KR102475935B1 - Absorbable hemostatic pad comprising collagen, carboxymethyl cellulose-based compound and thrombin, and manufacturing method thereof - Google Patents

Abstract

An absorbable hemostatic sponge pad according to the present invention is manufactured by freeze-drying an aqueous solution obtained by mixing collagen, a carboxymethyl cellulose-based compound, and thrombin The absorbable hemostatic sponge pad can be used quickly and conveniently for bleeding patients whose life is at risk in scenes for first aid, operating rooms, emergency rooms, and the like; has an excellent hemostatic effect; has a high degree of fluid absorption and retention, and thus can absorb a large amount of body fluid and blood discharged from wounds or surgical sites; has excellent biocompatibility; and has biodegradability.

Description

Absorbable hemostatic pad comprising collagen, carboxymethyl cellulose-based compound and thrombin, and manufacturing method thereof

The present invention relates to an absorbable hemostatic pad containing collagen, a carboxymethyl cellulose-based compound, and thrombin, and more specifically, it can be used quickly and conveniently for bleeding patients competing for vision in first aid sites, operating rooms, emergency rooms, etc., and has excellent hemostasis. The present invention relates to a biodegradable absorbable hemostatic pad that has excellent biocompatibility and can absorb a large amount of blood and exudate discharged from wounds or surgical sites because of its high liquid absorption and retention.

In addition, the present invention also includes a method for manufacturing such an absorbent hemostatic pad.

BACKGROUND OF THE INVENTION BACKGROUND BACKGROUND OF THE INVENTION BACKGROUND OF THE INVENTION BACKGROUND OF THE INVENTION BACKGROUND OF THE INVENTION BACKGROUND OF THE INVENTION BACKGROUND OF THE INVENTION Bleeding occurs when blood vessels are injured by physical traumas including surgical procedures. Depending on the degree of damage, hemorrhage can result in a degree of blood loss that can affect the normal body function of the individual, and in the case of bleeding in the non-expandable cavity of the bone, the blood flowing out of the blood vessel accumulates and becomes soft. It can also cause damage due to the increased pressure on the tissue. If bleeding is left untreated, bleeding is stopped by a physiological process characterized by a complex chain reaction between blood vessels, platelets and plasma factors. This process is called physiological hemostasis. In the case of mild superficial bleeding, this physiological hemostasis is sufficient to stop the bleeding.

However, if the bleeding results from a more serious injury, especially if these injuries involve large arteries or blood leaks from larger mucosal surfaces, or from cavities with no outlet, surgical and/or medical treatment is recommended. Red hemostatic means are required. Surgical bleeding control may include ligation or suturing of ruptured blood vessels, filling with cotton balls in the case of cavities, application of heated instruments, caustic agents, or coagulation of tissue surfaces exposed to ruptured blood vessels by heated air. have.

Appropriately sized blocks, plates, and films of biologically absorbable hemostatic sponges may be applied to the wound site to assist in surgical hemostasis.

Meanwhile, for effective hemostasis, various hemostatic agents may be mixed and used. For example, collagen can absorb blood from a bleeding site and attract platelets to produce a hemostatic effect, and collagen can be used together with thrombin.

However, when first aid is required at the scene of an accident, it is time-consuming and inconvenient to mix and use these various hemostatic components for bleeding patients competing for time in an emergency room or operating room, and there is a possibility of contamination when mixing.

Therefore, for effective hemostasis, there is a need for a hemostatic agent made by mixing various hemostatic components.

On the other hand, the hemostatic sponge should be able to absorb and retain exudate or blood discharged from a surgical site or wound, but the existing hemostatic sponge has a problem in that it lacks such absorption and retention capabilities.

The present invention has been proposed to solve the above problems, and can be used quickly and conveniently for bleeding patients who compete for time in first aid sites, operating rooms, emergency rooms, etc. The purpose is to provide a biodegradable absorbable hemostatic pad capable of absorbing a large amount of body fluid and blood discharged from the surgical site and having excellent biocompatibility.

Another object of the present invention is to provide a method for manufacturing such an absorbent hemostatic pad.

