WO2011084326A2 - Hemostatic agents and wound dressings - Google Patents

Hemostatic agents and wound dressings

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Publication number
WO2011084326A2
WO2011084326A2 PCT/US2010/059497 US2010059497W WO2011084326A2 WO 2011084326 A2 WO2011084326 A2 WO 2011084326A2 US 2010059497 W US2010059497 W US 2010059497W WO 2011084326 A2 WO2011084326 A2 WO 2011084326A2
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WO
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Prior art keywords
poly
cmc
particle
block
acrylic acid
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PCT/US2010/059497
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French (fr)
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WO2011084326A3 (en )
Inventor
Fangxiao Yang
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Resodyn Corporation
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    • 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
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/60Liquid-swellable gel-forming materials, e.g. super-absorbents
    • 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
    • A61L15/225Mixtures of macromolecular compounds
    • 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
    • A61F2013/00361Plasters
    • A61F2013/00365Plasters use
    • A61F2013/00463Plasters use haemostatic
    • 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
    • A61F2013/00361Plasters
    • A61F2013/00365Plasters use
    • A61F2013/00463Plasters use haemostatic
    • A61F2013/00472Plasters use haemostatic with chemical means
    • 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
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/04Materials for stopping bleeding

Abstract

Hemostatic compositions are disclosed comprising hydrogels and polyglucosamines and/or polyglucosamine derivatives. The hemostatic compositions can also contain coagulation acceleration agents and antibiotics, antifungals, anti-infectives, antimicrobials, anti-inflammatories, analgesics, and antihistamines. A method of promoting blood clotting is disclosed which comprises contacting blood with a disclosed hemostatic composition. Wound dressings are comprised of the disclosed hemostatic compositions and a substrate such as fabrics made from natural and/or synthetic fibers. The wound dressings containing the disclosed hemostatic compositions have high water adsorption capacity and good bleeding control and also exhibit strong adhesion to wet, bloody wounds. The wound dressings typically adhere to, or are held against, or placed into a wound site, to seal the wound site, to accelerate blood clot formation at the wound site, to reinforce clot formation at the wound site and prevent bleed out from the wound site, and to substantially stop the flow of blood out of the wound site.

Description

HEMOSTATIC AGENTS AND WOUND DRESSINGS

BACKGROUND OF THE INVENTION

1 . Field of the Invention

The present invention refers to hemostatic compositions, wound dressings containing the hemostatic compositions, and a method of promoting blood clotting comprised of contacting blood with the hemostatic compositions.

2. Brief Description of the Prior Art

Severe bleeding is the leading cause of death from wounds on the battlefield, accounting for approximately 50 percent of such deaths. It is estimated that one-third of these deaths could be prevented with enhanced hemorrhage control methods and devices. Such enhanced hemorrhage control would also prove very useful in non- military settings, e.g., in hospitals or veterinary clinics, or as a result of traumatic accidents, where hemorrhage is the second leading cause of death following trauma.

Moreover, severe wounds can often be inflicted in remote areas, or in situations where adequate medical assistance is not immediately available such as on a battlefield. In these instances it is important to stop bleeding, even in less severe wounds, long enough to allow the injured person or animal to receive medical attention.

To date, the application of continuous pressure with gauze bandage has been the preferred primary intervention technique used to stem blood flow, especially flow from severely bleeding wounds. However, this procedure neither effectively nor safely stanches severe blood flow. This method requires the use of constant pressure on applied gauze, and in most severe bleeding cases the injured person can not achieve such a requirement. Due to gauze shape and form, it is sometimes difficult for the injured person himself to apply it to the injured site. This has been, and continues to be, a major survival problem in the case of severe life-threatening bleeding from a wound. In an effort to address the above-described problems, materials have been developed for controlling excessive bleeding in situations where conventional aid is unavailable or is less than optimally effective. Unfortunately, these materials are sometimes ineffective and can be difficult to apply as well as difficult to remove from a wound.

Recently, many novel anti-hemorrhage bandages have been tested using a swine model and their performance compared. Although all the new bandages were proven to be superior to the traditional hemorrhage bandage, it appears that the wound bandages TraumaCure's WoundStat™, Z-Medica's S-Spongue and chitosan flake from Celox™ were best in regard to puncture hemorrhage and prevention of re-bleeding.

