KR101649792B1 - Polymer Foam Composition for Noncompression Hemostasis, Method Of Producing Polymer for Noncompression Hemostasis Foam Using The Same, And Polymer Foam for Packing Noncompression Hemostasis Therefrom - Google Patents

Polymer Foam Composition for Noncompression Hemostasis, Method Of Producing Polymer for Noncompression Hemostasis Foam Using The Same, And Polymer Foam for Packing Noncompression Hemostasis Therefrom Download PDF

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KR101649792B1
KR101649792B1 KR1020140089507A KR20140089507A KR101649792B1 KR 101649792 B1 KR101649792 B1 KR 101649792B1 KR 1020140089507 A KR1020140089507 A KR 1020140089507A KR 20140089507 A KR20140089507 A KR 20140089507A KR 101649792 B1 KR101649792 B1 KR 101649792B1
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polymer foam
weight
hemostasis
collagen
example
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KR1020140089507A
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Korean (ko)
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KR20160009724A (en
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장지욱
조미란
이시우
이선황
손소라
김현정
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주식회사 제네웰
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00Bandages or dressings; Absorbent pads
    • A61F13/02Adhesive plasters or dressings
    • A61F13/0203Adhesive plasters or dressings having a fluid handling member
    • A61F13/0223Adhesive plasters or dressings having a fluid handling member characterized by parametric properties of the fluid handling layer, e.g. absorbency, wicking capacity, liquid distribution
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28Polysaccharides or their derivatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin

Abstract

The present invention relates to a composition for preparing a polymer foam, a method for producing a polymer foam using the same, and a polymer foam for packing obtained therefrom. More specifically, the present invention relates to a polymer foam having a high moisture absorption rate based on three components of collagen, a hyaluronic acid derivative and carboxymethyl cellulose , And a polymer foam using the same to provide a first-order hemostatic effect of collagen itself when applied to the upper surface of a sinus or a nasal cavity by the provision of a polymer foam, and a second hemostatic effect by compression due to absorption and expansion of body fluids and blood It is possible to provide a double hemostatic effect of hemostatic effect, while preventing the adhesion to wound.

Description

TECHNICAL FIELD [0001] The present invention relates to a composition for preparing a polymer foam for non-compression hemostasis, a method for producing a polymer foam for non-compression hemostasis using the same, and a polymer foam for non-compression hemostasis packing Foam for Packing Noncompression Hemostasis Therefrom}

The present invention relates to a composition for the production of a polymer foam for non-compression hemostasis, a method for producing a polymer foam for non-compression hemostasis using the same, and a polymer foam for non-compression hemostasis packaging. More particularly, the present invention relates to a composition for collagen, hyaluronic acid derivative and carboxymethyl cellulose The present invention relates to a polymer foam composition capable of providing a high water absorption rate on the basis of the composition of the present invention, and a polymer foam using the polymer foam composition to provide a first hemostatic effect of collagen itself when applied to the upper surface of a sinus or nasal cavity, The present invention relates to a method for producing a polymer foam for non-compression hemostatic blood vessels, which can provide a double hemostatic effect of compression due to compression of the polymer, .

Vaseline gauze or wound dressings are used for the purpose of hemostasis after intranasal or intranasal surgery. These packings can control bleeding, but they are known to cause frequent nasal adhesions and cause severe pain to the patient when replacing gauze or wound dressings. To overcome these problems, packing products for sinus have recently been developed and marketed.

The use of gauze or vaseline gauze was the traditional method of nasal packing. Recently, non-absorbable PVA (polyvinyl acetate sponge, Merocel ), polyurethane (co-polyether-ester urethane, nasopore ), biodegradable synthetic material, the castle of natural hyaluronic acid (Merogel ⓡ) based products have been developed and sold.

Characteristics of ideal packing agent should be excellent hemostatic effect, prevention of excessive blood clot formation, maintenance of the middle hepatocyte space, promotion of epithelial regeneration and prevention of adhesion, and most importantly, minimizing patient inconvenience.

Especially, the most essential condition of packing agent is hemostatic performance. If postoperative hemorrhage is not controlled, the patient can become dangerous, and the leaked blood can form blood clots, which can lead to wound closure due to blood clots and tissue closure. The maintenance of the medial space should be maintained physically until the mucosa is regenerated. If the space is not maintained, tissue closure may occur and reoperation may be necessary. When the epithelium regeneration occurs, the packing is removed. At this time, if the packing is adhered to the tissue, re-injury and hemorrhage of the epithelium may be caused, and regeneration may be delayed and the pain may be caused.

Most of the packaging products developed so far are hemostatic products due to physical compression. Although the actual hemostatic agent is used as a packing agent, the hemostatic hemostatic agent is excellent in hemostatic performance, but it causes adhesion of the wound and forms granuloma. Non-degradable PVA products are known to be removed and cause pain and bleeding when removed and cause chronic inflammation when left. In the case of biodegradable synthetic materials, the toxicity of the degradation products and the degradation of the wounds before they are recovered are too fast. In order to overcome these disadvantages, a product using a hyaluronic acid derivative as a natural material has been developed and sold, but the physical properties thereof are so weak that it is impossible to perform compression hemostasis and the overall performance is low.