In order to achieve the above object, the absorbent hemostatic pad according to a preferred embodiment of the present invention is made by freeze-drying an aqueous solution in which collagen, a carboxymethyl cellulose-based compound, and thrombin are mixed.

The hemostatic pad contains 1 to 20 weight of carboxymethyl cellulose compound (preferably 1 to 10 weight) and 1 to 10 weight of thrombin per weight of collagen, and a plurality of pores are formed on the surface and inside by freeze drying and at least some of these pores have a sponge structure connected to each other.

The carboxymethyl cellulose-based compound is biocompatible and biodegradable as an absorbent carrier, and collagen and thrombin are dispersed in the carrier.

The absorbent hemostatic pad may have a fluid absorption of greater than 40 and less than 80, preferably greater than 50 and less than 70, and more preferably greater than 55 and less than 68. In comparison, the liquid absorption of the existing absorbent hemostatic pad is approximately 10 to less than 40. The degree of liquid absorption can be calculated by the formula below.

[ceremony]

(The weight of the hemostatic pad after liquid absorption is measured after immersing the hemostatic pad in 0.9% physiological saline at 25°C for 10 minutes)

The degree of fluid retention of the absorbent hemostatic pad may be greater than 30 and less than 60, preferably greater than 35 and less than 50, and more preferably greater than 40 and less than 50. The degree of liquid retention can be calculated by the formula below.

[ceremony]

(The weight of the hemostatic pad after pressurization was obtained by immersing the hemostatic pad in 0.9% physiological saline at 25 ° C for 10 minutes, applying a pressure of 40 mmHg to the hemostatic pad absorbed for 1 minute, and then measuring the weight)

Another aspect of the present invention, a method for manufacturing an absorbent hemostatic pad, includes (a) mixing collagen, a carboxymethyl cellulose compound, and thrombin with water and then stirring; And, (b) freeze-drying the stirred mixed solution; may include.

In step (a), the mixing ratio of the three components is preferably 0.1 to 2% (w/v) of collagen, 0.1 to 2% (w/v) of carboxymethyl cellulose compound, and 50 to 500 IU/ml of thrombin. .

More preferably, the carboxymethyl cellulose-based compound is sodium carboxymethyl cellulose, and the mixing ratio of the three components is collagen 0.1-1% (w / v), carboxymethyl cellulose-based compound 0.1-1% (w /v), thrombin 50-200 IU/ml.

The absorbent hemostatic pad according to the present invention can be quickly and conveniently used for bleeding patients competing for time in emergency treatment sites, operating rooms, emergency rooms, etc. It can absorb a large amount of body fluids and blood, etc., has excellent biocompatibility and is biodegradable.

In addition, the present invention provides a method for manufacturing such an absorbent hemostatic pad.

1 is a flow chart showing a manufacturing process of an absorbent hemostatic pad according to a preferred embodiment of the present invention.

Hereinafter, the present invention will be described in detail with reference to the accompanying drawings. Prior to this, the terms or words used in this specification and claims should not be construed as being limited to the usual or dictionary meaning, and the inventor appropriately uses the concept of the term in order to explain his/her invention in the best way. It should be interpreted as a meaning and concept consistent with the technical idea of the present invention based on the principle that it can be defined. Therefore, since the embodiments described in this specification and the configurations shown in the drawings are merely embodiments of the present invention and do not represent all of the technical spirit of the present invention, various equivalents that can replace them at the time of the present application It should be understood that there may be variations and examples.

An absorbent hemostatic pad according to a preferred embodiment of the present invention is made by freeze-drying an aqueous solution in which collagen, a carboxymethyl cellulose-based compound, and thrombin (or thrombin precursor) are mixed. Therefore, the absorbent hemostatic pad has a sponge structure in which a plurality of pores are formed on the surface and inside thereof by freeze drying, and at least some of the pores are connected to each other.

In the following, each component will be described first.

