KR101588633B1 - Composition and kit for forming gel for hemostasis and adhesion inhibition - Google Patents

Abstract

More particularly, the present invention relates to an oxidized regenerated cellulose having an alkali metal-substituted carboxyl group (-COOM, M: alkali metal) in the form of a short fiber or powder Oxidized Regenerated Cellulose (ORC), which is capable of forming a gel that can be used appropriately and conveniently in an area or situation where it is difficult to apply conventional hemostatic materials such as woven, knitted or nonwoven fabrics to exhibit an excellent hemostatic effect and anti- Compositions and kits.

Description

TECHNICAL FIELD The present invention relates to a composition and kit for forming a gel for hemostasis or adhesion prevention,

More particularly, the present invention relates to an oxidized regenerated cellulose having an alkaline-metal-substituted carboxyl group (-COOM, M is an alkali metal) in the form of short fiber or powder Oxidized Regenerated Cellulose (ORC), which is capable of forming a gel that can be used appropriately and conveniently in an area or situation where it is difficult to apply conventional hemostatic materials such as woven, knitted or nonwoven fabrics to exhibit an excellent hemostatic effect and anti- Compositions and kits.

The Oxidized Regenerated Cellulose (ORC) hemostatic agent does not participate in the coagulation cascade in the body, but swells when it comes into contact with the blood at the bleeding site and serves as a kind of 'Cork stopper' (A New Surgical Absorbable Hemostatic Agent; American Society of Surgery, Volume 100, 439). In addition, the hematopoietic stem cells have been implicated in hemorrhage, -446, September 1960).

However, the oxidized regenerated cellulose has an acidic characteristic in the hemostatic action, which can denature the activities of thrombin and fibrinogen involved in blood coagulation cascade. In order to prevent such denaturation, collagen and gelatin use.

On the other hand, a biocompatible biodegradable polymer material has been disclosed as a woven fabric, a non-woven fabric, or a knit, and a thrombin immobilized thereon has been introduced Japanese Patent Application Laid-Open No. 2005-0084954). However, the hemostatic effect and the wound healing effect are insufficient.

In addition, most conventional hemostatic agents are in the form of woven, nonwoven, or knitted fabrics. However, such hemostatic agents are often difficult to apply to situations such as joints, gynecology, and laparoscopic surgery.

Accordingly, there is a demand for development of a technique capable of forming a gel which can be applied to a site or circumstance in which conventional staple fibers, knitted fabrics or nonwoven fabrics are difficult to apply and exhibits excellent hemostatic effect and anti-adhesion effect.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and it is an object of the present invention to provide a hemostatic composition which is suitable for a site or circumstance in which a conventional hemostatic agent in the form of a woven fabric, And a method for producing the composition.

SUMMARY OF THE INVENTION In order to solve the above technical problems, the present invention provides a method for producing a hemostatic composition comprising an oxidized regenerated cellulose (ORC) having an alkali metal-substituted carboxyl group (-COOM, M: alkali metal) Or a composition for forming a gel for preventing adhesion.

According to another aspect of the present invention, there is provided a method for producing an oxidized regenerated cellulose, comprising: (1) treating an oxidized regenerated cellulose with an alkali metal salt compound to prepare an oxidized regenerated cellulose having an alkali metal substituted carboxyl group (-COOM, M: alkali metal); And (2) forming oxidized regenerated cellulose having an alkali metal-substituted carboxyl group in the step (1) in the form of a short fiber or powder, to form the gel for preventing hemostasis or adhesion, ≪ / RTI >

According to a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition comprising: i) oxidized regenerated cellulose having an alkali metal substituted carboxy group (-COOM, M: alkali metal) in the form of short fiber or powder; ii) aqueous medium; And optionally, iii) a gel-enhancing substance and iv) a hemostatic effect enhancing component. The kit for forming a gel for in-situ hemostatic or anti-adhesion inhibition is provided.