Chitosan-based bandages (HemCon®) and zeolite-derived bandages (Z-Medica) were ranked the lowest. Clay-based inorganic hemostatic agents, such as WoundStat™, which are typically not soluble in water, have been observed to produce emboli in the swine test.

Chitosan has been used as hemostatic agent in both non-woven block (sheet) and granule form. A chitosan block and sheet produced by HemCon® were chosen as a hemostatic agent by the United States Army but were later dropped due to

inconvenience in application and replaced with WoundStat™.

In order to supply chitosan in particle form, Celox™ has produced a chitosan- based hemorrhage control agent in flake form. The drawback of this preparation is that the flake particles are too light. Furthermore, the water adsorption rate and uptake capacity of unmodified chitosan are not satisfactory for use as a hemostatic agent.

For severe hemorrhage control, two functions are desired in a wound dressing agent: (1 ) physically blocking the blood flow from a puncture wound; and (2)

accelerating the clotting reactions of the blood itself. An agent with very high

dehydration capacity and moderate stickiness under wet condition is a good candidate for blocking blood loss at a wound site. The minimum requirements for such agent are biocompatibility and solubility in the event that they migrate back into the blood.

There is a need for compositions for use in wound treatments having high water adsorption capacity, good blood clotting control and good adhesion to wounds under wet conditions. BRIEF SUMMARY OF THE INVENTION

As used herein, the following terms and variations thereof have the meanings given below, unless a different meaning is clearly intended by the context in which such term is used.

"A," "an" and "the" and similar referents used herein are to be construed to cover both the singular and the plural unless their usage in context indicates otherwise.

"Comprise" and variations of the term, such as "comprising" and "comprises," as well as ""having" and "including" are not intended to exclude other additives,

components, integers or steps.

"Exemplary," "illustrative," and "preferred" mean "another."

One aspect of the present invention pertains to biocompatible compositions useful in hemostatic agents and wound dressings. These compositions comprise hydrogels and a sub-class of polysaccharides known as polyglucosamines. The hemostatic compositions according to the invention may optionally contain coagulation acceleration agents, antibiotics, antifungals, anti-infectives, antimicrobials, antiinflammatories, analgesics, antihistamines and combinations thereof.

Another aspect of the present invention pertains to wound dressings comprising the compositions according to the invention and a substrate such as fabrics made from natural and/or synthetic fibers.

Another aspect of the present invention pertains to methods of promoting blood clotting comprising contacting blood with a composition according to the invention.

Wound dressings containing hemostatic compositions according to the invention have high water adsorption capacity and good bleeding control and also exhibit strong adhesion to wet, bloody wounds.

The wound dressing according to the invention typically adheres to, or is held against, or is placed into the wound site, to seal the wound site, to accelerate blood clot formation at the wound site, to reinforce clot formation at the wound site and prevent bleed out from the wound site, and to substantially stop the flow of blood out of the wound site.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a graph of simulated bodily fluid adsorption rate and adsorption capacity test results for selected samples. DETAILED DESCRIPTION OF THE INVENTION

The hemostatic agent according to the invention is comprised of a hydrogel and a polyglucosamine polysaccharide and/or a polyglucosamine derivative as its major components. The hemostatic compositions according to the invention may optionally contain a coagulation acceleration agent.

Hydrogels that can be used in the compositions according to the invention are superabsorbent polymers that can absorb up to hundreds of times of their dry weight of water. Such materials are well known and include, but are not limited to, acrylonitrile grafted onto starch, poly(acrylamide) (PAAm), poly(acrylic acid) (PAA), and their copolymers such as poly(acrylamide-co-acrylic acid) (PAAA) and the like. Chitosan can also be made into a hydrogel by cross-linking. Conventional chitosan cross-linking reactions involve reaction of chitosan with formaldehyde and dialdehydes, such as glutaraldehyde, diglycidyl ethers or epoxides which can produce a hydrogel with a swelling ability in acidic media.