(1) thrombin or its precursor

In the present invention, known thrombin and its precursors may be used. As is known, thrombin is a proteolytic enzyme related to blood coagulation, and catalyzes a reaction in which soluble fibrinogen in the blood, which is the essence of blood coagulation, is hydrolyzed and changed into insoluble fibrin. In addition, thrombin can induce platelet activation in the process of forming fibrin by activation of blood coagulation factor, which is a secondary hemostasis process.

(2) Collagen

First, collagen is preferably type 1 collagen made using pig dermis, but is not necessarily limited thereto. Commercially available collagen may also be used. This collagen is obtained by treating the dermis with pepsin to remove telopeptides, and is suitable for medical use. In addition, the collagen may be freeze-dried to have a sponge form. This collagen sponge has a structure in which many pores are included on its surface and inside, and at least some of these pores are interconnected.

(3) carboxymethyl cellulose compounds

The carboxymethyl cellulose-based compound refers to carboxymethyl cellulose or a salt thereof, and the salt may include sodium carboxymethyl cellulose (CMC), carboxymethyl cellulose potassium, or a mixture thereof, but is not necessarily limited thereto. it is not going to be Preferably, the carboxymethyl cellulose-based compound is carboxymethyl cellulose sodium (Sodium CMC).

In the absorbent hemostatic pad according to the present invention, the carboxymethyl cellulose-based compound is an absorbent carrier, which has excellent biocompatibility and is biodegradable, and collagen and thrombin are dispersed in the carrier.

The carboxymethyl cellulose-based compound has excellent liquid absorption and liquid retention properties at the same time. Therefore, when used as a component of a hemostatic sponge, it can absorb and retain a large amount of blood or exudate from a bleeding site and at the same time maintain the shape of the hemostatic sponge.

For reference, the degree of liquid absorption is calculated by measuring the weight of the hemostatic sponge (hemostatic pad) (weight before liquid absorption), then immersing in 0.9% physiological saline at 25 ° C for 10 minutes, and then measuring the weight after liquid absorption and calculating the following formula. .

[Equation 1]

The degree of liquid retention was measured by measuring the weight (weight before liquid absorption) of the hemostatic sponge (hemostatic pad), immersing in 0.9% physiological saline at 25 ° C for 10 minutes, and then applying 40 mmHg to the hemostatic sponge (hemostatic pad) absorbed. After applying pressure for 1 minute, measure the weight of the hemostasis sponge (hemostasis pad) (weight after pressure) and calculate it by the following formula.

[Equation 2]

According to the present invention, the absorption degree of the absorbent hemostatic pad may be greater than 40 and less than 80, preferably greater than 50 and less than 70, and more preferably greater than 55 and less than 68.

In addition, the degree of fluid retention of the absorbent hemostatic pad may be greater than 30 and less than 60, preferably greater than 35 and less than 50, and more preferably greater than 40 and less than 50.

On the other hand, 'sponge made by lyophilizing a mixture of collagen and thrombin (i.e., a sponge containing collagen and thrombin but not containing carboxymethyl cellulose-based compounds)' cannot measure liquid absorption and retention because the sponge gels. Therefore, it can be seen that if the hemostatic sponge (hemostatic pad) contains a carboxymethyl cellulose-based compound such as sodium CMC, it has excellent liquid absorption and excellent shape stability, maintaining a high level of liquid absorption even after pressurization, thereby exhibiting excellent liquid retention. can That is, it can be seen that if the hemostatic sponge (hemostatic pad) contains a carboxymethyl cellulose-based compound such as sodium CMC, most of the hemostatic components can be retained therein.

[Method of manufacturing absorbent hemostatic pad]

Hereinafter, a method for manufacturing an absorbent hemostatic pad will be described. 1 is a flow chart showing a method of manufacturing an absorbable hemostatic pad.

First, collagen, a carboxymethyl cellulose-based compound, and thrombin (or thrombin precursor) are mixed with water and stirred (S10).

The collagen is preferably type 1 collagen made using pig dermis. Type 1 collagen may be commercially available. This collagen is obtained by treating the dermis with pepsin to remove telopeptides, and is suitable for medical use. In addition, the collagen may be in the form of a powder, but may also be in the form of a lyophilized sponge. The collagen sponge includes many pores on its surface and inside, and at least some of these pores have a structure connected to each other.

