US20130096063A1 - Hemostatic compositions - Google Patents

Hemostatic compositions Download PDF

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Publication number
US20130096063A1
US20130096063A1 US13/648,902 US201213648902A US2013096063A1 US 20130096063 A1 US20130096063 A1 US 20130096063A1 US 201213648902 A US201213648902 A US 201213648902A US 2013096063 A1 US2013096063 A1 US 2013096063A1
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United States
Prior art keywords
hemostatic composition
polymer
composition according
hemostatic
present
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Abandoned
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US13/648,902
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English (en)
Inventor
Hans Christian Hedrich
Joris Hoefinghoff
Katarzyna Gorna
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Baxter Healthcare SA
Baxter International Inc
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Baxter Healthcare SA
Baxter International Inc
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Priority to US13/648,902 priority Critical patent/US20130096063A1/en
Assigned to BAXTER INTERNATIONAL INC., BAXTER HEALTHCARE S.A. reassignment BAXTER INTERNATIONAL INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HOEFINGHOFF, JORIS, GORNA, KATARZYNA, HEDRICH, HANS CHRISTIAN
Publication of US20130096063A1 publication Critical patent/US20130096063A1/en
Priority to US15/004,520 priority patent/US9821025B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0031—Hydrogels or hydrocolloids
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular materials
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0052—Mixtures of macromolecular compounds
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/008—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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 hemostatic compositions and processes for making such compositions.
  • Hemostatic compositions in dry storage-stable form that comprise biocompatible, biodegradable, dry stable granular material are known e.g. from WO98/008550A or WO 2003/007845A. These products have been successfully applied on the art for hemostasis.
  • Floseal® is an example for a powerful and versatile hemostatic agent consisting of a granular gelatin matrix swollen in a thrombin-containing solution to form a flowable paste.
  • the present invention provides a hemostatic composition comprising:
  • crosslinking reaction Upon contact with bleeding tissue, a crosslinking reaction of the hydrophilic polymeric component with the blood proteins leads to formation of a gel with sealing and hemostatic properties. Crosslinking also occurs to the tissue surface proteins and, depending on the nature of the biocompatible polymer material, may also occur to the biocompatible polymer material. The latter reaction contributes to an improved adhesion of the composition material to the wounded tissue surface.
  • a further aspect relates to a method of treating an injury comprising administering a hemostatic composition to the site of injury.
  • kits for the treatment of an injury comprising a hemostatic composition as herein disclosed and instructions for use.
  • the present invention also refers to a method for producing the hemostatic composition according to the invention in a convenient manner allowing the composition to be easily at hand for medical use.
  • the invention further relates to a method for delivering a hemostatic composition to a target site in a patient's body, said method comprising delivering a hemostatic composition produced by the process of the present invention to the target site.
  • the present invention relates to a finished final container obtained by the process according of the present invention containing the present hemostatic composition.
  • the invention also relates to a method for providing a ready-to-use hemostatic composition
  • a method for providing a ready-to-use hemostatic composition comprising contacting a hemostatic composition produced by the process of the present invention with a pharmaceutically acceptable diluent as well as to a kit comprising the finished final container and other means for applying the composition (e.g. a diluent container).
  • the compositions according to the present invention are particularly useful for providing hemostasis at bleeding sites, including surgical bleeding sites, traumatic bleeding sites and the like.
  • An exemplary use of the compositions may be in sealing the tissue tract above a blood vessel penetration created for vascular catheterization.
  • the biocompatible polymers in particulate form suitable for use in hemostasis may include dimensionally isotropic or non-isotropic forms.
  • the biocompatible polymers according to the present invention may be granules or fibers; and may be present in discontinuous structures, for example in powder forms.
  • the biocompatible polymer and the hydrophilic polymeric component are present in dry form, preferably in mixed dry form.
  • Suitable biologic polymers include polysaccharides, such as glycosaminoglycans, starch, cellulose, dextran, hemicellulose, xylan, agarose, alginate and chitosan; and derivatives and combinations thereof.
  • Suitable non-biologic polymers will be selected to be degradable by either of two mechanisms, i.e. (1) break down of the polymeric backbone or (2) degradation of side chains which result in aqueous solubility.
  • non-biologic biocompatible polymers suitable for use in hemostasis include synthetics, such as polyacrylates, polymethacrylates, polyacrylamides, polymethacrylamides, polyethyleneimines, polyvinyl resins, polylactide-glycolides, polycaprolactones, and polyoxyethlenes; and derivatives and combinations thereof. Also combinations of different kinds of polymers are possible (e.g. proteins with polysaccharides, proteins with non-biologic hydrogel-forming polymers, etc.).
  • Preferred hemostatic polymers comprise amino-groups, specifically if the hydrophilic polymeric component has reactive groups which react with amino-groups upon administration (e.g. in the wound environment).