By using the composition and kit of the present invention, it is possible to form a gel exhibiting an appropriate hemostatic effect and an anti-adhesion effect, conveniently and easily, even in a site or situation where conventional hemostatic agents in the form of woven fabric, knitted fabric or nonwoven fabric are difficult to apply.

Hereinafter, the present invention will be described in detail.

In the present invention, Oxidized Regenerated Cellulose (ORC) having an alkali metal salt substituted carboxyl group (-COOM, M: alkali metal) is obtained by treating an oxidized regenerated cellulose with an alkali metal salt compound to obtain an oxidized regenerated cellulose Can be obtained by replacing the active hydrogen of the carboxylic acid group (-COOH) present in the reaction product with an alkali metal. Examples of the alkali metal which can be used include lithium, sodium, potassium and the like, more preferably sodium or potassium, and most preferably sodium. By doing so, the solubility of oxidized regenerated cellulose in water can be increased. The carboxyl group content in the oxidized regenerated cellulose used may be 12 to 24% by weight. As the alkali metal salt compound, for example, sodium acetate, potassium acetate, sodium citrate, sodium fumarate and the like can be used. In the treatment, an alkyll metal salt compound equivalent to the content of the carboxyl group of the oxidized regenerated cellulose is used But the present invention is not limited thereto. The proportion of the carboxyl group of the regenerated cellulose oxidized by the treatment with the alkali metal salt compound is converted to -COOM (M: alkali metal) is preferably 30 to 70%, more preferably 40 to 60%, most preferably 50 %, But is not limited thereto.

When the oxidized regenerated cellulose having an alkali metal-substituted carboxyl group is in the form of a short fiber, the length thereof is suitably about 5 to 50 mm. In the case of powder form, the particle size is preferably 5 to 50 μm, It is not. The sodium substituted oxidized regenerated cellulose in such short fiber or powder form can be prepared by cutting the sodium substituted oxidized regenerated cellulose in the form of a long fiber, woven or knitted fabric into the short fiber length described above or by pulverizing it into powder form.

The amount of the oxidized regenerated cellulose having a sodium-substituted carboxyl group in the form of a short fiber or powder contained in the composition of the present invention is not particularly limited and may be appropriately selected according to the desired hemostatic and anti-adhesion effect. According to one embodiment of the present invention, the amount of the oxidized (or non-oxidized) alkali metal-substituted carboxyl group in the form of short fiber or powder in the form of short fiber or powder is preferably 1 to 50 parts by weight, more preferably 10 to 30 parts by weight, Recycled cellulose may be used, but is not limited thereto.

Preferably, the composition of the present invention may comprise one or more gel-reinforcing materials. As long as the objects of the present invention can be achieved, gel-reinforcing materials commonly used in medical technology can be used without any particular limitation in the present invention. But are not limited to, methoxy poly (ethylene glycol) -poly (lactide) copolymer (mPEG-PLA), microcrystalline cellulose ), Carboxymethylcellulose (CMC), collagen, gelatin, and combinations thereof may be used.

The amount of the gel-strengthening substance that can be contained in the composition of the present invention is not particularly limited and can be suitably selected according to a desired effect. According to one embodiment of the present invention, preferably 0.5 to 10 parts by weight, more preferably 1 to 5 parts by weight, of the gel-strengthening material may be used based on 100 parts by weight of the total composition, but is not limited thereto.

Also preferably, the composition of the present invention may comprise one or more hemostatic effect enhancing components. As long as the object of the present invention can be achieved, a hemostatic effect enhancing component commonly used in the technical field of hemostatic agents can be used without any particular limitation in the present invention. But are not limited to, thrombin, thromboplastin, fibrinogen, casein-kinase II, tissue factors, and combinations thereof. The hemostatic effect enhancing component selected from the group can be used. According to one preferred embodiment of the present invention, thrombin, fibrinogen or a mixture thereof may be used as the hemostatic effect enhancing component.