The carboxymethyl cellulose-based compound may be sodium carboxymethyl cellulose (Sodium CMC).

The mixing ratio of the three components may be 1 to 20 mg of collagen, 1 to 20 mg of a carboxymethyl cellulose compound such as Sodium CMC, and 50 to 500 IU of thrombin (or a precursor thereof) in 1 ml of the mixed solution. That is, the concentration of collagen in the mixed solution may be 0.1 to 2% (w/v), 0.1 to 2% (w/v) of a carboxymethyl cellulose compound, and 50 to 500 IU/ml of thrombin (or a precursor thereof).

If the mixing ratio of collagen is less than 0.1% (w/v), regeneration and recovery of damaged tissue and inhibition of scar formation are not performed properly. And, if the mixing ratio of thrombin is less than 50 IU/ml, the hemostatic effect is reduced. If the mixing ratio of collagen is more than 2% (w / v) or the mixing ratio of thrombin is more than 500 IU / ml, it is not preferable because the increase in hemostatic effect is insignificant compared to the additional amount of collagen and thrombin.

And, if the mixing ratio of the carboxymethyl cellulose compound is less than 0.1% (w/v), the hemostatic pad cannot sufficiently absorb exudate or blood. If the mixing ratio of the carboxymethyl cellulose-based compound exceeds 2% (w/v), it is not preferable because the increase in absorption of exudate or blood is insignificant compared to the amount of the added carboxymethyl cellulose-based compound.

Preferably, the mixing ratio of the three components may be collagen 0.1 ~ 1% (w / v), carboxymethyl cellulose compound 0.1 ~ 1% (w / v), thrombin 50 ~ 200 IU / ml.

When the stirring is completed, the mixed solution is poured into a tray and freeze-dried to prepare a sponge pad for hemostasis (S20). And, after lyophilization is completed, blister packaging is performed. Sponges for hemostasis (hemostatic agents) have a structure in which a plurality of pores are included in the inside and on the surface, and at least some of the pores are connected to each other.

The component ratio (weight ratio) of the prepared absorbent hemostatic pad is that the weight of the carboxymethyl cellulose-based compound is 1 to 20 (preferably, the weight of the carboxymethyl cellulose-based compound is 1 to 10), when collagen is 1 weight. The weight of thrombin can be 1-10.

When the amount of thrombin is less than 1 weight relative to 1 weight of collagen, the hemostatic effect is poor, and when the amount of thrombin exceeds 10 weight relative to 1 weight of collagen, the amount of collagen is relatively reduced, resulting in regeneration and recovery of damaged tissues and formation of scars. Suppression does not work properly. And, if the mixing ratio of the carboxymethyl cellulose-based compound is less than 1 relative to 1 weight of collagen, the carboxymethyl cellulose-based compound cannot have excellent liquid absorption and liquid retention performance, so it absorbs and retains a large amount of blood or exudate from the bleeding site. It can be difficult to do. In addition, when the mixing ratio of the carboxymethyl cellulose-based compound exceeds 20 relative to 1 weight of collagen, the increase in liquid absorption and liquid retention is insignificant compared to the amount of the added carboxymethyl cellulose-based compound, which is not preferable.

[exam]

Hereinafter, an experimental example will be described to aid understanding of the present invention. However, the experimental examples according to the present invention may be modified in various forms, and the scope of the present invention should not be construed as being limited to the following experimental examples. Experimental examples of the present invention are provided to more completely explain the present invention to those skilled in the art.

(1) Example 1

An absorbent hemostatic pad is prepared by the method described in the above 'Method of Manufacturing Absorbent Hemostatic Pad'. Specifically, 0.5% (w/v) of collagen, 1.2% (w/v) of sodium carboxymethyl cellulose (CMC), and 200 IU/ml of thrombin were mixed in ultrapure water (UPW) and stirred.

When the stirring is completed, the mixed solution is poured into a tray and lyophilized to prepare a sponge pad for hemostasis.

(2) Comparative Example 1

An absorbent hemostatic pad was prepared in the same manner as in Example 1, except that the mixing ratio of sodium carboxymethyl cellulose (Sodium CMC) was 0.05% (w/v).

