WO2018106076A1 - Matériau styptique comprenant une poudre de carboxyméthylcellulose de calcium et une poudre de composé de chitosane soluble dans l'eau, et son procédé de production - Google Patents

Matériau styptique comprenant une poudre de carboxyméthylcellulose de calcium et une poudre de composé de chitosane soluble dans l'eau, et son procédé de production Download PDF

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WO2018106076A1
WO2018106076A1 PCT/KR2017/014428 KR2017014428W WO2018106076A1 WO 2018106076 A1 WO2018106076 A1 WO 2018106076A1 KR 2017014428 W KR2017014428 W KR 2017014428W WO 2018106076 A1 WO2018106076 A1 WO 2018106076A1
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absorbance
blood
hemostatic
hemostatic material
water
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PCT/KR2017/014428
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English (en)
Korean (ko)
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임정남
도성준
김태희
김윤진
김채화
이규동
김가희
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한국생산기술연구원
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS 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
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS 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
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/00051—Accessories for dressings
    • A61F13/00063—Accessories for dressings comprising medicaments or additives, e.g. odor control, PH control, debriding, antimicrobic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS 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
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/01—Non-adhesive bandages or dressings
    • A61F13/01034—Non-adhesive bandages or dressings characterised by a property
    • A61F13/01042—Absorbency
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS 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
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00361—Plasters
    • A61F2013/00365—Plasters use
    • A61F2013/00463—Plasters use haemostatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the present invention relates to a hemostatic material comprising calcium carboxymethyl cellulose powder and a water-soluble chitosan compound powder, and a method for manufacturing the same, and more particularly, to a hemostatic material having excellent blood absorption ability and improved blood coagulation properties and a method for producing the same. will be.
  • hemorrhage In the case of common gauze or bandages, hemorrhage is effective for minor bleeding, but its application is limited for severe, life-threatening bleeding.
  • hemostatic materials such as collagen wound dressings or dry fibrin or thrombin wound dressings
  • mammalian raw materials there are easy physical property differences between products, weak storage and problems of infection risk and hypersensitivity.
  • Hemostatic agents using cellulose oxide are based on vegetable materials, but hemostatic performance is not satisfactory.
  • inorganic hemostatic agents such as zeolites have been studied to promote clot formation in the blood, but the use of such activated zeolites in the coagulation of blood has been reported to exhibit undesirable exothermic effects.
  • Inorganic hemostatic products with improved fever have also been developed, but they are still not excellent in blood coagulation ability to be applied to excessive bleeding.
  • the problem to be solved by the present invention is to provide a hemostatic material which is excellent in blood absorption capacity and fast blood clotting time.
  • Another object of the present invention is to provide a method of manufacturing the hemostatic material.
  • the hemostatic material of the following embodiment is provided.
  • the first embodiment is a first embodiment.
  • hemostatic layer comprising a calcium carboxymethyl cellulose powder; relates to a hemostatic material having a.
  • the hemostatic layer relates to a hemostatic material further comprising a water-soluble chitosan compound powder.
  • It relates to a hemostatic material in which the weight ratio of calcium carboxymethyl cellulose powder and water-soluble chitosan compound powder in the hemostatic layer is 99: 1 to 1:99.
  • the fourth embodiment is any one of the first to third embodiments,
  • the hemostatic layer relates to a hemostatic material further comprising sodium carboxymethylcellulose.
  • the fifth embodiment is any one of the first to fourth embodiments.
  • It relates to a hemostatic material having a weight ratio (Ca: Na) of Ca and Na in the calcium carboxymethyl cellulose powder of 50:50 to 100: 0.
  • the sixth embodiment is any one of the first to fifth embodiments.
  • the calcium carboxymethyl cellulose powder relates to a hemostatic material having an average particle diameter of 5 to 500 ⁇ m.
  • the seventh embodiment is any one of the first to sixth embodiment
  • the eighth embodiment is any one of the second to seventh embodiments.
  • the water-soluble chitosan compound powder relates to a hemostatic hemostatic material having an average particle diameter of 100 to 1,000 ⁇ m.
  • the ninth embodiment is any one of the second to eighth embodiments.
  • the water-soluble chitosan compound relates to a hemostatic material having a deacetylation degree of 60 to 100% and a weight average molecular weight of 5,000 to 500,000 g / mol.
  • the tenth embodiment is any one of the second to ninth embodiments,
  • the water-soluble chitosan compound relates to a hemostatic material which is at least one of chitosan and chitosan derivatives.
  • the eleventh embodiment is any one of the first to tenth embodiments,
  • the sheet-like base material relates to a hemostatic material including at least one selected from the group consisting of nonwoven fabric, woven fabric, knitted fabric, sponge, and polymer film.
  • the twelfth embodiment is any one of the first to eleventh embodiments,
  • the sheet-like substrate is a hemostatic material that is a perforated spunlace nonwoven.
  • the thirteenth embodiment is any one of the first to twelfth embodiment
  • the liquid absorption of the sheet-like substrate relates to a hemostatic material of 4.0 g / 100 cm 2 or more based on 0.9% physiological saline.
  • the fourteenth embodiment is any one of the first to thirteenth embodiments.
  • the hemostatic layer relates to a hemostatic material having a weight of 20 to 200 g / m 2 per unit area of the sheet-like substrate.
  • the fifteenth embodiment is any of the first to fourteenth embodiments.
  • the hemostatic layer relates to a hemostatic material formed of a patterned layer on at least one surface of the sheet-like substrate.