Hyaluronic acid was first discovered in 1934 by Meyer and Palmer in the vitreous humor. It is a long linear polysaccharide that is a biopolymer widely found in nature. Hyaluronic acid is a high molecular weight polysaccharide with a molecular weight ranging from 10 3 to 10 7 dalton, depending on the origin of the liquid, which is dissolved in water to form a highly viscous liquid. Hyaluronic acid is a biocompatible, biodegradable, and anti-tissue adhesion-inhibiting agent. Since hyaluronic acid products are easily dissolved in water, such as blood, body fluids, etc., a method has been developed in which insolubility is improved by crosslinking with divinyl sulfone, bis epoxide or formaldehyde.

Collagen is also widely used for medical use as a biomaterial having low antigenicity, hemostatic effect and excellent tissue regeneration effect. Products currently commercialized include hemostatic agents, wound dressings, bone grafts, cosmetic implants and sutures. Collagen is a matrix protein that promotes the aggregation and activity of platelets. It is known that platelets are rapidly attached, dispersed and activated when blood flows out, thereby promoting aggregation of platelets and promoting the activity of blood coagulation factor XII.

Furthermore, carboxymethyl cellulose in which the hydroxy group of glucose, which constitutes cellulose, is substituted with a carboxymethyl group, is also widely used in the field of medicine for use as an adhesion inhibitor, wound dressing, hemostatic agent and the like. Carboxymethylcellulose is also hydrophilic and dissolved in water, so that the shape can not be maintained. Crosslinking (PCT / US1995 / 006860) methods have also been proposed by mixing with polyacrylic acid polymers to increase the insolubility of carboxymethylcellulose.

In order to overcome these disadvantages, there is a continuing need to study a packing agent that reinforces physical properties while using natural materials, and in particular, can provide compression hemostasis.

In order to overcome the above-mentioned problems, the inventors of the present invention have conducted intensive researches, and as a result, they have found that a polymer foam based on three components of collagen, hyaluronic acid and carboxymethyl cellulose is excellent in compression strength and elasticity And the secondary hemostatic effect such as compression due to swelling upon body fluids or blood uptake, as well as the primary hemostatic effect by collagen, and securing the antiadherence property, and accomplished the present invention.

That is, an object of the present invention is to provide a composition for preparing a polymer foam capable of providing a high water absorption rate based on three components of collagen, a hyaluronic acid derivative and carboxymethyl cellulose, and a polymer foam using the same, Which is capable of providing a double hemostatic effect of collagen itself and a secondary hemostatic effect by compression due to the swelling of body fluids and blood, And to provide a polymer foam for non-pressurized hemopoietic packaging obtained therefrom.

According to the present invention, there is provided a composition comprising collagen, hyaluronic acid, carboxymethylcellulose, a crosslinking compound and water, wherein the collagen, hyaluronic acid, carboxymethyl cellulose, By weight and the water is from 90 to 99% by weight; Wherein the collagen is 30 to 70% by weight, the hyaluronic acid is 10 to 25% by weight, the carboxymethyl cellulose is 20 to 45% by weight, and the carboxymethylcellulose is 20 to 45% by weight of the collagen, hyaluronic acid and carboxymethylcellulose. ego; Wherein the crosslinking compound is at least one selected from polyacrylic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide and polyethylene oxide.

In addition, according to the present invention, there is provided a method for producing a polymer foam for non-pressurized hemostasis, which comprises lyophilizing a multi-stage lyophilization process using the composition for preparing a polymer foam for non-pressurized hemostasis, ≪ / RTI >

Further, according to the present invention, there is provided a polymer foam obtained by the above method, which has an absorbency against physiological saline of 10 g / g or more, a compressive strength of 0.1 N or more at 0.5 Hz as measured by a rheometer, Is 1000 pa or more, and provides a non-pressurized hemostatic packing polymer foam having non-compression hemostatic properties.

In addition, A method for producing a polymer foam for non-pressurized hemostasis, which comprises preparing a polymer foam by thermal drying using a composition for preparing a polymer foam for non-pressurized hemostasis as a starting material.

The polymer foam produced by the present invention has high absorption and compressive strength expansion rate in water and absorbs body fluids and blood when used as nasal and ear or other implantable wound dressings, And it is possible to provide an anti-adhesion effect that does not adhere to the wound.