  • crosslinking may be achieved by using oxidizers and other agents, such as periodates, which activate side-chains or moieties on the polymer so that they may react with other side-chains or moieties to form the crosslinking bonds.
  • An additional method of crosslinking comprises exposing the polymers to radiation, such as gamma radiation, to activate the polymer chains to permit crosslinking reactions.
  • Dehydrothermal crosslinking methods may also be suitable. Preferred methods for crosslinking gelatin molecules are described below.
  • the pH should be held from about 6 to 11, preferably from 7 to 10.
  • the crosslinks are formed via Schiff bases which may be stabilized by subsequent reduction, e.g., by treatment with sodium borohydride.
  • the resulting granules may be washed in water and optionally rinsed in an alcohol, and dried. The resulting dry powders may then be provided in the final container as described herein.
  • powders are defined herein as a special sub-class of granular materials.
  • powders refer to those granular materials that have the finer grain sizes, and that therefore have a greater tendency to form clumps when flowing.
  • Granules include coarser granular materials that do not tend to form clumps except when wet.
  • the particles used are those which can be coated by suitable coating techniques Particle size of the polymer granules according to the present invention can therefore easily be adapted and optimized to a certain coating technique by the necessities of this technique.
  • the hydrophilic reactive polymer has the ability to crosslink blood proteins and also tissue surface proteins. Crosslinking to the biomaterial is also possible.
  • the hydrophilic crosslinker according to the present invention is a polymer, i.e. a large molecule (macromolecule) composed of repeating structural units which are typically connected by covalent chemical bonds.
  • the hydrophilic polymer component according to the present invention should have a molecular weight of at least 1000 Da (to properly serve as crosslinker in the hemostatic composition according to the present invention); preferably the crosslinking polymers according to the present invention has a molecular weight of at least 5000 Da, especially of at least 8000 Da.
  • hydrophilic crosslinkers For some hydrophilic crosslinkers, the presence of basic reaction conditions (e.g. at the administration site) is preferred or necessary for functional performance (e.g. for a faster crosslinking reaction at the administration site).
  • carbonate or bicarbonate ions e.g. as a buffer with a pH of 7.6 or above, preferably of 8.0 or above, especially of 8.3 and above
  • may be additionally provided at the site of administration e.g. as a buffer solution or as a fabric or pad soaked with such a buffer), so as to allow an improved performance of the hemostatic composition according to the present invention or to allow efficient use as a hemostatic and/or wound adherent material.
  • the hemostatic compositions according to the present invention are preferably provided as dry composition, e.g. as a physical mixture, of the hemostatic polymer and the hydrophilic reactive component, wherein the biocompatible polymer and the hydrophilic polymeric component are present in dry form, preferably in mixed dry form.
  • “Mixed” according to the present invention includes powder mixing, coating, impregnating, blending, agglomerating, co-lyophilizing, drying from suspension, subsequent or concurrent co-filling, co-extruding, etc.
  • a “dry” hemostatic composition according to the present invention has only a residual content of moisture which may approximately correspond to the moisture content of comparable available products, such as Floseal® (Floseal, for example, has about 12% moisture as a dry product).
  • the dry composition according to the present invention has a residual moisture content below these products, preferably below 10% moisture, more preferred below 5% moisture, more preferred below 2.5%, especially below 1% moisture.
  • the hemostatic composition according to the present invention can also have lower moisture content, e.g. 0.1% or even below.
  • Preferred moisture contents of the dry hemostatic composition according to the present invention are 0.1 to 10%, especially 0.5 to 5%. It is clear that the dryer the composition is, the longer their shelf life is and the lower is the risk that the hemostatic properties of the composition as a whole suffer.
  • the biocompatible polymer in particulate form suitable for use in hemostasis is preferably gelatin in powder form, especially wherein the powder particles have a median particle size of 10 to 1000 ⁇ m, preferably from 50 to 750 ⁇ m, more preferred from 150 to 700 ⁇ m, especially from 150 to 500 ⁇ m.
  • the hemostatic compositions according to the present invention may further comprise a substance selected from the group consisting of antifibrinolytic, procoagulant, platelet activator, antibiotic, vasoconstrictor, dye, growth factors, bone morphogenetic proteins and pain killers.
  • the hemostatic composition according to the present invention may comprise a further composition of gelatin and a polyvalent nucelophilic substance, preferably human serum albumin, optionally at a basic pH (e.g. pH 8 to 11, preferably 9 to 10, especially at a pH of 9.5).
  • a basic pH e.g. pH 8 to 11, preferably 9 to 10, especially at a pH of 9.5.
  • the 2 components may then be co-applied to an injury.
  • the present invention also relates to a method for producing a hemostatic composition according to the present invention comprising the step of mixing, a biocompatible polymer suitable for use in hemostasis and one hydrophilic polymeric component comprising reactive groups in dry form.