Chitosan hydrogels can also be prepared by graft copolymerization of anionic monomers such as acrylic acid onto chitosan (in the presence of a divinyl cross-linking agent monomer), an ampholytic hydrogel containing both cationic and anionic charges results. Therefore, by introducing anionic charges (-COO-) onto chitosan, a hydrogel with swelling ability at various pHs may be prepared. The synthesis of ampholytic hydrogels by hydrolysis of chitosan-g-poly(acrylonitrile) has been reported, as has binary graft copolymerization of the acrylamide (AAm) and acrylic acid monomers onto chitosan.

The polyglucosamines and polyglucosamine derivatives that can be used in the compositions according to the invention are modified polysaccharides wherein the anhydroglucose units contain an N-acetyl amine functionality (more precisely, 2-

(acetylamino)-2-deoxy-D-glucose) in the case of chitin or, in the case of chitosan, the amine form (more precisely, 2-(amino)-2-deoxy-D-glucose). Chitin is such a modified polysaccharide which contains nitrogen; it is synthesized from units of N- acetylglucosamine. Typically, the degree of deacetylation in chitosan is between 70 to 100 percent. Both chitin and chitosan are insoluble in water but chitosan is soluble in dilute aqueous acids, e.g., carboxylic acids. A particularly preferred chitosan derivative is Ν,Ο- carboxymethyl chitosan, abbreviated herein as CMC. The term CMC encompasses N- carboxymethyl chitosan, O-carboxymethyl chitosan, Ν,Ο-carboxymethyl chitosan and mixtures of each of these compounds. CMC can be prepared by reaction of chitosan and chloroacetic acid as described in Example 1 herein. Polyglucosamine derivatives also include copolymers of N-acetylglucosamine and various glycan sugars, e.g.

hyaluronic acid, chondroitin, heparin, keratan and dermatan.

A granular or particle form of the hemostatic agent according to the invention can be used when it is desirable or necessary to apply it directly into a wound without the use of pressure on the wound. In such instances, the polylgucosamine particle density and hydrophilicity must be adjusted to enhance its water adsorption rate.

The hemostatic compositions according to the invention can be prepared by co- polymerization, grafting, or physical adsorption of one or more polysaccharides onto hydrogel particles, or physical blending of hydrogel particles and polysaccharides particles. Another method involves cross-linking of a modified chitosan (e.g., CMC) and a hydrogel through hydroxylation reactions with epichlorohydrin as a cross-linker or through esterification reactions with an enzyme as catalyst. In these embodiments, the hydroxylation reaction takes place between -OH group on the CMC and the hydrogel and the esterification reaction takes place between -COOH and -OH groups on both reactants.

Another method involves coating CMC onto hydrogel particles to form a composite with high water adsorption rate as well as good adhesion capacity. Super- adsorbent hydrogels such as a PAAm, PAAA and PAA as mentioned above, as well as a Poly (isobutylene-co-maleic acid) (PBMA), Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) may be used for this purpose.

The hemostatic compositions according to the invention can also be made by graft copolymerization. Acrylamide monomer is grafted onto chitosan to form chitosan-g- poly(acrylamide) (chitosan-g-PAAm) or acrylic acid to form chitosan-g-poly(acrylic acid) (chitosan-g-PAA). Examples of hemostatic compositions according to the invention include, but are not limited to the following: (1 ) a carboxylmethylchitosan (CMC) in granule, block or sheet form; (2) one or more CMC - calcium ion cross-linked compounds in granule, block or sheet form; (3) a CMC and a Poly(acrylamide) (PAAm) physical blend in granule or powder form; (4) a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC physically adsorbed on the surface of the particle; (5) a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC chemically linked to the backbone of the hydrogel via hydroxylation using epichlorohydrin; (6) a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC chemically linked to the backbone of the hydrogel via

esterification; (7) a CMC and a Poly(acrylic acid) (PAA) physical blend in granule or powder form; (8) a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle; (9) a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrin; (10) a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; (1 1 ) a CMC and a Poly(acrylamide-co-acrylic acid) (PAAA) physical blend in granule or powder form; (12) a Poly(acrylamide-co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; (13) a Poly(acrylamide-co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation; (14) a Poly(acrylamide-co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; (15) a CMC and a Poly(isobutylene-co-maleic acid) (PBMA) physical blend in granule or powder form; (16) a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; (17) a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrin; (18) a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; (19) a CMC and a Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) physical blend in granule or powder form; (20) a Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; (21 ) a Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrin; (22) a Poly(acrylic acid)-graft- poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; (23) a Chitosan-g-PAA with partial hydrolysis treatment; (24) a Chitosan-g-PAA with carboxylation treatment; (25) a Chitosan-g-PAAm with partial hydrolysis treatment; and (26) a Chitosan-g-PAAm with carboxylation treatment.