FIG. 1 is a photograph of a foam prepared according to the production method of the present invention, the left side is a photograph of a polymer foam for packaging in a dried state and the right side is a photograph of a polymer foam for packing in an expanded state after moisture absorption.
2 is an electron micrograph (upper left and lower right x100, right upper and lower right x200) of the polymer foam for packing prepared according to the production method of the present invention.
FIG. 3 is a graph showing the relationship between the absorbance of moisture of the packing polymeric foam prepared in Examples 1 and 2, Comparative Examples 1, 2, 3, 4, 5, It's a picture.
4 is a graph showing the collagenase decomposition test results of the samples prepared in Example 1 and Comparative Example 3. Fig.
5 is a photograph showing the decomposition tendency of the sample prepared in Example 1 after the collagenase decomposition test.
6 is a graph comparing the results of the whole blood coagulation test of the sample prepared in Example 1 and the comparative group.
FIG. 7 is a graph comparing the results of the hepatic hemostasis test of the comparative group with the sample prepared in Example 1. FIG.
FIG. 8 is a graph comparing the results of the hepatic arterial hemostasis test of the comparative group with the sample prepared in Example 1. FIG.
FIG. 9 is a photograph of the wound healing results of the sample prepared in Example 1 and the comparative group visually.
Fig. 10 is a photograph showing the results of wound healing of the sample prepared in Example 1 and the comparative group in comparison with tissue staining. Fig.

Hereinafter, the present invention will be described in detail.

The composition for preparing a polymer foam of the present invention is a composition comprising collagen, hyaluronic acid, carboxymethyl cellulose, a crosslinking compound and water, wherein the collagen, hyaluronic acid, carboxymethyl cellulose, 1 to 10% by weight, and the water is 90 to 99% by weight; Wherein the collagen is 30 to 70% by weight, the hyaluronic acid is 10 to 25% by weight, the carboxymethyl cellulose is 20 to 45% by weight, and the carboxymethylcellulose is 20 to 45% by weight of the collagen, hyaluronic acid and carboxymethylcellulose. ego; The crosslinking compound is characterized by being at least one selected from the group consisting of polyacrylic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide and polyethylene oxide.

The term "polymer foam for packing" used in the present invention refers to a polymer foam that is inserted into the tissue of the surgical incision after incision for surgical operation and then applied to seal the incision, unless otherwise specified.

Such tissue includes, for example, tissues requiring elasticity such as skin tissue and inner ear tissues, tissues having a space requiring both compressive strength and elasticity such as ear, eye and nose.

The collagen can be used for mammals such as cows and pigs, which are extracted from human beings or used for medical purposes, such as collagen, atelocollagen and skin, myocardial membrane, bone, cartilage, small intestinal submucosa, amniotic membrane and soft tissue- Or more.

The hyaluronic acid may have a weight average molecular weight (Mw) of 1,000,000 to 8,000,000 g / mol, or 1,000,000 to 3,000,000 g / mol.

The carboxymethyl cellulose may have a weight average molecular weight (Mw) of 1,000 to 100,000 g / mol or 5,000 to 50,000 g / mol.

The polymer composition may contain glycosaminoglycans such as carboxyethylcellulose, hydroxymethylcellulose and alginic acid, alginate, chitin, chitosan, dextran, glycogen, starch, pectin and heparin, heparin sulfate, chondroitin sulfate , And may further include, for example, 5 to 100 parts by weight based on 100 parts by weight of the total components constituting the composition for preparing a polymer foam.

The active ingredient may be, for example, collagen 20 of 100 wt% of total collagen, hyaluronic acid and carboxymethyl cellulose To 99 wt% of hyaluronic acid, 0.5 to 30 wt% of hyaluronic acid, and 0.5 to 50 wt% of carboxymethylcellulose. Within this range, physical properties such as swelling degree, compressive strength and elasticity, There is an effect that can be provided while adjusting.

As a specific example, the active ingredient may comprise 20 to 80 wt% of collagen, 1 to 25 wt% of hyaluronic acid and 20 to 40 wt% of carboxymethylcellulose in 100 wt% of total collagen, hyaluronic acid and carboxymethylcellulose.

As another example, the active ingredient may comprise 30-80 wt% collagen, 2.5-25 wt% hyaluronic acid, and 25-35 wt% carboxymethylcellulose in 100 wt% total of collagen, hyaluronic acid and carboxymethylcellulose.

The active ingredient and cross-linking compound of collagen, hyaluronic acid, and carboxymethyl cellulose are used in an amount of 1 to 10% by weight, or 2 to 5% by weight based on 100% by weight of the total amount of the active ingredient and the crosslinking compound and water, The remainder, that is, 90 to 99% by weight, or 95 to 98% by weight, of the foam, and the properties such as the degree of swelling, the compressive strength and the elasticity of the foam and the decomposition period can be adjusted as needed.

The hyaluronic acid has a molecular weight (Mw) of, for example, 10,000 to 3,000,000 g / mol. The hyaluronic acid may be prepared in various concentrations depending on the molecular weight of the kind of the composition.

The collagen may be extracted from mammals (such as cow, pig, etc.) or used for medical use, for example, a tissue obtained by decellularization of extracted tissue.

For example, the tissue may be selected from the group consisting of skin, myocardial membrane, bone, cartilage, small intestinal submucosa, amniotic membrane and soft tissue.

A decellularizing agent may be used for the decellularization treatment.