There is no particular limitation on the amount of the hemostatic effect enhancing component contained in the composition of the present invention, and the hemostatic effect enhancing component can be appropriately selected according to the kind of the hemostatic effect enhancing component and the desired hemostatic effect. According to one embodiment of the present invention, the amount of thrombin is preferably 100 to 500 IU, more preferably 200 to 300 IU per ml of the composition, more preferably 20 to 50 mg of fibrinogen The hemostatic effect enhancing component may be used in an amount of 30 to 40 mg, but is not limited thereto.

As long as the object of the present invention can be achieved, the gel-forming composition of the present invention may further contain ingredients commonly used in hemostatic agents or anti-adhesion agents in addition to the above-mentioned components.

Preferably, the composition for forming a gel for preventing hemostasis or adhesion of the present invention is prepared by (1) treating an oxidized regenerated cellulose with an alkali metal salt compound to convert an alkali metal-substituted carboxyl group (-COOM, M: alkali metal) ≪ / RTI > And (2) making the oxidized regenerated cellulose having an alkali metal-substituted carboxyl group prepared in the step (1) into a short fiber or powder form.

In the above step (1), the method for producing the oxidized regenerated cellulose having an alkali metal-substituted carboxyl group is as described above.

In the step (2), the oxidized regenerated cellulose having an alkali metal-substituted carboxyl group prepared in the step (1) is formed into a short fiber or powder. Suitable short fiber length to powder particle size are as described above, and there are no particular restrictions on the methods and equipment used for single fiberization or milling.

(3) A method for producing a composition for forming a hemostatic or anti-adhesion gel of the present invention, comprising the steps of: (3) preparing an oxidized regenerated cellulose having an alkali metal-substituted carboxyl group in the form of short fibers or powder prepared in the step (2) An effect enhancing component, one or more gel-forming materials, or all of them. The hemostatic effect enhancing components and the gel-forming substances usable in this additional step (3) are as described above. In the case of the hemostatic effect enhancing component, it can be used in the form of dissolving in purified water, physiological saline, a buffer (for example, a buffer solution having a pH of 8.0 to 8.5), or an aprotinin solution or a calcium chloride solution.

According to a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition comprising: i) oxidized regenerated cellulose having an alkali metal substituted carboxy group (-COOM, M: alkali metal) in the form of short fiber or powder; And ii) an aqueous medium. A kit for forming a gel for preventing hemostasis or adhesion in situ is provided.

The kit according to the present invention may further comprise at least one of iii) a gel-enhancing substance and iv) a hemostatic effect-enhancing ingredient.

According to one embodiment of the present invention, the component i) may be prepared in a vial and dissolved in an aqueous medium followed by incorporation into a single syringe.

According to another embodiment of the present invention, at least one of the above components i), iii) and iv) is prepared in each vial and dissolved in an aqueous medium and then incorporated into a dual syringe .

The aqueous medium may be selected from the group consisting of distilled water, physiological saline, injection water, buffer solution, aprotinin solution, calcium chloride solution, and combinations thereof.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited by these examples.

[ Example ]

Manufacturing example  One: Thrombin  Preparation of solution

Thrombin as a component for enhancing the hemostatic effect was dissolved in a solution containing calcium chloride to prepare thrombin solution (thrombin concentration: 200 IU / ml).

Manufacturing example  2: Preparation of fibrinogen solution

As a hemostatic effect enhancing component, fibrinogen was dissolved in an aprotinin solution to prepare a fibrinogen solution (fibrinogen concentration: 30 mg / ml).

Manufacturing example  3: Staple fiber  Preparation of oxidized regenerated cellulose having a sodium-substituted carboxyl group in powder form

72 g of oxidized regenerated cellulose (Samyang Biofarm) having a carboxyl group content of about 15.2% by weight and 33.05 g of sodium acetate were prepared, treated with water and an alcohol solution, and subjected to short fiber formation (length: 10 To 20 mm) to pulverize (particle diameter: 20 to 40 μm).