The wound dressings according to the invention are comprised of the

compositions according to the invention and a substrate. The substrate can be any solid substance that is biocompatible with blood and can serve as a support for or be a part of the hemostatic composition according to the invention. The substrate is preferably a fibrous web wherein the fibers can be natural or synthetic fibers in the form of woven and/or non-woven fabrics. Examples of natural fibers are well known and include, but are not limited to, cellulose fibers obtained from wood pulp or cotton, polyamide fibers such as silk and proteins. Examples of synthetic fibers are well known and include, but are not limited to, polyamides such as nylons, polyesters such as polyethylene terephthalate, acrylic fibers, and the like. A preferred substrate is gauze. The

hemostatic compositions according to the invention and/or wound dressings may also contain coagulation acceleration agents such polyphosphate, and antibiotics, antifungals, anti-infectives, antimicrobials, anti-inflammatories, analgesics, antihistamines and combinations thereof.

The wound dressings may be made by a variety of methods. These methods include coating of the substrate with one or more of the hemostatic compositions according to the invention and a polymeric binder prepared from biocompatible material(s), water-soluble material(s), water-swellable material(s), bio-resorbable material(s) and/or other material(s) containing embedded and/or co-deposited active and/or functional water soluble particles. Another method is incorporation of the hemostatic composition into a fabric during the process of forming the fabric. The present invention also pertains to a method of promoting blood clotting comprising contacting blood with a composition according to the invention. Typically, the method is carried out by contacting a bleeding wound with a wound dressing according to the invention thereby substantially stanching the flow of blood from the wound. The wound dressing according to the invention typically adheres to, or is held against, or is placed into the wound site, to seal the wound site, to accelerate blood clot formation at the wound site, to reinforce clot formation at the wound site and prevent bleed out from the wound site, and to substantially stop the flow of blood out of the wound site.

The following Examples are meant to illustrate but not to limit the invention.

EXAMPLES

Example 1

A quantity of 40.0 g of commercial chitosan (viscosity of 1080 cps, 1 % solution in 1 % acetic acid, Brookfield Viscometer No. 4 spindle, 50 rpm) is slurried in 695 ml isopropanol at room temperature; 131 .5 g of 10.161 M aqueous sodium hydroxide solution was gradually added to the slurry over a period of 20 minutes, with stirring which was continued for one hour. Next, a quantity of 48.0 g of monochloroacetic acid was added with stirring over a 20-minute interval. Then the temperature of the mixture was raised to 60 'Ό and held there for three hours. Thereafter, when the mixture had cooled, the solid product was separated by filtration and resuspended in one liter of 70% (v/v) methanol-water for 15 minutes as a wash, then three ml of glacial acetic acid were added and stirring continued for one hour. The solid product was collected by filtration then reslurried in one liter of 80% methanol-water for 15 minutes for a final wash, collected by filtration, and air dried. The white N, O-carboxymethyl chitosonium acetate product weighed 52 g.

Example 2

Physical deposition of a CMC on a hydrogel particle surface may be achieved by dissolving an amount of a modified chitosan (CMC) in water or a water solution which may contain soluble coagulation acceleration agents such as a polyphosphate (PolyP). PolyP concentration can be 1 .0 g/l to 100 g/l. A desired amount of hydrogel particle is then added under strong agitation. The hydrogel added can be 100 g/l to 2000 g/l. The mixture is then lyophilized for typically 48 hours. The dried mixture is then sieved to remove fine free particles and the product may be directly used as a hemostatic agent.