The decellularizing treatment agent is based on an alkali and a polar solvent, for example, and is capable of primarily removing the immunological and foreign matter-inducing substances in the extracted tissues.

As the alkali, for example, at least one selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium carbonate, magnesium hydroxide, calcium hydroxide and ammonia may be used in a concentration range of 0.01M to 1M.

As a specific example, the alkali may be sodium hydroxide 0.4M to 0.6M.

As the polar solvent, for example, at least one selected from alcohols having 1 to 4 carbon atoms may be used in a concentration range of 10 to 100%.

As a specific example, the polar solvent may be 50% to 80% ethanol.

The alkali and polar solvent may be used in a blending ratio of 1: 9 to 9: 1 at a concentration of 0.1 to 1 M.

If necessary, the pretreatment may be performed with at least one polar solvent selected from alcohols having 1 to 4 carbon atoms before the decolorizing treatment.

The entire process including the pretreatment and decellularization treatment can be performed as follows, for example.

That is, the dermal layer is physically separated from the biotissue (first step), the separated dermal layer is pretreated with a polar solvent (second step), the pretreatment is treated with the above- 3), and the resulting decellularized product is washed and then adjusted to the required pH using an acid (Step 4).

Specifically, the dermal layer is separated from the skin layer to a thickness of 100 μm to 2 mm through the first step, and at least one polar solvent selected from alcohols having 1 to 4 carbon atoms and having a concentration of 10 to 100% For 1 to 72 hours. In the third step, 50 to 80% ethanol and 0.4 to 0.6 M of sodium hydroxide are blended as the decolorizing agent. In the fourth step, hydrochloric acid, sulfuric acid , Peracetic acid, acetic acid, and the like, to adjust the pH to 2 to 10.

The second to fourth steps may be carried out by physically stirring at a temperature of 0 to 37 ° C.

The crosslinking compound may be at least one selected from the group consisting of polyacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide and polyethylene oxide, and at least one selected from the group consisting of collagen, hyaluronic acid and carboxymethylcellulose constituting the polymer foam composition May be added in the range of 0.01 to 10 parts by weight, or 0.05 to 1 part by weight based on 100 parts by weight in total, and the physical properties such as the degree of swelling, the compressive strength and the elasticity and the decomposition period of the foam may be adjusted There is an effect that can be provided.

The method for producing a polymer foam according to the present invention is characterized in that a polymer foam is prepared by a multistage lyophilization process using the composition for preparing a polymer foam as a starting material, followed by a high-temperature thermal crosslinking and a pressing process.

The multistage lyophilization is carried out by, for example, one-stage drying under rapid freeze-drying at 0 ° C or below 0 ° C to -40 ° C, two-stage drying in which freeze-drying is carried out slowly at low pressure below 10 mmHg in a freeze- , And such effects can be provided by controlling the physical properties such as the degree of swelling, the compressive strength and the elasticity, and the decomposition period of the foam by the multistage freeze drying.

The high-temperature thermal crosslinking may be, for example, a rapid crosslinking of the foam at a temperature of 80 to 200 ° C or a temperature of 100 to 180 ° C for about 1 hour by adding a crosslinking compound. In this way, the degree of swelling, Can be provided while adjusting the physical properties and the decomposition period of the product.

The pressing step may be performed at a pressure of 1,000 to 5,000 Psi using a press or the like, and the properties such as the degree of swelling, compressive strength and elasticity of the foam and the decomposition period may be adjusted as needed There is an effect that can be provided.

In the present invention, a polymer foam can be obtained by the above-mentioned method. The polymer foam has an absorbency of not less than 10 g / g for physiological saline, a compressive strength of not less than 0.1 N at 0.5 Hz as measured by a rheometer , An elasticity of 1000 pa or more, and a polymer foam for packing having non-compression hemostatic properties.

As used herein, the term "non-compression hemostatic property" refers to providing hemostatic properties even when not stressed unless otherwise specified.

In addition, it has stability against moisture, can absorb the exudate properly, and has a characteristic that the thickness expansion rate is decomposed to 200% or more.

Also, the sponge type polymer foam according to the present invention can rapidly absorb exudates and blood from wounds with high absorption power, and can provide a hemostatic effect by non-compression, a compression hemostatic effect by elasticity and compressive strength, a wound healing and adhesion It can help prevent. In addition, the sponge-type polymer foam can be inserted into the nasal cavity or the ear, and the elasticity and compressive strength can be maintained, so that the polymer foam can be prevented from being adhered to the affected area. In addition, physical barriers are formed for a certain period of time, and after a certain period of time, they can be decomposed and absorbed by the living body or artificially removed.

As described above, the packing is to pack a tissue having elasticity, such as a skin tissue and an inner ear tissue, such as ear tissue, ear, nose, and nose, together with a space requiring both compressive strength and elasticity, An example would be packing for sinus or nasal cavity.

In the present invention, the polymer foam may be prepared by thermal drying using the composition for preparing a polymer foam as a starting material instead of the above-described multistage freeze-drying.

