic material was 90 g/m ² per unit area of the nonwoven fabric, and the basis weight of the hemostatic material was 130 g/m ² .

Example 3 Preparation of hemostatic material containing Ca-CMC powder/water-soluble chitosan powder (weight ratio 50/50)

A hemostatic material in which a hemostatic layer of calcium carboxymethyl cellulose powder and water-soluble chitosan powder was formed on one side of the nonwoven fabric in the same manner as in Example 2, except that calcium carboxymethyl cellulose powder and water-soluble chitosan powder were used at a weight ratio of 50:50. Manufactured. At this time, the content of the hemostatic layer in the hemostatic material was 90 g/m ² per unit area of the nonwoven fabric, and the basis weight of the hemostatic material was 130 g/m ² .

Example 4 Preparation of hemostatic material containing Ca-CMC powder/water-soluble chitosan powder (weight ratio 30/70)

A hemostatic material in which a hemostatic layer of calcium carboxymethyl cellulose powder and water-soluble chitosan powder was formed on one side of the nonwoven fabric in the same manner as in Example 2, except that calcium carboxymethyl cellulose powder and water-soluble chitosan powder were used at a weight ratio of 30:70. Manufactured. At this time, the content of the hemostatic layer in the hemostatic material was 90 g/m ² per unit area of the nonwoven fabric, and the basis weight of the hemostatic material was 130 g/m ² .

Example 5 Preparation of hemostatic material containing Ca-CMC powder/water-soluble chitosan powder (weight ratio 50/50)

Calcium carboxymethyl cellulose powder and water-soluble chitosan powder are used in a weight ratio of 50:50, except that the content of the hemostatic layer is 70 g/m ² per unit area of nonwoven fabric, and the basis weight of the hemostatic material is 110 g/m ² Then, a hemostatic material was manufactured in the same manner as in Example 2.

Example 6 Preparation of hemostatic material containing Ca-CMC powder/water-soluble chitosan powder (weight ratio 50/50)

Calcium carboxymethyl cellulose powder and water-soluble chitosan powder are used in a weight ratio of 50:50, except that the content of the hemostatic layer is 50 g/m ² per unit area of nonwoven fabric, and the basis weight of the hemostatic material is 90 g/m ² Then, a hemostatic material was manufactured in the same manner as in Example 2.

Example 7 Preparation of hemostatic material containing Ca-CMC powder/water-soluble chitosan powder (weight ratio 50/50)

Calcium carboxymethyl cellulose powder and water-soluble chitosan powder are used in a weight ratio of 50:50, except that the content of the hemostatic layer is 30 g/m ² per unit area of nonwoven fabric, and the basis weight of the hemostatic material is 70 g/m ² Then, a hemostatic material was manufactured in the same manner as in Example 2.

Example 8 Preparation of hemostatic material containing Ca-CMC powder/water-soluble chitosan powder (weight ratio 50/50) (perforated spunlace)

Calcium carboxymethyl cellulose powder and water-soluble chitosan powder are used in a weight ratio of 50:50, and instead of spunlace nonwoven fabric made of plain type cotton with a basis weight of 40 g/m ² , a perforated type cotton material spun with a basis weight of 40 g/m ² is used. A lace nonwoven fabric was used as a filter, and the content of the hemostatic layer was 90 g/m ² per unit area of the nonwoven fabric, and the basis weight of the hemostatic material was 130 g/m ^2. Hemostatic material was prepared in the same manner as in Example 2. was manufactured. A photograph of the appearance of the prepared hemostatic material is shown in Figure 1b.

Comparative Example 1 Preparation of hemostatic material containing water-soluble chitosan powder

Hemostatic material was prepared in the same manner as step 2 of Example 1, except that water-soluble chitosan powder (average diameter 235 ㎛, degree of deacetylation 80%, weight average molecular weight 183,000 g/mol) was used instead of calcium carboxymethyl cellulose powder. Manufactured. At this time, the content of the hemostatic layer in the hemostatic material was 90 g/m ² per unit area of the nonwoven fabric, and the basis weight of the hemostatic material was 130 g/m ² .

Experimental example: Observation of calcium and sodium content (ICP-OES)

In order to confirm whether calcium ions were introduced by calcium treatment in <Step 1> of Example 1, the contents of calcium ions and sodium ions in carboxymethyl cellulose powder before and after calcium treatment were measured using inductively coupled plasma spectroscopy (ICP-OES). Measurements were made three times and the average value was obtained.