  • hemostatic compositions according to the present invention in dry form in an administration container, preferably in a syringe, optionally together with a pharmaceutically acceptable diluent.
  • such products are usually provided in a dry form and brought into the “ready-to-use” form (which is usually in the form of a (hydro-)gel, suspension or solution) immediately before use, necessitating the addition of wetting or solvation (suspension) agents.
  • the hemostatic composition is provided in dry form in the final container.
  • degradation or inactivation processes for the components are significantly and appropriately reduced to enable storage stability.
  • a suitable diluent comprises water for injection, and—independently of each other—50 to 200 mM NaCl (preferably 150 mM), 10 to 80 mM CaCl 2 (preferably 40 mM) and 1 to 50 mM sodium acetate (preferably 20 mM).
  • the diluent can also include a buffer or buffer system so as to buffer the pH of the reconstituted dry composition, preferably at a pH of 3.0 to 10.0, more preferred of 6.4 to 7.5, especially at a pH of 8.9 to 7.1.
  • the thrombin preparation contains human albumin.
  • Preferred salts are NaCl and/or CaCl 2 , both used in the usual amounts and concentrations applied for thrombin (e.g. 0.5 to 1.5% NaCl (e.g. 0.9%) and/or 20 to 80 mM CaCl 2 (e.g. 40 mM)).
  • the pharmaceutically acceptable diluent is provided In a separate container.
  • This can preferably be a syringe.
  • the diluent in the syringe can then easily be applied to the final container for reconstitution of the dry hemostatic compositions according to the present invention. If the final container is also a syringe, both syringes can be finished together in a pack. It is therefore preferred to provide the dry hemostatic compositions according to the present invention in a syringe which is finished with a diluent syringe with a pharmaceutically acceptable diluent for reconstituting said dry and stable hemostatic composition.
  • the final container further contains an amount of a stabilizer effective to inhibit modification of the polymer when exposed to the sterilizing radiation, preferably ascorbic acid, sodium ascorbate, other salts of ascorbic acid, or an antioxidant.
  • a stabilizer effective to inhibit modification of the polymer when exposed to the sterilizing radiation, preferably ascorbic acid, sodium ascorbate, other salts of ascorbic acid, or an antioxidant.
  • the present invention also provides a method for delivering a hemostatic composition according to the invention to a target site in a patient's body, said method comprising delivering a hemostatic composition produced by the process according to the present invention to the target site.
  • the dry composition can be directly applied to the target site (and, optionally be contacted with the diluent a the target site, if necessary), it is preferred to contact the dry hemostatic composition with a pharmaceutically acceptable diluent before administration to the target site, so as to obtain a hemostatic composition in a wetted form, especially a hydrogel form.
  • the present invention also refers to a finished final container obtained by the process according to the present invention.
  • This finished container contains the combined components in a sterile, storage-stable and marketable form.
  • the final container can be any container suitable for housing (and storing) pharmaceutically administrable compounds.
  • Syringes, vials, tubes, etc. can be used; however, providing the hemostatic compositions according to the present invention in a syringe is specifically preferred.
  • Syringes have been a preferred administration means for hemostatic compositions as disclosed in the prior art also because of the handling advantages of syringes in medical practice.
  • the compositions may then preferably be applied (after reconstitution) via specific needles of the syringe or via suitable catheters.
  • the reconstituted hemostatic compositions (which are preferably reconstituted to form a hydrogel) may also be applied by various other means e.g. by a spatula, a brush, a spray, manually by pressure, or by any other conventional technique. Administration of the reconstituted hemostatic composition to a patient by spraying is specifically preferred.
  • the reconstituted hemostatic compositions according to the present invention will be applied using a syringe or similar applicator capable of extruding the reconstituted composition through an orifice, aperture, needle, tube, or other passage to form a bead, layer, or similar portion of material.
  • the hemostatic compositions can be performed by extrusion through an orifice in the syringe or other applicator, typically having a size in the range from 0.01 mm to 5.0 mm, preferably 0.5 mm to 2.5 mm.
  • the hemostatic composition will be initially prepared from a dry form having a desired particle size (which upon reconstitution, especially by hydration, yields subunits of the requisite size (e.g. hydrogel subunits)) or will be partially or entirely mechanically disrupted to the requisite size prior to a final extrusion or other application step. It is, of course evident, that these mechanical components have to be provided in sterile form (inside and outside) in order to fulfill safety requirements for human use.
  • Another aspect of the invention concerns a method for providing a ready-to-use hemostatic composition comprising contacting a hemostatic composition produced by the process according to the present invention with a pharmaceutically acceptable diluent.
  • This process provides a suitable “ready-to-use” form of the compositions according to the present invention which can easily and efficiently be made also within short times, eg. in emergency situations during surgery.