The polymer foam provided in this manner may be a film type or a block type.

The film-type or block-type polymer foam thus provided can be applied to dressings for sinus surgery, nasal surgery, hemostasis and wound protection after otitis surgery.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope and spirit of the invention, And modifications that fall within the scope of the appended claims.

≪ Example 1 >

(CMC, Mw 10,000 g / mol, CP) of 45 wt% of collagen (extracted from pig skin), 10 wt% of hyaluronic acid (Shiseido Sodium Hyaluronate, Mw 1,300,000 g / mol, Shiseido) and 45 wt% of carboxymethylcellulose KELCO) were mixed.

At this time, polyacrylic acid as a crosslinking compound was contained in an amount of 0.1 part by weight based on 100 parts by weight of the total content of collagen, hyaluronic acid, and carboxymethyl cellulose.

Under the above conditions, 4% by weight of dry solid content and 95% by weight of purified water were mixed by a homomixer. The prepared aqueous solution was rapidly frozen at 0 to -40 ° C and freeze-dried for 2 days at a temperature of -40 to 20 ° C and a pressure of 10 mmHg or less in a freeze dryer (FVTFD 50R, Ilshin Biotech, Korea).

The lyophilized sponge type foam was thermally crosslinked at 120 < 0 > C for 1 hour in a high temperature oven and pressurized to 2,000 psi in a press to produce a polymer foam for packaging.

The polymer foam for packing obtained by the method of Example 1 thus prepared is shown in Fig. For reference, the left side of FIG. 1 is a photograph of a polymer foam for packaging in a dried state, and the right side is a photograph of a polymer foam for packing in an expanded state after moisture absorption.

Table 2 also shows photographs of the surface and cross section of the polymer foam obtained in Example 1 using a scanning electron microscope (magnification x 100, x 200). As shown in Fig. 2, the porous structure of the open structure can be confirmed.

≪ Example 2 >

The same procedure as in Example 1 was repeated, except that collagen was mixed in an amount of 50 wt%, hyaluronic acid was mixed in 25 wt%, and carboxymethylcellulose was mixed in 25 wt%, to prepare a polymer foam for packing.

≪ Comparative Example 1 &

As in Example 1, except that polyacrylic acid was not added as the crosslinking compound in Example 1, and the thermal crosslinking process for the lyophilized sponge type foam was omitted and the pressure was increased to 2,000 psi in the press The process was repeated to prepare a polymer foam for packing.

≪ Comparative Example 2 &

The same procedure as in Example 1 was repeated except that 0 wt% of collagen, 75 wt% of hyaluronic acid and 25 wt% of carboxymethylcellulose were mixed in Example 1 to prepare a polymer foam for packing.

≪ Comparative Example 3 &

The same procedure as in Example 1 was repeated to prepare a polymer foam for packing, except that the dry solid content of the mixed raw materials was changed to 2 wt% and 98 wt% of purified water in Example 1.

≪ Comparative Example 4 &

The same steps as in Example 1 were repeated except that the freeze-drying step in Example 1 was not performed (the freeze-drying step was not performed, and the resultant solution was thermally crosslinked) to prepare a polymer foam for packing.

≪ Comparative Example 5 &

The same procedure as in Example 1 was repeated except that the lyophilized sponge type foam in Example 1 was pressurized at 2,000 psi in a press without thermal crosslinking at 120 ° C for 1 hour, Foam.

≪ Additional Experimental Example 1 &

The same procedure as in Example 1 was repeated except that collagen as the starting material in Example 1 was treated with pig skin degranulation as follows to prepare a polymer foam for packing.

That is, physically separating the dermal tissue from the pig tissue and the skin layer to a thickness of 100 탆 to 2 mm, separating the separated dermal layer from 1 to 4 alcohol selected from alcohols having 1 to 4 carbon atoms and using a polar solvent having a concentration of 10 to 100% And pretreated at room temperature for 72 hours.

The pretreatment product was treated at room temperature using a decellularizing agent containing 50 to 80% ethanol and 0.4 to 0.6 M sodium hydroxide. The obtained decellularized product was washed and washed with hydrochloric acid, sulfuric acid, peracetic acid, acetic acid At least one of which was adjusted to pH 2 to 10 at room temperature.

≪ Additional Experimental Example 2 &

The heat-crosslinking performance of the lyophilized sponge-type foam in Example 1 was replaced by drying in an oven at 60 ° C for 24 hours at 120 ° C for 1 hour and then pressurized to 2,000 psi in a press, The same steps as in Example 1 were repeated to prepare a polymer foam for packing.

The following tests were carried out for each of Examples 1 to 2, Comparative Examples 1 to 5, and Additional Experiments 1 and 2, and the results were compared.

≪ Test Example 1: Absorption Analysis >

The water absorption of the obtained polymer foam was measured as follows, and the results are summarized in Table 1 and FIG.