  • the pattern layer from a group consisting of a dot, a circle, a polygon, a donut, a stripe, a step, an uneven shape, and a grid;
  • a hemostatic material which is one or a combination of two or more selected.
  • the seventeenth embodiment is 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 Equation 1 below, wherein the blood coagulation property evaluation absorbance in Equation 1 is a blood and anticoagulant (sodium citrate, sodium citrate, 3.8w) in a hemostatic material having a size of 1 cm ⁇ 1 cm (width ⁇ length).
  • the blood coagulation property evaluation absorbance in Equation 1 is a blood and anticoagulant (sodium citrate, sodium citrate, 3.8w) in a hemostatic material having a size of 1 cm ⁇ 1 cm (width ⁇ length).
  • the absorbance [AI] of the used blood in Equation 1 is obtained by mixing 50 ⁇ l of the used blood with 6.25 ml of distilled water, taking 200 ⁇ l of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and measuring 200 ⁇ l of distilled water at 540 nm.
  • the present invention relates to a hemostatic material calculated by the following Equation 3 in order to exclude the absorbance effect of distilled water contained in the blood eluate after measuring the absorbance [AW] at the wavelength.
  • the eighteenth embodiment can be 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 Equation 1 below, wherein the blood coagulation property evaluation absorbance in Equation 1 is a blood and anticoagulant (sodium citrate, sodium citrate, 3.8w) in a hemostatic material having a size of 1 cm ⁇ 1 cm (width ⁇ length). / v%) was added dropwise to 100 ⁇ l of the mixed solution in a volume ratio of 9: 1, and 10 ⁇ l of 0.2M CaCl 2 aqueous solution was added to coagulate in an incubator at 37 ° C for 1 minute, and the blood not participating in coagulation was again 12.5 in distilled water.
  • the blood coagulation property evaluation absorbance in Equation 1 is a blood and anticoagulant (sodium citrate, sodium citrate, 3.8w) in a hemostatic material having a size of 1 cm ⁇ 1 cm (width ⁇ length). / v%) was added dropwise to 100 ⁇ l of the mixed solution in a volume ratio of 9: 1, and 10 ⁇ l of 0.2M CaCl
  • the absorbance [AI] of the used blood in Equation 1 was measured by mixing 100 ⁇ l of the used blood with 12.5 ml of distilled water, taking 200 ⁇ l of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and measuring 200 ⁇ l of distilled water at 540 nm.
  • the present invention relates to a hemostatic material calculated by the following Equation 3 in order to exclude the absorbance effect of distilled water contained in the blood eluate after measuring the absorbance [AW] at the wavelength.
  • a method for producing a hemostatic material of the following embodiment is provided.
  • It relates to a method of manufacturing a hemostatic material comprising the step of drying the sheet-like substrate.
  • the step of applying the composition for forming the hemostatic layer further comprising the step of adding a hydrous solvent on at least one surface of the sheet-like substrate,
  • the present invention relates to a method of manufacturing a hemostatic material further comprising the step of exposing the coated sheet-like substrate with water vapor.
  • It relates to a method of manufacturing a hemostatic material further comprising a water-soluble chitosan compound powder in the composition for forming a hemostatic layer.
  • It relates to a method for producing a hemostatic material wherein the hydrous solvent is water or a mixture of water and an organic solvent.
  • 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 a carboxyl group of carboxymethyl cellulose, thereby inducing crosslinking between the carboxymethyl cellulose molecular chains, thereby reducing gel blocking and thus absorbing rate.
  • hemostatic performance can be further improved by promoting blood coagulation by releasing calcium ions upon contact with blood or body fluids.
  • the hemostatic material according to an embodiment of the present invention is prepared in a powder form compared to the calcium carboxymethyl cellulose material prepared in the conventional fibrous, sheet or foam form, the manufacturing process is very simple, the specific surface area It is wider, and the hemostatic effect is greatly improved, and it can be easily cut and applied according to the shape of the surgical site when used.
  • the hemostatic material according to an embodiment of the present invention is an excellent hemostatic function of the water-soluble chitosan compound, excellent absorption and retention performance of calcium carboxymethyl cellulose, thickening effect of water absorption, and coagulation promoting function by the release of calcium ion at the same time
  • the problem of the slow absorption rate of the conventional chitosan alone low hemostatic performance of poorly water-soluble chitosan, hemostatic function deterioration when using sodium carboxymethyl cellulose alone, and problems of morphological stability due to gelation, etc. Hemostatic function can exhibit mutual synergies.
  • Hemostatic material can be used in a variety of medical materials, such as hemostatic agents, anti-adhesion materials, wound dressings.
  • Figure 1a is a photograph of the appearance of the hemostatic material prepared in Example 1
  • Figure 1b is a photograph of the appearance of the hemostatic material prepared in Example 8.
  • FIG. 2 is a photograph showing the results of blood coagulation after 1 minute of evaluation of the hemostatic material prepared in Examples 1 to 4 and Comparative Example 1 according to the blood coagulation property evaluation 1 (blood volume 50 ⁇ l / cm 2 ) method.
  • FIG 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 property evaluation 1 (blood volume 50 ⁇ l / cm 2 ) method.
  • Figures 4a and 4b is a SEM photograph of 100 times and 3,000 times magnification observed the blood coagulation shape of the hemostatic material prepared in Example 1.
  • 4C and 4D are SEM photographs of 100 times and 3,000 times magnification observing the blood coagulation shape of the hemostatic material prepared in Example 2.