Example 3

A number of samples of hemostatic agents were tested for water absorption, adhesion and Flow stop capacity; that is, the ability to stop liquid flow at a pressure equal to normal average blood pressure. The composition of illustrative samples is set forth below in Table 1 . In this table, PAAA is Ploy(acrylamide-co-acrylic acid), CMC is

Carboxylmethylchitosan, CMCc is Carboxylmethylcellulose, ST is Sodium

tripolyphosphate, PG is Phosphate glass, CTS is Chitosan, CMC (AK) is

Carboxylmethylchitosan from AK Scientific Inc, CTS (MMw) is Chitosan with medium molecule weight, CMC (MMw) is Carboxylmethylchitosan synthesized from medium molecule weight chitosan, Semectite is called WoundStat is a hemorrhage control dressing from TraumaCure and Kaolin is a majority ingredient in QuickClot from Z- Medica.

Table 1 . Selected Hemostatic Agent Samples

Sample Sample composition Sample

No. (weight ratio) weight, g

No. 1 PAAA:CMC:ST = 5:1 ;2 0.8413

No. 2 PAAA:CMC:PG = 5:1 :2 0.4231

No. 3 PAAA:CMC = 5:0.5 0.4381

No. 4 PAAA:CMCc = 5:1 0.4560

No. 5 CTS (MMw) 0.7155

No. 6 CMC (MMw) 0.6122

No. 7 CMC (AK) 0.6826

No. 8 Semectite 3.031 1

No. 9 Kaolin 2.2935

Water adsorption: One additional function of the hemostatic composites according to the invention as hemorrhage control agents is adhesion to the open wound which forms a physical barrier to stop bleeding and simultaneously adsorb water from the blood. The adsorption of water by a hemostatic agent concentrates the platelets and clotting factors and therefore promotes rapid clot formation. Coagulation acceleration agents such polyphosphate can be incorporated into the hemostatic agent composite. These agents are preferably water soluble and biocompatible. High water adsorption capacity is one of the most desired properties as a hemorrhage control agent. This characteristic is important because the adsorption of water concentrates the platelets and clotting factors and promotes rapid clot formation. The hemostatic agents and wound dressings disclosed herein increase, improve or maximize utilization of the absorbent capacity of the dressing so as generate instant blood clotting, reduce or eliminate maceration and facilitate healing of the wound.

A water sorption test was used to determine the absorbency of formulated organic granule to a wound fluid mimic solution (Solution A) expressed in grams water per gram of dressing (g water/g dressing). The absorbency of the dressings was determined using tea bag method. Solution A contained 142 micromoles per liter

(mmol/l) sodium chloride and 2.5 mmol/l calcium chloride. This solution mimics serum and wound fluid.

The test setup included 200 milliliter (ml_) of solution A in a 250 ml_ beaker that was placed on a hot plate stirrer to heat to 37 ± 1 °C and maintained at this temperature. A weighed amount of hemostatic granule was placed in a tea bag and the tea bag was dipped into the solution A while stirring. After soaking a predetermined time, the bag was taken out and free water on the bottom of the bag was wiped out. The bag was then weighed and the weight difference (before and after soaking) was equal to the water that had been adsorbed by the granule particles. The water adsorption results for selected samples are plotted in FIG. 1 .

Adhesion capacity: The stickiness of a hemostatic agent can be described in terms of cohesion (particle-particle stickiness) and adhesion (particle-wet surface stickiness). Cohesion is an internal property of a powder or granule and is a measure of the forces holding the particles together whereas adhesion is an interfacial property and is a measure of the forces holding the particles to the surface of another material.

Particle cohesion is the important parameter for powder agglomeration. To make the hemostatic agent easy to remove when removal is required, particles sticking together (cohesion) is required. The adhesion forces of hemorrhage control agents are required to form a physical barrier to prevent blood flow from injured site. This adhesion however, is preferably not so strong as to prevent removal. The adhesion of a sample of an embodiment of the invention was tested. The PAA + CMC composite granule hydration and adhesion was accomplished in a series steps: (1 ) a sample of dry hemostatic agent granules was placed on a watch glass, (2) solution A was added to the dry granule sample, (3) a water adsorption transition was allowed to occur over a period of 10 seconds, and (d) the watch glass was placed in a vertical position. The hemostatic agent granule, after hydration, sticking to the smooth surface such as watch glass when the surface is in vertical position indicates the adhesion is satisfactory for bleeding control purpose.