The water absorption rate is determined by weighing the dry weight of each sample, placing it in a 100 ml flask, and then adding 50 ml of physiological saline, and allowing to stand for 5 minutes. After 5 minutes, remove the specimen and weigh the weight. The absorbency was calculated by the following formula.

[Formula 1]

Absorption of sample = (weight of absorbed sample - weight of dried sample) / weight of dried sample

division 3 times average absorbency (g / g) Example 1 (23.44. + -. 0.73) g / g Example 2 (7.25 + - 0.43) g / g Comparative Example 1 (6.31 ± 0.62) g / g Comparative Example 2 (7.73 + - 1.2) g / g Comparative Example 3 (40.26 + 2.49) g / g Comparative Example 4 (1.24 0.21) g / g Comparative Example 5 (3.99. + -. 1.11) g / g Additional Experimental Example 1 (18.36 + 4.18) g / g Further Experimental Example 2 (6.27 ± 0.91) g / g

As shown in Table 1 and FIG. 2, the absorbency analysis results showed an average absorbency of 23 g / g or more in Example 1 and an average absorbency of 7 g / g or more in the case of Example 2.

On the other hand, the absorbency of 6.31 g / g was confirmed in Comparative Example 1, which is a non-crosslinked sample, but the absorbency after the absorption was not maintained, and in Comparative Example 2 in which the mixing ratio was inadequate, 3, it was not able to maintain its shape after water absorption.

In Comparative Example 3, the solid content was reduced to 2% in Example 1, and the absorbance was 40 g / g. However, as shown in the following Experimental Examples, the other physical properties were poor. Comparative Example 4, Comparative Example 5, In the case of Experimental Example 2, low absorbency was shown. In the case of Experimental Example 1, excellent absorbency of 18 g / g was shown, but the form was not maintained.

≪ Test Example 2: Analysis of compressive strength and elastic modulus >

The compressive strength and elastic modulus of polymeric foams of Examples 1 to 2 and Comparative Examples 1 to 5 and further Experimental Examples 1 to 2 and the products Nasopore (based on biodegradable polyurethane) and Merocel (based on biodegradable hyaluronic acid) The results are shown in Table 2 and Fig. 3 below.

Specifically, the compressive strength and the modulus of elasticity were measured using a rheometer (HAAKE MARS II, Thermo Scientific, Inc) .The sample was cut into 2 × 2 cm size, swollen in physiological saline for 5 minutes, placed on the specimen, And the sample was measured at a frequency of 0.5 Hz after the specimen was pressurized 5 mm and the sample was analyzed at a frequency of 0.5 Hz after the sample was pressurized by 5 mm because the material is similar to the environment in which the material is inserted into the nasal cavity and the ear.

division Elasticity (pa) Compressive strength (N) Remarks Example 1 710 1.315 Example 2 50 0.259 Comparative Example 1 40 0.171 Comparative Example 2 - - Deformation after swelling Comparative Example 3 396 0.37 Comparative Example 4 556 0.33 Comparative Example 5 421 0.20 Additional Experimental Example 1 512 0.12 Further Experimental Example 2 262 0.23 Nasopore 336 0.77 Merocel 2577 0.63

As shown in Table 2, the elasticity and the compressive strength test result showed that the elasticity of 710 pa and the compressive strength of 1.3 N were measured in Example 1. In Example 2, the elasticity of 50 pa and the compressive strength of 0.25 N were obtained.

On the other hand, in Comparative Example 1, the physical strength was very weak with an elasticity of 40 pa and a compressive strength of 0.17 N, and in Comparative Example 2, no measurement was possible due to loss of shape after moisture absorption.

In Comparative Example 3, the elasticity was 396 pa and the compression strength was 0.37 N, and in Comparative Example 4, the elasticity was 556 pa, the compression strength was 0.33 N, the elasticity was 421 pa and the compression strength was 0.20 in Comparative Example 5, In Example 1, the elasticity was 512 pa, the compressive strength was 0.12 N, the elasticity was 262 pa in the additional test example 2, and the compressive strength was 0.23 N, which was lower than that in Example 1.

In addition, the commercially available biodegradable polyurethane product, Nasopore, exhibited an elasticity of 336 pa and a compressive strength of 0.77 N, and a commercially available biodegradable hyaluronic acid product, Merocel, exhibited an elasticity of 2577 pa and a compressive strength of 0.77 N, And the compressive strength was confirmed.

≪ Test Example 3: Expansion ratio analysis >

The thickness expansion rates of Examples 1 to 2 and Comparative Examples 1 to 5, Additional Experiments 1 to 2, and Nasopore of a commercially available polyurethane product were measured as follows and summarized in Table 3.