  • 4E and 4F are SEM photographs of 100 times and 3,000 times magnification observing the blood coagulation shape of the hemostatic material prepared in Example 3.
  • 4G and 4H are SEM photographs of 100 times and 3,000 times magnification observing the blood coagulation shape of the hemostatic material prepared in Example 4.
  • 4I and 4J are SEM photographs of 100 times and 3,000 times magnification of bleeding of the hemostatic material prepared in Comparative Example 1.
  • FIG. 4I and 4J are SEM photographs of 100 times and 3,000 times magnification of bleeding of the hemostatic material prepared in Comparative Example 1.
  • a blood coagulation property evaluation 2 (blood volume 100 ⁇ l /) of the hemostatic material prepared in Examples 1 to 4, commercial hemostatic dressing products of Comparative Examples 2 and 3, spunlace nonwoven fabric of Comparative Example 4, and blood of Comparative Example 5; cm 2 ) is a graph showing the blood coagulation index evaluated according to the method.
  • FIG. 6 is a graph showing the blood coagulation index of the hemostatic materials prepared in Examples 3 and 5 to 7 according to the blood coagulation property evaluation 2 (blood volume 100 ⁇ l / cm 2 ) method.
  • FIG. 7 is a graph showing a blood coagulation index of the hemostatic materials prepared in Examples 3 and 8 according to the blood coagulation property evaluation 2 (blood volume 100 ⁇ l / cm 2 ) method.
  • Hemostatic material according to an aspect of the present invention is a sheet-like substrate; And calcium carboxymethyl cellulose powder formed on at least one surface of the sheet-like substrate.
  • the sheet-like substrate may have the form of a nonwoven fabric, a woven fabric, a knitted fabric, a sponge, a polymer film, or a mixture of two or more thereof. That is, two or more of these may be stacked on each other, or a sheet-like substrate having different kinds of one substrate layer may be formed in a form in which two or more regions are adjacent to each other.
  • the sheet-like substrate may be a knitted or nonwoven fabric, more preferably a nonwoven fabric, and more specifically, a perforated spunlace nonwoven fabric.
  • the manufacturing process may be simple, the pore property may be easily controlled, and the liquid absorption may be further improved.
  • the degree of absorption of the sheet-like substrate may be 4.0g / 100cm 2 or more, specifically 4.5g / 100cm 2 or more, and more specifically 5.0g / 100cm 2 or more based on 0.9% physiological saline.
  • the absorbency of the sheet-like substrate satisfies this range, the amount of absorption of blood components increases, so that there is a high possibility of contact between the hemostatic material and the component acting on the blood coagulation mechanism, and the moisture in the blood selectively moves to the substrate quickly.
  • the viscosity of the blood may increase, which may lead to faster clotting.
  • the material of the sheet-like base material is a synthetic material such as polyurethane, polyester, nylon, polypropylene, polyethylene, polylactic acid, polyglycolic acid, polydioxanone, polycaprolactone, polyvinyl alcohol, and natural materials such as cotton and viscose rayon. Or recycled fibers may be used, but is not limited thereto.
  • the powder refers to a powder or powder collectively referred to as crushed grains, and may be classified into three-dimensional, powder, fine powder, and ultra fine powder according to the size thereof, for example, 1 to 1,000 ⁇ m, Or from 10 to 1,000 ⁇ m, or from 100 to 1,000 ⁇ m.
  • 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.
  • the hemostatic layer includes calcium carboxymethyl cellulose powder and sodium carboxymethyl cellulose powder, or calcium carboxymethyl cellulose powder and water-soluble chitosan compound powder, in addition to containing only calcium carboxymethyl cellulose powder alone. Or a mixture of calcium carboxymethyl cellulose powder, sodium carboxymethyl cellulose powder, and water soluble chitosan compound powder.
  • the calcium carboxymethyl cellulose means that calcium divalent ions are bonded to the carboxyl group of the carboxymethyl cellulose.
  • the carboxymethyl cellulose means that the hydroxy group of glucose constituting cellulose is substituted with a carboxymethyl group.
  • Such carboxymethyl cellulose has a thickening effect of increasing viscosity due to gelation upon contact with water, and is used in various fields such as grass, food, cosmetics, pharmaceutical additives, and petroleum excavation. In particular, it is widely used as a medical material because of its excellent biocompatibility.
  • the calcium carboxymethyl cellulose powder is analyzed by, for example, ICP-OES (Inductively Coupled Plasma Optical Emission Spectrometry) based on the total weight of calcium carboxymethyl cellulose, 0.5 to 16% by weight, or 1.0 to 10% by weight, Or calcium content of 2 to 8% by weight. If the calcium content satisfies this range, hemostatic performance is further enhanced when in contact with blood, and the absorption rate can be improved.
  • ICP-OES Inductively Coupled Plasma Optical Emission Spectrometry
  • the weight ratio (Ca: Na) of Ca and Na in the calcium carboxymethyl cellulose powder is 50:50 to 100: 0, or 60:40 to 95: 5, or 70:30 to 90:10. If the ratio of sodium ions is high, the gel blocking phenomenon is increased and blood absorption rate is slow.However, if the ratio of calcium ions is high, calcium divalent ions bind to the carboxyl group of carboxymethyl cellulose, thereby inducing crosslinking between carboxymethyl cellulose and gel blocking. The phenomenon can be reduced and the absorption speed can be very high.
  • calcium ions may be released upon contact with blood and thus serve as a catalyst for further promoting blood coagulation.