As a result of ICP analysis, before calcium treatment, Na atoms were detected from sodium carboxymethyl cellulose (weight ratio of Na: 4.78%), and Ca atoms were not detected. After calcium treatment, Na atoms were detected (weight ratio of Na atoms: 0.91%) and Ca atoms were detected (weight ratio of Ca: 4.73%). From this, it was confirmed that Ca ions were effectively introduced, and the weight ratio of Ca/Na was 84/16.

In the case of sodium carboxymethyl cellulose that has not been treated with calcium ions, a slight gel blocking phenomenon occurs and the absorption rate is slow, whereas in the case of sodium carboxymethyl cellulose that has been treated with calcium ions, the divalent calcium ions combine with the carboxyl group of carboxymethyl cellulose to form carboxymethyl cellulose. By inducing cross-linking between cellulose, the gel blocking phenomenon is reduced and the absorption speed becomes very fast. Additionally, calcium is released upon contact with blood, which is expected to further promote blood coagulation.

Experimental example : Evaluation of blood coagulation characteristics 1 - Blood volume 50 ㎕/cm ²

The blood coagulation properties of the hemostatic materials prepared in Examples 1 to 4 and Comparative Example 1 were evaluated.

Blood coagulation characteristics were evaluated by the blood clotting index (BCI) defined by the following equation 1. In this case, the absorbance for evaluating blood coagulation characteristics in equation 1 was obtained from a specimen of hemostatic material with a cross-sectional area of 1 cm × 1 cm (width × height). 50㎕ of a mixture of blood and anticoagulant (sodium citrate, 3.8w/v%) at a volume ratio of 9:1 was added dropwise, and 5㎕ of 0.2M CaCl ₂ aqueous solution was added dropwise, followed by incubation in an incubator at 37°C. , After coagulating the blood for 5 minutes, the blood that did not participate in the coagulation was eluted again with 6.25 ml of distilled water, 200 ㎕ of the eluate was collected, the absorbance [AB] was measured at a wavelength of 540 nm, and 200 ㎕ of distilled water was dissolved in 540 ㎖. The absorbance [AW] was measured at a wavelength of nm, and the absorbance was calculated using Equation 2 below to exclude the influence of distilled water contained in the blood eluate on the absorbance.

In addition, the absorbance [AI] of the used blood in Equation 1 is obtained by mixing 50 ㎕ of used blood with 6.25 ㎖ of distilled water, collecting 200 ㎕ of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and mixing 200 ㎕ of distilled water at 540 ㎕. After measuring the absorbance [AW] at a wavelength of nm, it was calculated using Equation 3 below to exclude the influence of the absorbance of distilled water contained in the blood eluate.

[Equation 1]

Blood coagulation index (BCI, %) = blood coagulation characteristic evaluation absorbance [AS] *100/absorbance of used blood [AI]

[Equation 2]

Evaluation of blood coagulation characteristics Absorbance [AS] = Absorbance of blood eluate [AB] - Absorbance of distilled water [AW]

[Equation 3]

Absorbance of used blood [AI] = Absorbance of blood [AB] - Absorbance of distilled water [AW].

Photos and blood coagulation index graphs of the above evaluation results are shown in Figures 2 and 3, respectively.

Experimental example: Observation of blood clot shape (SEM)

Blood coagulation characteristics were measured by mixing blood and an anticoagulant (sodium citrate, 3.8 w/v%) in a specimen of the hemostatic material of Examples 1 to 4 and Comparative Example 1 (cross-sectional area 1 cm × 1 cm (width × height)) at a volume ratio of 9:1. 50㎕ of the mixed solution was added dropwise, 5㎕ of 0.2M CaCl ₂ aqueous solution was added, and coagulated in an incubator at 37°C for 1 minute.