Specifically, the thickness was measured in a dry state, dipped for 10 minutes to sufficiently hydrate in physiological saline solution, taken out, and the thickness was measured three times.

division Drying (Thickness) Absorption state (thickness) Remarks Example 1 1.83 + - 0.12 13.98 ± 0.2 Example 2 5.17 ± 0.28 13.1 ± 0.2 Comparative Example 1 2.6 ± 0.14 6.57 ± 1.0 Comparative Example 2 2.7 ± 0.77 - Deformation after swelling Comparative Example 3 5.0 ± 0.2 15.8 ± 1.85 Comparative Example 4 6.25 ± 0.98 11 ± 3.06 Comparative Example 5 17.25 + 0.19 16.5 ± 1 Additional Experimental Example 1 10.9 ± 0.65 6.79 ± 1.53 Further Experimental Example 2 15.27 ± 0.20 10 ± 1.63 Nasopore 12.62 ± 0.19 13.29 ± 0.19

As shown in Table 3, in Example 1, the average thickness of the dry state was increased from 1.83 to 13.98 after absorption of water to about 7.6 times. In Example 2, the average state thickness of the dry state was increased from 5.17 to 13.1 after moisture absorption by about 2.5 times.

On the other hand, in Comparative Example 1, the average thickness of the dry state was increased from 2.6 to 6.57 after the water absorption, and in Comparative Example 2, the average state of the dry state was 2.7.

In Comparative Example 3, the average thickness increased from 5 to 15.8. In Comparative Example 4, the average thickness increased from 6.25 to 11, and in Comparative Example 5, the average thickness decreased from 17 to 16. In the case of Additional Test Example 1, it was reduced from 10 to 6, and in the case of Additional Test Example 2, it was decreased from 15 to 10. The group with reduced thickness is uncompressible and can not maintain its shape after melting and absorbing water. In particular, in Comparative Example 3, the dry thickness was larger than that in Example 1, but it was confirmed that the thickness after the final absorption was similar.

For reference, commercially available polyurethane Nasopore, a third-party product, showed little change in thickness after drying and moisture absorption.

≪ Test Example 4: Analysis of decomposition characteristics &

In order to confirm the decomposition characteristics of the samples prepared in Example 1 and Comparative Example 3, the decomposition period was analyzed using a collagenase degradation test simulating the human environment. Type 1 collagenase PBS solution of 1 u / ml was prepared, and the sample was placed and stirred for 14 days at 37 DEG C and 50 rpm on a stirrer. 3, 7, 10 and 14 days later, the sample was taken out and the compressive strength was measured using the rheometer in the method of Experimental Example 1. The number of n was 4 to 5, and the compressive strength values were converted into 100% units based on the samples before decomposition test (day 0). As a result of the experiment, it was confirmed that the physical property value gradually decreased with the lapse of time in the case of Example 1, and the complete decomposition was observed on the 14th day. The decomposition tendency of Comparative Example 3 was faster than that of Example 1, and it was confirmed that it was completely decomposed after 10 days. Figure 6 is a photograph of the degradation of the sample of Example 1 and after 14 days it turned into a gel form which can be easily removed into sections.

<Test Example 5: Analysis of hemostasis performance>

In order to confirm hemostasis of the sample prepared in Example 1, rat hepatica model and portal vein model and whole blood coagulation experiment were evaluated. Surgicel fibrillar (Johnson &amp; Johnson, Ethicon, USA) was used as a control group.

5-1. Whole blood coagulation test

Whole blood coagulation test is done by putting the product in a glass tube tube at 10 ㎣ size and injecting 1 ㎖ blood of mouse. The time for the blood to be hardened was measured by comparing the test group with the blood-only group as the negative control group. Hemostatic efficacy of the Example 1 sample was evaluated by a hemostasis time test using an animal whole blood. As shown in Fig. 4, the blood was completely solidified at 2 minutes in the negative control group (control), and blood was completely solidified in the positive control group (Surgicel, J & J) It was confirmed that the blood was solidified in the invitro. Compared with the negative control group, a faster hemostasis time was observed in the positive control group and the experimental group.

5-2. A snack model

Animal experiments were conducted according to ISO 10993-2, 'Animal welfare requirements'. The pre-operative rats were anesthetized using inhalation anesthesia (isoprolan 2%), and the hair was removed and sterilized with povidone. In the liver resection model, the midline of the abdomen of the anesthetized animal is opened, the middle lobe is visible, and then resected to a diameter of 8 mm using Biopy punch. After the liver resection, the product is covered with the bleeding site and a constant force (50 g weight) is applied and the blood is kept for 5 minutes. The amount of blood spilled out after 5 minutes was weighed. As shown in FIG. 5, the hemostasis control experiment using the hepatic system model showed an average of 3.53 g of hemorrhage. The control group (Surgicel, J & J) was 1.57 g and the sample of Example 1 was 1.83 g of blood. There was no statistically significant difference between the control and experimental groups in both groups.

5-3. Portal vein injury model

The portal vein injury model is prepared by incising the center of the abdomen of the anesthetized animal, making the portal vein visible, and punching it into the blood vessel with a 21 G needle. Cover the product at the bleeding site, and bleed for 5 minutes. Weigh out the leaked blood. As shown in FIG. 8, the hemorrhage control using the portal vein injury model showed an average of 2.72 g of hemorrhage, 0.89 g of the control group Surgicel and 0.39 g of the experimental group 1 Respectively. There was no statistically significant difference between the control group and the experimental group.