  • the weight ratio (Ca: Na) of Ca and Na in the calcium carboxymethyl cellulose powder is 70:30 to 90:10
  • water is used in the process of attaching the hemostatic material to the substrate with the effect of introducing calcium ions.
  • the hemostatic material can be easily attached to the substrate without a separate binder component.
  • the weight ratio of calcium carboxymethyl cellulose powder and sodium carboxymethyl cellulose powder may be, for example, 50:50 to 100: 0.
  • the degree of substitution of the calcium carboxymethyl cellulose may be, for example, 0.3 to 3.0, preferably 0.4 to 1.5, more preferably 0.5 to 1.2.
  • the degree of substitution satisfies this range, a larger amount of calcium ions can be introduced, thereby improving dissociation of calcium ions that can promote blood coagulation when in contact with water or body fluids.
  • carboxymethyl cellulose dissociated with calcium ions may partially dissolve, thereby increasing the viscosity of blood.
  • the degree of substitution means the degree to which the hydroxy group of glucose constituting cellulose is substituted with a carboxymethyl group. When the average of one hydroxy group out of three hydroxy groups in cellulose is substituted with carboxymethyl group, the degree of substitution is 1. do.
  • the calcium carboxymethyl cellulose powder may have an average particle diameter of 5 to 500 ⁇ m, specifically 10 to 200 ⁇ m, more specifically 50 to 100 ⁇ m.
  • the average particle diameter of the calcium carboxymethyl cellulose powder satisfies this range, the blood absorption rate is high, the specific surface area of the calcium carboxymethyl cellulose powder can be expanded to promote blood coagulation, and the calcium carboxymethyl cellulose powder inside the substrate. Excessive amount can reduce the phenomenon that the hemostatic performance falls, and as the average particle diameter is too large, the specific surface area becomes small, thereby preventing the problem of deteriorating the blood coagulation effect.
  • Chitosan compounds are deacetylated forms of chitin, the major constituents of shrimp, crabs, lobsters and cuttlefish, and are commercially available in various forms.
  • Such chitosan compounds can provide positively charged surfaces with strong permeability, high specific surface areas, and these positively charged surfaces can produce surfaces that are highly reactive to the interaction of erythrocytes and platelets.
  • the erythrocyte membrane is negatively charged, which is attracted to the positively charged surface of the chitosan compound, and the attracted erythrocyte cell membrane contacts the chitosan compound and fuses to form a blood clot very quickly.
  • chitosan compounds exhibit very good blood coagulation properties and can also bind to bacteria, endotoxins, and microorganisms, thereby killing bacteria, microorganisms, and / or viral agents.
  • the hemostatic material according to an embodiment of the present invention may further include a water-soluble chitosan compound powder in the hemostatic layer.
  • water-soluble chitosan compound means a chitosan compound that is dissolved in neutral water, that is, dissolved in water without adding an additional acid for dissolution.
  • water-insoluble chitosan compound does not dissolve in neutral water, but when the pH is lowered by adding an additional acid, for example, when the pH is 6.5 or less, it means that it is dissolved.
  • the water-soluble chitosan compound powder as the chitosan compound powder in one embodiment of the present invention, while having excellent absorption and retention performance of calcium carboxymethyl cellulose, thickening effect due to water absorption and the role of a catalyst for promoting blood coagulation by calcium ions
  • the hemostatic function can exhibit a mutual synergistic effect by having a blood coagulation effect due to the cationicity of the water-soluble chitosan compound.
  • the water soluble chitosan compound can provide a positively charged surface (-NH 3+ ) with strong permeability and a high specific surface area, which can form a surface that is highly reactive to the interaction of erythrocytes and platelets. .
  • the erythrocyte membrane is negatively charged, which is attracted to the positively charged surface of the chitosan compound, and the attracted erythrocyte cell membrane contacts the chitosan compound and fuses to form a blood clot very quickly.
  • the poorly water-soluble chitosan compound is difficult to provide the positively charged surface even when it comes into contact with blood or body fluid.
  • the water-soluble chitosan compound is more preferable as a hemostatic material because it is likely to bear a positive charge when it comes in contact with blood or body fluid.
  • the water-soluble chitosan compound may be at least one of chitosan and chitosan derivatives.
  • the degree of deacetylation of the water-soluble chitosan compound may be, for example, 60 to 100%, or 80 to 100%
  • the weight average molecular weight of the water-soluble chitosan compound is, for example, 5,000 To 500,000 g / mol, or 10,000 to 300,000 g / mol.
  • the degree of deacetylation and the weight average molecular weight satisfy this range, the water solubility of the chitosan compound can be improved, and the hemostatic function and the wound coating effect can be further improved.
  • the water-soluble chitosan compound powder may have an average particle diameter of, for example, 100 to 1,000 ⁇ m, specifically 100 to 500 ⁇ m, and more specifically 200 to 400 ⁇ m.
  • the average particle diameter of the water-soluble chitosan compound powder satisfies this range, the blood absorption rate is high, and the phenomenon in which an excessive amount of the water-soluble chitosan compound powder enters into the base material reduces blood coagulation effect.
  • the average particle diameter of the water-soluble chitosan compound powder satisfies such a range, as the average particle diameter of the water-soluble chitosan compound is too small and the specific surface area becomes excessively large, the dissolution of the water-soluble chitosan compound occurs excessively quickly, and the blood component becomes The problem of lowering the absorption or decreasing the blood coagulation effect can also be solved as the average particle diameter of the water-soluble chitosan compound is so large that the specific surface area becomes small.
  • 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 30:70.