After blood coagulation, blood components were fixed by immersing in 2% paraformaldehyde/phosphate-buffered saline for 2 hours. It was sequentially washed with ethanol/distilled water while gradually increasing the ratio of ethanol, and then dried at room temperature. The sample with fixed blood components was sputter-coated with gold, and the shape was observed using a scanning electron microscope (FE-SEM; Hitachi SU-8010, Hitachi High Technologies Co. Japan), and the results are shown in FIGS. 4A to 4J. Specifically, Example 1 is shown in Figures 4a (100x magnification) and Figure 4b (3,000x magnification), Example 2 is shown in Figures 4c (100x magnification) and Figure 4d (3,000x magnification), and Example 3 is shown in Figures 4e (100x magnification) and FIG. 4f (3,000x magnification), Example 4 in FIG. 4g (100x magnification) and FIG. 4h (3,000x magnification), and Comparative Example 1 in FIG. 4i (100x magnification) and FIG. Each is shown at 4j (3,000 times magnification).

Referring to Figure 3, it was confirmed that the hemostatic materials of Examples 1 to 4 had excellent blood coagulation properties as the blood coagulation index after 1 minute was significantly lower than 20%. In the case of Comparative Example 1, which was a nonwoven fabric to which only water-soluble chitosan powder was attached, the blood coagulation characteristics were significantly poor compared to the Example containing calcium carboxymethyl cellulose.

Referring to FIGS. 4A to 4J, it was observed that fibrin was formed in the hemostatic materials of Examples 1 to 4 even after 1 minute of blood coagulation time. In particular, in the case of Examples 2 to 4, which had a hemostatic layer mixed with calcium carboxymethyl cellulose powder and water-soluble chitosan powder, it was observed that more fibrin was formed compared to Example 1. In Comparative Example 1, as the water-soluble chitosan powder was dissolved and the surface became smooth, it was relatively difficult to observe fibrin formation.

Considering FIGS. 2, 3, 4a to 4j comprehensively, the hemostatic material of Examples 1 to 4 having a hemostatic layer containing calcium carboxymethyl cellulose powder is better than the hemostatic material of Comparative Example 1 having a hemostatic layer containing only water-soluble chitosan powder. It was found that the hemostatic material showed excellent blood coagulation properties, and that the hemostatic materials of Examples 2 to 4, which were a composite of calcium carboxymethyl cellulose powder and water-soluble chitosan powder, showed better blood coagulation properties.

Experimental example : Evaluation of blood coagulation characteristics 2 - Blood volume 100 ㎕/cm ²

In order to examine the blood coagulation characteristics in situations where more bleeding occurs, the blood volume was increased and the hemostatic materials of Examples 1 to 8, various currently commercially available hemostatic dressing products in Table 1 (Comparative Examples 2 and 3), and 40 g /m ² Blood coagulation characteristics were evaluated for cotton spunlace nonwoven fabric (Comparative Example 4) and blood (Comparative Example 5).

product name manufacturing company main ingredient Comparative example 2 ^QuikClot® Z-MEDICA Clay mineral (kaolin) attached to cotton gauze Comparative Example 3 ^SURGICEL® ETHICON Oxidized regenerated cellulose Comparative Example 4 cotton gauze 40 g/m ² cotton spunlace nonwoven fabric Comparative Example 5 blood sole

That is, 100㎕ of a mixture of blood and anticoagulant (sodium citrate, 3.8w/v%) at a volume ratio of 9:1 was added dropwise to the specimen, 10㎕ of 0.2M CaCl ₂ aqueous solution was added to coagulate the blood, and then distilled water was used for coagulation. The blood clotting index (BCI) was evaluated in the same manner as the blood coagulation characteristic evaluation 1 described above, except that the blood that did not participate was eluted again in 12.5 ml of distilled water, and the results are shown in Figure 5. It is shown in Figures 7 to 7.

Referring to Figure 5, the hemostatic materials of Examples 1 to 4 are commercially available products, Comparative Examples 2 and 3, compared to Comparative Examples 2 and 3, which are cotton non-woven fabrics, and Comparative Example 5, which are blood, compared to Comparative Examples 2 and 3, which are commercially available cotton non-woven fabrics. In Comparative Example 4, the blood did not coagulate well as the blood coagulation index was over 80% after 1 minute of blood coagulation time. On the other hand, in Examples 1 to 4, the blood remaining without coagulation was small, and the blood coagulation index after 1 minute was significantly lower than 60%, confirming excellent blood coagulation characteristics.