  • This flowable form of the hemostatic composition provided by such a method is specifically suitable for use in the treatment of an injury selected from the group consisting of a wound, a hemorrhage, damaged tissue, bleeding tissue and/or bone defects.
  • FIG. 1 shows crosslinked gelatin mixed with 20 wt % of NHS-PEG hydrated with saline solution at neutral pH (Example 1) in a liver punch lesion model 5 min post application.
  • Example 1 In order to obtain a faster reactive flowable hemostat the mixture as described in Example 1 was hydrated by using 3.5 ml of a basic buffer having pH of 9.5 as a diluent.
  • a product obtained was allowed to hydrate for 2 minutes and was applied to a blending wound.
  • Example 1 In order to obtain a reactive flowable hemostat with prolonged stability the mixture as described in Example 1 was hydrated with 3.5 ml of saline solution having pH adjusted to 1.5 with 1 M of HCl as a diluent.
  • Example 1 A preparation of Example 1 was tested for hemostatic efficacy on heparinized animal (pig) in a punch or biopsy liver lesion. Each lesion in the series was topically treated with the product applied from the syringe through applicator tip. Moistened gauze was used to help approximate the test product to the lesion and the timer was started. A saline moistened approximation gauze was removed after 30 seconds and the degree of bleeding was assessed at 30 seconds, 1, 2, 5 and 10 minutes after the test articles were applied. Product saturated with blood but without active bleeding was scored as 0. Saline solution was used to irrigate the excess test articles away from the lesions after the 5 minutes assessment. Performance of selected formulations at 5 minutes assessment is shown in FIG. 1 .

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  • Health & Medical Sciences (AREA)
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  • Gastroenterology & Hepatology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Surgery (AREA)
  • Dispersion Chemistry (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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US13/648,902 2011-10-11 2012-10-10 Hemostatic compositions Abandoned US20130096063A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US13/648,902 US20130096063A1 (en) 2011-10-11 2012-10-10 Hemostatic compositions
US15/004,520 US9821025B2 (en) 2011-10-11 2016-01-22 Hemostatic compositions

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US201161545909P 2011-10-11 2011-10-11
US13/648,902 US20130096063A1 (en) 2011-10-11 2012-10-10 Hemostatic compositions

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EP (2) EP2766059B1 (es)
JP (2) JP6195569B2 (es)
KR (1) KR102102002B1 (es)
CN (1) CN103957949B (es)
AU (1) AU2012318257B2 (es)
CA (1) CA2851321C (es)
ES (1) ES2938568T3 (es)
IL (1) IL231961A0 (es)
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US20210001002A1 (en) * 2017-11-28 2021-01-07 Dalim Tissen Co., Ltd. Composition for hemostasis and container comprising same
CN114096285A (zh) * 2019-07-12 2022-02-25 加特技术公司 生物相容性柔性止血片
CN115944771A (zh) * 2022-12-27 2023-04-11 合肥工业大学 一种具有强效湿粘附与止血功能的仿生止血糊剂及其制备方法
EP3989875A4 (en) * 2019-06-26 2023-07-26 Davol Inc. REAGENT DRY PULVERULENT HEMOSTATIC MATERIALS COMPRISING A NUCLEOPHILE AND A MULTIFUNCTIONAL MODIFIED POLYETHYLENE GLYCOL CROSS-LINKING AGENT

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US8642831B2 (en) 2008-02-29 2014-02-04 Ferrosan Medical Devices A/S Device for promotion of hemostasis and/or wound healing
CA2851332C (en) * 2011-10-11 2020-08-25 Baxter International Inc. Hemostatic compositions
MX346958B (es) 2011-10-11 2017-04-06 Baxter Int Composición hemostatica.
CN104159527B (zh) 2012-03-06 2017-04-12 弗罗桑医疗设备公司 包含止血糊剂的压力容器
CN104349797B (zh) 2012-06-12 2017-10-27 弗罗桑医疗设备公司 干止血组合物
CA2912357C (en) 2013-06-21 2019-12-31 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
JP6489485B2 (ja) * 2013-12-11 2019-03-27 フェロサン メディカル デバイシーズ エイ／エス 押し出し増強因子を含んでいる乾燥組成物
CN106999621B (zh) 2014-10-13 2020-07-03 弗罗桑医疗设备公司 用于止血和伤口愈合的干组合物
BR112017013565B1 (pt) 2014-12-24 2021-12-28 Ferrosan Medical Devices A/S Seringa para retenção e mistura de primeira e segunda substâncias
GB201508024D0 (en) 2015-05-11 2015-06-24 Haemostatix Ltd Haemostatic compositions
CN107771093B (zh) 2015-07-03 2021-06-15 弗罗桑医疗设备公司 用于混合两种组分和用于在存储条件下保持真空的注射器
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