  • the weight ratio satisfies this range, the shape stability is excellent, the absorption speed is fast, the thickening effect is improved, and the hemostatic effect may 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 , more preferably 80 to 150 g / m 2 .
  • the blood coagulation property may be improved, and the problem of stiffness of the hemostatic material may be solved by increasing the thickness of the hemostatic layer, and may be in contact with the hemostatic material.
  • the amount of blood is limited so that the problem of less blood coagulation efficiency compared to the amount of hemostatic substances can be prevented.
  • the hemostatic layer when the hemostatic layer is formed on at least one surface of the sheet-like substrate, the hemostatic layer may be entirely formed on one surface of the sheet-like substrate, or may be formed only in part. Even when the hemostatic layer is entirely formed on one surface of the sheet-like substrate or only a portion thereof, the hemostatic layer may be formed of various three-dimensional pattern layers having different thicknesses.
  • Such a pattern layer is a group consisting of a dot, a circle, a polygon, a donut, a stripe, a step, an uneven shape, and a grid. It may be one or a combination of two or more selected from, and may be an amorphous pattern without various regular regular patterns.
  • calcium ions when applying a pattern layer in which a large amount and a small amount of the hemostatic layer are laminated, calcium ions may be rapidly released from the powder into calcium carboxymethyl cellulose upon body fluid or blood contact, thereby further exerting a hemostatic effect.
  • the water-soluble chitosan compound powder when the water-soluble chitosan compound powder is further included in the hemostatic layer, hemostatic function and blood absorption rate may be improved.
  • Such a composite pattern layer may be stepped or uneven.
  • 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, more specifically 20% or less.
  • BCI blood clotting index
  • the blood coagulation index is defined by Equation 1 below, wherein the blood coagulation property evaluation absorbance of the formula 1 is 1 cm ⁇ 1 cm (horizontal ⁇ vertical) in the hemostatic material of the size of blood and anticoagulant (sodium citrate, sodium citrate, 3.8w / v%) was added dropwise to 50 ⁇ l of the mixed solution mixed at a volume ratio of 9: 1, and 5 ⁇ l of 0.2M CaCl 2 aqueous solution was added to coagulate in an incubator at 37 ° C.
  • the blood coagulation property evaluation absorbance of the formula 1 is 1 cm ⁇ 1 cm (horizontal ⁇ vertical) in the hemostatic material of the size of blood and anticoagulant (sodium citrate, sodium citrate, 3.8w / v%) was added dropwise to 50 ⁇ l of the mixed solution mixed at a volume ratio of 9: 1, and 5 ⁇ l of 0.2M CaCl 2 aqueous solution was added to coagulate in an incubator at 37 ° C.
  • the absorbance [AI] of the used blood in Equation 1 was measured by mixing 50 ⁇ l of the used blood with 6.25 ml of distilled water, taking 200 ⁇ l of the mixed solution, and measuring absorbance [AB] at a wavelength of 540 nm. After measuring the absorbance [AW] at the wavelength of nm, it is calculated by the following equation 3 to exclude the absorbance effect of distilled water contained in the blood eluate.
  • Absorbance of used blood [AI] absorbance of blood [AB]-distilled water absorbance [ AW ].
  • the hemostatic material according to an embodiment of the present invention is a blood and anticoagulant (sodium citrate, sodium citrate, 3.8w) in the evaluation of blood coagulation properties in a situation where more bleeding occurs than the above-described blood coagulation index evaluation conditions / v%) in a volume ratio of 9: 1, in which 100 ⁇ l is used instead of 50 ⁇ l, 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 or equal to%.
  • BCI Blood Clotting Index
  • the blood coagulation index is defined by Equation 1 below, wherein the blood coagulation property evaluation absorbance of the formula 1 is 1 cm ⁇ 1 cm (horizontal ⁇ vertical) in the hemostatic material of the size of blood and anticoagulant (sodium citrate, sodium citrate, 3.8w / v%) was added dropwise to 100 ⁇ l of the mixed solution mixed at a volume ratio of 9: 1, and 10 ⁇ l of 0.2M CaCl 2 aqueous solution was added thereto to coagulate in an incubator at 37 ° C for 1 minute, and the blood which did not participate in the coagulation was again Elution was carried out in 12.5 ml of distilled water, and 200 ⁇ l of the eluate was taken, measured by absorbance [AB] at a wavelength of 540 nm, and 200 ⁇ l of distilled water was measured by absorbance [AW] at a wavelength of 540 nm. Calculated by the following formula 2 to exclude the effect,
  • the absorbance [AI] of the used blood in Equation 1 was measured by mixing 100 ⁇ l of the used blood with 12.5 ml of distilled water, taking 200 ⁇ l of the mixed solution, measuring the absorbance [AB] at a wavelength of 540 nm, and measuring 200 ⁇ l of distilled water at 540 nm. After measuring the absorbance [AW] at the wavelength is calculated by the following equation 3 to exclude the absorbance effect of distilled water contained in the blood eluate.
  • Absorbance of used blood [AI] absorbance of blood [AB]-distilled water absorbance [ AW ].
  • the hemostatic layer may further include an additive, and such an additive may be freely selected according to required properties, for example, a bioactive substance, a softener, and a hemostatic Substances, antibacterial substances, cells, enzymes, antigens, pigments and the like.
  • an appropriate amount of a softening agent such as glycerol or Tween® may be mixed.
  • antimicrobial substances such as silver, silver compounds, triclosan, biguanide compounds, methylene blue, and the like may be added to block the penetration of microorganisms such as bacteria.