Flow stop capacity: A hemostatic agent must stop liquid flow with normal average blood pressure. A pressure of 70 millimeters of mercury (mm Hg) or 952 millimeters of water (mm H20) pressure is normally used. Such a flow stop test was performed on a sample of an embodiment of the invention. In this test, a liquid (solution A) level was set at about 1 ,000 mm or 1 meter and a sample of hemostatic agent granules were poured into a watch glass after the valve had been opened, causing solution A to flow over the watch glass.

Example 4

In-Vivo Animal Testing

The tests were carried out to evaluate the ability of hemostatic compositions to control bleeding in rats due to common carotid artery injury and uncontrolled liver hemorrhage. Preliminary small animal tests (adult Sprauge-Dawley rats; weights from 600 to 650 grams) were conducted in order to demonstrate the bleeding control of the hemostatic compositions according to the invention. These tests were performed at Surgical Research lab of International Heart Institute of Montana at Missoula, Montana. The tests include common carotid artery transection and liver laceration. The model development, validation and the comparative study was performed in accordance with the guide lines of good laboratory practice and approved by the Institute Animal Care and Use Committee (IACUC) of University of Montana. Liver Laceration

In the animal studies, rats were anesthetized, venous and arterial catheters placed (fluid resuscitation and direct blood pressure measurement respectively) and body temperature maintained by a heating pad at 37.5 'C. The liver was exposed by a midline laparotomy. The median lobe of the liver was marked on the lateral, midline and medial aspects approximately -1 -1 .3 cm from the suprahepatic vena cava using cautery. The marked portion was then sharply excised and the hemostatic agent applied immediately to the cut surface. Crystalloid fluids, e.g. lactated ringers solution, were utilized intra-operatively to maintain direct blood pressure with an endpoint of fluid resuscitation of 100 mmHg. The abdominal cavity was left open and blood/fluid collected using pre-weighed gauze pads. Monitoring was continued for 30 minutes or until the death of the rat (whichever occurs first), and animals alive after 30 minutes were euthanized, while still under anesthesia. The volume of blood/fluid lost was calculated by weight (pre-weighed gauze pads and the weight of blood absorbed by the hemostatic material).

Carotid Artery Transection

After an isoflurane anesthetic induction the rat was incubated and

maintained on isoflurane gas duration of the surgical procedure. The right and left inguinal region and ventrolateral neck was shaved. The right and left femoral artery and vein were dissected and exposed. The left femoral artery was

cannulated and instrumented for direct pressure monitoring. The femoral vein was cannulated for fluid resuscitation and drug administration. The tail was

instrumented with the Topo™ indirect blood pressure monitor should the direct pressure monitoring fail. A direct pressure wave was attained but was lost approximately 1 0 minutes after cannulation. Gaskets were removed and replaced from the Topo™ indirect blood pressure monitor and indirect pressure monitoring functioned beautifully through the experiment. The right carotid artery was dissected and exposed. 90 IU of Heparin was given IV. The proximal

carotid artery was ligated and the artery transected distal to this ligature. The

hemostatic agent (#2) was immediately applied. Hemorrhage was noted to absorb throughout the hemostatic agent and hemorrhage was not immediately apparent except for slow oozing from the lateral edge. Hemorrhage was abated at 1 minute and 50 seconds after transection. The hemostatic agent was removed and no further hemorrhage was noted. After the carotid artery was transected the blood pressure varied between 99/81 - 1 13/94. After 30 minutes the rat was euthanized with 1 cc of KCL IV.

Group Size

A total of ten rats were used for the investigation, five in the liver laceration group and five in the carotid transaction model. Hemostatic agents were tested sequentially, with results from previous tests used to adjust formulation for the subsequent test. The hemostatic agents were applied to the vessel and were removed after a pre-determined period. Two (2.0) grams of hemostatic agent was used for artery injury and four (4.0) grams of agent was used for liver injury. Carotid injury was achieved within ten seconds and liver injury was achieved in less than six minutes. No further hemorrhage was noted after the hemostatic agent was removed in all tests.

The compositions tested in these tests are set forth in Table 2 below. The results of the tests are listed in Table 3.