Figure 6 is an evaluation of the hemostatic properties according to the weight of the hemostatic layer attached to the sheet-shaped substrate. Even when the weight of the hemostatic layer was 30 to 70 g/m ² per unit area of the sheet-shaped substrate, the blood coagulation index was 60% or less after 1 minute. In Example 3, where the weight of the hemostatic layer was 90 g/m ² per unit area of the sheet-like substrate, it was confirmed that blood coagulation occurred well with a blood coagulation index of 40% or less after 1 minute.

Figure 7 is a comparison of blood coagulation characteristics according to the shape of the sheet-like substrate. Hemostasis of Example 3 in which a plain-type nonwoven fabric with a liquid absorption of 4.5 g/100 cm ² in 0.9% saline solution was used as the sheet-like substrate. Compared to the material, the hemostatic material of Example 8, which used a perforated type nonwoven fabric with a liquid absorption of 5.0 g/100 cm ² , showed a lower blood coagulation index after 1 minute. If the sheet-type substrate has a high absorbency, blood is absorbed quickly, and in particular, moisture in the blood moves quickly and selectively to the substrate, increasing the possibility that the hemostatic component that acts on the blood coagulation mechanism contained in the hemostatic material will come into contact with blood or water. By selectively absorbing it quickly, blood viscosity increases and blood coagulation appears to accelerate.

The degree of liquid absorption of the substrate was calculated as follows by measuring the weight and area of the dried substrate, immersing it in 0.9% physiological saline solution for 10 minutes, and measuring the weight of the absorbed substrate.

of the description Liquid absorption (g/100cm ² ) = [ After absorption Weight of substrate (g) - before absorption Weight of substrate (g)]/[Area of substrate before liquid absorption ( cm ² )]

Claims (24)