  • the physiologically active substance refers to a substance having a great influence on the function of the living body in a small amount, and may include vitamins, hormones, enzymes, neurotransmitters, and the like, but is not limited thereto, or the nature of the wound or 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, depending on the patient's medical condition Factor, platelet-induced growth factor, von bilbrand factor, tumor necrosis factor (TNF), TNF-alpha, converting growth factor (TGF), TGF-alpha, TGF-beta, insulin-like growth factor, fibroblast growth factor, keratinocytes Growth factor, nerve growth factor, penicillin, ampicillin, methicillin, amoxicillin, clabamox, clavul
  • the hemostatic material according to an embodiment of the present invention is excellent in physical properties may be used as a filling hemostatic agent in the hole, perforation, etc. of the body, may be used as a hemostatic material during surgery.
  • preparing a sheet-like substrate Applying a composition for forming a hemostatic layer comprising calcium carboxymethyl cellulose powder on at least one surface of the sheet-like substrate; And it is provided a method of producing a hemostatic material comprising the step of drying the sheet-like substrate.
  • the calcium carboxymethyl cellulose powder comprises at least one selected from sodium carboxymethyl cellulose powder or carboxymethyl cellulose powder, water, non-solvent of sodium carboxymethyl cellulose powder, and calcium compound It may be prepared by a method comprising the step of mixing in solution.
  • the non-solvent of the sodium carboxymethyl cellulose powder may be methanol, ethanol, isopropyl alcohol, acetone, methylene chloride, ethyl acetate, chloroform and the like.
  • the nonsolvent may be an alcohol.
  • the solvent used for the calcium ion treatment is water;
  • the reason for using a mixed solvent of sodium carboxymethyl cellulose powder is that sodium carboxymethyl cellulose powder or carboxymethyl cellulose powder is prevented by excess water used in the treatment step while increasing the efficiency of introducing calcium ions in the aqueous solution. This is to prevent the powder from dissolving or gelling and losing its form.
  • the water; And a non-solvent of sodium carboxymethyl cellulose powder may be prepared as a mixed solution in which a non-solvent and water are mixed at a volume ratio of, for example, 70:30 to 95: 5, or 75:25 to 90:10. Can be.
  • the calcium compound may be at least one selected from the group consisting of calcium chloride, calcium carbonate, calcium citrate, calcium gluconate, calcium gluobate, calcium hydroxide and calcium oxalate, but is not limited thereto.
  • the water; And non-solvents of sodium carboxymethyl cellulose powder; And calcium carboxymethyl cellulose powder by adding sodium carboxymethyl cellulose powder or carboxymethyl cellulose powder to a solution containing a calcium compound and stirring using a stirrer or the like. At this time, it can be heated to increase the reaction efficiency.
  • the content of the calcium compound in the calcium compound solution may be at least 0.25 molar ratio, or at least 0.5 molar ratio, or at least 1 molar ratio relative to sodium carboxymethyl cellulose powder or carboxymethyl cellulose powder.
  • amount of the calcium compound satisfies this range, calcium carboxymethyl cellulose powder containing an appropriate amount of calcium ions may be prepared.
  • the obtained calcium carboxymethyl cellulose powder was water; And a mixed solution containing a non-solvent of calcium carboxymethyl cellulose, which may be 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 an alcohol.
  • the alcohol may be used one or two or more of methanol, ethanol, propanol and the like, but is not limited thereto.
  • the hemostatic layer-forming composition may further include a water-soluble chitosan compound powder.
  • the composition for forming the hemostatic layer is a mixture of calcium carboxymethyl cellulose powder and sodium carboxymethyl cellulose powder, or calcium carboxymethyl cellulose, in addition to containing calcium carboxymethyl cellulose powder alone.
  • 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 are as described above.
  • the hemostatic layer-forming composition may further include an additive according to the properties required for the hemostatic material, for example, bioactive substances, softeners, hemostatic substances, antibacterial substances, cells, enzymes, antigens, pigments, etc. Can be.
  • an additive according to the properties required for the hemostatic material, for example, bioactive substances, softeners, hemostatic substances, antibacterial substances, cells, enzymes, antigens, pigments, etc. Can be.
  • the method before the step of applying the composition for forming a hemostatic layer, may further include adding a hydrous solvent on at least one surface of the sheet-like substrate, or applying the composition for forming a hemostatic layer. After the step of, may further comprise exposing the coated sheet-like substrate to water vapor. Or before applying the composition for forming a hemostatic layer, further comprising adding a hydrous solvent on at least one surface of the sheet-like substrate, and at the same time, after applying the composition for forming a hemostatic layer, applying the applied sheet-like substrate It may also include all the steps of exposing to water vapor.
  • the composition for forming a hemostatic layer having water solubility or water swellability is applied to the aqueous solvent by applying the composition for hemostatic layer formation.
  • a small amount of glycerol for example, 1 to 10% by volume relative to the aqueous solvent may be added to the aqueous solvent.
  • the composition for forming the hemostatic layer is applied to the substrate, followed by spraying water containing a water-containing solvent, for example, a small amount of softener, to partially dissolve the composition for forming the hemostatic layer, and then drying the composition. It can be easily attached to a substrate without the binding component of.
  • a water-containing solvent for example, a small amount of softener
  • the hydrous solvent may be water or a mixture of water and an organic solvent.