Manufacturing example  4 to 10: Preparation and test of composition for gel formation

The ingredients shown in Table 1 below were mixed to prepare a composition for gel formation.

The kidneys of the pigs were partially resected to a depth of 15 mm and a depth of 3 mm, and then the hemostatic effect and the anti-adhesion effect were tested using each composition. The time required for hemostasis is shown in Table 1, and whether or not the wound was adhered was visually observed, and the results are shown in Table 1.

ORC-Na: oxidized regenerated cellulose prepared in Production Example 3

Thrombin: Thrombin solution prepared in Preparation Example 1 (usage: IU / ml)

Fibrinogen: The fibrinogen solution prepared in Preparation Example 2

mPEG-PLA: methoxypoly (ethylene glycol) -poly (lactic acid) copolymer

As shown in Table 1, the gel formed from the composition according to the present invention was excellent in hemostatic effect and anti-adhesion effect.

Claims (13)

An agent for forming a hemostatic or anti-adhesion gel, comprising oxidized regenerated cellulose having an alkali metal substituted carboxy group (-COOM, wherein M is an alkali metal) in the form of short fiber or powder. The preparation according to claim 1, wherein the alkali metal is sodium or potassium. The formulation according to claim 1, wherein the content of carboxyl groups in the oxidized regenerated cellulose is 12 to 24% by weight. The preparation for forming a hemostatic or anti-adhesion gel according to claim 1, wherein the oxidized regenerated cellulose is in the form of a short fiber having a length of 5 to 50 mm or a powder having a particle diameter of 5 to 50 탆. The preparation according to claim 1, further comprising a gel-enhancing substance, to form a gel for preventing hemostasis or adhesion. 6. The composition of claim 5 wherein the gel enhancing material is selected from the group consisting of methoxy poly (ethylene glycol) -poly (lactic acid) copolymer (mPEG-PLA), microcrystalline cellulose, carboxymethylcellulose, collagen, gelatin, Wherein the composition is selected from the group consisting of a gel, a gel, and a gel. The agent for forming a hemostatic gel according to claim 1, further comprising a hemostatic effect enhancing component. 8. The agent according to claim 7, wherein the hemostatic effect enhancing component is selected from the group consisting of thrombin, thromboplastin, fibrinogen, casein kinase II, tissue factor and combinations thereof. (1) treating the oxidized regenerated cellulose with an alkali metal salt compound to prepare an oxidized regenerated cellulose having an alkali metal-substituted carboxyl group (-COOM, wherein M is an alkali metal); And
(2) making the oxidized regenerated cellulose having an alkali metal-substituted carboxyl group prepared in the step (1) into a short fiber or powder form;
9. A method for producing a preparation for forming a hemostatic or anti-adhesion gel according to any one of claims 1 to 8. 10. The formulation of claim 9, wherein the alkali metal salt compound is selected from the group consisting of sodium acetate, potassium acetate, sodium citrate, sodium fumarate, and combinations thereof. Gt; 9. A preparation for forming a hemostatic or anti-adhesion gel according to any one of claims 1 to 8; And an aqueous medium, in situ to form a gel for preventing hemostasis or adhesion. The method according to claim 11, wherein i) an oxidized regenerated cellulose having an alkali metal-substituted carboxyl group is prepared in a vial, ii) dissolved in an aqueous medium and then contained in a single syringe, or i) used with an alkali metal substituted carboxy group Characterized in that it is used in a dual syringe after one or more of: (iii) a gel-strengthening substance and (iv) a hemostatic effect enhancing component, each of which is prepared in a vial and dissolved in an aqueous medium, A kit for forming a gel for hemostasis or adhesion prevention in the field. 12. The method according to claim 11, wherein the aqueous medium is selected from the group consisting of distilled water, physiological saline, injection water, buffer solution, aprotinin solution, calcium chloride solution and combinations thereof. .