delete As a hemostatic material,
Sheet-like substrate; and
A hemostatic layer formed on at least one side of the sheet-like substrate and containing calcium carboxymethylcellulose powder,
The hemostatic material has a blood clotting index (BCI) of 40% or less,
The blood coagulation index is defined by the following equation 1, where the blood coagulation characteristic evaluation absorbance in equation 1 is the blood and anticoagulant (sodium citrate, 3.8w) in a hemostatic material measuring 1 cm × 1 cm (width × height). /v%) in a volume ratio of 9:1 was added dropwise, 5 μl of 0.2M CaCl ₂ aqueous solution was added and coagulated in an incubator at 37°C for 1 minute, and then the blood that did not participate in the coagulation was again washed in 6.25% distilled water. Elute in ㎖, collect 200㎕ of the eluate and measure the absorbance [AB] at a wavelength of 540 nm, measure the absorbance [AW] of 200㎕ of distilled water at a wavelength of 540 nm, and then measure the effect of the distilled water contained in the blood eluate on the absorbance. Calculated by equation 2 below to exclude,
The absorbance [AI] of used blood in Equation 1 is obtained by mixing 50 ㎕ of used blood with 6.25 ㎖ of distilled water, collecting 200 ㎕ of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and measuring 200 ㎕ of distilled water at 540 nm. Hemostatic material calculated by equation 3 below to exclude the absorbance effect of distilled water contained in the blood eluate after measuring the absorbance [AW] at the wavelength.
[Equation 1]
Blood coagulation index (BCI, %) = blood coagulation characteristic evaluation absorbance [AS] × 100 / absorbance of used blood [AI]
[Equation 2]
Evaluation of blood coagulation characteristics Absorbance [AS] = Absorbance of blood eluate [AB] - Absorbance of distilled water [AW]
[Equation 3]
Absorbance of used blood [AI] = Absorbance of blood [AB] - Absorbance of distilled water [AW]. As a hemostatic material,
Sheet-like substrate; and
A hemostatic layer formed on at least one side of the sheet-like substrate and containing calcium carboxymethylcellulose powder,
The hemostatic material has a blood clotting index (BCI) of 60% or less,
The blood coagulation index is defined by the following equation 1, where the blood coagulation characteristic evaluation absorbance in equation 1 is the blood and anticoagulant (sodium citrate, 3.8w) in a hemostatic material measuring 1 cm × 1 cm (width × height). /v%) in a volume ratio of 9:1 was added dropwise, 10 μl of 0.2M CaCl ₂ aqueous solution was added and coagulated in an incubator at 37°C for 1 minute, and the blood that did not participate in the coagulation was again washed in 12.5% distilled water. Elute in ㎖, collect 200㎕ of the eluate and measure the absorbance [AB] at a wavelength of 540 nm, measure the absorbance [AW] of 200㎕ of distilled water at a wavelength of 540 nm, and then measure the effect of the distilled water contained in the blood eluate on the absorbance. Calculated by equation 2 below to exclude,
The absorbance [AI] of used blood in Equation 1 is obtained by mixing 100 ㎕ of used blood with 12.5 ㎖ of distilled water, collecting 200 ㎕ of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and measuring 200 ㎕ of distilled water at 540 nm. Hemostatic material calculated by equation 3 below to exclude the absorbance effect of distilled water contained in the blood eluate after measuring the absorbance [AW] at the wavelength.
[Equation 1]
Blood coagulation index (BCI, %) = blood coagulation characteristic evaluation absorbance [AS] ×100/absorbance of used blood [AI]
[Equation 2]
Evaluation of blood coagulation characteristics Absorbance [AS] = Absorbance of blood eluate [AB] - Absorbance of distilled water [AW]
[Equation 3]
Absorbance of used blood [AI] = Absorbance of blood [AB] - Absorbance of distilled water [AW]. According to paragraph 2 or 3,
A hemostatic material wherein the hemostatic layer further includes water-soluble chitosan compound powder. According to paragraph 4,
A hemostatic material in which the weight ratio of calcium carboxymethylcellulose powder and water-soluble chitosan compound powder in the hemostatic layer is 99:1 to 1:99. According to paragraph 2 or 3,
A hemostatic material wherein the hemostatic layer further includes sodium carboxymethylcellulose. delete delete According to paragraph 2 or 3,
A hemostatic material in which the calcium carboxymethylcellulose powder has an average particle diameter of 5 to 500㎛. According to paragraph 2 or 3,
A hemostatic material having a degree of substitution of the calcium carboxymethylcellulose of 0.3 to 3.0. According to paragraph 4,
A hemostatic material in which the water-soluble chitosan compound powder has an average particle diameter of 100 to 1,000 ㎛. According to paragraph 4,
A hemostatic material in which the water-soluble chitosan compound has a degree of deacetylation of 60 to 100% and a weight average molecular weight of 5,000 to 500,000 g/mol. According to paragraph 4,
A hemostatic material wherein the water-soluble chitosan compound is one or more types of chitosan and chitosan derivatives. According to paragraph 2 or 3,
A hemostatic material wherein the sheet-like substrate includes at least one selected from the group consisting of non-woven fabric, fabric, knitted fabric, sponge, and polymer film. According to paragraph 2 or 3,
A hemostatic material wherein the sheet-like substrate is a perforated spunlace nonwoven. According to paragraph 2 or 3,
A hemostatic material in which the sheet-like substrate has a liquid absorption rate of 4.0 g/100 cm ² or more based on 0.9% physiological saline solution. According to paragraph 2 or 3,
A hemostatic material wherein the hemostatic layer has a weight of 20 to 200 g/m ² per unit area of the sheet-like substrate. According to paragraph 2 or 3,
A hemostatic material in which the hemostatic layer is formed as a pattern layer on at least one surface of the sheet-like substrate. According to clause 18,
The pattern layer is selected from the group consisting of dot, circle, polygon, doughnut, stripe, step, concavo-convex, and grid. Hemostatic material that is one selected type or a combination of two or more types. Preparing a sheet-like substrate;
Applying a composition for forming a hemostatic layer containing calcium carboxymethylcellulose powder on at least one side of the sheet-like substrate; and
The method for producing the hemostatic material of claim 2 or 3, comprising the step of drying the sheet-like substrate. According to clause 20,
Before applying the composition for forming a hemostatic layer, it further includes adding a water-containing solvent to at least one surface of the sheet-like substrate, or
After applying the composition for forming a hemostatic layer, the method of producing a hemostatic material further includes exposing the applied sheet-like substrate to water vapor. According to clause 20,
A method of producing a hemostatic material further comprising water-soluble chitosan compound powder in the composition for forming a hemostatic layer. According to clause 21,
A method of producing a hemostatic material wherein the hydrous solvent is water or a mixture of water and an organic solvent. According to clause 20,
A method for producing a hemostatic material, further comprising a softener in the composition for forming a hemostatic layer.