  • the organic solvent used is a non-solvent of the hemostatic layer-forming composition, for example, alcohols such as methanol, ethanol and propanol, and in the case of a mixture of water and an organic solvent, the volume ratio of water and the organic solvent is 100/0. To 10/90, specifically 100/0 to 20/80, and specifically 100/0 to 30/70. When the volume ratio is satisfied, the composition for hemostasis layer formation can be partially dissolved to easily adhere to the substrate. In the case of the organic solvent, it is preferable that the boiling point is lower than that of water.
  • an additional gamma irradiation step may be further performed.
  • This gamma irradiation step has the effect of sterilizing the hemostatic material applied directly to the skin without using heat or chemicals.
  • the treatment by gamma irradiation can be performed even in a state where the hemostatic material is sealed with the final product.
  • the gamma irradiation may be performed, for example, at an irradiation dose of 5 to 30 kGy.
  • a solution of 0.41 mol / L was prepared by dissolving CaCl 2 in 2,500 mL of a mixed solution of ethanol (94.5%) and distilled water in a volume ratio of 80:20, and sodium carboxymethyl cellulose powder (Sodium Carboxymethyl Cellulose, Na-CMC). 50 g of substitution degree) was added thereto and treated with a stirrer at 60 ° C. for about 60 minutes to prepare calcium carboxymethyl cellulose (Calcium Carboxymethyl Cellulose, Ca-CMC) powder.
  • the calcium carboxymethyl cellulose powder thus prepared was washed for 20 minutes using a mixed solution of ethanol and distilled water (80:20 volume ratio), followed by a reduced pressure filtration device with a mixed solution of ethanol and distilled water (80:20 volume ratio) at 60 ° C. Washed twice. The water was washed twice through a vacuum filter with 99.5% methanol to remove moisture. The washed calcium carboxymethyl cellulose powder was sufficiently dried at 50 ° C. in a vacuum oven. In this case, the average particle size of the obtained calcium carboxymethyl cellulose powder was 81 ⁇ m, and the weight fraction of Ca was 4.7% and the weight fraction of Na was 0.9% when ICP-OES was measured.
  • methanol and distilled water were mixed at a volume ratio of 80:20 and vigorously stirred with a stirrer to prepare a dispersion medium.
  • calcium carboxymethyl cellulose powder prepared by the method of step 1 was added, followed by sufficient kneading, followed by manual preparation.
  • a spunlace nonwoven fabric of plain type cotton with a basis weight of 40 g / m 2 was used as a strainer on the hand sheet former to form a hemostatic layer of calcium carboxymethyl cellulose powder on one side of the nonwoven fabric by removing the dispersion medium. Then, it was dried at 50 °C in a convection oven to prepare a hemostatic material.
  • the amount of bleeding in the hemostasis material layer had a weight per area unit of non-woven fabric 90 g / m 2, the basis weight of the hemostatic materials was 130 g / m 2.
  • the appearance photo of the prepared hemostatic material is shown in Figure 1a.
  • Example 2 calcium carboxymethyl cellulose powder prepared in Step 1 of Example 1 and water-soluble chitosan powder (average diameter of 235 ⁇ m, deacetylation degree of 80%, weight average molecular weight of 183,000 g / mol) were used.
  • a hemostatic material was prepared in which a hemostatic layer of calcium carboxymethyl cellulose powder and a water-soluble chitosan powder was formed on one surface of the nonwoven fabric in the same manner as in Example 1, except that it was used at a weight ratio of 30. At this time, the hemostatic layer content of 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 .
  • the hemostatic layer content of 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 .
  • the hemostatic layer content of 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 .
  • Spun of perforated type cotton material having a basis weight of 40 g / m 2 instead of the spunlace nonwoven fabric of plain type cotton material having a basis weight of 40 g / m 2 , using calcium carboxymethyl cellulose powder and water-soluble chitosan powder in a weight ratio of 50:50.
  • the lace nonwoven fabric is used as a strainer, and the content of the hemostatic layer is 90 g / m 2 per unit area of the nonwoven fabric, and the hemostatic material is the same as in Example 2 except that the basis weight of the hemostatic material is 130 g / m 2 .
  • the appearance photo of the prepared hemostatic material is shown in Figure 1b.
  • a hemostatic material was prepared in the same manner as in Step 2 of Example 1, except that a water-soluble chitosan powder (average diameter of 235 ⁇ m), a deacetylation degree of 80%, and a weight average molecular weight of 183,000 g / mol were used instead of the calcium carboxymethyl cellulose powder. Prepared. At this time, the hemostatic layer content of 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 .
  • Equation 1 Blood coagulation characteristics were evaluated by the Blood Clotting Index (BCI) defined by Equation 1 below, wherein the coagulation property evaluation absorbance in Equation 1 was a specimen of hemostatic material having a cross-sectional area of 1 cm ⁇ 1 cm (width ⁇ length). 50 ⁇ l of a mixture of blood and anticoagulant (sodium citrate, 3.8w / v%) in a volume ratio of 9: 1 was added dropwise, and 5 ⁇ l of 0.2M CaCl 2 aqueous solution was added to the solution at 1, 2, 3 in a 37 ° C. incubator.
  • BCI Blood Clotting Index
  • the blood which did not participate in coagulation was again eluted in 6.25 ml of distilled water, and 200 ⁇ l of the eluate was collected, and the absorbance [AB] was measured at a wavelength of 540 nm.
  • the absorbance [AW] was measured at a wavelength of nm, and the absorbance was calculated by the following equation 2 to exclude the absorbance effect of distilled water contained in the blood eluate.