Table 2. A List of Compositions of Tested Samples Corresponding to Table 1

Sample No. Composition

# 1 CTS-g-PAAm (CTS : PAAm = 10 :40)

# 2 CMC : PAA = 1 : 2 (physical blend)

# 3 CTS-g-PAAm saponified (CTS : PAAm = 10 :40)

# 5 CTS-g-PAAm (CTS : PAAm = 10 :40) second batch

# 6 CTS-g-PAAm (CTS : PAAm = 20 :40)

Note: CTS - chitosan, CMC - carboxyl methyl chitosan, CTS-g-PAAm - chitosan grafted poly(acrylamide), All ratios are weight ratios. Table 3. Summary of Rat Test with Various Hemostatic Agents

The above summary shows that Sample #2 was most effective. The composition of Sample #2 is shown in Table 2.

Claims

What is claimed is:
Claim 1 . A composition comprising a hydrogel and polyglucosamine.
Claim 2. The composition of claim 1 wherein the polyglucosamine is chitin, chitosan or a combination thereof.
Claim 3. The composition of claim 2 wherein the polyglucosamine is
chitosan.
Claim 4. The composition of claim 1 wherein the hydrogel is acrylonitrile grafted onto starch, poly(acrylamide) (PAAm), poly(acrylic acid) (PAA), poly(acrylamide-co- acrylic acid) (PAAA), or a combination thereof.
Claim 5. The composition of claim 4 wherein the hydrogel is PAA.
Claim 6. The composition of claim 1 wherein the composition is selected from the group consisting of a CMC and a Poly(acrylamide) (PAAm) physical blend in granule or powder form; a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC physically adsorbed on the surface of the particle; a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC chemically linked to the backbone of the hydrogel via hydroxylation using epichlorohydrin; a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(acrylic acid) (PAA) physical blend in granule or powder form; a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle; a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrine; a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(acrylamide-co-acrylic acid) (PAAA) physical blend in granule or powder form; a Poly(acrylamide-co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; a Poly(acrylamide-co- acrylic acid) (PAAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation; a Poly(acrylamide-co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(isobutylene-co-maleic acid) (PBMA) physical blend in granule or powder form; (16) a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrin; a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) physical blend in granule or powder form; a Poly(acrylic acid)-graft- poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; a Poly(acrylic acid)-graft- poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrin; a
Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a Chitosan-g-PAA with partial hydrolysis treatment; a Chitosan-g-PAA with carboxylation treatment; a Chitosan-g-PAAm with partial hydrolysis treatment; a Chitosan-g-PAAm with carboxylation treatment, and combinations thereof.
Claim 7. The composition of claim 6 wherein the composition is comprised of a CMC and a PAA physical blend in granule or powder form.
Claim 8. The composition of claim 1 further comprising a coagulation acceleration agent, an antibiotic, an antifungal, an anti-infective, an antimicrobial, an antiinflammatory, an analgesic, an antihistamine and combinations thereof.
Claim 9. The composition of claim 8 wherein the coagulation accelerating agent is sodium tripolyphosphate.
Claim 10. A composition comprising the composition of claim 1 and a substrate.
Claim 1 1 . The composition of claim 10 wherein the substrate is a fibrous web.
Claim 12. The composition of claim 1 1 wherein the fibrous web is comprised of natural and/or synthetic fibers in the form of woven and/or non-woven fabrics.
Claim 13. The composition of claim 12 wherein the natural fibers are cellulosic fibers obtained from wood pulp or cotton.
Claim 14. The composition of claim 10 wherein the substrate is gauze.
Claim 15. The composition of claim 10 wherein the composition of claim 1 is selected from the group consisting of a CMC and a Poly(acrylamide) (PAAm) physical blend in granule or powder form; a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC physically adsorbed on the surface of the particle; a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC chemically linked to the backbone of the hydrogel via hydroxylation using epichlorohydrin; a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(acrylic acid) (PAA) physical blend in granule or powder form; a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle; a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrine; a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(acrylamide-co-acrylic acid) (PAAA) physical blend in granule or powder form; a Poly(acrylamide-co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; a