(3) Comparative Example 2

An absorbent hemostatic pad was prepared in the same manner as in Example 1, except that sodium carboxymethyl cellulose (Sodium CMC) was not mixed with ultrapure water (UPW). That is, the absorbent hemostatic pad of Comparative Example 2 contains collagen and thrombin but does not contain sodium carboxymethyl cellulose (Sodium CMC).

(4) Liquid Absorption and Liquid Retention Test

The absorbent hemostatic pads of Example 1 and Comparative Examples 1 and 2 were tested for liquid absorption and liquid retention.

The degree of liquid absorption is calculated by the following formula by measuring the weight (weight before liquid absorption) of a hemostatic sponge (hemostatic pad), then immersing in 0.9% physiological saline at 25 ° C. for 10 minutes, and measuring the weight after liquid absorption.

[Equation 1]

The degree of liquid retention is measured by measuring the weight (weight before liquid absorption) of the hemostatic sponge (hemostatic pad), then immersing in 0.9% physiological saline at 25 ° C for 10 minutes, and then applying 40 mmHg to the hemostatic sponge (hemostatic pad) absorbed. After applying a pressure of 1 minute, measure the weight of the hemostasis sponge (hemostatic pad) (weight after pressure) and calculate it by the following formula.

[Equation 2]

The results of testing the absorbent hemostatic pads of Example 1 and Comparative Examples 1 and 2 for liquid absorption and liquid retention are shown in the table below.

degree of absorption Complementary degree Example 1 63.9 46.3 Comparative Example 1 26 14 Comparative Example 2 Cannot be measured due to gelation Cannot be measured due to gelation

As shown in the table above, in the case of Example 1, it can be seen that the liquid absorption and liquid retention are significantly higher than those of Comparative Examples 1 and 2. In contrast, in Comparative Example 1, since the mixing ratio of sodium carboxymethyl cellulose (Sodium CMC) is less than 0.1% (w/v), it can be seen that the degree of absorption and retention of liquid is very low. It can be seen that it is impossible to measure the degree of liquidity and the degree of preservation.

Therefore, the absorbent hemostatic pad having the composition ratio according to the present invention is different from other conventional absorbent hemostatic pads, for example, absorbable hemostatic pads (having a sponge structure) containing thrombin and collagen but not containing sodium carboxymethyl cellulose (Sodium CMC). It can be seen that the exudate or blood can be absorbed and retained more than the exudate.

Claims (6)

delete delete delete (a) mixing collagen, a carboxymethyl cellulose-based compound, and thrombin in water and stirring; and,
(b) freeze-drying the stirred mixed solution; including,
In the step (a), the mixing ratio of the three components is collagen 0.1-2% (w / v), carboxymethyl cellulose compound 0.1-2% (w / v), thrombin 50-500 IU / ml,
The absorbent hemostatic pad made by the freeze-drying is biocompatible and biodegradable, and the carboxymethyl cellulose-based compound is an absorbent carrier, and collagen and thrombin are dispersed in the carrier,
The carboxymethyl cellulose-based compound is sodium carboxymethyl cellulose,
The absorbent hemostatic pad has a degree of absorption greater than 50 and less than 70 and a degree of retention of greater than 30 and less than 60, and the degree of absorption and retention of fluid is calculated by the formula below.
[ceremony]

Weight of hemostatic pad after liquid absorption: Weight measured after immersing the hemostatic pad in 0.9% physiological saline at 25 ° C for 10 minutes.
Weight of hemostatic pad after pressurization: Weight measured after immersing the hemostatic pad in 0.9% physiological saline at 25 ° C. for 10 minutes and applying a pressure of 40 mmHg to the hemostatic pad absorbed for 1 minute. According to claim 4,
The mixing ratio of the three components is collagen 0.1 ~ 1% (w / v), carboxymethyl cellulose compound 0.1 ~ 1% (w / v), thrombin 50 ~ 200 IU / ml, characterized in that, of the absorbent hemostatic pad manufacturing method. delete

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