  • the absorbance [AI] of the used blood in Equation 1 was measured by mixing 50 ⁇ l of the used blood with 6.25 ml of distilled water, taking 200 ⁇ l of the mixed solution, and measuring absorbance [AB] at a wavelength of 540 nm. After absorbance [AW] was measured at a wavelength of nm, it was calculated by Equation 3 to exclude the absorbance effect of distilled water contained in the blood eluate.
  • Absorbance of used blood [AI] absorbance of blood [AB]-distilled water absorbance [ AW ].
  • the photograph and the blood coagulation index graph of the evaluation results are shown in FIGS. 2 and 3, respectively.
  • Blood coagulation characteristics of the hemostatic material of Examples 1 to 4 and Comparative Example 1 (cross section 1 cm ⁇ 1 cm (width ⁇ length) size) to the blood and anticoagulant (sodium citrate, 3.8w / v%) in a volume ratio of 9: 1 50 ⁇ l of the mixed solution was added dropwise, and 5 ⁇ l of 0.2M CaCl 2 aqueous solution was added thereto, and the mixture was coagulated in a 37 ° C incubator for 1 minute.
  • Example 1 is shown in FIGS. 4A (100 times magnification) and 4B (3,000 times magnification), Example 2 is shown in FIGS.
  • Example 4C 100 times magnification
  • FIG. 4D 3,000 times magnification
  • Example 3 is shown in FIG. 4E (100 times magnification) and FIG. 4F (3,000 times magnification)
  • Example 4 is FIG. 4G (100 times magnification) and FIG. 4H (3,000 times magnification)
  • Comparative Example 1 is FIGS. 4I (100 times magnification) and FIG. 4j (3,000 times magnification), respectively.
  • the hemostatic material of Examples 1 to 4 was confirmed that the blood coagulation index is remarkably low at 20% or less when 1 minute has elapsed, excellent blood coagulation characteristics.
  • Comparative Example 1 which is a nonwoven fabric having only water-soluble chitosan powder, blood coagulation property was remarkably inferior as compared with Examples containing calcium carboxymethyl cellulose.
  • Examples 1 to 4 having a hemostatic layer containing calcium carboxymethyl cellulose powder rather than the hemostatic material of Comparative Example 1 having a hemostatic layer containing only water-soluble chitosan powder.
  • the hemostatic material showed excellent blood coagulation properties, and it was found that the hemostatic material of Examples 2 to 4 in which calcium carboxymethyl cellulose powder and water-soluble chitosan powder were combined showed better blood coagulation properties.
  • the hemostatic material of Examples 1 to 4 is a commercially available products Comparative Examples 2 and 3, Comparative Examples 4 and 2, cotton non-woven fabrics, Comparative Examples 2 and 3, non-woven fabrics of the market compared to Comparative Example 5 blood
  • Comparative Example 4 when the blood coagulation time passed 1 minute, the blood coagulation index was 80% or more, and the blood did not coagulate well. On the contrary, in Examples 1 to 4, the blood coagulation index was significantly lowered to 60% or less when one minute passed due to less blood remaining without coagulation.
  • Example 6 is that in a review hemostatic properties according to the weight of the hemostatic layer attached to the sheet-like substrate, was, even if the weight of the coagulation layer is 30 to 70g / m 2 per sheet-shaped base unit is blood coagulation factor after 1 minute or less to 60% , In the case of Example 3, the weight of the hemostatic layer is 90g / m 2 per unit area of the sheet-like base material, it was confirmed that blood coagulation occurs well after 40 minutes or less.
  • Figure 7 is a comparison of the blood coagulation characteristics according to the shape of the sheet-like substrate, hemostasis of Example 3 using a plain type nonwoven fabric having a liquid absorption of 4.5g / 100cm 2 for 0.9% physiological saline as the sheet-like substrate
  • the hemostatic material of Example 8 in which a perforated type nonwoven fabric having a degree of liquid absorption of 5.0 g / 100 cm 2 was used, showed a lower blood coagulation index after 1 minute than the material.
  • the high degree of absorption of the sheet-like substrate facilitates the absorption of blood, particularly the rapid movement of moisture in the blood to the substrate, thereby increasing the likelihood that the hemostatic components acting on the blood coagulation mechanism contained in the hemostatic material will come into contact with the blood, or Selective fast absorption appears to increase blood viscosity, resulting in faster blood coagulation.
  • the degree of absorption of the substrate was measured by measuring the weight and area of the dried substrate, immersing in 0.9% saline for 10 minutes, and then measuring the weight of the substrate absorbed as follows.
  • Absorption degree of substrate [weight of substrate after absorption (g)-weight of substrate before absorption (g)] / [area of substrate before absorption (cm 2 )] X 100

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Abstract

L'invention concerne un matériau styptique et son procédé de production, le matériau styptique comprenant : un substrat sous forme de feuille; et une couche styptique formée sur au moins une surface du substrat sous forme de feuille et comprenant de la poudre de carboxyméthylcellulose de calcium.
PCT/KR2017/014428 2016-12-09 2017-12-08 Matériau styptique comprenant une poudre de carboxyméthylcellulose de calcium et une poudre de composé de chitosane soluble dans l'eau, et son procédé de production WO2018106076A1 (fr)

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CN114681659A (zh) * 2020-12-31 2022-07-01 广州迈普再生医学科技股份有限公司 复合止血粉及其制备方法和应用

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KR102164484B1 (ko) * 2018-09-14 2020-10-13 주식회사 티앤엘 키토산으로 표면 코팅된 폴리우레탄 폼 및 이의 제조방법
KR102442848B1 (ko) 2022-05-13 2022-09-15 주식회사 티앤엘 지혈부직포

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