Poly(acrylamide-co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation; a Poly(acrylamide- co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(isobutylene-co-maleic acid) (PBMA) physical blend in granule or powder form; (16) a Poly(isobutylene-co- maleic acid) (PBMA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrin; a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) physical blend in granule or powder form; a Poly(acrylic acid)-graft- poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; a Poly(acrylic acid)-graft- poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrin; a
Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a Chitosan-g-PAA with partial hydrolysis treatment; a Chitosan-g-PAA with carboxylation treatment; a Chitosan-g-PAAm with partial hydrolysis treatment; a Chitosan-g-PAAm with carboxylation treatment, and combinations thereof.
Claim 16. The composition of claim 15 wherein the composition of claim 1 is a CMC and a PAA physical blend in granule or powder form.
Claim 17. The composition of claim 15 wherein the composition of claim 1 is comprised of a CMC and a PAAA physical blend in granule or powder form.
Claim 18. The composition of claim 10 further comprising a coagulation acceleration agent, an antibiotic, an antifungal, an anti-infective, an antimicrobial, an antiinflammatory, an analgesic, an antihistamine and combinations thereof.
Claim 19. The composition of claim 18 wherein the coagulation accelerating agent is sodium tripolyphosphate.
Claim 20. A method of promoting blood clotting comprising contacting blood with a composition of claim 1 .
Claim 21 . The method of claim 20 wherein, in the composition of claim 1 , the polyglucosamine is chitin, chitosan or a combination thereof.
Claim 22. The method of claim 21 wherein the polyglucosamine is chitosan.
Claim 23. The method of claim 20 wherein the hydrogel is acrylonitrile grafted onto starch, poly(acrylamide) (PAAm), poly(acrylic acid) (PAA), poly(acrylamide-co-acrylic acid) (PAAA), or a combination thereof.
Claim 24. The method of claim 20 wherein the hydrogel is PAA.
Claim 25. The method of claim 20 wherein the composition of claim 1 is selected from the group consisting of a CMC and a Poly(acrylamide) (PAAm) physical blend in granule or powder form; a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC physically adsorbed on the surface of the particle; a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC chemically linked to the backbone of the hydrogel via hydroxylation using epichlorohydrin; a Poly(acrylamide) (PAAm) in particle, block, or sheet form with CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(acrylic acid) (PAA) physical blend in granule or powder form; a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle; a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrine; a Poly(acrylic acid) (PAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(acrylamide-co-acrylic acid) (PAAA) physical blend in granule or powder form; a Poly(acrylamide-co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; a Poly(acrylamide-co- acrylic acid) (PAAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation; a Poly(acrylamide-co-acrylic acid) (PAAA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(isobutylene-co-maleic acid) (PBMA) physical blend in granule or powder form; (16) a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrin; a Poly(isobutylene-co-maleic acid) (PBMA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a CMC and a Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) physical blend in granule or powder form; a Poly(acrylic acid)-graft- poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC physically adsorbed on the surface of the particle, block or sheet; a Poly(acrylic acid)-graft- poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via hydroxylation with epichlorohydrin; a
Poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-PEA) in particle, block, or sheet form with a CMC chemically linked to the backbone of the hydrogel via esterification; a Chitosan-g-PAA with partial hydrolysis treatment; a Chitosan-g-PAA with carboxylation treatment; a Chitosan-g-PAAm with partial hydrolysis treatment; a Chitosan-g-PAAm with carboxylation treatment, and combinations thereof.
Claim 26. The method of claim 25 wherein the composition of claim 1 is a CMC and a PAA physical blend in granule or powder form.
Claim 27. The method of claim 20 wherein the composition of claim 1 is further comprised of a coagulation acceleration agent, an antibiotic, an antifungal, an anti- infective, an antimicrobial, an anti-inflammatory, an analgesic, an antihistamine and combinations thereof.
Claim 28. The method of claim 27 wherein the coagulation accelerating agent is sodium tripolyphosphate.
PCT/US2010/059497 2009-12-21 2010-12-08 Hemostatic agents and wound dressings WO2011084326A3 (en)

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EP2954778A4 (en) * 2013-02-06 2016-07-27 Innotherapy Inc Animal model for evaluating performance of hemostatic agent for inducing hemorrhage in common carotid artery or superior sagittal sinus, and use thereof
WO2018005145A1 (en) * 2016-06-28 2018-01-04 Victor Matthew Phillips Flowable hemostatic gel composition and its methods of use

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