&Lt; Test Example 6: Wound healing ability analysis &

An animal model (Sprague Dawley Rat) was used to evaluate the healing efficacy and safety of the sponge type elastic wound dressings of Example 1 and the sponge type elastic wound dressings of the control group against wound, burns and scars.

The wound area was protected with the experimental group (Example 1) and the positive control group (Collaheal ) at 2, 4, 7, 10, and 14 days by using a digital camera. Size and inflammatory response (Fig. 9). On the 14th day, grafts were collected and evaluated for safety and efficacy by histopathological evaluation method (Fig. 10).

Test results No specific symptoms or deaths occurred in the experimental animals during the test period. As a result of the analysis, both the experimental group and the positive control group (Collaheal ) were effective in regenerating the new tissue at the wound site in both FIGS. 9 and 10, It was confirmed to have the ability. Additionally, no specific inflammation or immune response could be identified in both groups.

Claims (15)

  1. A composition comprising collagen, hyaluronic acid, carboxymethylcellulose, a crosslinking compound and water,
    The content of collagen, hyaluronic acid, carboxymethylcellulose, and the crosslinking compound is 1 to 10% by weight and the content of water is 90 to 99% by weight;
    Wherein the collagen is 30 to 70% by weight, the hyaluronic acid is 10 to 25% by weight, the carboxymethyl cellulose is 20 to 45% by weight, and the carboxymethylcellulose is 20 to 45% by weight of the collagen, hyaluronic acid and carboxymethylcellulose. ego;
    Wherein the crosslinking compound is at least one selected from polyacrylic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide and polyethylene oxide.
  2. delete
  3. The method according to claim 1,
    Wherein the collagen is extracted from a mammal other than a human and is a decellularized preparation.
  4. The method according to claim 1,
    Wherein the hyaluronic acid has a weight average molecular weight (Mw) of 1,000,000 to 1,900,000 g / mol.
  5. The method according to claim 1,
    Wherein the carboxymethyl cellulose has a weight average molecular weight (Mw) of 1,000 to 80,000 g / mol.
  6. The method according to claim 1,
    Wherein the composition for preparing a polymer foam is selected from the group consisting of carboxyethyl cellulose, hydroxymethylcellulose and alginic acid, alginate, chitin, chitosan, dextran, glycogen, starch, pectin and heparin, heparin sulfate and glycosaminoglycans of chondroitin sulfate A composition for the production of a polymer foam for non-pressurized hemostasis characterized by further comprising at least one kind of carboxy polysaccharide.
  7. The method according to claim 1,
    Wherein the cross-linking compound is in a range of 0.01 to 10 parts by weight based on 100 parts by weight of the total content of the collagen, hyaluronic acid, and carboxymethyl cellulose.
  8. A method for producing a polymer foam comprising the steps of: preparing a polymer foam by using a composition for preparing a polymer foam for non-pressurized hemostasis as set forth in any one of claims 1 to 7 as a starting material, (Method for producing polymer foam for compression hemostasis).
  9. 9. The method of claim 8,
    The multistage freeze-drying is a one-step drying in which rapid freeze-drying is carried out at 0 to -40 캜,
    And drying at a speed of 10 mmHg or less in a freeze dryer at -40 to 20 占 폚.
  10. 9. The method of claim 8,
    Wherein the high-temperature thermal crosslinking is carried out by introducing a crosslinking compound and rapidly crosslinking the polymer at 100 to 200 ° C.
  11. 9. The method of claim 8,
    Wherein the pressing step is performed under a pressure of 1,000 to 5,000 Psi.
  12. 9. A polymer foam obtained by the method of claim 8,
    A compressive strength of at least 0.1 N at 0.5 Hz when measured with a rheometer, an elasticity of at least 1000 pa, a non-compression hemostatic packing with a non-compression hemostatic characteristic Polymer foam for.
  13. 13. The method of claim 12,
    Wherein the packing is a packing for sinus or nasal cavity.
  14. A process for producing a polymer foam for non-pressurized hemostasis, which comprises preparing a polymer foam by thermal drying using the composition for preparing a polymer foam according to any one of claims 1 to 7 as a starting material.
  15. 15. The method of claim 14,
    Wherein the polymer foam is a film type or a block type.
KR1020140089507A 2014-07-16 2014-07-16 Polymer Foam Composition for Noncompression Hemostasis, Method Of Producing Polymer for Noncompression Hemostasis Foam Using The Same, And Polymer Foam for Packing Noncompression Hemostasis Therefrom KR101649792B1 (en)

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JP2017523751A JP2017522162A (en) 2014-07-16 2015-07-14 Polymer foam composition, method for producing polymer foam using the same, and polymer foam for packing
PCT/KR2015/007280 WO2016010330A1 (en) 2014-07-16 2015-07-14 Polymer foam composition, method for preparing polymer foam composition using same, and polymer foam for packing
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